Late onset Leigh syndrome and ataxia due to a T to C mutation at bp 9,185 of mitochondrial DNA.
A T-to-C missense mutation at nucleotide position 9,185 in the protein-coding ATP6 gene of the mitochondrial genome was present at high heteroplasmy in members of a Canadian family with Leigh syndrome with predominant ataxia and peripheral neuropathy. This mutation results in the substitution of a proline residue for an evolutionary-conserved leucine at position of amino acid 220 near the carboxyl terminus of the mitochondrial protein. The index patient and brother, who had an identical clinical presentation, had >90% mutant mtDNA in cultured skin fibroblasts, lymphocytes, and whole blood. Their mother and a maternal uncle, symptomatic with a peripheral neuropathy alone, had 86% and 85% heteroplasmy, respectively. Symptomatic maternal cousins with early onset revealed 90% and 91% mutant mtDNA in all tissues analyzed. Studies of lymphoblasts from the asymptomatic maternal grandmother and eldest brother of the proband were heteroplasmic for mutant mtDNA with 56% and 17%, respectively. Biochemical analysis demonstrated normal respiratory chain enzyme activity in muscle and fibroblasts, normal ATP synthesis, but reduced oligomycin-sensitive H(+)ATPase in cultured lymphoblast mitochondria. We propose that the 9,185T > C mtDNA mutation is pathogenic even though the initial phenotype is mild and the biochemical phenotype not easily detectable.
Castagna
Avril E
AE
Scarborough General Hospital, Hospital for Sick Children, Toronto, Ontario.
Addis
Jane
J
McInnes
Roderick R
RR
Clarke
Joe T R
JT
Ashby
Peter
P
Blaser
Susan
S
Robinson
Brian H
BH
D000328:Adult; D017668:Age of Onset; D001259:Ataxia / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D017124:Conserved Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D010523:Peripheral Nervous System Diseases; D017354:Point Mutation
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins