MULTIPLE SCLEROSIS–LIKE DISORDER IN OPA1-RELATED AUTOSOMAL DOMINANT OPTIC ATROPHY

Case report.

A 44-year-old man was referred to our neurology unit for sudden onset of pain in the lower left limb. His medical history was noteworthy for an insidious, bilateral loss of visual acuity that had appeared 1 year earlier, followed a few months later by trigeminal neuralgia. At that time, the brain MRI was normal. There was no family history of ocular or neurologic diseases. Neurologic examination revealed proprioceptive dysfunction, brisk tendon reflexes, and ankle clonus in the left lower limb. The gait was spastic and the results of motor examination revealed only abnormal tone. Ophthalmologic examination indicated visual acuity of 4/10 in each eye, cecocentral scotoma, blue–yellow dyschromatopsia, and moderate bilateral optic atrophy. MRI of the cerebrum and the spinal cord showed T2-weighted high intensity lesions, and fluid-attenuated inversion recovery revealed white matter hyperintensities predominantly in the periventricular region (figure, A) and in the calloso-septal interface (figure, B). Signal alterations were also scattered throughout the cervical and thoracic spinal cord (figure, C and D). T1-weighted images were normal and there was no enhancement on gadolinium-enhanced MRI. The CSF protein level was 60 mg/dL, with oligoclonal bands present. The synchronous, bilateral involvement of the optic nerves prompted a search for hereditary optic atrophy.

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Figure MRI

(A) Axial fluid attenuated inversion recovery cerebral MRI showing high signal intensity mostly in the posterior periventricular regions. (B) Sagittal T2-weighted MRI showing hyperintense corpus callosum lesions (arrows). (C) Sagittal T2-weighted MRI showing high signal intensity lesions at C7 and T1, with no enlargement of the spinal cord (arrows). (D) Axial T2-weighted MRI at T6 showing a left lateral high intensity signal (arrow).

Methods.

Mitochondrial function was investigated in fibroblasts obtained from the patient with the OPA1 mutation and MS-like features (OPA1-MSL), and from seven normal controls. Details of the methods used and figures showing the results are provided in appendix e-1 and figure e-1 on the Neurology® Web site at www.neurology.org.

Results.

None of three main mutations or the nine secondary mutations in mitochondrial DNA (mtDNA) responsible for Leber hereditary optic neuropathy (LHON) was found. The sequencing of the OPA1 gene revealed a heterozygous S646L mutation. This mutation, involving the highly conserved dynamin domain of OPA1, was absent in 200 control chromosomes and in public SNP databases.

The mitochondrial coupling efficiency (measured by the ratio of ATP production to oxygen consumption) was sharply reduced in OPA1-MSL fibroblasts as compared to controls (p < 0.001) (figure e-1A). This low coupling efficiency was not compensated by enhanced cellular respiration as shown by the collapsed basal respiration (figure e-1B). The respiratory capacity (measured by the FCCP-uncoupled respiration rate) was also severely depressed (figure e-1C). As a consequence, ATP synthesis was lower in the OPA1-MSL patient as compared to controls (p < 0.03) (figure e-1D).

Discussion.

OPA1 encodes a dynamin-related GTPase associated with the inner mitochondrial membrane that participates in the process of mitochondrial fusion² and provides protection from apoptosis by preventing the release of cytochrome c.³ Most OPA1 mutations lead to isolated optic atrophy, except for the R455H mutation that consistently results in optic atrophy and deafness.⁴ To our knowledge, MSL features have not been reported so far in association with optic atrophy in patients harboring OPA1 mutations. The probability of MS and ADOA occurring simultaneously is 1/10⁷ since the MS prevalence is 1/2,000 and ADOA prevalence is 1/50,000 in the European population. However, it is worth noting that hereditary optic neuropathy has been reported to be associated with features indistinguishable from MS in patients carrying mtDNA mutations responsible for LHON.⁵ Further cases are needed to firmly establish association between OPA1-related optic atrophy and MS-like disorder.

OPA1 mutations are associated with a reduced rate of mitochondrial ATP synthesis as has been demonstrated in skeletal muscle⁶ or in fibroblasts from patients with ADOA and deafness.⁴ In these studies, the reduced ATP production was associated with an altered respiratory function. The fact that a more severe energetic defect (reduced ATP synthesis and decreased respiratory function) was found in fibroblasts from the patient with MSL features suggests a relationship between the level of mitochondrial dysfunction and central demyelination. Interestingly, a mitochondrial dysfunction and, more particularly, a mismatch between energy demand and reduced ATP supply, associated with a reduction in the functional activity of the respiratory chain, have been recently implicated in the degeneration of chronically demyelinated axons in MS.⁷ Finally, this type of energetic defect has also been associated with Charcot-Marie-Tooth type 2A disease in patients with mutations of mitofusin 2, a protein involved in the fusion of outer mitochondrial membranes.⁸ These observations taken together with the findings reported here reinforce the hypothesis of the implication of mitochondrial energy metabolism in neurodegenerative disorders.