Clinical characteristics.

McLeod neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males:

• CNS manifestations are a neurodegenerative basal ganglia disease including movement disorders, cognitive alterations, and psychiatric symptoms.
• Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees.
• Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia.
• Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod) that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in affected male newborns of Kell-negative mothers.

Females heterozygous for XK pathogenic variants have mosaicism for the Kell and Kx blood group antigens. Although they usually lack CNS and neuromuscular manifestations, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline.

Diagnosis/testing.

The diagnosis of MLS is established in a male proband with: suggestive clinical, laboratory, and neuroimaging studies; a family history consistent with X-linked inheritance; and either a hemizygous XK pathogenic variant (90% of affected males) or a hemizygous deletion of Xp21.1 involving XK (10% of affected males) identified on molecular genetic testing.

Management.

Treatment of manifestations: The following recommendations apply to affected males (although symptomatic heterozygous females may undergo the same procedures, no scientific data are available): use of dopamine antagonists (e.g., tiapride, clozapine, quetiapine) and the dopamine depletory (tetrabenazine) to ameliorate chorea; assessment of cardiac involvement initially with cardiac MRI (if available), Holter electrocardiogram (EKG), echocardiography, cardiac biomarkers, and specialized electrophysiological investigations (if indicated); consideration of placement of prophylactic cardiac pacemaker / implantable cardioverter-defibrillator; treatment of psychiatric problems and seizures based on clinical findings; long-term and continuous multidisciplinary psychosocial support for affected individuals and their families.

Agents/circumstances to avoid: Blood transfusions with Kx antigens in males with MLS. Kx-negative blood or, if possible, banked autologous or homologous blood should be used.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic male and female at-risk relatives of any age in order to identify as early as possible those who would benefit from (1) detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products, (2) possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions, and (3) interventions to prevent sudden cardiac events.

Surveillance: For those with known cardiac involvement, follow up per treating specialist; for those without known cardiac involvement, Holter EKG, echocardiography, and cardiac biomarkers (e.g., troponin T/I, pro BNP) every two years; monitor for seizures; monitor serum CK concentrations for evidence of rhabdomyolysis if excessive movement disorders are present or if neuroleptic medications are being used.

Genetic counseling.

MLS is inherited in an X-linked manner. If the mother of an affected male is heterozygous, the chance of transmitting the XK pathogenic variant in each pregnancy is 50%. Males who inherit the XK variant will be affected; females who inherit the XK variant will be heterozygous and will usually not be affected. Affected males pass the XK pathogenic variant to all of their daughters and none of their sons. Once the XK pathogenic variant has been identified in an affected family member, carrier testing for at-risk females, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

The diagnosis of McLeod neuroacanthocytosis syndrome (MLS) should be suspected/considered in an individual with the following clinical and laboratory findings and family history.

Establishing the Diagnosis

Male proband. The diagnosis of McLeod neuroacanthocytosis syndrome is established in a male proband with suggestive clinical and laboratory findings, neuroimaging studies, and family history, as well as one of the following identified on molecular genetic testing (see Table 1):

• A hemizygous pathogenic variant involving XK (~90% of affected individuals) [Dotti et al 2000, Danek et al 2001a, Jung et al 2001b, Jung et al 2003]
• A hemizygous deletion of Xp21.1 involving XK (10% of affected individuals) [Kawakami et al 1999, El Nemer et al 2000, Danek et al 2001a, Wendel et al 2004]
  Note: Deletions involving XK vary in size from intragenic to larger multigene deletions. Failure to generate XK sequence in a male proband is consistent with a deletion; however, other techniques are needed to define the breakpoints of the deletion (see Table 1).

Female proband. The diagnosis of McLeod neuroacanthocytosis syndrome is usually established in a female proband with one of the following: (1) detection by flow cytometry of two populations of RBC, one with normal expression of Kell antigens and one with reduced expression, or (2) detection of a heterozygous pathogenic variant in XK by molecular genetic testing.

Note: Based on published cases, heterozygous females do not have RBC acanthocytosis or elevated CK serum levels.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

There are three options for establishing the diagnosis of McLeod neuroacanthocytosis syndrome:

• Option 1. Determination of the McLeod blood group phenotype followed by CMA for individuals with findings suggestive of a contiguous-gene deletion
• Option 2. Determination of the McLeod blood group phenotype followed by single-gene testing for those in whom McLeod blood group phenotyping supports the diagnosis
• Option 3. Multigene panel or comprehensive genomic testing for symptomatic individuals in whom the diagnosis of McLeod neuroacanthocytosis syndrome has not been considered

Clinical Description

McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males. Heterozygous females have mosaicism for the Kell and Kx blood group antigens but usually lack CNS and neuromuscular manifestations; however, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline.

Genotype-Phenotype Correlations

Data presently available are insufficient to draw conclusions about genotype-phenotype correlations in McLeod neuroacanthocytosis syndrome [Danek et al 2001a]. MLS shows considerable phenotypic variability, even among family members with identical XK variants [Danek et al 2001b, Walker et al 2007a].

Only three pathogenic XK missense variants have a possible genotype-phenotype correlation. Although rare, they are potentially useful in the elucidation of structural and functional relationships. For more details see Table 6.

