Stepwise partitioning of Xp21: a profiling method for XK deletions causative of the McLeod syndrome

Gassner, Christoph; Brönnimann, Chantal; Merki, Yvonne; Mattle-Greminger, Maja P.; Sigurdardottir, Sonja; Meyer, Eduardo; Engström, Charlotte; O’Sullivan, John D.; Jung, Hans H.; Frey, Beat M.

doi:10.1111/trf.14172

Cited by 9 publications

(8 citation statements)

References 27 publications

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“…Patient blood samples are first evaluated serologically for KEL and Kx antigen reactivity which is expected to be either negative or weakened (further details and flowchart in Frey et al [74]). At the level of genetic analysis, a specific approach to overcome diagnostic difficulties with XK gene deletions has been proposed [75]. Similar to the diagnosis of MLS that is based on the absence of the XK protein (carrier of the Kx antigen) and/ or presence of XK gene mutations, diagnosis of VPS13A disease should be based upon the absence of the chorein protein in erythrocyte membrane Western blot [76] and/ or the identification of mutations in the VPS13A gene.…”

Section: Diagnosis and Managementmentioning

confidence: 99%

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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Section: Diagnosis and Managementmentioning

confidence: 99%

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

Peikert

Hermann

Danek³

2022

Transfus Med Hemother

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“…This study is the first in silico of XK gene based on functional and structural analysis, while all previous studies (Gassner et al 2017;Ho et al 1992) were based on in vivo and in vitro analysis. There is an extended phenotypic overlap between McLeod syndrome, Huntington's disease, and chorea-acanthocytosis (Cardoso 2014;Danek et al 2001;Gantenbein et al 2011;Peikert et al 2018;Shah et al 2013;Zhang et al 2013), this may help to achieve a better should be understating of those diseases through our findings.…”

Section: Discussionmentioning

confidence: 93%

Unmasking of two mutations within XK gene that could be used as diagnostic markers to predict McLeod Syndrome: using in silico analysis

Mustafa

Hassan

2022

MSJ

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McLeod syndrome (MSL) is a rare X-linked disorder. Approximately 150 cases have been reported worldwide ("McLeod neuroacanthocytosis syndrome," 2019). Characterized by misshapen red blood cells and progressive degeneration of the basal ganglia disease, which manifest as: movement disorders, cognitive alterations, psychiatric symptoms, and cardiac manifestations. The hematological features are strongly related to abnormalities of different degrees in other organ systems, including neuromuscular involvement (Jung et al 1993). Hematologically, MLS is defined as a specific blood group phenotype that results from the absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens (Jung et al 1993;Jung et al 2001). The KEL gene encodes kell antigens on the long arm of chromosome 7. The XK gene encodes kx antigen on the short arm of the X chromosome (Bansal et al 2008).MSL is caused by mutations of XK gene, an X-chromosomal gene of unknown function. But all we know is different XK mutations may have different effects on the XK gene product and thus may account for the variable phenotype (

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“…Sequential analysis of the XK gene is a highly specific diagnostic marker for McLeod syndrome ( Gassner et al, 2017 ). Previous studies have investigated the importance of early and accurate diagnosis for McLeod syndrome, outlining the crucial role of hematology analyses in early detection ( Kelly et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…The patients often require repeated medical attention over a long period of time before achieving a definitive diagnosis. The XK variant is a highly specific diagnostic marker for McLeod syndrome ( Gassner et al, 2017 ). Thus, the detection of the XK gene variant is the “gold standard” for the diagnosis of McLeod syndrome.…”

Section: Introductionmentioning

confidence: 99%

A case of McLeod syndrome caused by a nonsense variation c.942G>A in the XK gene: A case report

Ying

Zhang

et al. 2023

Front. Genet.

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McLeod syndrome is a rare XK gene-related progressive, debilitating disease involving multiple systems. The blood group phenotypes in McLeod syndrome patients usually display the Kx antigen loss and a decrease in the Kell blood group system antigen expression. This paper describes a 41-year-old male Chinese patient with McLeod syndrome. He first attended a hospital in 2015 and developed progressively worsening symptoms 4 years ago. As the disease progressed, the patient exhibited memory loss, unresponsiveness, and chorea and displayed elevated creatine kinase levels. However, McLeod syndrome could not be diagnosed by these signs and laboratory results. The patient was readmitted to the hospital in 2020 and was suspected of having McLeod syndrome. Serological analysis of the Kell blood group system and genotyping for the XK blood group system were performed, revealing the weak expression of the K antigen and the negative K antigen. Sequencing of the coding region of the XK gene showed a hemizygous c.942G>A variation in the XK gene, which resulted in a premature stop codon at position 314 (p.Trp314Ter). Therefore, the patient was diagnosed with McLeod syndrome. In conclusion, this paper presents a case of McLeod syndrome caused by a nonsense variation c.942G>A in the XK gene. The analysis of the XK gene and blood group antigen is helpful for the diagnosis of McLeod syndrome and for distinguishing it from many other diseases.

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Stepwise partitioning of Xp21: a profiling method for XK deletions causative of the McLeod syndrome

Cited by 9 publications

References 27 publications

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

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

Unmasking of two mutations within XK gene that could be used as diagnostic markers to predict McLeod Syndrome: using in silico analysis

A case of McLeod syndrome caused by a nonsense variation c.942G>A in the XK gene: A case report

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