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Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Balaraju, Sunitha 
Töpf, Ana 
McMacken, Grace 
Kumar, Veeramani Preethish 
Pechmann, Astrid 

Abstract

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.

Description

Keywords

Adult, Female, Haplotypes, Homozygote, Humans, Intellectual Disability, Male, Mitochondrial Proteins, Muscle, Skeletal, Mutation, Missense, Myasthenic Syndromes, Congenital, Organic Anion Transporters

Journal Title

European Journal of Human Genetics

Conference Name

Journal ISSN

1018-4813
1476-5438

Volume Title

Publisher

Springer Nature
Sponsorship
MRC (MR/N027302/2)
Wellcome Trust (109915_A_15_Z)
Medical Research Council (MR/N025431/2)
Includes MRC, BBSRC, EPSRC, Wellcome Trustm NIHR and ERC.