Purpose: To describe and distinguish clinical phenotypes with the overlapping feature of optic atrophy caused by distinct mutations in the same gene, OPA3. We report 3 affected siblings in a consanguineous family harboring a novel OPA3 mutation causing 3-methylglutaconic aciduria type III with optic atrophy.Methods: Retrospective case series.Results: Three siblings (2 male, 1 female) among 6 children in a consanguineous Afghani family developed decreased vision from early childhood. Both parents and all extended family members were unaffected. All 3 affected siblings suffered from severe visual impairment ranging from visual acuities of 20/150 to counting fingers. All had spastic lower extremity weakness and ataxia. Two of the three affected siblings also had a history of seizures, and the female sibling had limited cognition with diffuse atrophic changes on brain MRI. Two of the three individuals also had migraine-like headaches. Urine organic acid analysis revealed mildly elevated 3-methylglutaconic acid for the male siblings. Whole exome sequencing and subsequent PCR confirmation revealed a novel variant in OPA3 (intron1, c.142 + 2_142 + 3dupTG), affecting the consensus sequence of the splice site, for which all 3 clinically affected siblings were homozygous.Discussion: Mutations in OPA3 can cause optic atrophy in a dominant pattern of inheritance associated with cataract or in a recessive pattern associated with spastic paresis and ataxia. The novel recessive mutation and clinical presentations described herein further support how different mutation types affecting OPA3 can produce distinct clinical phenotypes and underscore the critical and susceptible role of mitochondrial health in optic nerve function.
Keywords: 3-methylglutaconic aciduria type III; OPA3; Optic atrophy; ataxia; costeff syndrome.