XK – McLeod Neuroacanthocytosis Syndrome

McLeod neuroacanthocytosis syndrome (MLS) is an X-linked recessive disorder caused by loss-of-function mutations in the XK gene, encoding the Kx protein of the Kell blood group system. Clinically, MLS presents with erythrocyte acanthocytosis, absent Kx antigen and reduced Kell expression, choreatic movements, peripheral neuropathy, cardiomyopathy, and cognitive impairment. (PMID:8004674)

Genetic evidence includes >22 hemizygous males with distinct truncating or splice-site mutations across >15 unrelated families, all demonstrating absent Kx protein and Kell antigen. Notable variants include c.397C>T (p.Arg133Ter) causing premature termination of XK protein translation in a patient lacking acanthocytes. (PMID:8004674; PMID:17870653)

Segregation studies report manifesting carrier females with skewed X-inactivation and multiple affected male relatives, such as a Japanese kindred with a codon 151 frameshift and a heterozygous mother. (PMID:10930599)

Functional assays confirm that XK null alleles abrogate Kx cell-surface expression and disrupt Kell protein binding, as demonstrated by Western blot and flow cytometry in both patient erythrocytes and transfected cell models. (PMID:11375401)

Mechanistic studies reveal that XK interacts with the lipid transport protein VPS13A at membrane contact sites, and that disruption of VPS13A-XK binding recapitulates lipid transfer defects underlying the shared neurodegenerative features of MLS and chorea-acanthocytosis. (PMID:35950506)

One missense variant (c.979G>A encoding p.Glu327Lys) segregates with the McLeod blood phenotype but retains partial XK function and lacks neuromuscular and central nervous system involvement, highlighting variable expressivity and potential hypomorphic alleles. (PMID:12823753)

Integration of genetic and functional data establishes a definitive gene-disease association with a clear loss-of-function mechanism. Diagnosis of MLS via XK genetic testing and Kell/Kx serology informs clinical management, including transfusion planning, cardiac monitoring, and genetic counseling.

Key Take-home: XK sequencing and blood group serology are critical for diagnosing McLeod syndrome and guiding multidisciplinary care.

References

• Cell • 1994 • Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. PMID:8004674
• Annals of neurology • 2001 • McLeod neuroacanthocytosis: genotype and phenotype. PMID:11761473
• Parkinsonism & related disorders • 2008 • The McLeod syndrome without acanthocytes. PMID:17870653
• The Journal of biological chemistry • 2001 • Molecular defects underlying the Kell null phenotype. PMID:11375401
• Journal of cell science • 2022 • Interaction between VPS13A and the XK scramblase is important for VPS13A function in humans. PMID:35950506
• Transfusion • 2003 • McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement. PMID:12823753
• Journal of the neurological sciences • 2000 • A novel mutation of the McLeod syndrome gene in a Japanese family. PMID:10930599

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