Table 4 contains one example of a Mendelian mutation that underlies pure MD: Wolfram syndrome, a rare autosomal recessive disorder due to a mutation on the short arm of chromosome 4 (Polymeropoulos et al., 1994). The important point here is that Wolfram is a recessive condition. The disease itself (in homozygotes) is characterized by a broad spectrum of psychiatric and neurological disorders, but heterozygote carriers show a purer MD phenotype: in one report, out of 11 individuals carrying a Wolfram mutation, eight were hospitalized for major MD, significantly more than the three relatives expected if there were no association between psychiatric hospitalizations and mutations at this locus (Swift and Swift, 2005). The authors argue that “if the population frequency of wolframin mutations that predispose carriers to psychiatric illness is about 1%, with an odds ratio of 7.1, wolframin mutation carriers would be estimated to be about 7% of patients hospitalized for MD” (Swift and Swift, 2005).
