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-2hydroxyglutaric 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.

Congenital Myasthenic Syndrome Associated With SLC25A1 Gene Variant: The First Reported Case in Saudi Arabia

“…One patient responded well to 3,4-diamino pyridine (DAP), consistent with presynaptic NMJ defects [ 8 , 9 ]. Patients with a mild phenotype and minimal symptoms may not require treatment with AChE inhibitors or 3,4-DAP [ 10 ]. However, it is worthwhile to try these drugs to assess and verify potential benefits, especially if lethargy and excessive fatigue are vital concerns [ 10 ].…”

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…SLC25A1 -CMS has been reported in 19 patients in 10 pedigrees since 2014 [ 417 , 418 , 419 , 420 , 421 ]. Limb myasthenia and palpebral ptosis are shared features.…”

Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease

“…While a diagnosis of myasthenia gravis can frequently be excluded, the line between some subtypes of CMS and mitochondrial myopathy is less obvious. Recently, two nuclear encoded mitochondria-associated genes were identified as causative for CMS-SLC25A1 [18,[84][85][86][87] and TEFM [19]. Notably, it is only specific "milder" genetic mutations to SLC25A1 and TEFM that cause CMS; other previously identified mutations are associated with more severe and classical mitochondrial disease.…”

“…SLC25A1-related disease is typically associated with D2 and L2 hydroxyglutaric aciduria (D/L-2-HGA), a severe neurometabolic mitochondrial disease characterized by encephalopathy, severe muscle weakness, seizures, respiratory distress, psychomotor delay, and early death [93]. However, a subset of patients with SLC25A1 mutations have been identified with a less severe clinical presentation more representative of CMS, including fatigable muscle weakness and increased neuromuscular jitter [18,[84][85][86][87]. As is commonly observed in CMS, patients had a variable presentation in addition to the fatigable weakness, including intellectual disability, epilepsy, and developmental delay.…”