Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nature communications 2016; 7: 10713-?
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.
View details for DOI 10.1038/ncomms10713
View details for PubMedID 26888176
A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency NEW ENGLAND JOURNAL OF MEDICINE 2015; 373 (11): 1010-1020
Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society GENETICS IN MEDICINE 2015; 17 (9): 689-701
The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients.The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve.Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease.The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.Genet Med 17 9, 689-701.
View details for DOI 10.1038/gim.2014.177
View details for Web of Science ID 000360898500002
View details for PubMedID 25503498
Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. journal of pediatrics 2015; 166 (6): 1455-61 e1
To assess biochemical, surgical, and long-term outcomes of liver (LT) or liver-kidney transplantation (LKT) for severe, early-onset methylmalonic acidemia/acid (MMA).A retrospective chart review (December 1997 to May 2012) of patients with MMA who underwent LT or LKT at Lucile Packard Children's Hospital at Stanford.Fourteen patients underwent LT (n = 6) or LKT (n = 8) at mean age 8.2 years (range 0.8-20.7). Eleven (79%) were diagnosed during the neonatal period, including 6 by newborn screening. All underwent deceased donor transplantation; 12 (86%) received a whole liver graft. Postoperative survival was 100%. At a mean follow-up of 3.25 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. One patient underwent liver re-transplantation because of hepatic artery thrombosis. After transplantation, there were no episodes of hyperammonemia, acidosis, or metabolic decompensation. The mean serum MMA at the time of transplantation was 1648 1492 mol/L (normal <0.3, range 99-4420). By 3 days, post-transplantation levels fell on average by 87% (mean 210 154 mol/L), and at 4 months, they were 83% below pre-transplantation levels (mean 305 108 mol/L). Developmental delay was present in 12 patients (86%) before transplantation. All patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning.LT or LKT for MMA eradicates episodes of hyperammonemia, results in excellent long-term survival, and suggests stabilization of neurocognitive development. Long-term follow-up is underway to evaluate whether patients who undergo early LT need kidney transplantation later in life.
View details for DOI 10.1016/j.jpeds.2015.01.051
View details for PubMedID 25771389
Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway GENETICS IN MEDICINE 2014; 16 (10): 751-758
Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genetics in medicine 2014; 16 (10): 751-758
Purpose:The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.Methods:Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.Results:All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.Conclusion:NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.Genet Med advance online publication 20 March 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.22.
View details for DOI 10.1038/gim.2014.22
View details for PubMedID 24651605
Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status PLOS ONE 2014; 9 (6)
Degree of glutathione deficiency and redox imbalance depend on subtype of mitochondrial disease and clinical status. PloS one 2014; 9 (6)
Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential -251 mV 9.7, p<0.0001) with an increased level of oxidation by 9 mV compared to controls (-260 mV 6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at -242 mV 7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox-modulating therapies in clinical trials.
View details for DOI 10.1371/journal.pone.0100001
View details for PubMedID 24941115
A new LC-MS/MS method for the clinical determination of reduced and oxidized glutathione from whole blood JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES 2013; 929: 51-55
Reduced levels of glutathione (-glutamylcysteinylglycine, GSH) and the ratio of GSH to glutathione disulfide (GSSG) can serve as important indicators of oxidative stress and disease risk. Measured concentrations of GSH and GSSG vary widely between laboratories, largely due to the instability of GSH during sample handling and variables arising from different analytical methods. We have developed a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring whole blood GSH and GSSG that minimizes preanalytic and analytic variability, reliably eliminates interference from ion suppression, and can easily be implemented in clinical laboratories. Samples were deproteinized with sulfosalicylic acid (SSA) and derivatized with N-ethylmaleimide (NEM) in a single preparative step, and the resulting supernatants combined with stable-isotope internal standards (GSH-(13)C, (15)N-NEM and GSSG-(13)C,(15)N), subjected to chromatographic separation using a Hypercarb column, and analyzed by MS/MS in the positive-ion mode. Results showed excellent linearity for both GSH and GSSG over the ranges of physiologic normal, with inter- and intra-assay CV's of 3.1-4.3% and accuracy between 95% and 101%. The lower limits of detection (LLOD) were 0.4M for GSH and 0.1M for GSSG and the lower limits of quantitation (LLOQ) were 1.5M for GSH and 0.1M for GSSG. Derivatized samples are stable for at least 3 years when stored at -80C, and underivatized samples for at least 24h at either 4C or room temperature. Reference intervals were determined for 59 control samples, and were (meanSD): GSH 900140M; GSSG 1.170.43M; GSH/GSSG 880370.
View details for DOI 10.1016/j.jchromb.2013.04.004
View details for Web of Science ID 000320085300009
Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease MOLECULAR GENETICS AND METABOLISM 2012; 107 (4): 690-699
While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase ? deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.
View details for DOI 10.1016/j.ymgme.2012.09.023
View details for Web of Science ID 000311816200010
View details for PubMedID 23084792
Leigh syndrome caused by a novel m.4296G > A mutation in mitochondrial tRNA isoleucine MITOCHONDRION 2012; 12 (2): 258-261
Leigh syndrome is a severe neurodegenerative disease with heterogeneous genetic etiology. We report a novel m.4296G>A variant in the mitochondrial tRNA isoleucine gene in a child with Leigh syndrome, mitochondrial proliferation, lactic acidosis, and abnormal respiratory chain enzymology. The variant is present at >75% heteroplasmy in blood and cultured fibroblasts from the proband, <5% in asymptomatic maternal relatives, and is absent in 3000 controls. It is located in the highly conserved anticodon region of tRNA(Ile) where three other pathogenic changes have been described. We conclude that there is strong evidence to classify m.4296G>A as a pathogenic mutation causing Leigh syndrome.
View details for DOI 10.1016/j.mito.2011.09.006
View details for Web of Science ID 000301906600011
View details for PubMedID 21982779
Initial experience in the treatment of inherited mitochondrial disease with EPI-743 MOLECULAR GENETICS AND METABOLISM 2012; 105 (1): 91-102
Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase ? deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase ? deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.
View details for DOI 10.1016/j.ymgme.2011.10.009
View details for Web of Science ID 000299363800014
View details for PubMedID 22115768
High-quality DNA sequence capture of 524 disease candidate genes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2011; 108 (16): 6549-6554
The accurate and complete selection of candidate genomic regions from a DNA sample before sequencing is critical in molecular diagnostics. Several recently developed technologies await substantial improvements in performance, cost, and multiplex sample processing. Here we present the utility of long padlock probes (LPPs) for targeted exon capture followed by array-based sequencing. We found that on average 92% of 5,471 exons from 524 nuclear-encoded mitochondrial genes were successfully amplified from genomic DNA from 63 individuals. Only 144 exons did not amplify in any sample due to high GC content. One LPP was sufficient to capture sequences from <100-500 bp in length and only a single-tube capture reaction and one microarray was required per sample. Our approach was highly reproducible and quick (<8 h) and detected DNA variants at high accuracy (false discovery rate 1%, false negative rate 3%) on the basis of known sample SNPs and Sanger sequence verification. In a patient with clinical and biochemical presentation of ornithine transcarbamylase (OTC) deficiency, we identified copy-number differences in the OTC gene at exon-level resolution. This shows the ability of LPPs to accurately preserve a sample's genome information and provides a cost-effective strategy to identify both single nucleotide changes and structural variants in targeted resequencing.
View details for DOI 10.1073/pnas.1018981108
View details for Web of Science ID 000289680400046
View details for PubMedID 21467225
Novel Deoxyguanosine Kinase Gene Mutations and Viral Infection Predispose Apparently Healthy Children to Fulminant Liver Failure JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION 2009; 49 (1): 130-132
Mapping Gene Associations in Human Mitochondria using Clinical Disease Phenotypes PLOS COMPUTATIONAL BIOLOGY 2009; 5 (4)
Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes.
View details for DOI 10.1371/journal.pcbi.1000374
View details for Web of Science ID 000266214200033
View details for PubMedID 19390613
Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2009; 106 (10): 3941-3945
Disorders affecting mitochondria, including those that directly affect the respiratory chain function or result from abnormalities in branched amino acid metabolism (organic acidemias), have been shown to be associated with impaired redox balance. Almost all of the evidence underlying this conclusion has been obtained from studies on patient biopsies or animal models. Since the glutathione (iGSH) system provides the main protection against oxidative damage, we hypothesized that untreated oxidative stress in individuals with mitochondrial dysfunction would result in chronic iGSH deficiency. We confirm this hypothesis here in studies using high-dimensional flow cytometry (Hi-D FACS) and biochemical analysis of freshly obtained blood samples from patients with mitochondrial disorders or organic acidemias. T lymphocyte subsets, monocytes and neutrophils from organic acidemia and mitochondrial patients who were not on antioxidant supplements showed low iGSH levels, whereas similar subjects on antioxidant supplements showed normal iGSH. Measures of iROS levels in blood were insufficient to reveal the chronic oxidative stress in untreated patients. Patients with organic acidemias showed elevated plasma protein carbonyls, while plasma samples from all patients tested showed hypocitrullinemia. These findings indicate that measurements of iGSH in leukocytes may be a particularly useful biomarker to detect redox imbalance in mitochondrial disorders and organic acidemias, thus providing a relatively non-invasive means to monitor disease status and response to therapies. Furthermore, studies here suggest that antioxidant therapy may be useful for relieving the chronic oxidative stress that otherwise occurs in patients with mitochondrial dysfunction.
View details for DOI 10.1073/pnas.0813409106
View details for Web of Science ID 000264036900054
View details for PubMedID 19223582
Survival after treatment with phenylacetate and benzoate for urea-cycle disorders NEW ENGLAND JOURNAL OF MEDICINE 2007; 356 (22): 2282-2292
The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects.We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes.Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.
View details for Web of Science ID 000246816500007
View details for PubMedID 17538087
Molecular-clinical correlations in a family with variable tissue mitochondrial DNA T8993G mutant load MOLECULAR GENETICS AND METABOLISM 2006; 88 (4): 364-371
Unlike many pathogenic mitochondrial DNA mutations, the T8993G mutation associated with Leigh syndrome (LS) and neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP) typically shows little variation in mutant load between different tissue types. We describe the molecular and clinical findings in a family with variable disease severity and tissue T8993G mutant loads. Real-time ARMS qPCR testing showed that two brothers with features of NARP and LS had high mutant loads (>90%) in all tissues tested, similar to previously reported cases. Their sister, who has mild speech delay but attends normal school, was found to have a relatively high mutant load (mean 93%) in tissues derived from endoderm (buccal mucosa) and mesoderm (blood and skin fibroblasts). However, in tissue derived from ectoderm (hair bulbs), she carried a considerably lower proportion of mutant mtDNA. Because both surface ectoderm, which gives rise to outer epithelia and hair, and neuroectoderm, which gives rise to the central nervous system, are derived from ectoderm, it is tempting to speculate that the mutant load detected in the oligosymptomatic sister's hair bulbs is a reflection of the brain mutant load. We conclude that significant variation in tissue mutant load may occur in at least some individuals that harbor the T8993G mutation. This adds additional complexity to genetic counseling and prenatal diagnosis in such instances. Given the shared embryonic origin of hair bulbs and brain, we recommend performing hair bulb mtDNA analysis in asymptomatic or oligosymptomatic individuals that have high blood mutant loads in order to understand better the genotype-phenotype correlations related to the T8993G mutation.
