OPA3 gene

Overview

Gene (OMIM No.)	OPA3 (#606580)
Function of gene/protein	Protein: outer mitochondrial membrane lipid metabolism regulator Expressed in mitochondria but exact role uncertain at present May play a role in regulating mitochondrial morphology and fission
Clinical phenotype (OMIM phenotype no.)	Optic atrophy 3 with cataract, also known as autosomal dominant optic atrophy and cataract (ADOAC) (#165300) 3-methylglutaconic aciduria, type III (#258501)
Inheritance	Autosomal dominant: Optic atrophy 3 with cataract The p.Gln105Glu mutation is the most common OPA3 variant associated with dominant disease Autosomal recessive: 3-methylglutaconic aciduria, type III/Costeff syndrome (most patients are of Iraqi Jewish descent)
Ocular features	Progressive bilateral optic atrophy and vision loss without spontaneous recovery Dyschromatopsia Nystagmus may present from birth Retinal ganglion cells (RGCs) of the papillomacular bundle primarily affected Severity of visual impairment is highly variable among patients, even among family members (some may be asymptomatic though this is rare) Usually associated with early-onset/congenital cataracts but may not be present in all cases
Systemic features	Costeff syndrome is characterised by early-onset bilateral optic atrophy, later-onset movement disorder (spasticity, ataxia and extrapyramidal dysfunction) and increased urinary excretion of 3-methylglutaconic acid Visual symptoms usually manifest in the first decade of life Developmental delays may be present Seizures and electrical status epilepticus during slow wave sleep have been reported in some patients Neurological symptoms may be present in heterozygous cases such as sensorineural hearing loss (most common), movement disorders (spasticity and extrapyramidal dysfunction), peripheral neuropathy and gastrointestinal dysmotility
Key investigations	Orthoptic assessment and refraction Colour vision testing Perimetry: central/centrocaecal scotoma Optic nerve head photograph OCT of the optic disc: Global thinning of the peripapillary retinal nerve fibre layer (nasal aspect is often relatively spared) Electrophysiology MRI brain Audiology Urine organic acid analysis to detect increased excretion of 3-methylglutaconate and 3-methylglutaric acids (level of increment is variable and some may have levels that overlap with normal controls) Systemic assessment with a pediatricians, neurologists and other relevant specialists to exclude other causes of optic neuropathies
Molecular diagnosis	Next generation sequencing Targeted gene panels (optic atrophy) Whole exome sequencing Whole genome sequencing
Management	Ocular Management of congenital cataract Supportive management Smoking cessation Avoid excessive alcohol consumption Systemic Multidisciplinary approach coordinated by paediatrician and/or neurologist Hearing aids/cochlear implants helpful in those with sensorineural hearing loss Involvement of physiotherapists and occupational therapists to address motor disability Early involvement of practitioners familiar with developmental surveillance and intervention for children with visual impairment
Therapies under research	None at present
Further information	Medline Plus

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Additional information

Biallelic OPA3 variants are associated with Costeff syndrome, where the c.143-1G>C variant is found in all patients of Iraqi-Jewish origin, but intra- and interfamilial variability in phenotypic severity exist.^[5]

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References

Reynier P, Amati-Bonneau P, Verny C, et al. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. 2004;41(9):e110
Sergouniotis PI, Perveen R, Thiselton DL, et al. Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy. Neurogenetics. 2015;16(1):69-75
Grau T, Burbulla LF, Engl G, et al. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network. J Med Genet. 2013;50(12):848-858
Horga A, Bugiardini E, Manole A, et al. Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy. Neurol Genet. 2019;5(2):e322
Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet. 2001;69(6):1218-1224
Ho G, Walter JH, Christodoulou J. Costeff optic atrophy syndrome: new clinical case and novel molecular findings. J Inherit Metab Dis. 2008;31 Suppl 2:S419-S423
Anikster Y. Costeff Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; July 28, 2006
Kleta R, Skovby F, Christensen E, Rosenberg T, Gahl WA, Anikster Y. 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. Mol Genet Metab. 2002;76(3):201-206
Gaier ED, Sahai I, Wiggs JL, McGeeney B, Hoffman J, Peeler CE. Novel homozygous OPA3 mutation in an Afghani family with 3-methylglutaconic aciduria type III and optic atrophy. Ophthalmic Genet. 2019;40(6):570-573
Carmi N, Lev D, Leshinsky-Silver E, et al. Atypical presentation of Costeff syndrome-severe psychomotor involvement and electrical status epilepticus during slow wave sleep. Eur J Paediatr Neurol. 2015;19(6):733-736

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Updated on July 5, 2024

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