Dominant Optic Atrophy (DOA), Deafness and Nephropathy With Mitochondrial Myopathy Negative for OPA1 Mutations: A New Syndromic Form of DOA?

Abstract

Purpose: : To describe a dominantly inherited syndromic optic atrophy with evidence of mitochondrial dysfunction, negative for mutations in the OPA1 gene.

Methods: : We report an 8-years-old male proband and his 38-years-old father, who suffered early onset optic neuropathy (before age 10). Both presented chronic renal insufficiency and hypertension. The neurological exam showed pale optic disc, divergent strabismus and diffuse hyporeflexia. They underwent serum lactic acid evaluation after exercise, muscle and kidney biopsy (only the father), neurophysiological and laboratory investigations. Total DNA was extracted from blood and skeletal muscle and mtDNA was investigated for rearrangements and copy number. Complete sequence of the OPA1 gene was performed.

Results: : Serum lactic acid after exercise was abnormally elevated in both patients (33 mg/dl and 30.4 mg/dl; normal value 5.8-22 mg/dl). In the father visual evoked potentials showed absent right cortical responses; normal latencies with reduced amplitudes on the left. Skeletal muscle biopsy showed a few cytochrome c oxidase (COX) negative fibers. CT scan showed bilateral calcifications of basal ganglia. Audiogram revealed a bilateral sensorineural hypoacusia. Laboratory investigations were consistent with chronic renal insufficiency in both patients and kidney biopsy in the father showed COX negative cells in the tubular epithelium. Assessment of respiratory complexes in platelets showed a consistent defect of complex III. Analysis of mtDNA from muscle failed to reveal deletions but demonstrated a partial mtDNA depletion. The complete sequence of the OPA1 gene was negative for pathogenic mutations.

Conclusions: : We describe two patients with dominantly inherited optic atrophy, myopathy and chronic nephropathy associated with evidence of mitochondrial dysfunction (COX deficiency), without mutations in the OPA1 gene. This report adds to the phenotypic variability of DOA, indicating further genetic heterogeneity.

Keywords: neuro-ophthalmology: optic nerve • mitochondria • genetics