View details for DOI 10.1016/j.ymgme.2006.02.001
View details for Web of Science ID 000240029700010
View details for PubMedID 16546428
Relationship of primary mitochondrial respiratory chain dysfunction to fiber type abnormalities in skeletal muscle CLINICAL GENETICS 2005; 68 (4): 337-348
Variation in the size and relative proportion of type 1 and type 2 muscle fibers can occur in a number of conditions, including structural myopathies, neuropathies, and various syndromes. In most cases, the pathogenesis of such fiber type changes is unknown and the etiology is heterogeneous. Skeletal muscle mitochondrial respiratory chain analysis was performed in 10 children aged 3 weeks to 5 years with abnormalities in muscle fiber type, size, and proportion. Five children were classified as having definite, four as probable, and one as possible mitochondrial disease. Type 1 fiber predominance was the most common histological finding (six of 10). On light microscopy, four cases had subtle concomitants of a mitochondriopathy, including mildly increased glycogen, lipid, and/or succinate dehydrogenase staining, and one case had more prominent evidence of underlying mitochondrial disease with marked subsarcolemmal staining. Most cases (nine of 10) had abnormal mitochondrial morphology on electron microscopy. All were found to have mitochondrial electron transport chain (ETC) abnormalities and met diagnostic criteria for mitochondrial disease. We did not ascertain any patients who had isolated fiber type abnormalities and normal respiratory chain analysis during the period of study. We conclude that mitochondrial ETC disorders may represent an etiology of at least a subset of muscle fiber type abnormalities. To establish an etiologic diagnosis and to determine the frequency of such changes in mitochondrial disease, we suggest analysis of ETC function in individuals with fiber type changes in skeletal muscle, even in the absence of light histological features suggestive of mitochondrial disorders.
View details for DOI 10.1111/j.1399-0004.2005.00499.x
View details for Web of Science ID 000231621900008
View details for PubMedID 16143021
The contribution of mitochondria to common disorders MOLECULAR GENETICS AND METABOLISM 2003; 80 (1-2): 11-26
Mitochondrial dysfunction secondary to mitochondrial and nuclear DNA mutations has been associated with energy deficiency in multiple organ systems and a variety of severe, often fatal, clinical syndromes. Although the production of energy is indeed the primary function of mitochondria, attention has also been directed toward their role producing reactive oxygen and nitrogen species and the subsequent widespread deleterious effects of these intermediates. The generation of toxic reactive intermediates has been implicated in a number of relatively common disorders, including neurodegenerative diseases, diabetes, and cancer. Understanding the role mitochondrial dysfunction plays in the pathogenesis of common disorders has provided unique insights into a number of diseases and offers hope for potential new therapies.
View details for DOI 10.1016/j.ymgme.2003.08.009
View details for Web of Science ID 000186304600002
View details for PubMedID 14567954
Mitochondrial respiratory chain complex I deficiency with clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency JOURNAL OF PEDIATRICS 2000; 136 (2): 251-254
The mitochondrial respiratory chain and the fatty acid oxidation cycle are theoretically interdependent on each other for normal function. We describe a patient with complex I deficiency who had clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency including liver failure, cardiomyopathy, and consistent urine organic acid pattern. Patients with features of either a respiratory chain or fatty acid oxidation disorder should have the defect characterized biochemically because of the implications with respect to potential therapy and genetic counseling.
View details for Web of Science ID 000085289400026
View details for PubMedID 10657835
Nutritional interventions in primary mitochondrial disorders: Developing an evidence base. Molecular genetics and metabolism 2016; 119 (3): 187-206
In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.
View details for DOI 10.1016/j.ymgme.2016.09.002
View details for PubMedID 27665271
Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine. Journal of inherited metabolic disease 2016; 39 (6): 821-829
Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria.
View details for PubMedID 27488560
Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders. Molecular genetics and metabolism 2016; 119 (3): 223-231
Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.
View details for DOI 10.1016/j.ymgme.2016.08.008
View details for PubMedID 27590926
De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms AMERICAN JOURNAL OF HUMAN GENETICS 2016; 99 (4): 934-941
Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the roleof CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.
View details for DOI 10.1016/j.ajhg.2016.08.001
View details for Web of Science ID 000385333700014
View details for PubMedID 27616479
Impaired Health-Related Quality of Life in Children and Families Affected by Methylmalonic Acidemia. Journal of genetic counseling 2016; 25 (5): 936-944
An understanding of health related quality of life (HRQoL) in children and families affected by methylmalonic acidemia (MMA) is important in planning counseling and therapeutic intervention. Liver transplantation (LT) is used as a treatment for MMA; however, its risks and benefits continue to be investigated. The purpose of this study was twofold: (1) to measure HRQoL in children and families affected by MMA using the Pediatric Quality of Life Inventory (PedsQL) parent version, and (2) to assess the impact of LT on HRQoL by comparing LT and non-LT patient scores and free responses. Parents/caregivers reported lower scores on the majority of the PedsQL scales as compared to samples of healthy children, children with solid organ transplants for indications other than MMA, and families affected by chronic conditions. Scores for children with MMA were lowest in school and social functioning and scores for families were lowest in worry and activity impairment. There were no significant differences in LT and non-LT patient scores on the PedsQL scales. Our results document the negative impact of MMA on HRQoL.
View details for DOI 10.1007/s10897-015-9921-x
View details for PubMedID 26667650
Living donor liver transplantation for inborn errors of metabolism - An underutilized resource in the United States. Pediatric transplantation 2016; 20 (6): 770-773
Inborn metabolic diseases of the liver can be life-threatening disorders that cause debilitating and permanent neurological damage. Symptoms may manifest as early as the neonatal period. Liver transplant replaces the enzymatically deficient liver, allowing for metabolism of toxic metabolites. LDLT for metabolic disorders is rarely performed in the United States as compared to countries such as Japan, where they report >2000 cases performed within the past two decades. Patient and graft survival is comparable to that of the United States, where most of the studies are based on deceased donors. No living donor complications were observed, suggesting that LDLT is as safe and effective as deceased donor transplants performed in the USA. Increased utilization of living donors in the USA will allow for early transplantation to prevent permanent neurological damage in those with severe disease. Pediatric transplant centers should consider utilizing living donors when feasible for children with metabolic disorders of the liver.
View details for DOI 10.1111/petr.12746
View details for PubMedID 27392539
The M405V allele of the glutaryl-CoA dehydrogenase gene is an important marker for glutaric aciduria type I (GA-I) low excretors. Molecular genetics and metabolism 2016; 119 (1-2): 50-56
Glutaric aciduria type I (GA-I) is an autosomal recessive organic aciduria resulting from a functional deficiency of glutaryl-CoA dehydrogenase, encoded by GCDH. Two clinically indistinguishable diagnostic subgroups of GA-I are known; low and high excretors (LEs and HEs, respectively). Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We report on nine cases of GA-I LE patients all sharing the M405V allele with two cases missed by newborn screening (NBS) using tandem mass spectrometry (MS/MS). We describe a novel case with the known pathogenic M405V variant and a novel V133L variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the M405V allele. Three of the nine patients are of African American ancestry, with two as siblings. GCDH activity was assayed in six of the nine patients and varied from 4 to 25% of the control mean. We support the use of urine glutarylcarnitine as a biochemical marker of GA-I by demonstrating that glutarylcarnitine is efficiently cleared by the kidney (50-90%) and that plasma and urine glutarylcarnitine follow a linear relationship. We report the allele frequencies for three known GA-I LE GCDH variants (M405V, V400M and R227P) and note that both the M405V and V400M variants are significantly more common in the population of African ancestry compared to the general population. This report highlights the M405V allele as another important molecular marker in patients with the GA-I LE phenotype. Therefore, the incorporation into newborn screening of molecular screening for the M405V and V400M variants in conjunction with MS/MS could help identify asymptomatic at-risk GA-I LE patients that could potentially be missed by current NBS programs.
View details for DOI 10.1016/j.ymgme.2016.06.012
View details for PubMedID 27397597
Prenatally Diagnosed Cases of Binder Phenotype Complicated by Respiratory Distress in the Immediate Postnatal Period. Journal of ultrasound in medicine 2016; 35 (6): 1353-1358
Binder phenotype, or maxillonasal dysostosis, is a distinctive pattern of facial development characterized by a short nose with a flat nasal bridge, an acute nasolabial angle, a short columella, a convex upper lip, and class III malocclusion. We report 3 cases of prenatally diagnosed Binder phenotype associated with perinatal respiratory impairment.
View details for DOI 10.7863/ultra.15.02050
View details for PubMedID 27162279
Clinical Course of Six Children With GNAO1 Mutations Causing a Severe and Distinctive Movement Disorder PEDIATRIC NEUROLOGY 2016; 59: 81-84
Mutations in GNAO1 have been described in 11 patients to date. Although most of these individuals had epileptic encephalopathy, four patients had a severe movement disorder as the prominent feature. We describe the largest series of patients with de novoGNAO1 mutations who have severe chorea, developmental delay, and hypotonia in the absence of epilepsy.Six patients with recurrent missense mutations in GNAO1 as detected by whole exome sequencing were identified at three institutions. We describe the presentation, clinical course, and response to treatment of these patients.All six patients exhibited global developmental delay and hypotonia from infancy. Chorea developed by age fouryears in all but one patient, who developed chorea at 14years. Treatments with neuroleptics and tetrabenazine were most effective in the baseline management of chorea. The chorea became gradually progressive and marked by episodes of severe, refractory ballismus requiring intensive care unit admissions in four of six patients. Exacerbations indirectly led to the death of two patients.Patients with GNAO1 mutations can present with a severe, progressive movement disorder in the absence of epilepsy. Exacerbations may be refractory to treatment and can result in life-threatening secondary complications. Early and aggressive treatment of these exacerbations with direct admission to intensive care units for treatment with anesthetic drips may prevent some secondary complications. However the chorea and ballismus can be refractory to maximum medical therapy.
View details for DOI 10.1016/j.pediatrneurol.2016.02.018
View details for Web of Science ID 000379452200016
View details for PubMedID 27068059
Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures AMERICAN JOURNAL OF HUMAN GENETICS 2016; 98 (5): 1001-1010
Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding proteinsubunit beta-1, G. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p=7.1 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known G binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for G-G interaction (resulting in a constitutively active G) or through the disruption of residues relevant for interaction between G and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.
View details for DOI 10.1016/j.ajhg.2016.03.011
View details for Web of Science ID 000375869300017
View details for PubMedID 27108799
Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants GENETICS IN MEDICINE 2016; 18 (5): 452-458
The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458.
