Wolfram Syndrome, Mitochondrial Form

A number sign (#) is used with this entry because of evidence that a form of Wolfram syndrome may be due to mutation in mtDNA.

For a general phenotypic description and a discussion of genetic heterogeneity of Wolfram syndrome, see 222300.

As indicated in 222300, Rotig et al. (1993, 1993) suggested that some cases of the syndrome of early-onset diabetes mellitus, optic atrophy, and deafness may have their basis in a mitochondrial mutation. They described a patient with this disorder in association with a 7.6-kb heteroplasmic deletion of mtDNA. The deletion extended from nucleotide 6466 to nucleotide 14134, inclusive. In this patient, the presence of mild hyperlactatemia suggested a possible abnormality of mitochondrial DNA. Rotig et al. (1993) speculated about why the endocrine pancreas was the first targeted tissue. One of the suggestions was that the creation of a chimeric protein containing a COX I moiety joined to an ND5 moiety might give rise to an anti-beta-islet antibody response.

Because of unusual phenotypic variability, even among sibs, and the occurrence of features commonly seen in mitochondrial disorders, Bundey et al. (1992) had suggested that DIDMOAD may be a mitochondrial disorder. They reported a patient with this condition who had both morphologic and biochemical abnormalities of the mitochondria; however, no abnormalities of the mitochondrial DNA were detected.

Pilz et al. (1994) described the case of a 19-year-old man with long-standing diabetes mellitus, optic atrophy, and grand mal seizures, as well as unilateral sensorineural hearing loss. It was found that he carried the 11778 mitochondrial mutation which is the most common cause of Leber hereditary optic neuropathy (516003.0001). Pilz et al. (1994) suggested that the DIDMOAD phenotype may have been the result of a combination of the 11778 mutation (inherited from the mother) with an as yet undetected mutation elsewhere in the mitochondrial genome or with a mutation in the nuclear genome.

Barrientos et al. (1996) provided evidence that a mutation in a gene in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome. This was the first evidence of the implication of both genomes in a recessive disease.

Hofmann et al. (1997) investigated 8 DIDMOAD patients with respect to point mutations of the mtDNA previously described as being associated with defined mitochondrial disorders such as MELAS (540000), MERRF (545000), and LHON (535000). Furthermore, to screen the patients for other mtDNA defects, they 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 CYTB gene for unknown mutations. Because of the overlapping clinical feature (optic atrophy) in DIDMOAD and LHON, Hofmann et al. (1997) used as a disease control group 17 LHON patients harboring one of the primary LHON mutations. They 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 defined certain major Caucasian haplotypes. They found that a high percentage of DIDMOAD patients harbor so-called secondary LHON mutations, and that both DIDMOAD and LHON patients are concentrated in 2 different mitochondrial haplotypes defined by sets of polymorphisms in ND and tRNA genes. Thus, the different clinical features of the mitochondrial disease groups investigated corresponded to different clusters of mtDNA variants, which might act as predisposing haplotypes, increasing the risk for the given disease.

In a study of 6 Spanish families with a total of 7 Wolfram syndrome patients, Domenech et al. (2004) detected no mitochondrial DNA abnormalities.