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 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 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 pathogenic variant (90% of affected males) or a hemizygous deletion of Xp21.1 involving (10% of affected males) identified on molecular genetic testing.

MANAGEMENT

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. Blood transfusions with Kx antigens in males with MLS. Kx-negative blood or, if possible, banked autologous or homologous blood should be used. : 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. 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 pathogenic variant in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygous and will usually not be affected. Affected males pass the pathogenic variant to all of their daughters and none of their sons. Once the 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.