View details for DOI 10.1038/gim.2015.108
View details for Web of Science ID 000375263600005
View details for PubMedID 26312827
Line intensities and temperature-dependent line broadening coefficients of Q-branch transitions in the v(2) band of ammonia near 10.4 mu m JOURNAL OF QUANTITATIVE SPECTROSCOPY & RADIATIVE TRANSFER 2016; 175: 90-99
Clinical Features of Lysosomal Acid Lipase Deficiency JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION 2015; 61 (6): 619-625
The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.Investigators reviewed medical records of LAL D patients ages 5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n=31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was 1.15 multiples of normal (MN) and median spleen volume was 2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years).This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.
View details for DOI 10.1097/MPG.0000000000000935
View details for Web of Science ID 000369423200004
View details for PubMedID 26252914
Reply: To PMID 25771389. journal of pediatrics 2015; 167 (5): 1173-1174
A congenital disorder of deglycosylation: Biochemical characterization of N-glycanase 1 deficiency in patient fibroblasts GLYCOBIOLOGY 2015; 25 (8): 836-844
N-Glycanase 1, encoded by NGLY1, catalyzes the deglycosylation of misfolded N-linked glycoproteins retrotranslocated into the cytosol. We identified nine cases with mutations in NGLY1. The patients show developmental delay, seizures, peripheral neuropathy, abnormal liver function and alacrima (absence of tears). The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in patient-derived fibroblasts. Applying a recently established cellular deglycosylation-dependent Venus fluorescence assay, we found that patient fibroblasts had dramatically reduced fluorescence, indicating a pronounced reduction in N-glycanase enzymatic activity. Using this assay, we could find no evidence of other related activities. Our findings reveal that NGLY1 mutations destroy both N-glycanase 1 protein and enzymatic activity.
View details for DOI 10.1093/glycob/cwv024
View details for Web of Science ID 000361834300004
View details for PubMedID 25900930
Treatment of Methylmalonic Acidemia by Liver or Combined Liver-Kidney Transplantation JOURNAL OF PEDIATRICS 2015; 166 (6): 1455-?
Long-term safety and efficacy of sapropterin: The PKUDOS registry experience MOLECULAR GENETICS AND METABOLISM 2015; 114 (4): 557-563
The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 382 mol/L at baseline to 392 239 mol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 959 mg/day (pre-sapropterin baseline) to 1539 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance.
View details for DOI 10.1016/j.ymgme.2015.02.003
View details for Web of Science ID 000353008900008
View details for PubMedID 25724073
Identification of HIBCH Gene Mutations Causing Autosomal Recessive Leigh Syndrome: A Gene Involved in Valine Metabolism PEDIATRIC NEUROLOGY 2015; 52 (3): 361-365
Leigh syndrome is a progressive neurodegenerative disorder with usual onset of symptoms during the first year of life. The disorder has been associated with mutations in over 30 genes. This difficulty with genetic heterogeneity makes whole exome sequencing a more cost-effective approach for investigation of etiology.We describe an individual with typical Leigh syndrome who was found to have compound heterozygous mutations in the gene HIBCH (3-hydroxyisobutyryl coenzyme A hydrolase), an enzyme involved in the catabolism of valine. She exhibited significant clinical improvement after a valine-restricted diet.A subset of patients with uncharacterized Leigh syndrome present with specific biochemical abnormalities. This report highpoints the challenges and restrictions of routine metabolic testing and features the recognition of inborn errors of metabolism as potential treatable causes of Leigh syndrome.
View details for DOI 10.1016/j.pediatrneurol.2014.10.023
View details for Web of Science ID 000351022000016
View details for PubMedID 25591832
Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency JOURNAL OF HEPATOLOGY 2014; 61 (5): 1135-1142
Abnormal Hepatocellular Mitochondria in Methylmalonic Acidemia ULTRASTRUCTURAL PATHOLOGY 2014; 38 (5): 309-314
Clinical whole-exome sequencing: are we there yet? GENETICS IN MEDICINE 2014; 16 (9): 717-719
Treatment of Mitochondrial Disorders: Antioxidants and Beyond JOURNAL OF CHILD NEUROLOGY 2014; 29 (9): 1235-1240
Although mitochondrial disorders are among the most common inherited conditions that cause neurologic impairment, there are currently no U.S. Food and Drug Administration (FDA)-approved medications designed to treat primary mitochondrial disease. This is in part related to the lack of biomarkers to monitor disease status or response to treatment and the paucity of randomized, controlled clinical trials focused on mitochondrial disease therapies. Despite this discouraging historical precedent, a number of new approaches to mitochondrial disease therapy are on the horizon. By studying metabolites central to redox chemistry, investigators are gaining new insights into potential noninvasive biomarkers. Controlled clinical trials designed to study the effects of novel redox-modulating therapies, such as EPI-743, in patients with inherited mitochondrial disease are also underway. Furthermore, several new compounds with potential effects on inner mitochondrial membrane function and mitochondrial biogenesis are in development. Such advances are providing the foundation for a new era in mitochondrial disease therapeutics.
View details for DOI 10.1177/0883073814538509
View details for Web of Science ID 000341812400016
View details for PubMedID 24985754
Clinical whole-exome sequencing: are we there yet? Genetics in medicine 2014; 16 (9): 717-719
Background:Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.Genet Med advance online publication 13 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.10.
View details for DOI 10.1038/gim.2014.10
View details for PubMedID 24525916
Points to Consider in the Clinical Use of NGS Panels for Mitochondrial Disease: An Analysis of Gene Inclusion and Consent Forms JOURNAL OF GENETIC COUNSELING 2014; 23 (4): 594-603
Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. The NGS panels varied markedly in number of genes (101-1204 genes), and the proportion of genes causing "classic" mitochondrial diseases and their phenocopies ranged widely between labs (18 %-94 % of panel contents). All panels included genes not associated with classic mitochondrial diseases (6 %-28 % of panel contents), including genes causing adult-onset neurodegenerative disorders, cancer predisposition, and other genetic syndromes or inborn errors of metabolism. Five of the panels included genes that are not listed in OMIM to be associated with a disease phenotype (5 %-49 % of panel contents). None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians. Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease.
View details for DOI 10.1007/s10897-013-9683-2
View details for Web of Science ID 000339374400018
View details for PubMedID 24399097
Clinical Interpretation and Implications of Whole-Genome Sequencing JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 2014; 311 (10): 1035-1044
Clinical interpretation and implications of whole-genome sequencing. JAMA 2014; 311 (10): 1035-1045
Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross , 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss , 0.24; P<001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.
View details for DOI 10.1001/jama.2014.1717
View details for PubMedID 24618965
Practice patterns of mitochondrial disease physicians in North America. Part 1: Diagnostic and clinical challenges MITOCHONDRION 2014; 14: 26-33
Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.
View details for DOI 10.1016/j.mito.2013.07.116
View details for Web of Science ID 000330912200004
View details for PubMedID 23891656
Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management MITOCHONDRION 2013; 13 (6): 681-687
Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care.
View details for DOI 10.1016/j.mito2013.09.003
View details for Web of Science ID 000327280500015
View details for PubMedID 24063850
Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene MOLECULAR GENETICS AND METABOLISM 2013; 110 (1-2): 153-161
Clinical Effect and Safety Profile of Recombinant Human Lysosomal Acid Lipase in Patients With Cholesteryl Ester Storage Disease HEPATOLOGY 2013; 58 (3): 950-957
Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once-weekly infusions (0.35, 1, or 3 mgkg(-1) ) in LAL-CL01, which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received four once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mgkg(-1) ) before transitioning to long-term every-other-week infusions (1 or 3 mgkg(-1) ). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL-CL04, the mean standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46 21 U/L (-52%) and 21 14 U/L (-36%), respectively (P 0.05). Through week 12 of LAL-CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 41 mg/dL (-22%; P = 0.047), low density lipoprotein-cholesterol of 29 31 mg/dL (-27%; P = 0.078), and triglycerides of 50 38 mg/dL (-28%, P = 0.016) and increases in high density lipoprotein-cholesterol of 5 mg/dL (15%; P = 0.016). Conclusion: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile.
View details for DOI 10.1002/hep.26289
View details for Web of Science ID 000329284000016
View details for PubMedID 23348766
Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. Molecular genetics and metabolism 2013; 110 (1-2): 153-161
Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency.
View details for DOI 10.1016/j.ymgme.2013.07.009
View details for PubMedID 23932787
Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2013; 110 (33): 13552-13557
Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.
View details for DOI 10.1073/pnas.1302764110
View details for Web of Science ID 000323069200075
View details for PubMedID 23898205
Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism MOLECULAR GENETICS AND METABOLISM 2013; 109 (4): 319-328
A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.
View details for DOI 10.1016/j.ymgme.2013.05.008
View details for Web of Science ID 000323084800001
View details for PubMedID 23806236
Glutathione: A redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies MOLECULAR GENETICS AND METABOLISM 2013; 109 (2): 208-214
Genetically defined Leigh syndrome (LS) is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6 months of treatment with EPI-743, a novel redox therapeutic.Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays.A significant impairment of all glutathione forms was detected in patients, including a profound decrease of total and reduced glutathione (GSH) associated with high levels of all oxidized glutathione forms (GSSG+GS-Pro; OX). These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. After treatment with EPI-743, all patients showed a significant increase in reduced glutathione levels and 96% decrease of OX/GSH ratio.The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.
View details for DOI 10.1016/j.ymgme.2013.03.011
View details for Web of Science ID 000320354800014
View details for PubMedID 23583222
Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders GENETICS IN MEDICINE 2013; 15 (5): 388-394
Purpose:The application of massively parallel sequencing technology to the analysis of the mitochondrial genome has demonstrated great improvement in the molecular diagnosis of mitochondrial DNA-related disorders. The objective of this study was to investigate the performance characteristics and to gain new insights into the analysis of the mitochondrial genome.Methods:The entire mitochondrial genome was analyzed as a single amplicon using a long-range PCR-based enrichment approach coupled with massively parallel sequencing. The interference of the nuclear mitochondrial DNA homologs was distinguished from the actual mitochondrial DNA sequences by comparison with the results obtained from conventional PCR-based Sanger sequencing using multiple pairs of primers.Results:Our results demonstrated the uniform coverage of the entire mitochondrial genome. Massively parallel sequencing of the single amplicon revealed the presence of single-nucleotide polymorphisms and nuclear homologs of mtDNA sequences that cause the erroneous and inaccurate variant calls when PCR/Sanger sequencing approach was used. This single amplicon massively parallel sequencing strategy provides an accurate quantification of mutation heteroplasmy as well as the detection and mapping of mitochondrial DNA deletions.Conclusion:The ability to quantitatively and qualitatively evaluate every single base of the entire mitochondrial genome is indispensible to the accurate molecular diagnosis and genetic counseling of mitochondrial DNA-related disorders. This new approach may be considered as first-line testing for comprehensive analysis of the mitochondrial genome.Genet Med 2013:15(5):388-394.
View details for DOI 10.1038/gim.2012.144
View details for Web of Science ID 000318888600011
View details for PubMedID 23288206
Mutations in B3GALNT2 Cause Congenital Muscular Dystrophy and Hypoglycosylation of alpha-Dystroglycan AMERICAN JOURNAL OF HUMAN GENETICS 2013; 92 (3): 354-365
Mutations in several known or putative glycosyltransferases cause glycosylation defects in -dystroglycan (-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of -DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in -1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a -1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of -DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement.
View details for DOI 10.1016/j.ajhg.2013.01.016
View details for Web of Science ID 000316161700008
View details for PubMedID 23453667
Liver transplantation for urea cycle disorders in pediatric patients: A single-center experience PEDIATRIC TRANSPLANTATION 2013; 17 (2): 158-167
LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long-term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole-liver graft, seven patients (30%) received a reduced-size graft, and one patient received a living donor graft. Mean five-yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH(3) ) at presentation was 772 mol/L (median 500, range 178-2969, normal <30-50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long-term follow-up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long-term follow-up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.
View details for DOI 10.1111/petr.12041
View details for Web of Science ID 000315467000017
View details for PubMedID 23347504
Long term safety and clinical activity of SBC-102, a recombinant human lysosomal acid lipase (rhLAL), in patients with late onset LAL deficiency ACADEMIC PRESS INC ELSEVIER SCIENCE. 2013: S22-S23
ARTHROGRYPOSIS, RENAL DYSFUNCTION AND CHOLESTASIS (ARC) SYNDROME: A NEW PATIENT CASE REPORT LIPPINCOTT WILLIAMS & WILKINS. 2013: 188-188
Pediatric Liver Transplantation as Definitive Therapy for Urea Cycle Disorders WILEY-BLACKWELL. 2013: 86-86
Enzyme Replacement with Recombinant Human Lysosomal Acid Lipase (rhLAL) in Patients with Cholesteryl Ester Storage Disease, the Late Onset Form of LAL Deficiency, Produces Sustained Decreases in Transaminases and Reduction in Liver Fat Content WILEY-BLACKWELL. 2012: 824A-825A
Atypical Amyoplasia Congenita in an Infant With Leigh Syndrome: A Mitochondrial Cause of Severe Contractures? AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2012; 158A (9): 2353-2357
Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs. Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita. His development was normal until age 10.5 months, at which time he developed severe hypotonia and choreoathetosis following an episode of viral gastroenteritis. Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity. Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present.
View details for DOI 10.1002/ajmg.a.35533
View details for Web of Science ID 000310068700041
View details for PubMedID 22887355
RECOMBINANT HUMAN LYSOSOMAL ACID LIPASE (LAL) DEMONSTRATES PHARMACODYNAMIC ACTIVITY IN CHOLESTERYL ESTER STORAGE DISEASE (CESD), THE LATE ONSET FORM OF LAL DEFICIENCY SPRINGER. 2012: S11-S11
Improved redox status after liver transplantation in a patient with MMA mut(0) subtype; functional evidence for EPI-743 therapy ELSEVIER SCI LTD. 2012: 557-557
Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening MOLECULAR GENETICS AND METABOLISM 2012; 106 (4): 439-441
3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases.A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis.There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common.Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.
View details for DOI 10.1016/j.ymgme.2012.04.006
View details for Web of Science ID 000307322100007
View details for PubMedID 22658692
Pediatric Liver Transplantation as Definitive Therapy for Urea Cycle Disorders WILEY-BLACKWELL. 2012: 344-344
Propionic acidemia: To liver transplant or not to liver transplant? PEDIATRIC TRANSPLANTATION 2012; 16 (3): 209-210
Low glutathione levels in a patient with succinic semialdehyde dehydrogenase (SSADH) deficiency ACADEMIC PRESS INC ELSEVIER SCIENCE. 2012: 345-345
Mutations in KAT6B, Encoding a Histone Acetyltransferase, Cause Genitopatellar Syndrome AMERICAN JOURNAL OF HUMAN GENETICS 2012; 90 (2): 282-289
Genitopatellar syndrome (GPS) is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. By exome sequencing, we found de novo heterozygous truncating mutations in KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in three subjects; then by Sanger sequencing of KAT6B, we found similar mutations in three additional subjects. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS. In addition, human pathological analyses and mouse expression studies point to systemic roles of KAT6B in controlling organismal growth and development. Myst4 (the mouse orthologous gene) is expressed in mouse tissues corresponding to those affected by GPS. Phenotypic differences and similarities between GPS, the Say-Barber-Biesecker variant of Ohdo syndrome (caused by different mutations of KAT6B), and Rubinstein-Taybi syndrome (caused by mutations in other histone acetyltransferases) are discussed. Together, the data support an epigenetic dysregulation of the limb, brain, and genital developmental programs.
View details for DOI 10.1016/j.ajhg.2011.11.023
View details for Web of Science ID 000300742200008
View details for PubMedID 22265014
Initial Human Experience with SBC-102, a Recombinant Enzyme Replacement Therapy in Adults with Lysosomal Acid Lipase Deficiency ACADEMIC PRESS INC ELSEVIER SCIENCE. 2012: S29-S29
Natural history of propionic acidemia MOLECULAR GENETICS AND METABOLISM 2012; 105 (1): 5-9
Propionic acidemia is an organic acidemia that can lead to metabolic acidosis, coma and death, if not treated appropriately in the acute setting. Recent advancements in treatment have allowed patients with propionic acidemia to live beyond the neonatal period and acute presentation. The natural history of the disease is just beginning to be elucidated as individuals reach older ages. Recent studies have identified the genomic mutations in the genes PCCA and PCCB. However, as of yet no clear genotype-phenotype correlations are known. As patients age, the natural progression of propionic acidemia illuminates intellectual difficulties, increased risk for neurological complications, including stroke-like episodes, cardiac complications, and gastrointestinal difficulties, as well as a number of other complications. This article reviews the available literature for the natural history of propionic acidemia.
View details for DOI 10.1016/j.ymgme.2011.09.022
View details for Web of Science ID 000299363800003
View details for PubMedID 21986446
A Novel Mutation in the HSD17B10 Gene of a 10-Year-Old Boy with Refractory Epilepsy, Choreoathetosis and Learning Disability PLOS ONE 2011; 6 (11)
Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme encoded by the HSD17B10 gene. Missense mutations in this gene result in HSD10 deficiency, whereas a silent mutation results in mental retardation, X-linked, syndromic 10 (MRXS10). Here we report a novel missense mutation found in the HSD17B10 gene, namely c.194T>C transition (rs104886492), brought about by the loss of two forked methyl groups of valine 65 in the HSD10 active site. The affected boy, who possesses mutant HSD10 (p.V65A), has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability. He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methyl-3-hydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal -ketothiolase activity. The c.194T>C mutation in HSD17B10 can be identified by the restriction fragment polymorphism analysis, thereby facilitating the screening of this novel mutation in individuals with intellectual disability of unknown etiology and their family members much easier. The patient's mother is an asymptomatic carrier, and has a mixed ancestry (Hawaiian, Japanese and Chinese). This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants.
View details for DOI 10.1371/journal.pone.0027348
View details for Web of Science ID 000297792400006
View details for PubMedID 22132097
Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development PSYCHOPHARMACOLOGY 2011; 217 (2): 211-219
This study evaluated the question whether length of in utero exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants might affect neonatal outcome and psychomotor development in infancy.Birth outcome was determined in the offspring of 55 women with major depressive disorder who used SSRI medication for different durations during their pregnancies. At an average age of 14months, children underwent a pediatric examination and an evaluation with the Bayley Scales of Infant Development (BSID-II).Duration of in utero exposure to SSRIs was negatively associated with total Apgar scores, specifically the activity subscale. Odds ratios for a low score (<2) on this scale were 3.8 and 6.0 at 1 and 5min, respectively. Newborns with longer exposure were more often admitted to the Neonatal Intensive Care Unit (p?.03). Mental Development Index scores of the infants were not associated with the length of gestational exposure to SSRIs. A longer duration of exposure increased the risk for lower Psychomotor Developmental Index and Behavioral Rating Scale scores in infancy (p?=?0.012 and p?=?0.007, respectively) on the BSID-II.The findings provide evidence that the length of prenatal SSRI antidepressant use can affect neonatal adjustment and can have an effect on psychomotor test scores in infancy. Importantly, the children's mental development and motor function by neurological examination were within the normal range. Timing of exposure to SSRIs during susceptible periods of fetal development and variations in the severity of maternal depression may have contributed to the associations.
View details for DOI 10.1007/s00213-011-2270-z
View details for Web of Science ID 000294224800006
View details for PubMedID 21499702
alpha-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2011; 21 (12): 3693-3698
We report that ?-tocotrienol quinone (ATQ3) is a metabolite of ?-tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging. ATQ3 is orally bioavailable, crosses the blood-brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling. ATQ3 may represent a broader class of unappreciated dietary-derived phytomolecular redox motifs that digitally encode biochemical data using redox state as a means to sense and transfer information essential for cellular function.
View details for DOI 10.1016/j.bmcl.2011.04.085
View details for Web of Science ID 000291145900038
View details for PubMedID 21600768
Clinical Report-Health Supervision for Children With Fragile X Syndrome PEDIATRICS 2011; 127 (5): 994-1006
Long-term follow-up of a patient with early onset CBLG disease ACADEMIC PRESS INC ELSEVIER SCIENCE. 2011: 306-307
Baseline characteristics of PKU patients enrolled in the PKUDOS registry ACADEMIC PRESS INC ELSEVIER SCIENCE. 2011: 273-273
MITOCHONDRIAL PATHOLOGY IN ANGELMAN SYNDROME LIPPINCOTT WILLIAMS & WILKINS. 2011: 165-166
Suboptimal outcomes in patients with PKU treated early with diet alone: Revisiting the evidence MOLECULAR GENETICS AND METABOLISM 2010; 101 (2-3): 99-109
The National Institute of Health (NIH) published a Consensus Statement on the screening and management of Phenylketonuria (PKU) in 2000. The panel involved in the development of this consensus statement acknowledged the lack of data regarding the potential for more subtle suboptimal outcomes and the need for further research into treatment options. In subsequent years, the approval of new treatment options for PKU and outcome data for patients treated from the newborn period by dietary therapy alone have become available. We hypothesized that a review of the PKU literature since 2000 would provide further evidence related to neurocognitive, psychosocial, and physical outcomes that could serve as a basis for reassessment of the 2000 NIH Consensus Statement.A systematic review of literature residing in PubMed, Scopus and PsychInfo was performed in order to assess the outcome data over the last decade in diet-alone early-treated PKU patients to assess the need for new recommendations and validity of older recommendations in light of new evidence.The majority of publications (140/150) that contained primary outcome data presented at least one suboptimal outcome compared to control groups or standardized norms/reference values in at least one of the following areas: neurocognitive/psychosocial (N=60; 58 reporting suboptimal outcomes); quality of life (N=6; 4 reporting suboptimal outcomes); brain pathology (N=32; 30 reporting suboptimal outcomes); growth/nutrition (N=34; 29 reporting suboptimal outcomes); bone pathology (N=9; 9 reporting suboptimal outcomes); and/or maternal PKU (N=19; 19 reporting suboptimal outcomes).Despite the remarkable success of public health programs that have instituted newborn screening and early introduction of dietary therapy for PKU, there is a growing body of evidence that suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology and maternal PKU outcomes are suboptimal. The time may be right for revisiting the 2000 NIH Consensus Statement in order to address a number of important issues related to PKU management, including treatment advancements for metabolic control in PKU, blood Phe variability, neurocognitive and psychological assessments, routine screening measures for nutritional biomarkers, and bone pathology.
