McLeod syndrome

McLeod syndrome (or McLeod phenomenon) is a genetic disorder that may affect the blood, brain, peripheral nerves, muscle and heart. It is caused by a variety of recessively-inherited mutations in the XK gene on the X chromosome. The gene is responsible for producing a specific protein (Kell antigen) on the red blood cell surface.

Clinical Features
Patients usually begin to notice symptoms in their 50s and the course is usually slowly progressive. Common features include peripheral neuropathy, cardiomyopathy and hemolytic anemia. Other features include limb chorea, facial tics, other oral movements (lip and tongue biting), seizures, a late-onset dementia and behavioral changes.

Laboratory Features
McLeod syndrome is one of three disorders in which acanthocytes may be found on the peripheral blood smear. Blood evaluation may show signs of hemolytic anemia. Elevated creatine kinase can be seen with myopathy in McLeod syndrome.

Radiologic and Pathologic Features
MRI shows increased T2 signal in the lateral putamen with caudate atrophy and secondary lateral ventricular dilation. Necropsy shows loss of neurons and gliosis in the caudate and globus pallidum. Similar changes may also be seen in the thalamus, substantia nigra and putamen. The cerebellum and cerebral cortex are generally spared.

History
McLeod syndrome was discovered in 1961 and, as with the Kell antigen system, was named after the first patient in which it was found: a Harvard dental student Hugh McLeod, whose red blood cells were observed to be hemolysed during blood donation, and his red cells were found to be acanthocytic (spiky) under the microscope.

Genetics
The McLeod phenotype is a recessive mutation of the Kell blood group system. The McLeod gene encodes the XK protein, which is located on the X chromosome, and has the structural characteristics of a membrane transport protein but an unknown function. Absence of the XK protein is an X-linked disease. Mutational variants result in McLeod syndrome either with or without neuroacanthocytosis: the gene on the X chromosome for McLeod syndrome is physically close to the gene for chronic granulomatous disease. As a result, individuals with one disease may have both.

Epidemiology and disease associations
McLeod syndrome is present in 0.5 to 1 per 100,000 of the population. McLeod males have variable acanthocytosis due to a defect in the inner leaflet bilayer of the red blood cell, as well as mild hemolysis. McLeod females have only occasional acanthocytes and very mild hemolysis; the lesser severity is thought to be due to X chromosome inactivation via the Lyon effect. Some individuals with McLeod phenotype develop myopathy, neuropathy or psychiatric symptoms, producing a syndrome that may mimic chorea.

McLeod syndrome can cause an increase in the enzymes creatine kinase (CK) and lactate dehydrogenase (LDH) found in routine blood screening.

Treatment
There is no cure for McLeod syndrome, but treatment is supportive depending on symptoms. Medication may assist management of epilepsy, cardiac and psychiatric features, although patients may respond poorly to treatment for chorea.