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We investigated the etiology of Leigh syndrome in 67 Australian cases from 56 pedigrees,35 with a firm diagnosis and 32 with atypical features. Biochemical or DNA defects were determined in both groups,ie,80%in the tightly defined group and 41%in the"Leigh-like"group.Eleven patients had mitochondrial DNA point mutations(nucleotide 8993 T to G,nt 8993 T to C,or nt 8344 A to G)and 1 Leigh-like patient had a heteroplasmic deletion. Twenty-nine patient had enzyme defects,ie,13 respiratory chain complex I,9 complex IV and 7 pyruvate dehydrogenase complex(PDHC).Complex I deficiency is more common than recognized previously.Six PDHC-deficient patients had mutations in the X-chromosomal gene encoding the E1a subunit of PDHC. Parental consanguinity suggested autosomal recessive inheritance in two complex IV-deficient sibships.We found no strong correlation between the clinical features and basic defects.As assumption of autosomal recessive inheritance(frequently made in the past)would have been wrong in nearly one-half(11 of 28 tightly defined and 18 of 41 total patients)of those in whom a cause was found.A specific defect must be identified if reliable genetic counseling is to be provided. |
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