View details for DOI 10.1016/j.ymgme.2010.05.017
View details for Web of Science ID 000283609600003
View details for PubMedID 20678948
Long-term outcome following pediatric liver transplantation for metabolic disorders PEDIATRIC TRANSPLANTATION 2010; 14 (2): 268-275
In order to determine long-term outcome, including survival, growth and development, following liver transplantation in children with metabolic disorders, we retrospectively reviewed charts of 54 children with metabolic disorders evaluated from 1989-2005 for presenting symptoms, transplantation timing and indications, survival, metabolic parameters, growth, and development. Thirty-three patients underwent liver transplantation (12 received combined liver-kidney transplants) at a median age of 21 months. At a median follow-up of 3.6 yr, patient survival was 100%, and liver and kidney allograft survival was 92%, and 100%, respectively. For the group as a whole, weight Z scores improved and body mass index at follow-up was in the normal range. Two yr post-transplantation, psychomotor development improved significantly (p < 0.01), but mental skills did not; however, both indices were in the low-normal range of development. When compared to patients with biliary atresia, children with metabolic disorders showed significantly lower mental developmental scores at one and two yr post-transplantation (p < 0.05), but psychomotor developmental scores were not significantly different. We conclude that, in patients with metabolic disorders meeting indications for transplantation, liver transplantation or combined liver-kidney transplantation (for those with accompanying renal failure) is associated with excellent long-term survival, improved growth, and improved psychomotor development.
View details for DOI 10.1111/j.1399-3046.2009.01228.x
View details for Web of Science ID 000274389600020
View details for PubMedID 19671092
EVIDENCE OF REDOX IMBALANCE IN A PATIENT WITH METHYLMALONIC ACIDEMIA (mut0) ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: 210-211
Nitrogen sparing therapy revisited 2009 ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S65-S71
Although the protocol that most experienced metabolic centers in the United States follow for treating acute hyperammonemia in urea cycle disorders (UCDs) is similar to that proposed by Brusilow and Batshaw in the early 1980s, over the years a steady evolution has taken place. Continued developments in intensive care, surgical and hemodialysis techniques, fluid and electrolyte management, cardiovascular support, and emergency transport have contributed to improved management of acute hyperammonemia. Compared to historical data, survival of urea cycle patients has also improved following treatment with alternative pathway therapy, in addition to appropriate supportive care, including the provision of adequate calories to prevent catabolism and promote anabolism and hemodialysis if needed. However, overall neurological outcomes have been suboptimal. There are currently a number of exciting prospective new therapies on the horizon, including novel medications or cell-based treatments. Nevertheless, the therapeutic expertise that is currently in place at centers specializing in management of metabolic emergencies already has the potential to improve survival and outcome in these children significantly. The early identification of UCD patients so that transport to a metabolic treatment center may be carried out without delay continues to be a major area of focus and challenge.
View details for DOI 10.1016/j.ymgme.2010.02.007
View details for Web of Science ID 000276985100011
View details for PubMedID 20202877
Future treatment strategies in phenylketonuria MOLECULAR GENETICS AND METABOLISM 2010; 99: S90-S95
Phenylketonuria (PKU) was the first inherited metabolic disease in which treatment was found to prevent clinical features of the disorder; dietary management was established almost 60 years ago. The institution of a low-phenylalanine (Phe) diet in the first few weeks of life was made possible by Guthrie neonatal screening, which further increased effectiveness of therapy. Indeed, neonatal diagnosis of PKU followed by institution of a low-Phe diet has been a remarkable success in preventing the devastating brain damage associated with untreated PKU. Nevertheless, significant difficulties exist in caring for PKU patients, including problems with adhering to the prescribed dietary regimen and the presence of neurocognitive deficits despite therapy. During the past few years, several ideas for new treatment strategies have emerged. This review aims to address these treatment strategies based on theoretical considerations of the biochemistry and pathogenesis of PKU. Recent times have seen the introduction of a wide array of novel treatments currently in clinical use, including more palatable medical foods, glycomacropeptide, large neutral amino acids, and tetrahydrobiopterin. Human trials are underway using an enzymatic therapeutic approach, while preclinical work continues in the fields of gene and cellular therapy. These therapeutic strategies propose to treat PKU at various levels, including nutritional intake, gut, liver, and blood-brain barrier, and have the potential to further improve outcome in PKU.
View details for DOI 10.1016/j.ymgme.2009.10.008
View details for Web of Science ID 000273758100016
View details for PubMedID 20123478
Pathological evidence of Wolman's disease following hematopoietic stem cell transplantation despite correction of lysosomal acid lipase activity BONE MARROW TRANSPLANTATION 2009; 44 (7): 449-450
Hypoplastic Glomerulocystic Kidney Disease and Hepatoblastoma A Potential Association not Caused by Mutations in Hepatocyte Nuclear Factor 1 beta JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY 2009; 31 (7): 527-529
Hypoplastic glomerulocystic kidney disease is an autosomal dominant disorder caused by mutations in hepatocyte nuclear factor-1beta. Hepatoblastoma is a sporadic occurring tumor of embryonal origin that has been associated with the several overgrowth syndromes. We report a case of concomitant hypoplastic glomerulocystic kidney disease and hepatoblastoma. Review of the literature identified 4 other patients with a similar association. We propose that hypoplastic glomerulocystic kidney disease and hepatoblastoma represent a possible association, and we excluded mutations in hepatocyte nuclear factor-1beta in our patient as causative of this putative association.
View details for Web of Science ID 000267567800014
View details for PubMedID 19564751
Clinical and Molecular Heterogeneity in Patients with the CblD Inborn Error of Cobalamin Metabolism JOURNAL OF PEDIATRICS 2009; 154 (4): 551-556
To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria.Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA.Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated homocystinuria, and patient 2 with combined methylmalonic aciduria and homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients.The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with homocystinuria.
View details for DOI 10.1016/j.jpeds.2008.10.043
View details for Web of Science ID 000264808000020
View details for PubMedID 19058814
A novel homozygous SCO2 mutation, p.G193S, causing fatal infantile cardioencephalomyopathy CLINICAL NEUROPATHOLOGY 2009; 28 (2): 143-149
Cytochrome c oxidase (COX) deficiency is a frequent cause of mitochondrial disease in infants. Mutations in the COX assembly gene SCO2 cause fatal infantile cardioencephalomyopathy. All patients reported to date with SCO2 deficiency share a common p.E140K mutation in at least 1 allele. In order to further the understanding of the genotype-phenotype spectrum associated with fatal infantile cardioencephalomyopathy, we describe a novel homozygous SCO2 mutation p.G193S in a patient with fatal infantile cardioencephalomyopathy born to consanguineous parents of Indian ancestry.
View details for Web of Science ID 000264437100011
View details for PubMedID 19353847
Successful pregnancy and cesarean delivery via noninvasive ventilation in mitochondrial myopathy JOURNAL OF PERINATOLOGY 2009; 29 (2): 166-167
We report a case study of a 22-year-old woman with mitochondrial thymidine kinase 2 deficiency and chronic respiratory failure due to severe neuromuscular weakness requiring noninvasive positive pressure ventilation (NIPPV) since 12 years of age. During pregnancy and cesarean delivery, she was successfully supported with NIPPV. A multidisciplinary team approach should be used in pregnant patients with these disorders with specific attention to management of pulmonary complications, selection of route of delivery, anesthesia, and analgesia.
View details for DOI 10.1038/jp.2008.178
View details for Web of Science ID 000263492700016
View details for PubMedID 19177045
Neurologic Damage and Neurocognitive Dysfunction in Urea Cycle Disorders SEMINARS IN PEDIATRIC NEUROLOGY 2008; 15 (3): 132-139
Although the survival of patients who have urea cycle disorders has improved with the use of modalities such as alternative pathway therapy and hemodialysis, neurologic outcome is suboptimal. Patients often manifest with a variety of neurologic abnormalities, including cerebral edema, seizures, cognitive impairment, and psychiatric illness. Current hypotheses of the pathogenesis underlying brain dysfunction in these patients have focused on several lines of investigation, including the role of glutamine in causing cerebral edema, mitochondrial dysfunction leading to energy failure and the production of free radicals, and altered neurotransmitter metabolism. Advances in understanding the pathogenetic mechanisms underlying brain impairment in urea cycle disorders may lead to the development of therapies designed to interfere with the molecular cascade that ultimately leads to cerebral edema and other brain pathological findings.
View details for DOI 10.1016/j.spen.2008.05.007
View details for Web of Science ID 000207789700006
View details for PubMedID 18708004
Cell-based therapies for metabolic liver disease MOLECULAR GENETICS AND METABOLISM 2008; 95 (1-2): 3-10
Liver transplantation is an important therapeutic option for many individuals with metabolic liver disease. Nevertheless, the invasive nature of surgery and limitations of donor organ availability have led to the search for alternatives to whole-organ transplantation. Cell-based therapies have been a particularly active area of investigation in recent years. Hepatocyte transplantations have been performed for a variety of indications, including acute liver failure, end-stage liver disease, and inborn errors of metabolism. Individuals with inborn errors of metabolism who have undergone hepatocyte transplantation have shown clinical improvement and partial correction of the underlying metabolic defect. In most cases, sustained benefits have not been observed. This may be related to inadequate cell dose, variations in the quality of hepatocyte preparations, rejection of the transplanted cells, or senescence of transplanted hepatocytes. Though initial proof of concept with hepatocyte transplantation has been demonstrated by a number of investigators, wide application of this technology has been hindered by the inability to secure a reliable and well-characterized cell source(s) for transplantation and by the challenges of sustained engraftment and expansion of transplanted cells in vivo. Cell-based therapies, including those based on stem cells or more differentiated progenitor cells, may represent the future of cell transplantation for treatment of metabolic liver disease.
View details for DOI 10.1016/j.ymgme.2008.06.001
View details for Web of Science ID 000259941000002
View details for PubMedID 18640065
Maternal phenylketonuria PEDIATRICS 2008; 122 (2): 445-449
Dopa-responsive dystonia presenting as delayed and awkward gait PEDIATRIC NEUROLOGY 2008; 38 (4): 273-275
Dopa-responsive dystonia is a hereditary disease characterized by inadequate dopamine production. Autosomal-dominant cases result from mutations in the GCH1 gene, encoding guanosine triphosphate (GTP)-cyclohydrolase 1. The most common presenting manifestation is dystonia of a lower extremity, often worsening late in the day. The onset and clinical severity are variable, sometimes even within a single family. Gender effects on allele penetrance have been reported. We present a male toddler with dopa-responsive dystonia caused by an autosomal-dominant GCH1 mutation. Three other family members were also found to carry the mutation, with widely different functional consequences.
