Alternative titles; symbols
SNOMEDCT: 115845005, 234411007; ORPHA: 59306; DO: 0112107;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp21.1 | McLeod syndrome | 300842 | X-linked | 3 | XK | 314850 |
A number sign (#) is used with this entry because of evidence that McLeod syndrome (MCLDS) is caused by mutation in the XK gene (314850) on chromosome Xp21. The XK gene encodes an antigen of the Kell blood group system (see 110900).
McLeod syndrome (MCLDS) is an X-linked disorder characterized hematologically by the absence of red blood cell Kx antigen, weak expression of Kell red blood cell antigens, acanthocytosis, and compensated hemolysis. Most carriers of this McLeod blood group phenotype have acanthocytosis and elevated serum creatine kinase levels and are prone to develop a severe neurodegenerative disorder. Onset of neurologic symptoms ranges between 25 and 60 years (mean onset, 30-40 years), and penetrance appears to be high. Additional symptoms include generalized seizures, neuromuscular symptoms leading to weakness and atrophy, and cardiomyopathy mainly manifesting with atrial fibrillation, malignant arrhythmias, and dilated cardiomyopathy (summary by Jung et al., 2007).
The McLeod phenotype was described by Allen et al. (1961) in a man of that surname. His red cells showed unaccountably weak reactivity to Kell antisera. In 1970, his red cells were noted to be acanthocytic in the absence of abetalipoproteinemia. (The precursor missing in McLeod's red cells is called Kx, and the X-linked gene determining this substance is called Xk). Wimer et al. (1977) restudied the patient reported by Allen et al. (1961) and observed a compensated hemolytic state. Evidence for X-linkage of Xk was provided by mosaicism in females for both acanthocytosis and red cell Kx. The observations showed that some blood group antigenic substances are important to both structure and function of cell membranes. Jung et al. (2007) stated that Hugh McLeod, the original propositus, died at the age of 69 after developing all major McLeod syndrome manifestations, presumably including neurologic deterioration.
Estes et al. (1967) and Levine et al. (1968) reported a family in which 19 persons in 4 generations had some degree of neurologic abnormalities, 15 with, and 4 without, acanthocytosis. Acanthocytes averaged from 1 to 20% of the total erythrocyte count, and there was no obvious association between the degree of acanthocytosis and the severity of the neurologic disability. There were no demonstrable quantitative defects of low density (beta) or high density (alpha) lipoproteins. Major neurologic symptoms included muscle weakness and atrophy, leg cramps, disturbances of coordination, hyporeflexia, chorea, and seizures. The pattern of inheritance appeared to be autosomal dominant; however, Walker et al. (2023) stated that descendants of the family reported by Levine et al. (1968) had been found to carry mutations in the XK gene, indicating that they had McLeod syndrome.
Symmans et al. (1979) described the second example of the McLeod phenotype and the first example of a rare blood group being recognized because of a morphologic abnormality of red cells. Heterozygous females showed mosaicism with a normal and an acanthocytic red cell population. Thus, lyonization of this locus occurs even though nonlyonization holds for the Xg (314700) and ichthyosis (steroid sulfatase) loci (308100) which are in the same small segment of Xp. All cases of X-linked CGD (306400) that had been studied had Kx-negative leukocytes (Marsh, 1979). At least two Xg:XK recombinants are known (Tippett, 1981).
The diagnosis of the McLeod phenotype in a boy with chronic anemia from a large New Zealand family led to the recognition of features such as hemolysis, hepatomegaly, and splenomegaly (Symmans et al., 1979) and proved the previous assumption of X-linked inheritance. Schwartz et al. (1982) reported areflexia and chorea in the New Zealand family.
Marsh et al. (1981) recognized muscle involvement with increased serum creatine kinase and proposed the designation 'McLeod syndrome.' Faillace et al. (1982) noted the presence of McLeod red cells in a patient with amyotrophic chorea and acanthocytosis. Swash et al. (1983) studied 2 healthy males with the McLeod syndrome. Both had raised creatine kinase levels, with myopathic EMG changes and 'active myopathy' changes on muscle biopsy.
In a patient with McLeod syndrome who had histopathologic evidence of a mild subclinical myopathy, Danek et al. (1990) detected no abnormality by immunologic studies of dystrophin (300377) in 2 separate biopsy specimens. Analysis of the dystrophin gene in blood samples detected no abnormality. They concluded that the dystrophin is probably normal and that the mechanism of the myopathy does not involve the dystrophin gene, which is located near at hand on Xp21.
Malandrini et al. (1994) described 2 brothers and their maternal uncle with 'atypical' McLeod syndrome presenting with a late-onset choreic syndrome mimicking Huntington disease. The proband also suffered from severe dilated cardiomyopathy and showed slight neuromuscular involvement. Acanthocytosis and weak antigenicity of the Kell blood antigen system were present in combination with prominent neurologic involvement.
