Molecular Basis and Clinical Overview of McLeod Syndrome Compared With Other Neuroacanthocytosis Syndromes

Abstract

IMPORTANCE McLeod syndrome, encoded by the gene XK, is a rare and progressive disease that shares important similarities with Huntington disease but has widely varied neurologic, neuromuscular, and cardiologic manifestations. Patients with McLeod syndrome have a distinct hematologic presentation with specific transfusion requirements. Because of its X-linked location, loss of the XK gene or pathogenic variants in this gene are principally associated with the McLeod blood group phenotype in male patients. The clinical manifestation of McLeod syndrome results from allelic variants of the XK gene or as part of a contiguous gene deletion syndrome involving XK and adjacent genes, including those for chronic granulomatous disease, Duchenne muscular dystrophy, and retinitis pigmentosa. McLeod syndrome typically manifests as neurologic and cardiologic symptoms that evolve in individuals beginning at approximately 40 years of age. OBSERVATIONS Diagnosis of McLeod syndrome encompasses a number of specialties, including neurology and transfusion medicine. However, information regarding the molecular basis of the syndrome is incomplete, and clinical information is difficult to find. The International Society of Blood Transfusion has recently compiled and curated a listing of XK alleles associated with the McLeod phenotype. Of note, McLeod syndrome caused by structural variants as well as those cases diagnosed as part of a contiguous gene deletion syndrome were previously classified under a singular allele designation. CONCLUSIONS AND RELEVANCE This review discusses the clinical manifestations and molecular basis of McLeod syndrome and provides a comprehensive listing of alleles with involvement in the syndrome published to date. This review highlights the clinical diversity of McLeod syndrome and discusses the development of molecular tools to elucidate genetic causes of disease. A more precise and systematic genetic classification is the first step toward correlating and understanding the diverse phenotypic manifestations of McLeod syndrome and may guide clinical treatment of patients and support for affected and carrier family members. This review provides a knowledge base for neurologists, hematologists, and clinical geneticists on this rare and debilitating disease.

Review of Hereditary and Acquired Rare Choreas

“…Patients also develop seizures, significant myopathy, and peripheral neuropathy. While less common than in choreaacanthocytosis, there can some times be tongue protrusion, feeding dystonia, and lipbiting or tonguebitting [25,66].…”

A Novel XK Gene Mutation Causative of McLeod Syndrome

“…Serum testing reveals low-level hemolysis and creatine phosphokinase elevation. 3 Neuroimaging shows progressive basal ganglia degeneration. Here we report a case of MLS as the result of a novel, distal XK mutation.A 53-year-old man presented with involuntary movements, starting in the left foot and progressing to the limbs and trunk over 1 year.…”

“…Serum testing reveals low-level hemolysis and creatine phosphokinase elevation. 3 Neuroimaging shows progressive basal ganglia degeneration. Here we report a case of MLS as the result of a novel, distal XK mutation.…”

“…2 Heterogeneous mutations have been described in MLS, including 39 point mutations and 17 largescale deletions. 3 These result in the disruption of the Kx antigen and reduced erythrocyte Kell antigen expression. Serum testing reveals low-level hemolysis and creatine phosphokinase elevation.…”

“…Of the identified mutations to date, this is the third most distal in the protein coding sequence and is adjacent to the Kell binding site at amino acid 347. 3 Distal disease-causing single nucleotide polymorphisms in XK imply that protein function relies on having a largely intact C-terminus, which may impact binding affinity to other components of the 4.1R multiprotein complex in the erythrocyte membrane. 4 Whether XK is involved in similar transmembrane multiprotein complex interactions in the central nervous system remains to be elucidated.…”