LEIGH-SYNDROME - CLINICAL-FEATURES AND BIOCHEMICAL AND DNA ABNORMALITIES

We investigated the etiology of Leigh syndrome in 67 Australian cases from 56 pedigrees, 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups, i e, 80% in the tightly defined group and 41% in the ''Leigh-like'' grou p. Eleven patients had mitochondrial DNA point mutations (nucleotide [ nt] 8993 T to G, nt 8993 T to C, or nt 8344 A to G) and 1 Leigh-like p atient had a heteroplasmic deletion. Twenty-nine patients had enzyme d efects, ie, 13 respiratory chain complex I, 9 complex IV, and 7 pyruva te dehydrogenase complex (PDHC). Complex I deficiency is more common t han recognized previously. Six PDHC-deficient patients had mutations i n the X-chromosomal gene encoding the E1 alpha subunit of PDHC. Parent al consanguinity suggested autosomal recessive inheritance in two comp lex IV-deficient sibships. We found no strong correlation between the clinical features and basic defects. An assumption of autosomal recess ive 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 identi fied if reliable genetic counseling is to be provided.