View details for DOI 10.1016/j.pediatrneurol.2007.12.005
View details for Web of Science ID 000254646800009
View details for PubMedID 18358407
Central nervous system therapy for lysosomal storage disorders NEUROSURGICAL FOCUS 2008; 24 (3-4)
Most lysosomal storage disorders are characterized by progressive central nervous system impairment, with or without systemic involvement. Affected individuals have an array of symptoms related to brain dysfunction, the most devastating of which is neurodegeneration following a period of normal development. The blood-brain barrier has represented a significant impediment to developing therapeutic approaches to treat brain disease, but novel approaches-including enzyme replacement, small-molecule, gene, and cell-based therapies-have given children afflicted by these conditions and those who care for them hope for the future.
View details for DOI 10.3171/FOC/2008/24/3-4/E11
View details for Web of Science ID 000256374100012
View details for PubMedID 18341388
Health supervision for children with neurofibromatosis PEDIATRICS 2008; 121 (3): 633-642
Neurofibromatosis 1 is a multisystem disorder that primarily involves the skin and nervous system. Its population prevalence is 1 in 3500. The condition usually is recognized in early childhood, when cutaneous manifestations are apparent. Although neurofibromatosis 1 is associated with marked clinical variability, most affected children do well from the standpoint of their growth and development. Some features of neurofibromatosis 1 are present at birth, and others are age-related abnormalities of tissue proliferation, which necessitate periodic monitoring to address ongoing health and developmental needs and to minimize the risk of serious medical complications. This clinical report provides a review of the clinical criteria needed to establish a diagnosis, the inheritance pattern of neurofibromatosis 1, its major clinical and developmental manifestations, and guidelines for monitoring and providing intervention to maximize the growth, development, and health of an affected child.
View details for DOI 10.1542/peds.2007-3364
View details for Web of Science ID 000253780100025
View details for PubMedID 18310216
Progressive cerebral vascular degeneration with mitochondrial encephalopathy AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2008; 146A (3): 361-367
MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a maternally inherited disorder characterized by recurrent cerebral infarctions that do not conform to discreet vascular territories. Here we report on a patient who presented at 7 years of age with loss of consciousness and severe metabolic acidosis following vomiting and dehydration. She developed progressive sensorineural hearing loss, myopathy, ptosis, short stature, and mild developmental delays after normal early development. Biochemical testing identified metabolites characteristic of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (hexanoylglycine and suberylglycine), but also severe lactic acidemia (10-25 mM) and, in urine, excess of lactic acid, intermediates of the citric cycle, and marked ketonuria, suggesting mitochondrial dysfunction. She progressed rapidly to develop temporary cortical blindness. Brain imaging indicated generalized atrophy, more marked on the left side, in addition to white matter alterations consistent with a mitochondrial disorder. Magnetic resonance angiography indicated occlusion of the left cerebral artery with development of collateral circulation (Moyamoya syndrome). This process worsened over time to involve the other side of the brain. A muscle biopsy indicated the presence of numerous ragged red fibers. Molecular testing confirmed compound heterozygosity for the common mutation in the MCAD gene (985A>G) and a second pathogenic mutation (233T>C). MtDNA testing indicated that the muscle was almost homoplasmic for the 3243A>T mutation in tRNALeu, with a lower mutant load (about 50% heteroplasmy) in blood and skin fibroblasts. These results indicate that mitochondrial disorders may be associated with severe vascular disease resulting in Moyamoya syndrome. The contribution of the concomitant MCAD deficiency to the development of the phenotype in this case is unclear.
View details for DOI 10.1002/ajmg.a.31841
View details for Web of Science ID 000253008300014
Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase HUMAN MUTATION 2008; 29 (2): 330-331
Published mutations in deoxyguanosine kinase (DGUOK) cause mitochondrial DNA depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c.766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology.
View details for DOI 10.1002/humu.9519
View details for Web of Science ID 000253033000018
View details for PubMedID 18205204
Inborn error of metabolism presenting as malformation syndrome: Hydrocephalus as a manifestation of cobalamin D disease LIPPINCOTT WILLIAMS & WILKINS. 2008: 19696
Glutaric acidemia type I: a neurosurgical perspective JOURNAL OF NEUROSURGERY 2007; 107 (2): 167-172
Glutaric acidemia type I (GA-I) is a rare, autosomal recessive metabolic disorder that leads to severe dystonia, basal ganglia degeneration, and bilaterally enlarged anterior middle cranial fossae. The current management of this disease includes early diagnosis with newborn screening, prevention of catabolism, carnitine supplementation, and a strict dietary protein restriction. Neurosurgical evaluation and intervention may be necessary in patients with structural lesions associated with this disease. In this report, the authors present two pediatric patients with GA-I and discuss the neurosurgical aspects of this rare medical disorder.
View details for DOI 10.3171/PED-07/08/167
View details for Web of Science ID 000248626600016
View details for PubMedID 18459892
Cobalamin C disease identified by expanded newborn screening: The California experience. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: 240-240
Early identification and aggressive treatment of cobalamin C disease. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: 249-250
Cobalamin c disease and expanded newborn screening: The California experience. LIPPINCOTT WILLIAMS & WILKINS. 2007: S90-S90
Systemic hyalinosis: A distinctive early childhood-onset disorder characterized by mutations in the anthrax toxin receptor 2 gene (ANTRX2) PEDIATRICS 2006; 118 (5): E1485-E1492
We sought to further characterize the phenotype and facilitate clinical recognition of systemic hyalinosis in children who present with chronic pain and progressive contractures in early childhood.We report on 3 children who presented in infancy with symptoms and signs that initially were not recognized to be those of systemic hyalinosis. Although the children were evaluated for a variety of problems, including lysosomal storage disorders and nonaccidental trauma, all eventually underwent genetic analysis of the anthrax toxin receptor 2 gene (ANTRX2) and were diagnosed as having systemic hyalinosis.We describe the recognizable but variable clinical phenotype of systemic hyalinosis and associated mutations in ANTRX2. Affected individuals presented in early infancy with severe pain and progressive contractures. Initial diagnostic evaluations were unrevealing; however, hyperpigmented skin over bony prominences, skin nodules, and fleshy perianal masses suggested a diagnosis of systemic hyalinosis. ANTRX2 analysis confirmed the diagnosis in each case. Although 2 of the children died in infancy as a result of complications of chronic diarrhea, the third child has survived into midchildhood. These data suggest that some ANTRX2 mutations, such as that identified in the long-term survivor, may be associated with a less severe course of disease.Although some aspects of systemic hyalinosis may resemble lysosomal storage disorders, the clinical features of systemic hyalinosis are distinctive, and detection of an ANTRX2 mutation can confirm the diagnosis. Early recognition of affected individuals should allow for aggressive pain control and expectant management of the multiple associated problems, including gastrointestinal dysfunction.
View details for DOI 10.1542/peds.2006-0824
View details for Web of Science ID 000241731700101
View details for PubMedID 17043134
Introduction to the newborn screening fact sheets PEDIATRICS 2006; 118 (3): 1304-1312
Newborn screening fact sheets were last revised in 1996 by the Committee on Genetics of the American Academy of Pediatrics. These fact sheets have been revised again because of advances in the field, including technologic innovations such as tandem mass spectrometry, as well as greater appreciation of ethical issues such as informed consent. The fact sheets provide information to assist pediatricians and other professionals who care for children in performing their essential role within the newborn screening public health system. The newborn screening system consists of 5 parts: (1) newborn testing; (2) follow-up of abnormal screening results to facilitate timely diagnostic testing and management; (3) diagnostic testing; (4) disease management, which requires coordination with the medical home and genetic counseling; and (5) continuous evaluation and improvement of the newborn screening system. The following disorders are reviewed in the newborn screening fact sheets (which are available at www.pediatrics.org/cgi/content/full/118/3/e934): biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia,homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies,and tyrosinemia.
View details for DOI 10.1542/peds.2006-1782
View details for Web of Science ID 000240959100058
View details for PubMedID 16960984
Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4. American journal of medical genetics. Part A 2006; 140 (14): 1567-1572
Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.
View details for PubMedID 16761293
Genitopatellar syndrome: Expanding the phenotype and excluding mutations in LMX1B and TBX4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2006; 140A (14): 1567-1572
Glutaryl-CoA dehydrogenase deficiency and newborn screening: Retrospective analysis of a low excretor provides further evidence that some cases may be missed MOLECULAR GENETICS AND METABOLISM 2005; 86 (3): 417-420
Glutaryl-CoA dehydrogenase deficiency (GA-I) is associated with the onset of irreversible, disabling dystonia between 3 and 18 months of age. Presymptomatic identification and treatment can prevent the devastating disability associated with this disorder. We report the retrospective analysis of the newborn blood spot of an affected child with a low excretor phenotype. The level of glutarylcarnitine was below the newborn screening program cut-off. This suggests that some cases of GA-I may be missed by newborn screening by tandem mass spectrometry.
View details for DOI 10.1016/j.ymgme.2005.08.005
View details for Web of Science ID 000233327600012
View details for PubMedID 16183314
Management of methylmalonic acidaemia by combined liver-kidney transplantation JOURNAL OF INHERITED METABOLIC DISEASE 2005; 28 (4): 517-524
Methylmalonic acidaemia (MMA) is a rare autosomal recessive inborn error of metabolism that typically presents in infancy with recurrent episodes of metabolic acidosis, developmental delay and failure to thrive. The disease course is complicated by the development of chronic tubulointerstitial nephritis progressing to end-stage renal disease in adolescence. We describe two adolescents with cobalamin-nonresponsive MMA (mut0) who developed polyuria, chronic tubulointerstitial nephritis, dystonia but normal synthetic liver function. Both patients received combined liver-kidney transplantation (CLKT), preceded by a single pretransplant haemodialysis for clearance of methylmalonic acid. Post CLKT there was 95-97% reduction in serum and urine methylmalonic acid, leading to significant liberalization of dietary protein intake and a consequent increase in body mass index, muscle strength and energy. In addition, renal function normalized and clinical neurological status stabilized. We propose that CLKT be considered as a therapeutic option early in the course of cobalamin-nonresponsive MMA. Progressive tubulointerstitial nephritis with disabling polyuria is a confounder in patient management even in the absence of end-stage renal disease. Successful CLKT restores methylmalonyl-CoA mutase enzyme levels in the liver and kidney, improves clearance of methylmalonic acid with resultant dietary protein liberalization, and offers excellent graft and patient outcomes with improvement in quality of life.
View details for DOI 10.1007/s10545-005-0517-8
View details for Web of Science ID 000229220200008
View details for PubMedID 15902554
Postpartum "psychosis" in mild argininosuccinate synthetase deficiency OBSTETRICS AND GYNECOLOGY 2005; 105 (5): 1244-1246
Urea cycle disorders are relatively rare but well-established causes of postpartum coma and death. Such clinical presentations have been reported previously in ornithine transcarbamylase and carbamyl phosphate synthetase deficiencies.We describe a woman, without prior symptoms of metabolic disease, who presented with hyperammonemia and psychiatric symptoms in the postpartum period. Initial diagnoses included acute fatty liver of pregnancy and postpartum psychosis. She was later found to have argininosuccinate synthetase deficiency after further metabolic investigations. Rare heterozygous mutations in the argininosuccinate synthetase gene were identified.Urea cycle disorders may present initially with postpartum psychiatric symptoms and may represent an underrecognized cause of "postpartum psychosis." We recommend obtaining metabolic studies in women with neurologic or severe psychiatric symptoms in the postpartum period.
