Résumé :
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Background:Extra-ocular neurological signs are frequent in autosomal dominant optic atrophy (ADOA) due to OPA1 mutations. However, time course and severity of this extra-ocular involvement can vary. Observations:We report three families with ADOA "plus" syndromes with various time courses of the neurological impairment.In the first family, four patients (a mother and her three children) exhibited a similar progression characterized by an onset of visual loss and extra-ocular symptoms between 6 and 8 years-old. Neurological symptoms comprised proximal myopathy, sensory axonal neuropathy, cerebellar ataxia and progressive external ophtalmoparesis. One patient had a cardiomyopathy discovered at 27 years old. The second family comprised three members ( a father, his daughter and his grand-son) in which onset of the disease was characterised by visual loss in 2 members occurring between 5 and 50 years, associated with ohptalmoplegia, bilateral ptosis, deafness and sensory neuropathy and myogenic pattern on EMG. In the third family (a mother and his daughter), visual loss occurred at about 3 years of age. At 66 years of age, she complained of dizziness. Neurological examination performed at 70 years of age was characterised by deafness, ophtalmoplegia, ataxia and a proximal motor deficit due to a combined axonal sensorimotor neuropathy and proximal myopathy. Muscle biopsy showed either mild mitochondrial proliferation and Cox negative fibers or only centralized nuclei. Complex I and complex III of the respiratory chain was diminished in a patient of the first family. Multiple mitochondrial DNA deletions was evidenced the proband of the third family.The clinical phenotype and the muscle biopsy findings were consistent with the diagnosis of mitochondrial disorders. The three primary Leber hereditary optic atrophy neuropathy mtDNA point mutations were negative in these 3 families. Sequencing of the OPA1 gene revealed heterozygous missense mutations located in the 5th and 14th respectively and a heterozygous duplication of 6 nucleotides in the 14th exon. Conclusion: Extra -ocular symptoms in ADOA "plus "syndrome may either follow the visual failure or develop in later life. This considerable variability in disease expression among patients carrying OPA1 mutations may lead to miss the right diagnostic during several years until the setting of the typical clinical picture.
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