McLeod neuroacanthocytosis syndrome (ORPHA:59306)
McLeod neuroacanthocytosis syndrome (MLS) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington's disease-like phenotype with an involuntary hyperkinetic movement disorder, psychiatric manifestations and cognitive alterations, and biochemically by absence of the Kx antigen and by weak expression of the Kell antigens.
Epidemiology
Prevalence and incidence are not known, but the disorder is very rare and a few hundred cases are suspected worldwide. MLS has been described in Europe, North and South America, and Japan without obvious clustering. The disease primarily affects males; female carriers rarely develop a neurological syndrome.
Clinical description
Onset of neurological symptoms is at 25-60 years of age and disease duration may be more than 30 years. About 1/3 of patients present with chorea indistinguishable from that observed in Huntington disease (see this term), and most patients will develop chorea during the course of the disease. Additional involuntary movements include facial dyskinesias, vocalizations and rarely feeding dystonia. Psychiatric manifestations including depression, schizophrenia-like psychosis and obsessive compulsive disorder (OCD) are frequent and may appear many years prior to the movement disorders. A subset of patients develops cognitive deficits, particularly in later disease stages. Generalized seizures and muscle weakness (rarely severe) and atrophy occur in about 1/2 of patients. MLS myopathy may predispose some to rhabdomyolysis, particular with neuroleptic medication use. Neuromuscular signs include sensorimotor axonal neuropathy, neurogenic muscle atrophy and variable additional myopathy. About 60% of patients develop cardiomyopathy manifesting with atrial fibrillation, malignant arrhythmias or dilated cardiomyopathy. Cardiac complications are a frequent cause of death. Some female heterozygote carriers show CNS manifestations related to MLS as well as corresponding neuropathological changes. MLS may be part of a ''contiguous gene syndrome'' on the X chromosome including chronic granulomatous disease, Duchenne muscular dystrophy or X-linked retinitis pigmentosa (see these terms).
Etiology
MLS is caused by mutations of the XK gene (Xp21.1) encoding the XK protein, which includes the Kx erythrocyte antigen. Most pathogenic mutations are nonsense mutations or deletions predicting an absent or shortened XK protein lacking the Kell protein binding site.
Diagnostic methods
Diagnosis may be challenging. CK levels are almost always elevated. The procedure of choice is determination of absent Kx antigen and reduced Kell antigens on erythrocytes in males, and fluorescence absorbent cell sorting with Kell antigens in female heterozygotes. Analysis of the XK gene revealing a mutation confirms the diagnosis.
Differential diagnosis
The differential diagnoses depend on the presenting symptoms and include chorea-acanthocytosis, Huntington disease, Huntington disease-like disorders, and Tourette's syndrome (see these terms).
Antenatal diagnosis
Routine methods for prenatal testing can be applied.
Genetic counseling
MLS is an X-linked disorder and genetic counseling is recommended. Affected males will pass on the mutant X chromosome to their daughters, whose sons will have a 1:2 risk of developing MLS and whose daughters will have a 1:2 risk of being carriers.
Management and treatment
So far, no curative or disease-modifying treatments are available and management is symptomatic. MLS patients and asymptomatic carriers of the McLeod blood group phenotype should undergo cardiologic evaluation due to serious cardiac complications.
Prognosis
MLS is relentlessly progressive and the prognosis is poor. Sudden death may be due to seizures, possibly autonomic dysfunction, and sudden cardiac death. There may be gradual generalized weakness with fatal aspiration pneumonia or systemic infections.

                            Last update: 
                            September 2012


                            - Expert reviewer(s): 
                            Pr Hans JUNG