R.A Sulaiman, N. Patel, H. Alsharif, S.T Arold, F.S Alkuraya
Clinical Genetics, (2017)
mutation in SLC25A46, optic atrophy, progressive limb spasticity, axonal neuropathy
Mutations in SLC25A46, encoding a member of the mitochondrial solute carrier family, have been reported in a syndromic form of peripheral neuropathy encompassing optic atrophy and cerebellar atrophy [1-3]. Here we report an SLC25A46-related phenotype that consistently lacks peripheral neuropathy and cerebellar atrophy. The proband, a 28-year-old Saudi woman presented with history of bilateral optic atrophy and progressive weakness. She denied history of bladder dysfunction or constipation. Her younger sister had optic atrophy with minimal limb spasticity, while her four first cousins had impaired vision and difficulty or inability to walk (Fig. 1). Examination revealed finger-counting vision, hypertonia with exaggerated tendon reflexes, mild muscle weakness, and intact sensation and coordination. Brain MRI was unremarkable. There was no electrophysiological evidence of peripheral neuropathy. EMG revealed evidence of proximal muscle myopathy. Muscle biopsy showed type 2 muscle fiber atrophy with occasional enlarged mitochondria, but no ragged red fiber or cytochrome c deficiency. An echocardiogram was normal. Plasma lactate, acylcarnitine profile, amino acids, CK and urine organic acids were unremarkable. Family was recruited with informed consent (KFSHRC IRB RAC# 2080006). Combined autozygome/exome analysis revealed a homozygous mutation in SLC24A46 (NM_001303249.2:c.775C>T;p.(Arg259Cys)). Segregation was confirmed by Sanger sequencing. This mutation was predicted to be pathogenic by PolyPhen , SIFT (0.0) and CADD (33), was absent in our in-house exome database (2200 exomes), and very rare in ExAC (0.0000412). R259 (isoform 3; corresponding to R340 in the canonical SLC25A46 isoform) is located at the mitochondrial matrix side of transmembrane helix 5. Together with E299, it is part of a salt bridge network on the matrix side, which is important for correct functioning of the carrier. R259 may also be H-bonding with EY285, and possibly with H51, and may compensate for the dipole charge of helix 1 (Fig. 1). The R259C mutation would lead to loss of all these interactions, and hence to a destabilization of the 3D fold and disruption of correct carrier function.