• The c.979G>A variant was associated with an isolated immunohematologic phenotype without evidence for muscular, central, and peripheral nervous system involvement [Jung et al 2003].
• An individual with the c.664C>G variant did not show significant neurologic or systemic abnormalities [Walker et al 2007b].
• A single-base substitution in an intron near a splice junction (c.508+5G>A, resulting in alternative splicing and some degree of normal splicing) did not lead to any significant neurologic abnormalities [Walker et al 2007b].

Penetrance

In males, the penetrance of neurologic and neuromuscular manifestations of MLS is high – perhaps even complete – after age 50 years. Available data indicate that most males with the McLeod blood group phenotype will develop clinical manifestations of McLeod neuroacanthocytosis syndrome [Bertelson et al 1988, Hardie et al 1991, Danek et al 2001a, Jung et al 2001b].

In a few individuals, however, neurologic and neuromuscular manifestations may be absent or only minor even after long-term follow up [Jung et al 2003, Walker et al 2007b]. See Genotype-Phenotype Correlations.

In the past, many reports (including that of the index case) described only hematologic findings, and no neurologic or neuroimaging workup was performed in these individuals [Allen et al 1961, Symmans et al 1979, Bertelson et al 1988, Lee et al 2000]. However, in many of these individuals neurologic manifestations were identified during long-term follow up [Bertelson et al 1988, Danek et al 2001a].

Nomenclature

The term "neuroacanthocytosis" refers to several genetically and phenotypically distinct disorders [Walker & Danek 2021] (see Differential Diagnosis).

The term "McLeod blood group phenotype" (named after the first proband, Hugh McLeod) describes the immunohematologic abnormalities consisting of absent expression of Kx RBC antigen and reduced expression of Kell RBC antigens in the index case originally described by Allen et al [1961].

The terms "Kell blood group precursor" and "Kell blood group precursor substance" for the XK protein or the Kx RBC antigen, respectively, are incorrect and no longer in use.

Prevalence

The prevalence of MLS cannot be determined based on the data available from the approximately 250 cases known worldwide. The prevalence is estimated at 1:10,000,000 [Walker et al 2019].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with McLeod neuroacanthocytosis syndrome (MLS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Blood transfusions with Kx antigens should be avoided in males with the McLeod blood group phenotype. Kx-negative blood or, if possible, banked autologous or homologous blood should be used for transfusions. Note that because heterozygous females have both Kx+ and Kx- red blood cells, they can be transfused with Kx+ homologous blood products.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk male relatives of any age in order to identify as early as possible those who would benefit from:

• Detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products;
• Possible prophylactic cryopreservation of autologous or homologous blood for use in future transfusions; and
• Prevention of sudden cardiac events.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In female heterozygotes, the probability of manifestations of the McLeod neuroacanthocytosis syndrome in the reproductive period is presumably very low; thus, no particular recommendations can be made.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

McLeod neuroacanthocytosis syndrome (MLS) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disease nor will he be hemizygous for the XK pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected son and the XK pathogenic variant cannot be detected in her leukocyte DNA, she may have germline mosaicism. No data regarding germline mosaicism in MLS are available to date.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo XK pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism.
  One de novo XK pathogenic variant has been described in MLS [Supple et al 2001].
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the variant will be affected. Significant interfamilial phenotypic variability has been observed in MLS (see Clinical Description).
  • Females who inherit the pathogenic variant will be heterozygotes. Females who are heterozygous for an XK pathogenic variant have mosaicism for the Kell and Kx blood group antigens but usually lack CNS and neuromuscular manifestations. However, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline. The typical MLS phenotype was reported in one female. (See Clinical Description, Heterozygous Females.)
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the XK pathogenic variant to:

• All of their daughters, who will be heterozygotes and will usually not be affected. Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description, Heterozygous Females).
• None of their sons.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having an XK pathogenic variant.

Heterozygote Detection

Identification of female heterozygotes requires either (a) prior identification of the XK pathogenic variant in the family or, (b) if an affected male is not available for testing, either molecular genetic testing first by sequence analysis, and if no XK pathogenic variant is identified, by gene-targeted deletion/duplication analysis or flow cytometric analysis of Kx and Kell erythrocyte antigens.

Note: Some heterozygous females may develop clinical manifestations such as chorea or late-onset cognitive decline (see Clinical Description, Heterozygous Females).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early identification of those who would benefit from detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being heterozygotes.

Prenatal Testing and Preimplantation Genetic Testing

Once the XK pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MLS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

XK encodes XK, a red blood cell antigen. The XK protein has ten transmembrane domains and the structural characteristics of a membrane transport protein [Ho et al 1994]. The XK protein attaches to the Kell glycoprotein, encoded by KEL on chromosome 7, by a single disulfide bond (XK p.Cys347- Kell p.Cys72) when they are coexpressed [Russo et al 1998]. In the red cell membrane, the heterodimeric protein complex XK-KEL is part of the larger membrane multiprotein complex subunit 4.1 (MMPC4.1) containing Band3 glycoprotein, glycophorin C, Rh protein, Rh-associated glycoprotein, and Duffy protein, which supports red cell cytoskeleton stability [Frey et al 2015, Lux 2016]. XK may also be important for transmembrane exchange of divalent cations (Ca++, Mg++) and Gardos channel function [De Franceschi et al 2005, Rivera et al 2013].

