Intellectual disability and bleeding diathesis due to deficient CMP-sialic acid transport

Miski Mohamed, Angel Ashikov, Mailys Guillard, Joris H. Robben, Samuel Schmidt, B. Van Den Heuvel, Arjan P.M. De Brouwer, Rita Gerardy-Schahn, Peter M.T. Deen, Ron A. Wevers, Dirk J. Lefeber, Eva Morava

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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 59-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.

Original languageEnglish (US)
Pages (from-to)681-687
Number of pages7
Issue number7
StatePublished - Aug 13 2013

ASJC Scopus subject areas

  • Clinical Neurology


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