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

Objective: To investigate a family with maternally inherited, adult-onset m ultisystem degeneration including prominent parkinsonism to determine wheth er clinical features can result from a mitochondrial DNA (mtDNA) mutation. The parkinsonism was levodopa responsive and was associated with the loss o f pigmented neurons in the Substantia nigra in at least one patient. Backgr ound: Mitochondrial dysfunction is hypothesized to play a role in late-onse t neurodegenerative diseases including PD and AD. Mitochondrial genetic mut ations are hypothesized to account for these defects, but attempts to ident ify specific mtDNA mutations have been inconclusive, Methods: Clinical exam inations, DNA sequencing, and restriction digestion and biochemical analyse s were performed. Results: Maternal relatives harbor a G-ta-A missense muta tion, heteroplasmic in some patients, at nucleotide position 11778 of the m itochondrial ND4 gene of complex I that converts a highly conserved arginin e to a histidine. Sequencing of the entire mitochondrial genome in an affec ted family member reveals no other mutations likely to be pathogenic. This mutation has been identified previously only in families with Leber's hered itary 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.