Mcleod Neuroacanthocytosis Syndrome

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 (1) movement disorders, (2) cognitive alterations, and (3) 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. Allo-antibodies 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 but usually lack CNS and neuromuscular manifestations; however, 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 identification on molecular genetic testing of either a hemizygous XK pathogenic variant (90% of affected males) or a hemizygous deletion of Xp21.1 involving XK (10% of affected males).

Management.

Treatment of manifestations: Dopamine antagonists (e.g., tiapride, clozapine, quetiapine) and the dopamine depletory (tetrabenazine) to ameliorate chorea; treatment of psychiatric problems, cardiac abnormalities, and seizures is based on the clinical findings; long-term and continuous multidisciplinary psychosocial support is needed for affected individuals and their families.

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

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic 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, and (2) possible prophylactic cryopreservation of autologous blood for use in future transfusions.

Surveillance: Holter ECG and echocardiography every two to three years in those without known cardiac complications; consider placement of prophylactic cardiac pacemaker; 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 diagnosis 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, exome array, 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, and hematologic manifestations in males. CNS manifestations of MLS resemble Huntington disease. Symptoms comprise the prototypic triad of a progressive neurodegenerative basal ganglia disease including (1) movement disorder, (2) cognitive alterations, and (3) psychiatric symptoms [Danek et al 2001a, Jung et al 2007]. It should be noted that each sign and symptom may develop in isolation or in variable combinations.

Choreiform movements are the presenting manifestation in about 30% of individuals with MLS, and develop in up to 95% of individuals over time [Danek et al 2001b, Jung et al 2001a, Hewer et al 2007]. Some individuals with MLS develop head drops, feeding dystonia, and gait abnormalities, manifestations formerly believed to be specific to another type of neuroacanthocytosis, the autosomal recessive chorea-acanthocytosis [Chauveau et al 2011, Gantenbein et al 2011].

Cognitive alterations are not a major presenting feature of MLS; however, frontal-type cognitive deficits are eventually found in at least 50% of individuals during the course of the disease [Danek et al 2001a, Jung et al 2001a, Danek et al 2004, Hewer et al 2007].

About 20% of individuals initially manifest psychiatric abnormalities including personality disorder, anxiety, depression, obsessive-compulsive disorder, bipolar disorder, or schizo-affective disorder. Psychopathology develops in about 80% of individuals over time [Danek et al 2001a, Jung et al 2001a, Jung & Haker 2004, Walterfang et al 2011].

Seizures are the presenting manifestation in about 20% of individuals. Up to 40% of individuals with MLS eventually have seizures, usually described as generalized seizures.

Neuromuscular manifestations are not a common presenting manifestation of MLS. However, almost all individuals with MLS have absent deep tendon reflexes as an indication of a (mostly subclinical) sensorimotor axonopathy [Danek et al 2001a, Jung et al 2001a]. About 50% of individuals develop clinically relevant muscle weakness or atrophy of a neurogenic nature during the disease course. Deterioration rate is slow, and few individuals develop severe weakness [Kawakami et al 1999, Danek et al 2001a, Jung et al 2001a, Hewer et al 2007].

Cardiac manifestations including dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia are rarely presenting signs and symptoms of MLS. About 60% of individuals develop cardiac manifestations over time [Witt et al 1992, Danek et al 2001a, Oechslin et al 2009]. In seven males with MLS, one presented with a cardiomyopathy and died from sudden cardiac death in the absence of any cardiovascular risk factors. Autopsy demonstrated eccentric hypertrophy and mild left ventricular dilatation. Histopathology was not specific and revealed focal myocyte hypertrophy, slight variation of myofiber size, and patchy interstitial fibrosis [Witt et al 1992, Oechslin et al 2009]. Comparable histologic findings were observed in the heart of the only individual with MLS who has undergone cardiac transplantation [Laurencin et al 2018].

Hepatosplenomegaly, most probably resulting from compensated hemolysis, occurs in about one third of males with MLS [Danek et al 2001a].

About 30% of males with the McLeod blood group phenotype do not have neuromuscular or CNS findings at the time of initial diagnosis of the blood group abnormalities and are only recognized during routine workup in blood banks or in the course of family evaluations [Danek et al 2001a, Jung et al 2001a, Jung et al 2007]. However, most males with the McLeod blood group phenotype developed neurologic manifestations during long-term follow up [Danek et al 2001a, Hewer et al 2007].

The age of onset of neurologic manifestations ranges from 18 to 61 years; the majority of individuals become symptomatic before age 40 years. Almost all clinical observations indicate a slowly progressive disease course [Danek et al 2001a, Jung et al 2001a, Valko et al 2010]. Because of difficulty in determining the exact onset of disease, few reliable data regarding disease duration are available. Activities of daily living may become impaired as a result of the movement disorder, psychiatric manifestations, intellectual disability, and/or cardiomyopathy.

The interval between reported disease onset and death ranges from seven to 51 years, and the mean age of death is 53 years (range: 31 to 69 years) [Danek et al 2001a, Jung et al 2001a, Hewer et al 2007, Walker et al 2019]. Mean disease duration from diagnosis to death was 21 years [Walker et al 2019]. Cardiac problems, in particular tachyarrhythmia, appear to be a major cause of premature death in MLS; other causes of death included pneumonia, seizure, suicide, and sepsis [Walker et al 2019].

The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Allo-antibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in newborns of Kell-negative mothers.

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 between 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].

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 [Danek et al 2004, Danek et al 2005]; 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].