McLeod neuroacanthocytosis syndrome

Other Names: McLeod syndrome; X-linked McLeod syndrome

McLeod neuroacanthocytosis syndrome is primarily a neurological disorder that occurs almost exclusively in males. The signs and symptoms of McLeod neuroacanthocytosis syndrome usually begin in mid-adulthood. Behavioral changes, such as lack of self-restraint, the inability to take care of oneself, anxiety, depression, and changes in personality may be the first signs of this condition. While these behavioral changes are typically not progressive, the movement and muscle problems and intellectual impairments tend to worsen with age.

Epidemiology

McLeod neuroacanthocytosis syndrome is rare; approximately 150 cases have been reported worldwide.

Cause

Mutations in the XK gene cause McLeod neuroacanthocytosis syndrome. The XK gene provides instructions for producing the XK protein, which carries the blood antigen Kx. Blood antigens are found on the surface of red blood cells and determine blood type. The XK protein is found in various tissues, particularly the brain, muscle, and heart. The function of the XK protein is unclear; researchers believe that it might play a role in transporting substances into and out of cells. On red blood cells, the XK protein attaches to another blood group protein, the Kell protein. The function of this blood group complex is unknown.

XK gene mutations typically lead to the production of an abnormally short, nonfunctional protein or cause no protein to be produced at all. A lack of XK protein leads to an absence of Kx antigens on red blood cells; the Kell antigen is also less prevalent. The absence of Kx antigen and reduction of Kell antigen is known as the "McLeod phenotype," and refers only to the red blood cells. It is not known how the lack of XK protein leads to the movement problems and other features of McLeod neuroacanthocytosis syndrome.

Inheritance

X-linked recessive inheritance

McLeod neuroacanthocytosis syndrome is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. Rarely, females with a mutation in one copy of the XK gene can have the characteristic misshapen blood cells and movement problems associated with McLeod neuroacanthocytosis syndrome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Signs and symptoms

This disorder affects movement in many parts of the body. People with McLeod neuroacanthocytosis syndrome also have abnormal star-shaped red blood cells (acanthocytosis). This condition is one of a group of disorders called neuroacanthocytoses that involve neurological problems and abnormal red blood cells.

McLeod neuroacanthocytosis syndrome affects the brain and spinal cord (central nervous system). Affected individuals have involuntary movements, including jerking motions (chorea), particularly of the arms and legs, and muscle tensing (dystonia) in the face and throat, which can cause grimacing and vocal tics (such as grunting and clicking noises). Dystonia of the tongue can lead to swallowing difficulties. Seizures occur in approximately half of all people with McLeod neuroacanthocytosis syndrome. Individuals with this condition may develop difficulty processing, learning, and remembering information (cognitive impairment). They may also develop psychiatric disorders, such as depression, bipolar disorder, psychosis, or obsessive-compulsive disorder.

People with McLeod neuroacanthocytosis syndrome also have problems with their muscles, including muscle weakness (myopathy) and muscle degeneration (atrophy). Sometimes, nerves that connect to muscles atrophy (neurogenic atrophy), leading to loss of muscle mass and impaired movement. Individuals with McLeod neuroacanthocytosis syndrome may also have reduced sensation and weakness in their arms and legs (peripheral neuropathy). Life-threatening heart problems such as irregular heartbeats (arrhythmia) and a weakened and enlarged heart (dilated cardiomyopathy) are common in individuals with this disorder.

Diagnosis

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).

Clinical Findings

CNS manifestations

• Progressive chorea syndrome similar to that seen in Huntington disease including the clinical triad of movement disorder, cognitive alterations, and psychiatric manifestations
• Seizures, mostly generalized

Neuromuscular manifestations

• Sensorimotor axonopathy
• Neurogenic muscle atrophy, including unexplained elevation of creatine phosphokinase
• Myopathy
• Cardiomyopathy

Echocardiography may demonstrate congestive cardiomyopathy or dilated cardiomyopathy . Electrocardiography (ECG) may demonstrate atrial fibrillation or tachyarrhythmia.

Family history consistent with X-linked inheritance

Laboratory/Electrophysiologic Findings In affected males the diagnosis of the McLeod blood group phenotype is based on the immunohematologic determination of absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigens using human anti-Kx and monoclonal anti-Kell antibodies, respectively . RBC acanthocytosis is found in virtually all males with MLS. Compensated hemolysis (i.e., hemolysis without anemia) is found in virtually all males with MLS. Neuromuscular studies Muscle enzymes. All males with MLS examined to date have had elevated serum creatine phosphokinase (CK) concentrations reaching values up to 4,000 U/L . Electromyography may demonstrate neurogenic and myopathic changes . Nerve conduction studies may demonstrate axonal damage of variable degree .

Muscle computed tomography (CT) may reveal a selective pattern of fatty degeneration of lower-leg muscles preferentially affecting the vastus lateralis, biceps femoris, and adductor magnus muscles, and sparing the gracilis, semitendinosus, and lateral head of the gastrocnemius muscle .

Central Nervous System Studies Neuroimaging In affected males, CT and [[]]magnetic resonance imaging (MRI) of the brain may demonstrate atrophy of the caudate nucleus and putamen of variable degree . Basal ganglia volumes are inversely correlated with disease duration. A follow-up study of three individuals with MLS over seven years using an automated subcortical segmentation procedure demonstrated decreasing caudate volumes . In two males with MLS, brain MRI demonstrated extended T2-weighted hyperintense white matter alterations

Treatment

There are currently no treatments to prevent or slow the progression of McLeod neuroacanthocytosis syndrome and treatment is symptomatic and supportive. Medications that block dopamine, such as some of the antipsychotics, may decrease the involuntary movements.

Botulinum toxin injections usually improve symptoms of dystonia. A feeding tube may be needed for individuals with feeding difficulties to maintain proper nutrition. Seizures may be treated with a variety of anticonvulsants, and antidepressants may also be appropriate for some individuals. Speech, occupational, and physical therapy may also be beneficial.

Prognosis

A typical patient with severe McLeod syndrome that begins in adulthood lives for an additional 5 to 10 years. Patients with cardiomyopathy have elevated risk for congestive heart failure and sudden cardiac death. The prognosis for a normal life span is often good in some patients with mild neurological or cardiac sequelae.

NIH genetic and rare disease info

• NIH info on McLeod neuroacanthocytosis syndrome

McLeod neuroacanthocytosis syndrome is a rare disease.

McLeod neuroacanthocytosis syndrome Resources
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