Mcleod Syndrome

A number sign (#) is used with this entry because the McLeod phenotype is caused by mutation in the XK gene (314850), encoding an antigen of the Kell blood group system (see 110900).

Description

Hematologically, McLeod syndrome is characterized 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 neurologic disorder resembling Huntington disease (143100). 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 cooccurrence of McLeod syndrome and chronic granulomatous disease (CGD; 306400) results from a contiguous gene deletion (Francke et al., 1985).

Clinical Features

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. The X-linked locus determining this substance is called Xk. McLeod had a compensated hemolytic state (Wimer et al., 1976). He did not have CGD. 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.

Symmans et al. (1979) described the second example of the McLeod phenotype in the absence of CGD 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 that had been studied had Kx-negative leukocytes (Marsh, 1979). At least two Xg:XK recombinants are known (Tippett, 1981).

Danek et al. (2001) remarked that, like other erythrocyte phenotypes, the peculiar pattern of weakly expressed Kell antigens received its name from the propositus. Acanthocytosis was noted much later (Wimer et al., 1977). 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. It was Marsh et al. (1981) who recognized muscle involvement and proposed the designation 'McLeod syndrome.' Schwartz et al. (1982) reported areflexia and chorea in the New Zealand family. Faillace et al. (1982) noted the presence of McLeod red cells in a patient with amyotrophic chorea and acanthocytosis.

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.

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.

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.

Mapping

In a patient with CGD and McLeod syndrome, Frey et al. (1988) demonstrated a deletion of the entire CGD gene. 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 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.

Molecular Genetics

Using nucleotide sequence analysis of the XK gene in 2 unrelated patients with McLeod syndrome, Ho et al. (1994) demonstrated point mutations at invariant residues of 5-prime and 3-prime donor sites (e.g., 314850.0001).

Danek et al. (2001) demonstrated that the original propositus carried a 13-bp deletion in the XK gene (314850.0006).