GENETIC AND BIOCHEMICAL IMPAIRMENT OF MITOCHONDRIAL COMPLEX-I ACTIVITY IN A FAMILY WITH LEBER HEREDITARY OPTIC NEUROPATHY AND HEREDITARY SPASTIC DYSTONIA

A rare form of Leber hereditary optic neuropathy (LHON) that is associ ated with hereditary spastic dystonia has been studied in a large Dutc h family. Neuropathy and ophthalmological lesions were present togethe r in some family members, whereas only one type of abnormality was fou nd in others. mtDNA mutations previously reported in LHON were not pre sent. Sequence analysis of the protein-coding mitochondrial genes reve aled two previously unreported mtDNA mutations. A heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene resulted in th e substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-->A transition at nucleotide posit ion 14596 in the ND6 gene, resulted in the substitution of a methionin e for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a l ink between these unique mtDNA mutations and this rare, complex phenot ype including Leber optic neuropathy.