McLeod syndrome

Overview

McLeod syndrome is a rare, X-linked multisystem disorder that affects the nervous system, muscles, red blood cells, and sometimes the heart. It is characterized by a combination of movement abnormalities, cognitive decline, psychiatric disturbances, peripheral neuropathy, and hematologic findings such as acanthocytosis (spiky red blood cells). The syndrome is named after a unique red blood cell phenotype discovered in 1961 by Dr. Alexander McLeod.

McLeod syndrome is classified under neuroacanthocytosis syndromes—a group of inherited conditions involving neurological symptoms and red blood cell membrane abnormalities. The onset typically occurs in mid-adulthood, although symptoms may develop earlier or later. The disease is progressive and can significantly impair quality of life over time.

Causes

McLeod syndrome is caused by mutations or deletions in the XK gene located on the X chromosome (Xp21.1). The XK gene encodes the XK protein, which is involved in the expression of the Kell blood group antigens on red blood cells and is also expressed in brain and muscle tissue.

The condition is inherited in an X-linked recessive pattern:

• Males with a mutation in the XK gene are affected because they have only one X chromosome.

• Females who carry one mutated copy are typically asymptomatic but may exhibit mild symptoms or laboratory abnormalities due to skewed X-inactivation.

In some cases, McLeod syndrome may be associated with contiguous gene deletion syndromes involving neighboring genes, leading to additional symptoms such as chronic granulomatous disease.

Symptoms

McLeod syndrome affects multiple systems, and symptoms may vary widely between individuals. Onset typically occurs between the ages of 30 and 50. Common signs and symptoms include:

Neurological and Psychiatric Symptoms

• Chorea: Involuntary, irregular movements resembling those of Huntington’s disease

• Dystonia and tics

• Parkinsonism: Rigidity, bradykinesia, and postural instability

• Peripheral neuropathy: Numbness, tingling, or weakness in the extremities

• Seizures (in some cases)

• Cognitive decline: Memory loss, executive dysfunction, or dementia

• Behavioral and psychiatric symptoms: Depression, anxiety, paranoia, apathy, or personality changes

Muscle and Movement Disorders

• Muscle weakness and atrophy

• Facial muscle involvement: May lead to difficulty speaking or swallowing

Hematologic Features

• Acanthocytosis: Red blood cells with spiked membranes visible on blood smear

• Hemolytic anemia: In some patients, mild to moderate anemia may develop

Cardiac Involvement

• Cardiomyopathy: Enlargement or weakening of the heart muscle

• Arrhythmias: Irregular heartbeat that may lead to syncope or sudden cardiac death

Diagnosis

Diagnosing McLeod syndrome involves a combination of clinical, hematological, neurological, and genetic assessments. Diagnostic steps include:

• Blood smear: Shows acanthocytes (spiculated red blood cells), a hallmark feature

• Red cell antigen testing:

  • Demonstrates absence of the Kx antigen and weakened Kell antigens (McLeod blood phenotype)

• Electromyography (EMG) and nerve conduction studies:

  • Evaluate peripheral neuropathy and muscle involvement

• Brain imaging (MRI):

  • May reveal basal ganglia atrophy, similar to Huntington’s disease

• Neuropsychological testing: For assessing cognitive decline and psychiatric symptoms

• Genetic testing:

  • Confirmation via identification of mutations or deletions in the XK gene

• Cardiac evaluation:

  • Electrocardiogram (ECG) and echocardiogram to assess for cardiomyopathy or arrhythmias

Given its similarity to Huntington’s disease and other neurodegenerative disorders, McLeod syndrome is often underdiagnosed or misdiagnosed without specific laboratory and genetic testing.

Treatment

There is no cure for McLeod syndrome. Treatment focuses on managing symptoms, slowing progression, and maintaining quality of life. A multidisciplinary approach involving neurologists, cardiologists, hematologists, and psychiatrists is essential. Treatment strategies include:

Neurological and Psychiatric Management

• Antichorea medications (e.g., tetrabenazine) to control involuntary movements

• Antipsychotics or antidepressants for psychiatric symptoms

• Physical, occupational, and speech therapy for motor and communication difficulties

Cardiac Management

• Medications for cardiomyopathy or heart failure

• Implantable cardioverter defibrillator (ICD) in patients at risk of sudden cardiac death

Hematological Monitoring

• Routine monitoring for signs of anemia

• Avoidance of blood transfusions with Kell antigen-positive red cells due to alloimmunization risk

Supportive Care

• Psychological support and counseling

• Genetic counseling for family members, especially female carriers

Prognosis

McLeod syndrome is a progressive, degenerative disorder. The rate of progression and severity of symptoms vary between individuals. Key factors influencing prognosis include:

• Degree of neurological involvement and cognitive decline

• Presence and severity of cardiac complications

• Early diagnosis and proactive management of symptoms

While the disease shortens life expectancy in some cases, particularly with cardiac involvement, many individuals live for years with appropriate medical care and support. Continued research may lead to better understanding and targeted treatments in the future.