Jenna Klotz, MD

View details for Web of Science ID 000472806000098

View details for Web of Science ID 000465236700032

View details for PubMedID 31027619

Abstract

BACKGROUND: Biallelic variants in PIGW have been suggested to cause infantile spasms and hyperphosphatasia. PIGW encodes for a protein involved in the third step of glycosylphosphatidylinositol (GPI) synthesis. GPI anchored proteins are increasingly recognized as important structures for cellular interactions and neuronal development.METHODS: Molecular testing of PIGW was performed followed by fluorescence activating cell sorting analysis of granulocytes, lymphocytes, and monocytes, and compared to controls.FINDINGS: An infant was homozygous for variants in PIGW (c.199C>G; p.Pro67Ala) with an associated phenotype of infantile spasms, myoclonic seizures, cortical visual impairment, developmental delay, and minor dysmorphic features. Alkaline phosphatase levels ranged from normal to mildly elevated. Flow cytometric studies showed significantly decreased expression of important GPIs, providing functional evidence of pathogenicity.CONCLUSION: Our data provide further evidence of a novel autosomal recessive PIGW-related epilepsy disorder. Flow cytometry provided functional evidence of the pathogenicity of homozygous variants of uncertain significance in PIGW, and supports the use of flow cytometry as a functional tool to demonstrate decreased surface expression of GPI anchored proteins in cases where there are variants of unknown significance.

View details for PubMedID 30078644

Abstract

Mutations in the SLC13A5 gene that codes for the Na(+)/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In the present study we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and treatment strategies. There are currently no effective treatments, but some anti-epileptic drugs targeting the GABA system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical anti-seizure medication decreases seizures in 4 patients. In contrast to previous reports, the ketogenic diet and fasting produce worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improve transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, our study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na(+)/citrate transporters.

View details for DOI 10.2119/molmed.2016.00077

View details for PubMedID 27261973

View details for DOI 10.1097/INF.0000000000000564

View details for PubMedID 25760569

View details for DOI 10.1542/pir.35-10-439

View details for PubMedID 25274971