Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees.

L eber hereditary optic neuropathy (LHON; OMIM #535000) is a mitochondrial genetic disease that causes blindness in young adults, with an estimated minimum prevalence of 3.2 per 100 000 in the north east of England. It classically presents as bilateral subacute loss of central vision due to the focal neurodegeneration of the retinal ganglion cell layer. Over 95% of cases are principally due to one of three ‘‘primary’’ mtDNA point mutations: 3460GRA, 11778GRA, and 14484TRC, all of which involve genes that encode complex I subunits of the mitochondrial respiratory chain. However, less than ,50% of male and ,10% of female LHON carriers will develop the optic neuropathy. 3 This marked incomplete penetrance and gender bias clearly indicates that additional genetic and/or environmental factors are required for the phenotypic expression of the pathogenic mtDNA mutations in LHON. However, these secondary factors remain poorly defined at the present time. There has recently been considerable interest in the possible role of the mtDNA background on the phenotypic expression of mitochondrial genetic disorders. The hypothesis is that on their own, some polymorphisms are selectively ‘‘neutral’’ but that in specific combinations, they act in a synergistic, deleterious manner with established pathogenic mtDNA mutations to increase the risk of disease expression or to produce a more severe clinical outcome. The following nucleotide substitutions are found at a higher frequency in LHON patients relative to controls: 4216TRC, 4917ARG, 9804GRA, 9438GRA, 13708GRA, 15257GRA, and 15812GRA. Phylogenetic analysis has shown that 4216TRC, 13708GRA, 15257GRA, and 15812GRA all cluster on a specific mtDNA background, haplogroup J, which is one of the nine haplogroups that define populations of European ancestry. 9 Several studies have subsequently found that LHON pedigrees that harbour the 11778GRA and 14484TRC mutations are apparently not randomly distributed along the phylogenetic tree, but tend to show a preferential association with haplogroup J (table 1). It has therefore been argued that these polymorphic variants interact with the primary mtDNA mutations, increasing the risk of visual loss among LHON carriers. However, the potential pathogenic role of these so-called ‘‘secondary’’ mtDNA mutations in LHON is still controversial. All the association studies published so far involved a relatively small number of pedigrees collected over a wide geographical area by centres with a specialist interest in LHON, thereby raising the possibility of ascertainment bias. To investigate further the presumed association between primary LHON mutations and haplogroup J, we determined the haplogroup distribution of a rigorously defined, population based LHON cohort from the north east of England, and carried out a systematic statistical review of the literature. MATERIALS AND METHODS Study population Patients presenting with unexplained visual failure or suspected LHON within the north east of England were referred to the Northern Genetics Service based in Newcastle upon Tyne over the 12 year period from January 1990 to May 2002. Diagnostic mitochondrial genetic analysis was then carried out within the Mitochondrial Research Group of the Department of Neurology, University of Newcastle upon Tyne. This led to the identification of 15 genealogically distinct LHON pedigrees, confirmed by sequencing of the mtDNA D-loop region (table 2).