Abstract
Purpose :
Heterozygous mutations in the nuclear encoded gene for the succinate dehydrogenase complex flavoprotein subunit A (SDHA) of the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) have been described in a rare syndrome including predominantly adult onset bilateral optic atrophy, progressive neurological impairment, and in some cases cardiomyopathy. They may disturb the electron transfer from succinate to ubiquinone and cause partial CII deficiency. Here, we describe a family featuring optic atrophy with autosomal dominant inheritance as the only symptom in multiple generations, segregating a pathogenic mutation in the SDHA gene, previously described in patients with progressive optic atrophy, ataxia, and myopathy.
Methods :
Clinical examinations included visual acuity testing, automated threshold perimetry, OCT-based measurement of peripapillary retinal nerve fiber layer (pRNFL) thickness and macular ganglion cell layer (mGCL) thickness, laboratory tests, cranial MRI, neurological and cardiological examination. Genetic analysis was performed by exome sequencing in the index patient and subsequent confirmation by conventional DNA sequencing in all affected individuals.
Results :
Four male patients, two adults and two children aged 7 and 9, from two generations of the same family presented with bilateral optic atrophy, central visual field defects, severely reduced pRNFL thickness (37-48 µm) and moderately reduced mGCL thickness (23-31 µm). Genetic analysis revealed the heterozygous missense mutation NM_004168.4:c.1351C>T p.(Arg451Cys) within the SDHA gene, affecting a highly conserved arginine residue in the FAD/NAD(P)-binding domain of SDHA. No other mutations in known optic atrophy genes were detected in the index patient. Cranial MRI, metabolic laboratory tests, neurological and cardiological examinations were all unremarkable.
Conclusions :
Information in this pedigree adds isolated dominant optic atrophy with childhood onset to the phenotype spectrum of heterozygous mutations in SDHA, which are known to cause a syndrome characterized by neurodegeneration with ataxia and late-onset optic atrophy (NDAXOA, OMIM #619259). Although being a rare cause, we advise to include SDHA in gene sequencing panels for dominant optic atrophy.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.