XK forms a complex with VPS13A, a protein that acts as lipid transporter protein at different membrane contact sites, for example, between the mitochondria and the endoplasmic reticulum [Kumar et al 2018, Urata et al 2019, Yeshaw et al 2019, Park & Neiman 2020]. XK is involved in the relocalization of VPS13A (e.g., from lipid droplets to subdomains of the endoplasmic reticulum), and may act as a phospholipid scramblase, like other proteins of the XK family [Park & Neiman 2020]. Of note, pathogenic VPS13A cause autosomal recessive chorea-acanthocytosis (ChAc), which is phenotypically very similar to MLS. Hence, dysfunction of an XK-VPS13A complex may represent the common molecular basis for both MLS and ChAc – which is a possible explanation for their phenotypic similarities [Kumar et al 2018, Urata et al 2019, Yeshaw et al 2019, Park & Neiman 2020].

XK and Kell are predominantly coexpressed in erythroid tissues, but their expression in non-erythroid tissues differs. XK is ubiquitously expressed in many other tissues, especially in high amounts in skeletal muscle and brain [Russo et al 2000, Camara-Clayette et al 2001, Jung et al 2001b]. XK is expressed in various cerebral regions, with high amounts in pontine region, olfactory lobe, and cerebellum [Lee et al 2007]. It has been proposed that the function of isolated XK in non-erythroid tissue differs from that of XK in combination with Kell.

Mechanism of disease causation. McLeod neuroacanthocytosis syndrome occurs through a loss-of-function mechanism.

XK-specific laboratory technical considerations. A naming convention for abnormal XK alleles has been established by the International Society of Blood Transfusion (IBST; scroll down and select Blood Group Allele Tables, then XK). The XK protein reference allele is defined as XK*01. Alleles associated with MLS are defined as XK*N.# beginning with 01, with N indicating null and # being assigned to each reported abnormal allele (e.g., c.664C>G [p.Arg222Gly] is designated XK*N.27).

Note: Stepwise partitioning of Xp21 has been used as an alternative method to define the exact breakpoints of contiguous-gene deletions [Gassner et al 2017].

Notable XK variants. All three of the pathogenic missense variants reported in Table 6 occurred in the transmembrane domains and on highly conserved amino acid residues that are evolutionarily related to XK, suggesting possible important roles in structure or function. The p.Arg222 and p.Glu327 residues may be involved in the basic structure of XK rather than in its function; the p.Cys294 residue, which is conserved specifically in the XK family, may be critical for normal function [Walker et al 2007b].

Author Notes

Hans H Jung is a leading senior consultant at the Department of Neurology, University Hospital Zurich, Switzerland where he is head of the Center for Neurogenetic and Neuromuscular Disorders. His research focuses on the clinical, pathologic, and molecular basis of chorea syndromes, in particular the McLeod neuroacanthocytosis syndrome.

Adrian Danek, a professor of cognitive neurology at the University of Munich, has contributed to neuroacanthocytosis research since 1990. His interests also include functional brain anatomy, problem solving (Towers of Hanoi/London), the frontotemporal lobe degeneration syndromes (see www.ftld.de), and other familial dementias.

Ruth H Walker is a movement disorders-trained neurologist whose research focuses on the functional neuroanatomy of the basal ganglia and clinicopathologic correlations of neurogenetic disorders. Her particular clinical interests are the hyperkinetic disorders, especially the rarer inherited causes of chorea.

Beat M Frey is a board certified hematologist/oncologist/transfusion specialist running the Swiss Transfusion Service SRC in Schlieren/Zürich, Switzerland. His research interests focus on functional and genetic aspects of blood group antigens and their implication for clinical practice.

Kevin Peikert is supported by the Rostock Academy for Clinician Scientists (RACS) and the FORUN program (both University of Rostock, Germany).

Acknowledgments

The authors thank the Advocacy for Neuroacanthocytosis Patients, in particular the late Glenn Irvine and his wife Ginger, for their continuous and ongoing support.

Author History

Adrian Danek, MD (2004-present)
Carol Dobson-Stone, DPhil; University of New South Wales (2004-2012)
Beat M Frey, MD (2012-present)
Christoph Gassner, PhD; Swiss Red Cross (2012-2021)
Hans H Jung, MD (2004-present)
Sohee Lee, PhD; New York Blood Center (2007-2012)
Kevin Peikert, MD (2021-present)
Colvin M Redman, PhD; New York Blood Center (2004-2007)
Ruth H Walker, MD, MBBS, PhD (2012-present)

Revision History

• 16 September 2021 (bp) Comprehensive update posted live
• 23 May 2019 (bp) Comprehensive update posted live
• 17 May 2012 (me) Comprehensive update posted live
• 26 March 2007 (me) Comprehensive update posted live
• 3 December 2004 (ca) Review posted live
• 8 April 2004 (hj, ad) Original submission

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