View details for DOI 10.1097/01.AOG.0000157769.90230.24
View details for Web of Science ID 000228842600028
View details for PubMedID 15863597
Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function BIOLOGICAL CHEMISTRY 2005; 386 (4): 319-324
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine, as well as of the widely used chemotherapeutic drug 5-fluorouracil (5FU). Analysis of the DPD gene ( DPYD ) in two patients presenting with complete DPD deficiency and the parents of an affected child showed the presence of three novel mutations, including one splice site mutation IVS11 + 1G-->T and the missense mutations 731A-->C (E244V) and 1651G-->A (A551T). The G-->T mutation in the invariant GT splice donor site flanking exon 11 (IVS11 + 1G-->T) created a cryptic splice site within exon 11. As a consequence, a 141-bp fragment encoding the aminoacid residues 400-446 of the primary sequence of the DPD protein was missing in the mature DPD mRNA. Analysis of the crystal structure of pig DPD suggested that the E244V mutation might interfere with the electron flow between NADPH and the pyrimidine binding site of DPD. The A551T point mutation might prevent binding of the prosthetic group FMN and affect folding of the DPD protein. The identification of these novel mutations in DPYD will allow the identification of patients with an increased risk of developing severe 5FU-associated toxicity.
View details for DOI 10.1515/BC.2005.038
View details for Web of Science ID 000228817700002
View details for PubMedID 15899693
Two cases of transient 5-oxoprolinuria resolving with antioxidant therapy. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2005: 223-224
Mutations in POMT1 are found in a minority of patients with Walker-Warburg syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2005; 133A (1): 53-57
Walker-Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o-mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran-Valero de Bernabe et al., 2002], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non-consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran-Valero de Bernabe et al.  and it can be as low as approximately 7%, as reported here.
View details for DOI 10.1002/ajmg.a.30487
View details for Web of Science ID 000226619200010
View details for PubMedID 15637732
Mild developmental delay in terminal chromosome 6p deletion AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2004; 129A (2): 201-205
Deletions involving the short arm of chromosome 6 are relatively rare. Although features of this condition are variable, common findings include developmental delay, ocular abnormalities, hearing loss, and cardiac defects. In an effort to define further the clinical variability of this condition, we report a 6-year-old female with a de novo terminal deletion of chromosome 6 at band 6p24, with mild gross motor delays and normal cognition.
View details for DOI 10.1002/ajmg.a.30127
View details for Web of Science ID 000223478900020
View details for PubMedID 15316977
Terminal 22q deletion syndrome: A newly recognized cause of speech and language disability in the autism spectrum PEDIATRICS 2004; 114 (2): 451-457
Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.
View details for Web of Science ID 000223040000017
View details for PubMedID 15286229
Head imaging abnormalities in dihydropyrimidine dehydrogenase deficiency JOURNAL OF INHERITED METABOLIC DISEASE 2004; 27 (4): 513-522
Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of pyrimidine metabolism. Patients may present with a wide range of neurological symptoms during the first years of life. Head imaging abnormalities have been reported only rarely and include diffuse cerebral atrophy and white-matter hyperintensity. The pathogenesis of the white-matter abnormalities is unknown, although environmental factors and altered energy metabolism may be involved. To further understanding of the spectrum of brain abnormalities associated with DPD deficiency, we report a 17-month-old girl, born to a consanguineous Pakistani couple, who had a history of encephalopathy, prolonged hypoventilation, developmental delay and failure to thrive. Head MRI showed prominent sulci and abnormal T2 prolongation in the cerebral white matter and brainstem. Thus, DPD deficiency may feature prominent brain abnormalities involving the cerebral white matter and brainstem. Anoxic stress may have contributed to the clinical presentation and brain findings in this case. In order to define more clearly the contribution of DPD deficiency to the pathogenesis of these MRI abnormalities, we recommend performing detailed analysis of urine pyrimidine metabolites in patients who have such findings.
View details for Web of Science ID 000223177000010
View details for PubMedID 15303009
Methotrexate/misoprostol embryopathy: Report of four cases resulting from failed medical abortion AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2003; 123A (1): 72-78
Methotrexate, a methyl derivative of aminopterin, is a folic acid antagonist and a known human teratogen; misoprostol is a synthetic prostaglandin E1 analog that causes uterine contractions. Recently, there has been resurgence in the use of methotrexate in combination with misoprostol or of methotrexate alone for the treatment of unwanted or ectopic pregnancies, respectively. This report documents the findings in four infants who were exposed prenatally to methotrexate alone or in combination with misoprostol in a failed attempt at medical abortion or treatment of ectopic pregnancy. All patients demonstrated growth deficiency, with growth parameters <10th centile, and all displayed features consistent with methotrexate and/or misoprostol embryopathy. Since an increasing number of medical abortions are being performed, it is important for physicians to recognize the associated teratogenic effects of these abortifacients. Data from the patients herein described should prompt obstetricians and other health care practitioners who prescribe these medications to counsel their patients regarding these risks, especially if the treatment regimen fails to induce an abortion.
View details for DOI 10.1002/ajmg.a.20503
View details for Web of Science ID 000186239400010
View details for PubMedID 14556250
Compensatory amplification of mtDNA in a patient with a novel deletion/duplication and high mutant load JOURNAL OF MEDICAL GENETICS 2003; 40 (11)
Congenital disorder of glycosylation Ic in patients of Indian origin MOLECULAR GENETICS AND METABOLISM 2003; 79 (3): 221-228
Congenital disorder of glycosylation type Ic (CDG-Ic) is caused by mutations in ALG6, encoding an alpha 1,3-glucosyltransferase. The most frequent mutation found in this gene (C998T resulting in an A333V substitution) has until now been found only in patients of European origin. Here we describe the first occurrence of this CDG-Ic mutation in patients of Indian origin. Of three Indian patients described in this study, patient 1 was homozygous and patient 2 heterozygous for the A333V mutation. In patient 2 we also found a new mutation, IVS3+2_3insT, just 3bp away from the previously described IVS3+5G>A substitution; both mutations resulted in exon 3 skipping. We screened a panel of >350 genomic DNA samples from an ethnically diverse American population to determine the frequency of the A333V mutation. None of the samples carried this mutation, indicating the frequency of patients carrying this homozygous mutation should be <1 in 5x10(5). The discovery of the common CDG-Ic mutation A333V in an Indian population raises questions as to its ethnic origin.
View details for DOI 10.1016/S1096-7192(03)00089-1
View details for Web of Science ID 000184304300010
View details for PubMedID 12855228
Severe liver disease in urea cycle disorders. LIPPINCOTT WILLIAMS & WILKINS. 2003: S118-S118
Bilateral cystic lung disease in a monoamnionic twin of an anencephalic: A case of glial heterotopia in the lungs. LIPPINCOTT WILLIAMS & WILKINS. 2003: S119-S120
Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins JOURNAL OF PEDIATRICS 2002; 141 (5): 695-700
To increase awareness of congenital disorders of glycosylation (CDG), we report the features of patients with a variety of clinical presentations ranging from mild hypotonia and strabismus to severe neurologic impairment.Nine North American patients with CDG type I and different ethnic origins were studied.All patients had transferrin isoelectric focusing studies with a type 1 sialotransferrin pattern. Molecular analysis showed the previously described R141H, V231M, and T237M PMM2 mutations in four patients as well as 3 rare mutations (DeltaC389, L104V, and IVS1 -1 G-->A) in the PMM2 gene in two Asian patients.The clinical features of these patients with diverse ethnic backgrounds confirm the variable course of CDG type I. Screening for CDG should be considered in children with relatively mild neurologic impairment, especially if they have suggestive findings such as cerebellar hypoplasia and abnormal fat distribution.
View details for DOI 10.1067/mpd.2002.128658
View details for Web of Science ID 000179182300025
View details for PubMedID 12410200
Post-partum "psychosis" in mild argininosuccinate synthetase deficiency. CELL PRESS. 2002: 425-425
The adolescent with an inborn error of metabolism: medical issues and transition to adulthood. Adolescent medicine (Philadelphia, Pa.) 2002; 13 (2): 315-?
As patients with inborn errors of metabolism survive longer, understanding of potential medical and psychiatric complications adolescence and adulthood has increased. In general, detailed therapeutic guidelines for specific metabolic disorders are not available, and medical management must be tailored to the individual patient. Close interaction between the biochemical genetics clinic staff, primary care physician, mental health professional, and other specialists is necessary to formulate an integrated care plan. The education of the patient and family is a critical function of the biochemical genetics clinic, and transition from dependence on parents or other care providers to full independence is gradual. The ultimate goal is for the patient to have the essential knowledge and motivation required to cope responsibly with dietary and medical therapeutic regimens by adolescence or early adulthood. Specific illustrative inborn errors of metabolism are discussed (aminoacidemias, urea cycle defects, organic acidemias, fatty acid oxidation defects, disorders of carbohydrate metabolism, lysosomal storage disorders) in light of potential problems encountered in adolescence and adulthood, including issues involving pregnancy and long-term medical, psychosocial, and psychiatric complications.
View details for PubMedID 11986039
Early neonatal diagnosis of long-chain 3-hydroxyacyl coenzyme A dehydrogenase and mitochondrial trifunctional protein deficiencies MOLECULAR GENETICS AND METABOLISM 2002; 75 (2): 120-127
Tandem mass spectrometry (MS/MS) has been introduced in several newborn screening programs for the detection of a large number of inborn errors of metabolism, including fatty acid oxidation disorders (FAOD). Early identification and treatment of FAOD have the potential to improve outcome and may be life-saving in some cases; an estimated 5% of sudden infant deaths are attributable to undiagnosed disorders of fatty acid oxidation. We report very early neonatal presentations of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (TFP) deficiencies confirmed by molecular analysis. Both patients had cardiorespiratory collapse and hypoglycemia, without a history of maternal pregnancy complications. Retrospective MS/MS analysis of the original newborn screening blood spots revealed characteristic acylcarnitine profiles. These cases are among the earliest reported presentations of LCHAD and TFP deficiencies and further illustrate the potential of MS/MS as a valuable tool for newborn screening of FAOD. However, timely analysis and reporting of results to clinicians are essential, because these disorders can manifest in the first few days of life.
