Leigh Syndrome: Clinical Features and Bi&he&al and DNA Abnormahties S. Rahman, MRCP(UK),*$ R. B. Blok, PhD,* H.-H. M. Dahl, PhD,* D. M. Danks, FRACP,’ D. M. Kirby, BSc(Hons),* C. W. Chow, FRCPA,? J. Christodoulou, FRACP, PhDJ and D. R. Thorburn, PhD’ We investigated the etiology of Leigh syndrome in 67 Australian cases from 56 pedigrees, zyxw 35 with a firm diagnosis and 32 with some atypical features. Biochemical or DNA defects were determined in both groups, ie, zyx 80% in the tightly defined group and 41% in the “Leigh-like’’ group. 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 patient had a heteroplasmic deletion. Twenty- nine patients had enzyme defects, ie, 13 respiratory chain complex I, 9 complex zyxw IV, and zyxw 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 Elcv 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. zyxwvutsr An 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. Rahman S, Blok RB, Dahl H-HM, Dank DM, Kirby DM, Chow CW, Christodoulou J, Thorburn DR. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol 1996;39:343-35 z 1 Leigh syndrome (subacute necrotizing encephalomye- lopathy; McKusick 256000) is a progressive neuro- degenerative disorder with onset usually in infancy or early childhood zyxwvutsrqp [l-41 and a characteristic neuropa- thology. Spongiform lesions, with vacuolation of the neuropil and relative preservation of the neurons, associated with demyelination, gliosis, and capillary proliferation, occur bilaterally and symmetrically espe- cially in the brainstem. Definitive diagnosis still de- pends on this distinctive neuropathology, although modern imaging techniques can give strong diagnostic support [4]. Frequently encountered clinical signs include motor and/or intellectual retardation, usually with regression, and signs of brainstem dysfunction, including respira- tory abnormalities, nystagnius, and ophthalmoparesis. Other neurological manifestations include ataxia, dys- tonia, and optic atrophy. Typically, symptoms begin in the first months and progress to death within zyxwvu 2 years, but later onset and/or slower progression occurs quite frequently. The similarity of the brain pathology to that of Wer- nicke’s encephalopathy raised the possibility of defects involving thiamine or aerobic energy production [ 1, 21. More recently, the emphasis has focused on disordered cerebral mitochondrial energy production, in particular deficiencies of the pyruvate dehydrogenase complex (PDHC) and of respiratory chain complexes IV (cyto- chrome c oxidase; COX) and I [3, 41. Despite early observations of an excess of affected males [2], and oc- casional pedigrees suggesting X linkage [5], it was con- sidered that these enzyme defects would show auto- sonial recessive inheritance, as would cases of Leigh syndrome without a known basic dcfecr. Genetic counseling of Leigh syndrome families be- came more complicated when the gene encoding the most frequently affected PDHC subunit (Ela) was found to be X chromosomal [GI and when maternal inheritance and mitochondrial gene defects were iden- tified. Four mitochondrial DNA (mrDNA) point mu- tations have been described in Leigh syndrome, at nu- cleotide (nt) 8993 (T to G [7-121 and T to C base changes [13, 14]), nt 8344 (A to G) [15-171, and nt 3243 (A to G) [18]. The following three of these mtDNA mutations were initially described in associa- tion with other specific phenotypes in older patients: NARP (neurogenic muscle weakness with ataxia and retinitis pigmentosa; nt 8993 T to (2 tnutation [19]), From ‘The Murdoch Institute for Research into Birth Defects, and t Department of Anatomical Parhology, Royal Children’s Hospital. Melbourne, and $Department of I’aediatrics and Child Health, Children’s Hospital, Sydney, Australia. Received Juii 23, 1395, and in revised form Sep 18. Accepted for publication Nov 6, 1395. Copyright $Present address: Departrnenr of Paediarrics, John Radcliffe Hospi- tal. Oxford OX3 3DU, UK. Address correspondence to Dr Thorburn, The Murdoch Institute. Royal Children’s Hospital, Flemirigton Road, Parkville, Victoria 3052, Australin. zyxwv 0 1996 by the Amcrican Neurological Association 343