Case Report: McLeod syndrome caused by a nonsense variant c.484C > T (p.Gln162Ter) in the XK gene in a Chinese Han family

Abstract

McLeod syndrome (MLS) is a rare X-linked neuroacanthocytosis caused by pathogenic variants in XK , and is characterized by hyperkinetic movements, peripheral neuropathy and myopathy with hyperCKemia, acanthocytosis and cardiomyopathy. Here, we report a mainland Chinese Han family with McLeod syndrome carrying the XK variant c.484C > T, which resulted in a premature stop codon at position 162 (p.Gln162Ter), which, to our knowledge, has not been reported in association with McLeod syndrome in Asian populations; notably, the variant is not listed in the ISBT online Kx allele table at the time of writing. Clinical, laboratory, imaging, electrophysiologic, immunohematologic, and genetic data were extracted from the proband’s medical records, with targeted evaluation of first-degree relatives. The variant was interpreted according to ACMG/AMP criteria; ColabFold v1.5.5 was used for in silico structural prediction using wild-type and mutant sequences. The case report was prepared in accordance with the CARE guidelines. A 59-year-old man was admitted with an 8-year history of progressive gait disturbance and choreiform movements, later accompanied by cognitive decline and distal-predominant upper limb weakness. Examination showed generalized areflexia, markedly elevated creatine kinase, bilateral caudate head atrophy on brain MRI, and axonal sensorimotor polyneuropathy on nerve conduction velocity (NCV) testing, with chronic neurogenic changes on needle electromyography (EMG). Peripheral smear revealed acanthocytosis in more than 60% of red blood cells, and serologic testing demonstrated markedly reduced reactivity with anti-Kell (K) and anti-Cellano (k) antibodies, suggesting reduced or absent Kx antigen and supporting a McLeod phenotype; whole-exome sequencing identified a hemizygous XK variant c.484C>T in the proband, and his asymptomatic daughter was heterozygous. The diagnosis of McLeod syndrome was established, and supportive management was recommended; at telephone follow-up, hyperkinetic movements persisted and symptomatic medication had not yet been initiated because of concerns about adverse effects. This family broadens the ethnic and clinical spectrum associated with the XK c.484C > T (p.Gln162Ter) variant and highlights the value of integrating acanthocyte assessment, McLeod blood group phenotyping, and genetic sequencing in the evaluation of males with hyperkinetic movements, peripheral neuropathy, and hyperCKemia to enable earlier diagnosis of MLS.