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Abstract
Objective: To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation.
Methods: Genetic studies involved homozygosity mapping by 250K single nucleotide polymorphism array and SLC35A1 sequencing. Functional studies included biochemical assays for N-glycosylation and mucin-type O-glycosylation and SLC35A1-encoded cytidine 5′-monophosphosialic acid (CMP–sialic acid) transport after heterologous expression in yeast.
Results: We performed biochemical analysis and found combined N- and O-glycosylation abnormalities and specific reduction in sialylation in this patient. Homozygosity mapping revealed homozygosity for the CMP–sialic acid transporter SLC35A1. Mutation analysis identified a homozygous c.303G>C (p.Gln101His) missense mutation that was heterozygous in both parents. Functional analysis of mutant SLC35A1 showed normal Golgi localization but 50% reduction in transport activity of CMP–sialic acid in vitro.
Conclusion: We confirm an autosomal recessive, generalized sialylation defect due to mutations in SLC35A1. The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter. Our study underlines the importance of sialylation for normal CNS development and regular organ function.
GLOSSARY
- CDG=
- congenital disorders of glycosylation;
- CHO=
- Chinese hamster ovary;
- CMP-Sia=
- cytidine 5′-monophosphosialic acid;
- GDP-Man=
- guanosine diphosphate–mannose;
- HA=
- hemagglutinin;
- m/z=
- mass-to-charge ratio;
- SLC35A1=
- solute carrier family 35 member A1
Footnotes
↵* These authors contributed equally.
↵‡ These authors contributed equally.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at www.neurology.org
- Received January 22, 2013.
- Accepted in final form April 26, 2013.
- © 2013 American Academy of Neurology
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