View details for DOI 10.1006/mgme.2001.3282
View details for Web of Science ID 000174355300003
View details for PubMedID 11855930
Redefining a case of Jarcho-Levin syndrome as Oculo-Auriculo-Vertebral Spectrum. CELL PRESS. 2001: 300-300
Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry MOLECULAR GENETICS AND METABOLISM 2001; 73 (1): 71-76
Congenital disorders of glycosylation (CDG) are caused by autosomal recessive mutations in genes affecting N-glycan biosynthesis. Mutations in the PMM2 gene, which encodes the enzyme phosphomannomutase (mannose 6-phosphate <--> mannose 1-phosphate), give rise to the most common form: CDG-Ia. These patients typically present with dysmorphic features and neurological abnormalities, cerebellar hypoplasia, ataxia, hypotonia, and coagulopathy, in addition to feeding problems. However, the clinical symptoms vary greatly. The great majority of known CDG-Ia patients are of European descent where the most common mutant alleles originated. This ethnic bias can also be explained by lack of global awareness of the disorder. Here we report an Asian patient with prominent systemic features that we diagnosed with CDG-Ia resulting from two new mutations in the PMM2 gene (310C --> G resulting in L104V and an intronic mutation IVS1-1G --> A). The latter mutation seems to result in lower mRNA levels, and the L104V has been functionally analyzed in a yeast expression system together with known mutations. The Filipino and Cambodian origins of the parents show that CDG-Ia mutations occur in these ethnic groups as well as in Caucasians.
View details for Web of Science ID 000168761300009
View details for PubMedID 11350185
Clinical course and biochemistry of sialuria JOURNAL OF INHERITED METABOLIC DISEASE 2001; 24 (3): 328-336
Sialuria is a rare inborn error of metabolism in which excessive free sialic acid (N-acetylneuraminic acid, NeuAc) is synthesized. A defect in the feedback inhibition of UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase by the end-product of the sialic acid synthetic pathway, CMP-NeuAc, is the mechanism underlying this overproduction. Recent evidence suggests that sialuria is an autosomal dominant disorder. Only five patients have been documented to have such an enzymatic defect. We report a longitudinal study of one of the original sialuria patients, to age 11 years. Although he has coarse features and massive hepatomegaly, he has shown normal growth and relatively normal development. Pulmonary function testing showed minimal small airway obstruction. At 11 years, he developed intermittent abdominal pain and transient transaminase elevation above his baseline. Sialuria should be considered in the differential diagnosis of a patient with a phenotype suggestive of a mucopolysaccharidosis or oligosaccharidosis in the absence of developmental regression or prominent dysostosis multiplex. We recommend close monitoring of liver and pulmonary function in sialuria patients.
View details for Web of Science ID 000169331400002
View details for PubMedID 11486897
Natural history of branchio-oto-renal (BOR) syndrome. CELL PRESS. 2000: 56-56
Molecular correlations in phenylketonuria: Mutation patterns and corresponding biochemical and clinical phenotypes in a heterogeneous California population PEDIATRIC RESEARCH 1999; 46 (5): 594-602
We studied 133 California phenylketonuria (PKU) patients and one obligate heterozygote to delineate the molecular basis of PKU in a population with greater ethnic diversity than in previous studies, and to determine whether a correlation exists between genotype and clinical phenotype, with the latter defined by both the diagnostic pretreatment blood phenylalanine (PHE) level and cognitive (IQ) test scores. To determine PAH genotypes, we used PCR-mediated amplification, denaturing gradient gel electrophoresis, and direct sequencing on dried whole blood samples. Where possible, mutation severity was defined according to predicted in vitro PAH enzyme activity estimated by using Cos cell expression analysis for a given mutation. We then asked whether mutation severity, as defined by such expression analysis, correlated with pretreatment PHE levels or with IQ test results. A mutation was identified in 236 (88%) of 267 mutant alleles. Seventeen new mutant alleles were found; A47E, T81P, I102T, E182G, T328D, Y343P, K371R, Y387H, A389E, E422K, IVS9nt5, IVS11nt20, delS70, del364-368/del198-220, delF299, delT323, and -1C/T. In striking contrast to a number of studies in other populations, in this study, based on predicted PAH activity, we observed no correlation between mutation severity and pretreatment PHE levels. There was also no correlation between genotype and IQ. We conclude that in samples collected from an ethnically heterogeneous population, there is no correlation of mutation severity with either pretreatment PHE levels or IQ measurement in treated patients. We caution that genetic counseling in PKU should incorporate the notion that prognosis may not be predicted with precision based on mutation analysis in a given patient.
View details for Web of Science ID 000083247000017
View details for PubMedID 10541324
Apparent cyclophosphamide (cytoxan) embryopathy: A distinct phenotype? AMERICAN JOURNAL OF MEDICAL GENETICS 1999; 86 (3): 237-241
Cyclophosphamide (CP) is an alkylating agent widely used in treating cancer and autoimmune disease. CP is classified as a pregnancy risk factor D drug and is teratogenic in animals, but population studies have not conclusively demonstrated teratogenicity in humans. Six isolated reports of prenatally exposed infants with various congenital anomalies exist, but to date no specific phenotype has been delineated. The purpose of this report is to document a new case of in utero CP exposure with multiple congenital anomalies and to establish an apparent CP embryopathy phenotype. The mother had systemic lupus erythematosus and cyclophosphamide exposure in the first trimester. She also took nifedipine, atenolol, clonidine, prednisone, aspirin, and potassium chloride throughout pregnancy. The infant had growth retardation and multiple anomalies including microbrachycephaly, coronal craniosynostosis, hypotelorism, shallow orbits, proptosis, blepharophimosis, small, abnormal ears, unilateral preauricular pit, broad, flat nasal bridge, microstomia, high-arched palate, micrognathia, preaxial upper limb and postaxial lower limb defects consisting of hypoplastic thumbs, and bilateral absence of the 4th and 5th toes. Chromosomes were apparently normal. The reported cases of in utero exposure to cyclosposphamide shared the following manifestations with our patient: growth deficiency, developmental delay, craniosynostosis, blepharophimosis, flat nasal bridge, abnormal ears, and distal limb defects including hypoplastic thumbs and oligodactyly. We conclude that (a) cyclophosphamide is a human teratogen, (b) a distinct phenotype exists, and (c) the safety of CP in pregnancy is in serious question.
View details for Web of Science ID 000082714300008
View details for PubMedID 10482872
Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin JOURNAL OF INHERITED METABOLIC DISEASE 1999; 22 (5): 599-607
Cobalamin C (cblC) defects result in decreased activity of both methylmalonyl-CoA mutase and N5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase), with subsequent methylmalonic acid-uria and homocystinuria. Patients typically show failure to thrive, developmental delay and megaloblastic anaemia. Vitamin B12 therapy has been beneficial in some cases. We report a now 4-year-old Hispanic girl with cblC disease documented by complementation analysis, with progressive neurological deterioration and worsening head MRI changes while on intramuscular hydroxocobalamin begun at age 3 weeks. Oral carnitine and folic acid were added at age 1 year. Blood levels of methylmalonic acid were reduced to treatment ranges. In the absence of acute metabolic crises, she developed microcephaly, progressive hypotonia and decreased interactiveness. Funduscopic examination was normal at age 13 months. At age 19 months, she developed nystagmus, and darkly pigmented fundi and sclerotic retinal vessels were observed on examination. Her neonatal head MRI was normal. By age 1 year, the MRI showed diffuse white-matter loss with secondary third and lateral ventricle enlargement, a thin corpus callosum, and normal basal ganglia. At age 15 months, progression of the white-matter loss, as well as hyperintense globi pallidi, were present. Interval progression of both grey- and white-matter loss was seen at age 27 months. We therefore caution that progressive neurological deterioration and head MRI abnormalities may still occur in cblC disease, despite early initiation of hydroxocobalamin therapy and improvement in toxic metabolite concentrations in physiological fluids.
View details for Web of Science ID 000080750600004
View details for PubMedID 10399092
Severe congenital anomalies requiring transplantation in children with Kabuki syndrome AMERICAN JOURNAL OF MEDICAL GENETICS 1998; 80 (4): 362-367
Kabuki syndrome (KS) is a rare multiple malformation disorder characterized by developmental delay, distinct facial anomalies, congenital heart defects, limb and skeletal anomalies, and short stature. Renal anomalies have been reported in a few cases of KS, but to our knowledge, hepatic anomalies have not. Here, we document two cases of KS requiring liver or kidney transplantation: one with severe hepatic and renal anomalies and one with severe renal anomalies. Both cases had the characteristic facial appearance of children with KS, postnatal growth deficiency, and developmental delay. At birth, case 1 presented with hypoglycemia, ileal perforation, right hydroureter, and hydronephrosis. The patient subsequently developed hyperbilirubinemia, hepatic abscess, and cholangitis. At age 8 months, he underwent a liver transplant. Hepatic pathology diagnosed neonatal sclerosing cholangitis. Case 2 presented with renal failure at age 6 years. Renal ultrasound study showed markedly dysplastic kidneys requiring transplantation. In addition to characteristic findings of KS, she had coronal synostosis and was shown to have immune deficiency and an autoimmune disorder manifesting as Hashimoto thyroiditis and vitiligo. We conclude: 1) severe hepatic and renal anomalies leading to organ failure can occur in KS; 2) patients with neonatal sclerosing cholangitis should be examined closely for features of KS; 3) coronal synostosis may occur in KS; and 4) immune deficiency and autoimmune disorder can be associated with KS.
View details for Web of Science ID 000077302900011
View details for PubMedID 9856564
Congenital diaphragmatic defects and associated syndromes, malformations, and chromosome anomalies: A retrospective study of 60 patients and literature review AMERICAN JOURNAL OF MEDICAL GENETICS 1998; 79 (3): 215-225
Congenital diaphragmatic defects (CDDs) may occur in malformation syndromes of varied causes. Syndromic cases of CDDs due to chromosomal defects, autosomal recessive, autosomal dominant, or X-linked inheritance have been described. In order to determine the frequency and nature of syndromes, malformations, and chromosome abnormalities associated with CDDs, we reviewed the records of all patients with CDDs evaluated over a 4-year period. During the 4-year interval, a total of 60 patients was evaluated. Of these, 29 had a therapeutic or spontaneous abortion, and 31 received postnatal care. On prenatal ultrasonography, 20 of 60 (33%) of patients with CDDs had additional anomalies. Additional anomalies, besides CDDs, were present in 15 of 31 (48%) of liveborn patients on newborn evaluation. In total, 16 patients with multiple anomalies were evaluated. Of these, 12 of 16 (75%) had additional abnormalities detected by prenatal ultrasonography. The 4 of 16 (25%) without additional anomalies on prenatal sonography had multiple anomalies found neonatally, lethal multiple pterygium syndrome being diagnosed in one case. Prenatal chromosome analysis was performed in 7 of 16 patients, and all had postnatal karyotypes. All initial karyotypes were normal. Tetrasomy 12p was documented on postnatal fibroblast analysis in one case who had percutaneous umbilical blood sampling (PUBS). Syndromes diagnosed postnatally in 7 of 16 patients (44%) include: Fryns syndrome (2), Simpson-Golabi-Behmel syndrome (2), tetrasomy 12p (1), Brachmann-de Lange syndrome (1), and lethal multiple pterygium syndrome (1). We were unable to make a specific diagnosis in 9 of 16 patients (56%) with multiple malformations. In patients with CDDs, a normal prenatal karyotype, especially if obtained by PUBS, and absence of other detected abnormalities by fetal ultrasonography, do not exclude the presence of other major anomalies, including chromosome abnormalities and severe multiple malformation syndromes.
View details for Web of Science ID 000076065100013
View details for PubMedID 9788565