Nina Horn

Menkes kinky hair disease: a search for closely linked restriction fragment length polymorphism

SummaryIn a large kindred with X-linked Menkes disease, linkage studies were performed with a restriction fragment length polymorphism (RFLP) that had been found with a cloned hybridisation probe from the proximal short arm of the X chromosome. This RFLP was considered as a potential genetic marker since the Menkes gene seems to be located near the centromere. Moreover, there is circumstantial evidence that in the (para) centric region of the X chromosome cross-overs are relatively rare. Unexpectedly, however, at least two cross-overs were detected in this family which suggests that the DNA sequence employed is of limited use for early diagnosis and carrier detection in this fatal hereditary disorder.

Evidence that the Menkes locus maps on proximal Xp

There is now convincing evidence that the gene defect responsible for X-linked Menkes kinky hair disease is located near Xcen, as shown by linkage to a centromeric C-banding polymorphism (Horn et al., to be published) and to a restriction fragment length polymorphism (RFLP) defined by a cloned DNA sequence, L1.28, from the proximal short arm of the X chromosome (Wieacker et al. 1983). The precise location of the Menkes gene locus relative to the centromere has not yet been defined, but there is reason to believe that it maps in the vicinity of the PGK gene on proximal Xq (see Wieacker et al. 1983). By using another cloned DNA probe, MGU22, which is located below L1.28 in the Xcen-Xq12 segment, we have now detected a HindIII RFLP in a family with Menkes disease which had been studied previously for linkage with the L 1.28 sequence. Unexpectedly our data indicate that MGU22 may be more closely linked to L 1.28 than to the Menkes locus (MS) (~ = 1.10 at 0 = 0.13 versus ~ = 0.024 at 0 = 0.45). For L 1.28 and MS, lod scores reach their maximum (2 = 0.82) at a recombination fraction of t) = 0.16 (Wieacker et al. 1983). Analysis of individual recombination events (Fig. 1) reveals that of the three possible gene orders (Xpter-L 1.28MGU 22-MS; Xpter-L 1.28-MS-MGU 22; and Xpter-MSL1.28-MGU 22) the last-mentioned is the most probable because it can explain the observed genotypes as the result of three single crossovers. In contrast, each of the two other gene orders would require a double crossover and two single crossovers between the respective external genetic markers. The likelihood of the pedigree has been calculated (a) for each of the three possible gene orders and (b) for each combination of recombination fractions between the three loci. Since only two of these distances can vary independently, a likelihood surface is obtained for each gene order which covers the area between orthogonal axes that define these distances (see Renwick and Bolling 1971; and Sturt 1975). This is illustrat-

Copper‐measurement in a muscle‐biopsy. A possible method for postmortem diagnosis of Menkes disease

A 5‐month‐old boy showed severe delay in mental and motor development. His hair was normal. He died at 18 months from bronchopneumonia. Autopsy of the brain revealed meningo‐cerebral angiodysplasia with tortuous vessels at the surface of the brain. This raised a suspicion of Menkes disease.