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Multi-system neurological disease is common in patients with OPA1 mutations
P Yu-Wai-Man1, P G Griffiths, G S Gorman
1Mitochondrial Research Group, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Brain : a Journal of Neurology
|February 17, 2010
Summary
Neurological complications are common in OPA1 disease, affecting up to 20% of carriers. These include deafness, ataxia, and myopathy, with worse outcomes in dominant optic atrophy plus phenotypes.
Area of Science:
- Genetics
- Neurology
- Ophthalmology
Background:
- Autosomal dominant optic atrophy (ADOA) is primarily caused by OPA1 gene mutations.
- Recently described neurological features suggest broader OPA1-related disease spectrum.
- The frequency and extent of these neurological complications remain unclear.
Purpose of the Study:
- To determine the frequency and spectrum of extra-ocular neurological complications in OPA1 disease.
- To investigate the association between OPA1 mutation subtypes and neurological involvement.
- To explore the role of mitochondrial dysfunction in OPA1-related neurological phenotypes.
Main Methods:
- Multi-center study of 104 patients from 45 families with OPA1 mutations.
- Clinical assessment for neurological and ophthalmological features.
- Genetic analysis of OPA1 mutations and correlation with phenotypes.
- Skeletal muscle biopsy analysis for mitochondrial abnormalities (cytochrome c oxidase, mtDNA deletions).
Main Results:
- Extra-ocular neurological complications affect up to 20% of OPA1 mutation carriers.
- Common manifestations include sensorineural deafness, ataxia, myopathy, peripheral neuropathy, and ophthalmoplegia.
- Novel presentations included spastic paraparesis and a multiple sclerosis-like illness.
- Missense mutations and mutations in the GTPase region were associated with increased neurological risk.
- Mitochondrial DNA deletions and cytochrome c oxidase deficiency were prevalent, especially in 'dominant optic atrophy plus' phenotypes.
- Patients with 'dominant optic atrophy plus' had worse visual outcomes.
Conclusions:
- Neurological complications are frequent in OPA1 disease, extending beyond optic neuropathy.
- Specific OPA1 mutation types are associated with a higher risk of multi-system involvement.
- Secondary mitochondrial DNA defects likely contribute to the pathophysiology of OPA1-related neurological disease.
- Proactive surveillance is crucial for managing neurological disability in affected individuals.
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