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McLeod neuroacanthocytosis syndrome (MLS) is a rare X-linked multisystem disease caused by XKgene mutations and characterized by hematological and neurological abnormalities. XK, a putative membrane transporter, is expressed ubiquitously and is covalently linked to Kell, an endothelin-3-converting enzyme (ECE-3). Absence of XK results in reduction of Kell at sites where both proteins are coexpressed. To elucidate the functional roles of XK, Kell, and the XK–Kell complex associated with pathogenesis in MLS, we studied the pathology of the spinal cord, anterior roots, sciatic nerve, and skeletal muscle from knockout mouse models, using Kel−/−, Xk−/−, Kel−/−Xk−/−, and wild-type mice aged 6 to 18 months. A striking finding was that giant axons were frequently associated with paranodal demyelination. The pathology suggests probable anterograde progression from the spinal cord to the sciatic nerve. The neuropathological abnormalities were found in all three genotypes, but were more marked in the double-knockout Kel−/−Xk−/−mice than in either Kel−/−or Xk−/−mice. Skeletal muscles from Xk−/−and Kel−/−Xk−/−mice showed mild abnormalities, but those from Kel−/−mice were similar to the wild type. The more marked neuropathological abnormalities in Kel−/−Xk−/−mice suggest a possible functional association between XK and Kell in nonerythroid tissues.

Limb girdle muscular dystrophy 2B and Miyoshi myopathy were recently found to be allelic disorders arising from defects in the dysferlin gene. We have developed a new diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy, which screens for dysferlin expression in blood using a commercially available monoclonal antibody. Unlike current methods that require muscle biopsy for immunodiagnosis, the new method is simple and entails a significantly less invasive procedure for tissue sampling. Moreover, it overcomes some of the problems associated with the handling and storage of muscle specimens. In our analysis of 12 patients with limb girdle muscular dystrophy 2B or Miyoshi myopathy, the findings obtained using the new assay are fully consistent with the results from muscle immunodiagnosis.

Limb girdle muscular dystrophy 2B and Miyoshi myopathy were recently found to be allelic disorders arising from defects in the dysferlin gene. We have developed a new diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy, which screens for dysferlin expression in blood using a commercially available monoclonal antibody. Unlike current methods that require muscle biopsy for immunodiagnosis, the new method is simple and entails a significantly less invasive procedure for tissue sampling. Moreover, it overcomes some of the problems associated with the handling and storage of muscle specimens. In our analysis of 12 patients with limb girdle muscular dystrophy 2B or Miyoshi myopathy, the findings obtained using the new assay are fully consistent with the results from muscle immunodiagnosis.

McLeod syndrome is caused by mutations of XK, an X‐chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XKmutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea‐acanthocytosis suggests that the corresponding proteins—XK, huntingtin, and chorein—might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.

The murine homologues of the loci for McLeod syndrome (XK), Dent's disease (C1CN5), and synaptophysin (SYP) have been mapped to the proximal region of the mouse X chromosome and positioned with respect to other conserved loci in this region using a total of 948 progeny from two separate Mus musculus× Mus spretusbackcrosses. In the mouse, the order of loci and evolutionary breakpoints (EB) has been established as centromere-(DXWas70, DXHXF34h)-EB-Clcn5-(Syp, DXMit55, DXMit26)-Tfe3-Gata1-EB-Xk-Cybb-telomere. In the proximal region of the human X chromosome short arm, the position of evolutionary breakpoints with respect to key loci has been established as DMD-EB-XK-PFC-EB-GATA1-C1CN5-EB-DXS1272E-ALAS2-EB-DXF34-centromere. These data have enabled us to construct a high-resolution genetic map for the ∼3-cM interval between DXWas70and Cybbon the mouse X chromosome, which encompasses 10 loci. This detailed map demonstrates the power of high-resolution genetic mapping in the mouse as a means of determining locus order in a small chromosomal region and of providing an accurate framework for the construction of physical maps.