Three new <scp>XK</scp> alleles; two associated with a <scp>McLeod RBC</scp> phenotype

Floch, Aline; Lomas‐Francis, Christine; Vege, Sunitha; Westhoff, Connie M.

doi:10.1111/trf.16650

Transfusion

2021

DOI: 10.1111/trf.16650

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Three new XK alleles; two associated with a McLeod RBC phenotype

Aline Floch

Christine Lomas‐Francis

Sunitha Vege

et al.

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Cited by 4 publications

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“…4,5 We recently evaluated a patient with chorea and cognitive decline who carried a missense variant of XK; however, his RBCs lacked the McLeod antigen expression profile, which is required to make a diagnosis of XK disease. 6 In addition, he lacked other typical features of XK disease, such as creatine kinase (CK) and liver enzyme elevation, cardiomyopathy, peripheral neuropathy, and myopathy. 6 A 67-year-old man of Scottish/German ancestry presented with an 11-year history of gradually progressive chorea that was most prominent in his arms.…”

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“…6 In addition, he lacked other typical features of XK disease, such as creatine kinase (CK) and liver enzyme elevation, cardiomyopathy, peripheral neuropathy, and myopathy. 6 A 67-year-old man of Scottish/German ancestry presented with an 11-year history of gradually progressive chorea that was most prominent in his arms. He had slow horizontal and vertical saccadic eye movements with interruptions in smooth pursuit.…”

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confidence: 99%

“…Kell blood group system serologic typing of RBCs revealed that K+k+, Kp(a-b+), Js b +, and Kx+ levels were comparable to those of the controls and thus not consistent with the McLeod phenotype. 6 Sequencing of the XK gene revealed a novel missense variant, c.121T>G, in exon 1 causing a p.Leu41Val amino acid change that is predicted to be located in the 2nd transmembrane-spanning region of the XK protein. 1,6 This variant is classified as PM2 (moderate evidence of pathogenicity) according to ACMG guidelines.…”

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confidence: 99%

“…6 Sequencing of the XK gene revealed a novel missense variant, c.121T>G, in exon 1 causing a p.Leu41Val amino acid change that is predicted to be located in the 2nd transmembrane-spanning region of the XK protein. 1,6 This variant is classified as PM2 (moderate evidence of pathogenicity) according to ACMG guidelines. Chorein Western blotting analysis demonstrated normal levels of chorein (VPS13A).…”

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confidence: 99%

See 3 more Smart Citations

Basal Ganglia Syndrome in a Male With an XK Gene Variant but Without XK Disease (McLeod Syndrome)

Yu,

Walker,

Danek

et al. 2024

JMD

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Basal Ganglia Syndrome in a Male With an XK Gene Variant but Without XK Disease (McLeod Syndrome)

Yu,

Walker,

Danek

et al. 2024

JMD

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Sleep disorders in McLeod syndrome: A case series

Lim¹,

Sarva²,

Hiller³

et al. 2022

Parkinsonism & Related Disorders

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XK-Associated McLeod Syndrome: Nonhematological Manifestations and Relation to VPS13A Disease

Peikert

Hermann

Danek³

2022

Transfus Med Hemother

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Background: McLeod syndrome (MLS) is an X-linked multisystemic progressive disorder caused by loss of function mutations in the XK gene. The rare blood group phenotype of MLS patients with absent Kx antigen requires the support of specialized transfusion institutions because of the risk of transfusion complications. Acanthocytosis of red blood cells occurs in almost all patients. Nonhematological manifestations of MLS are very similar to those of VPS13A disease (chorea-acanthocytosis), an autosomal-recessive condition. Their shared phenotype apart from acanthocytosis includes movement disorders such as chorea and dystonia, epilepsy, peripheral neuropathy, and muscle involvement, typically with creatine kinase (CK) elevation, cardiomyopathy included. Summary: In this review, we describe the nonhematological manifestations of MLS in comparison with those of VPS13A disease. While there are many similarities, differences such as mode of inheritance, sex distribution, age at manifestation, severity of heart involvement, frequency of feeding dystonia or of involuntary head drops may help to distinguish these disorders in the clinic. Immunohematological demonstration of the McLeod-Kell phenotype or detection of pathogenic mutations of XK (or VPS13A, respectively) is the gold standard for distinction. “Neuroacanthocytosis” was often used as an overarching term, but is potentially misleading, as the term does not refer to a defined disease entity. Its use, if continued, must not prevent clinicians to seek a final diagnosis on the basis of molecular findings. The clinical similarity of MLS and VPS13A disease has long suggested some shared pathophysiology. Evidence for molecular interaction between XK, the McLeod protein, and chorein, the VPS13A gene product, has recently been put forward: XK forms a complex with chorein/VPS13A, a bulk lipid transporter located at various membrane contact sites. The exact role of XK in this complex needs to be further elucidated. Impairment of bulk lipid transport appears as the common denominator of both MLS and VPS13A disease. A variety of further conditions may in time be added to the “bulk lipid transport diseases,” such as the recently recognized disorders caused by mutations in the VPS13B, VPS13C, and VPS13D genes. Key Messages: (1) Patients diagnosed with the rare red cell McLeod phenotype (McLeod syndrome, MLS) require interdisciplinary collaboration of transfusion medicine specialists, neurologists, and cardiologists for both their hematological and nonhematological disease manifestations. (2) The phenotypical similarity of MLS and VPS13A disease, often leading to either confusion or insufficient diagnostic depth (under the label of “neuroacanthocytosis”), is based on interaction of the respective proteins, XK and chorein, within the cellular machinery for bulk lipid transport. (3) Overall, the term “bulk lipid transport diseases” seems useful for further research on a group of conditions that may not only share pathophysiology, but may also share treatment approaches.

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Three new XK alleles; two associated with a McLeod RBC phenotype

Cited by 4 publications

References 5 publications

Basal Ganglia Syndrome in a Male With an XK Gene Variant but Without XK Disease (McLeod Syndrome)

Basal Ganglia Syndrome in a Male With an XK Gene Variant but Without XK Disease (McLeod Syndrome)

Sleep disorders in McLeod syndrome: A case series

XK-Associated McLeod Syndrome: Nonhematological Manifestations and Relation to VPS13A Disease

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