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