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Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation

From the Departments of Neurology (Drs. Simon and Johns) and Ophthalmology (Dr. Johns), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; the Rose Moss Laboratory for Parkinson’s Disease and Neurodegenerative Disorders (Dr. Pulst), Burns and Allen Research Institute, and Parkinson’s Disease and Movement Disorder Center, Division of Neurology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA; The Parkinson’s Center (Dr. Sutton), Oxnard, CA; and the Department of Neurology (Drs. Browne and Beal), Cornell University Medical College, New York, NY.

Address correspondence and reprint requests to Dr. D.K. Simon, Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, HIM 847, 77 Avenue Louis Pasteur, Boston, MA 02115.

OBJECTIVE: To investigate a family with maternally inherited, adult-onset multisystem degeneration including prominent parkinsonism to determine whether clinical features can result from a mitochondrial DNA (mtDNA) mutation. The parkinsonism was levodopa responsive and was associated with the loss of pigmented neurons in the substantia nigra in at least one patient.

BACKGROUND: Mitochondrial dysfunction is hypothesized to play a role in late-onset neurodegenerative diseases including PD and AD. Mitochondrial genetic mutations are hypothesized to account for these defects, but attempts to identify specific mtDNA mutations have been inconclusive.

METHODS: Clinical examinations, DNA sequencing, and restriction digestion and biochemical analyses were performed.

RESULTS: Maternal relatives harbor a G-to-A missense mutation, heteroplasmic in some patients, at nucleotide position 11778 of the mitochondrial ND4 gene of complex I that converts a highly conserved arginine to a histidine. Sequencing of the entire mitochondrial genome in an affected family member reveals no other mutations likely to be pathogenic. This mutation has been identified previously only in families with Leber’s hereditary optic neuropathy—a disorder also linked to complex I dysfunction but usually limited clinically to optic atrophy.

CONCLUSIONS: These data reveal previously unsuspected clinical heterogeneity of the G11778A mutation, and suggest that an inherited mtDNA mutation can contribute to the development of adult-onset parkinsonism and multisystem degeneration.

Key words: PD—Leber’s hereditary optic neuropathy—Progressive external ophthalmoplegia—Heteroplasmy—Mitochondrial DNA.

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