Danek et al. (2001) analyzed the mutations and clinical findings of 22 men, aged 27 to 72 years, with McLeod neuroacanthocytosis. All of the 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 indicated by 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 developed with age, mainly after the fourth decade. The resemblance of McLeod syndrome to Huntington disease and to autosomal recessive chorea-acanthocytosis (200150) suggested that the corresponding proteins--XK, huntingtin (613004), and chorein (605978)--may belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.
Jung et al. (2007) remarked that patients with McLeod syndrome usually show a slow progression of disease, with a mean onset between 30 and 40 years of age. A review of the literature found that disease duration ranged from 7 to 51 years, and mean age at death was 53 years, ranging from 31 to 69 years. Cardiovascular events, epileptic seizures, and aspiration pneumonia might be the major causes of death in older McLeod patients.
The transmission pattern of McLeod syndrome in the family reported by Symmans et al. (1979) was consistent with X-linked inheritance.
Francke et al. (1985) studied a male patient ('patient BB') with 3 X-linked disorders: chronic granulomatous disease with cytochrome b(-245) deficiency (CGD; 306400), McLeod red cell phenotype, Duchenne muscular dystrophy (DMD; 310200), and retinitis pigmentosa (RP3; 300029). A very subtle hemizygous interstitial deletion of part of chromosome Xp21 was demonstrated. That this was a deletion and not a translocation was demonstrated by the absence of one DNA probe from the genome of the patient. The close clustering of CGD, DMD, and RP suggested by these findings was inconsistent with separate linkage data, which indicated that McLeod and CGD are close to Xg and that DMD and RP are as much as 15 cM from each other and far from Xg (perhaps at least 55 cM). At least 4 possible explanations of the discrepancy were proposed by Francke et al. (1985). One suggestion was that the deletion contained a single defect affecting perhaps a cell membrane component with the several disorders following thereon. Kunkel et al. (1985) mapped the deleted DNA fragment of Xp21 in this patient.
By fine mapping in a boy with CGD, acanthocytosis, and McLeod syndrome, Frey et al. (1988) identified a hemizygous deletion on Xp21. They concluded that the CGD and XK loci are physically close in the Xp21 region and are proximal to DMD (300377).
Bertelson et al. (1988) studied male patients with the McLeod phenotype with or without CGD or DMD. Comparison of the cloned segments absent from 2 cousins with only the McLeod phenotype with the cloned segments absent from 2 DMD boys and a CGD/McLeod patient led to submapping of various cloned DNA segments within the Xp21 region. The results placed the locus for the McLeod phenotype within a 500-kb interval distal from the CGD locus and toward the DMD locus.
De Saint-Basile et al. (1988) described an instructive patient with CGD, retinitis pigmentosa, and McLeod phenotype, who had no microscopically detectable deletion, but had evidence of deletion on Xp21 with DNA markers. Findings in the mother were consistent with carrier status for all 3 disorders.
Using nucleotide sequence analysis of the XK gene in 2 unrelated patients with McLeod syndrome, Ho et al. (1994) identified point mutations at invariant residues of 5-prime and 3-prime donor sites (e.g., 314850.0001).
In the original propositus with McLeod syndrome, Danek et al. (2001) identified a hemizygous 13-bp deletion in the XK gene (314850.0006),
For a time it was thought that in addition to acanthocytosis and compensated hemolytic anemia, chronic granulomatous disease (CGD; 306400) might result from mutation at the XK locus. Mr. McLeod did not have CGD, but there were some patients with CGD whose red cells showed the McLeod phenotype. It was thought that because of the structural abnormality in the Kx substance of the white cell membrane, activation of NADH dehydrogenase was defective. Some patients with CGD lacked Kx in both white cells and red cells so that acanthocytosis and hemolysis were present in addition to granulomatous disease. This was called CGD II; in CGD I, the red cells are spared. Marsh (1979) thought that Kx 'makes a functional structure on leukocytes and red cells' and that XK (or the variant form thereof) is the CGD gene.
Densen et al. (1981) reported a highly informative family in which 4 of 8 brothers had CGD by clinical history and tests of neutrophil function. All 4 had Kx-negative neutrophils. The remaining 4 were in good health and had normal nitroblue tetrazolium reduction tests. However, 1 of these latter 4 had Kx-negative neutrophils that functioned normally. The findings were interpreted as indicating that closely linked but distinct genes code for CGD and Kx. In addition, close linkage of the XK and Xg loci was demonstrated; no recombinant was found in this sibship.
It turned out, however, that CGD with the McLeod phenotype is a contiguous gene syndrome, as defined by Schmickel (1986), due to the deletion of 2 very closely linked genes, XK and CYBB (300481), on Xp21. Indeed, Branch et al. (1986) showed that granulocytes lack Kx antigen. The previous finding of Kx on white cells was presumably due to contamination of the testing serum by anti-WBC antibodies of non-Kx specificity.
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