Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation

Abstract

A novel point mutation in the ND6 subunit of complex I at position 14,459 of the mitochondrial DNA (MTND6*LDY T14459A) was identified as a candidate mutation for the highly tissue-specific disease. Leber's hereditary optic neuropathy plus dystonia. Since the MTND6*LDYT14459A mutation was identified in a single family, other pedigrees with the mutation are needed to confirm its association with the disease. Clinical, biochemical, and genetic characterization is reported in two additional pedigrees. Leber's hereditary optic neuropathy developed in two family members in one pedigree. The daughter had clinically silent basal ganglia lesions. In a second pedigree, a single individual presented with childhood-onset generalized dystonia and bilateral basal ganglia lesions. Patient groups that included individuals with Leigh's disease, dystonia plus complex neurodegeneration, and Leber's hereditary optic neuropathy did not harbor the MTND6*LDYT14459A mutation, suggesting that this mutation displays a high degree of tissue specificity, thus producing a narrow phenotypic range. These results confirm the association of the MTND6*LDYT14459A mutation with Leber's hereditary optic neuropathy and/or dystonia. As the first genetic abnormality that has been identified to cause generalized dystonia, this mutation suggests that nuclear DNA or mitochondrial DNA mutations in oxidative phosphorylation genes are important considerations in the pathogenesis of dystonia.

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…For example, mutations in MT-ND1 and MT-ND4 can cause Leber hereditary optic neuropathy (LHON), a disease characterized by bilateral, painless central vision loss in early to late adulthood resulting from the specific degeneration of retinal ganglion cells in the optic nerve [40]. However, these same mutations can also be associated with more severe symptoms, including dystonia and short stature [41][42][43].…”

An mtDNA mutation, 14453G→A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome

“…Classical LHON is presenting with acute to subacute central vision loss, but pedigrees in which both LHON and dystonia are segregating, due to point mutations in the gene encoding ND6, have been reported. 8,9 Here we report a 6-year-old patient with the typical clinical features of MELAS and no signs of LHON, who harbours a novel mitochondrial point mutation in the gene encoding the ND6 subunit of NADH:ubiquinone oxidoreductase (complex I of the respiratory chain).…”

Mitochondria and dystonia: The movement disorder connection?

“…Molecular analysis of this pedigree revealed that both the LHON and the dystonia were the result of a mutation in the mtDNA complex I gene MTND6, resulting in the conversion of the highly conserved alanine codon at position 72 to a valine (7). This same mutation in different families can be associated with either LHON or dystonia or both (11). Cells containing this mutation have a 55% reduction in respiratory complex I activity, which can be transferred from one cell to another along with the mtDNA via the cytoplasmic (cybrid) transfer technique (12).…”