Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes.

Because Wolfram (or DIDMOAD) syndrome is supposed to be a mitochondrial (mt)-mediated disease, we investigated a group of eight DIDMOAD patients with respect to point mutations of the mtDNA thus far described as being associated with defined mitochondrial disorders such as MELAS, MERRF, and LHON. Furthermore, to screen DIDMOAD patients for other mtDNA defects we used Southern blot analysis to detect mtDNA length mutations and rearrangements as well as PCR-SSCP and direct sequencing to screen all ND genes (complex I of the respiratory chain), the 22 tRNAs, and a part of the cyt b gene for unknown mutations. As a disease control group, 17 LHON patients (harboring one of the primary LHON mutations) were included in this study because of the overlapping clinical symptoms (optic atrophy) in both syndromes. We compared mtDNA variants identified in DIDMOAD patients with those found in LHON patients as well as in a control group consisting of 67 healthy German blood donors. In total, the control group was characterized by 29 polymorphic sites in ND and tRNA genes that define certain major Caucasian haplotypes. We found that a cluster of nucleotide exchanges at nucleotide positions (nps) 4216 and 11,251 roughly discriminates controls (12/67 controls, 18%) from the disease groups (6/8 DIDMOAD patients, 75%; 10/17 LHON patients, 59%). All 4216-positive LHON patients (10 patients) were concentrated in a haplogroup defined by additional exchanges at nps 10,398, 12,612, and 13,708 (haplogroup A), while the bulk of 4216-positive DIDMOAD patients (5 patients) were found in a distinct haplogroup consisting of nucleotide exchanges at nps 4917, 10,463, 13,368, 14,233, and 15,928. The frequencies of both haplogroups were significantly lower in the control group versus the respective disease groups. A more detailed analysis was performed by sequencing the two hypervariable regions of the non-coding D-loop region from patients and controls and corroborated the ranging in the two major haplogroups. Thus, the different clinical features of the mitochondrial disease groups investigated here corresponded to different clusters of mtDNA variants, which might act as predisposing haplotypes, increasing the risk for disease.