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Arch Neurol. 2011 Jan;68(1):67-73. doi: 10.1001/archneurol.2010.228. Epub 2010 Sep 13.

Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations.

Author information

1
MR Spectroscopy Unit, Department of Internal Medicine, Aging, and Nephrology, University of Bologna, Bologna, Italy. raffaele.lodi@unibo.it

Abstract

OBJECTIVE:

To assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene.

DESIGN:

We used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis.

SETTING:

University neuromuscular and neurogenetics and magnetic resonance imaging units.

PATIENTS:

Eighteen patients with dominant optic atrophy were enrolled from 8 unrelated families, 7 of which carried an OPA1 mutation predicted to induce haploinsufficiency and 1 with a missense mutation in exon 27. Fifteen patients had documented optic atrophy.

MAIN OUTCOME MEASURES:

Presence of skeletal muscle mitochondrial oxidative phosphorylation dysfunction as assessed by phosphorus 31 magnetic resonance spectroscopy, serum lactate levels, and histological and mitochondrial DNA analysis.

RESULTS:

Phosphorus 31 magnetic resonance spectroscopy showed reduced phosphorylation potential in the calf muscle at rest in patients with an OPA1 mutation (-24% from normal mean; P = .003) as well as a reduced maximum rate of mitochondrial adenosine triphosphate synthesis (-36%; P < .001; ranging from -28% to -49% in association with different mutations). In 4 of 10 patients (40%), the serum lactate level after exercise was elevated. Only 2 of 5 muscle biopsies, from the 2 patients with a missense mutation, showed slight myopathic changes. Low levels of mitochondrial DNA multiple deletions were found in all muscle biopsies.

CONCLUSIONS:

Defective oxidative phosphorylation in skeletal muscle is a subclinical feature of patients with OPA1-related dominant optic atrophy, indicating a systemic expression of the OPA1 defect, similar to that previously reported for Leber hereditary optic neuropathy due to complex I dysfunction. This defect of oxidative phosphorylation does not appear to depend on the low amounts of mitochondrial DNA multiple deletions detected in muscle biopsies.

PMID:
20837821
DOI:
10.1001/archneurol.2010.228
[Indexed for MEDLINE]

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