Objective: To describe a case of adult-onset ataxia with a heterozygous p.Lys10Asn OPA3 mutation.

Background: Mutations in the OPA3 gene, which encodes a mitochondrial membrane protein, are associated with several syndromes that vary based on their mode of inheritance.  Optic atrophy and cataracts are seen in heterozygous mutations, whereas type III 3-methylglutaconic aciduria, also known as Costeff syndrome, is autosomal recessive with homozygous mutations. Ataxia, chorea and spastic paraparesis have been described in Costeff syndrome. Here we present a case of adult-onset ataxia in a patient with multiple family members affected by similar condition and found to have a heterozygous OPA3 mutation. To our knowledge, heterozygous OPA3 mutations with findings of ataxia have only been reported in three other families. Furthermore, neurological manifestation of a missense mutation in OPA3 gene has not been reported in literature.

Method: N/A

Results: 51-year-old man with bilateral hearing loss and cataracts since childhood and longstanding hand tremors presented with three years of gait instability. He reported no gait impairment until his late 40s with recurrent falls and progressed over time to needing a cane for ambulation. He also has had distal leg numbness since his teenage years that worsened over the past several years to significant numbness below his knees. His hand tremors that started more than ten years ago has been stable and responsive to propranolol. Family history is notable for multiple members on his paternal side including sister, father, and grandmother with feet numbness, childhood cataracts and ataxia. His sister was found to have a OPA3 mutation upon work up for neuropathy and ataxia. Of note, patient has two daughters with childhood cataracts. On physical exam, there was dysmetria on finger to nose and heel to shin, and dysdiadochokinesia on rapid alternative movement. He was areflexic throughout and had impairment in light touch, vibration and joint proprioception in distal legs. EMG/NCS showed moderate distal sensorimotor axonal polyneuropathy. Exome sequencing revealed a heterozygous c.30G>C, p.Lys10Asn mutation in exon 1 in OPA3 gene.

Conclusion: We described a novel heterozygous mutation in OPA3 gene as the cause of a complex presentation that includes early hearing loss and cataracts, progressive leg numbness, hand tremors, and adult-onset ataxia, expanding the phenotype of OPA3-related syndromes.

References: [1] Costeff H., Gadoth N., Apter N., Prialnic M., Savir H. A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia. Neurology 1989;39(4):595-5972494568
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[3] Huizing M., Dorward H., Ly L., et al. OPA, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Mol Genet Metab. 2010;100(2):149-15420350831
[4] Ayrignac X., Liauzun C., Lenaers G., Renard D., Amati-Bonneau P., de Seze J., Dollfus H., Hamel C., Bonneau D., Labauge P. OPA3-Related Autosomal Dominant Optic Atrophy and Cataract with Ataxia and Areflexia. Eur Neurol 2012;68:108-110
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MDS Abstracts - https://www.mdsabstracts.org/abstract/case-report-on-heterozygous-opa3-gene-mutation-causing-ataxia/