A case report of an intermediate phenotype between congenital myasthenic syndrome and D-2- and L-2-hydroxyglutaric aciduria due to novel SLC25A1 variants

Abstract

Background: Variants in the SLC25A1 gene are associated with a severe neurometabolic disease, D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). A report in 2014 presented the first account of congenital myasthenic syndrome (CMS) with mild intellectual disability (ID) caused by SLC25A1. To date, only two missense variants in SLC25A1 have been linked to CMS.

Case presentations: A Chinese boy presented fatigable muscular weakness, myasthenic crisis, epilepsy and developmental delay along with mild elevation of urinary 2-ketoglutarate (2-KG) and lactic acid levels. He showed a partial response to pyridostigmine. Genetic analysis using trio whole-exome sequencing (WES), Sanger sequencing, and cosegregation analyses revealed two novel pathogenic variants of SLC25A1 (c.628C > T, p.R210X; c.145G > A, p.V49M).

Conclusions: We report a boy who carries novel compound heterozygous variants of SLC25A1 and presents a phenotype intermediate between CMS and D/L-2-HGA. This case expands the range of known phenotypes and genotypes associated with SLC25A1.

Keywords: Congenital myasthenic syndrome; D-2- and L-2-hydroxyglutaric aciduria; Phenotype; SLC25A1.

Fig. 1

Results of the Sanger sequencing. Electropherograms of the Sanger sequencing show the two heterozygous variants (c.145G > A on the left and c.628C > T on the right) in the patient. The mother was heterozygous for c.145G > A, while the father was heterozygous for c.628C > T. The sister was heterozygous for c.628C > T (p.R210X). The variants are indicated by the black arrows

Fig. 2

Distribution of 27 novel and previously published SLC25A1 variants (including our case in red). The upper panel of the schematic shows all pathogenic variants in patients in whom CMS was the main feature, while the mutations in the lower panel correspond to the individuals who had been diagnosed with D/L-2-HGA