McLeod syndrome (pronounced ) is an X-linked recessive genetic disorder that may affect the blood, brain, peripheral nerves,

muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

, 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 the Kx protein, a secondary supportive protein for the

Kell antigen The Kell antigen system (also known as the Kell–Cellano system) is a human blood group system, that is, a group of antigens on the human red blood cell surface which are important determinants of blood type and are targets for autoimmune or al ...

on the red blood cell surface.

Presentation

Patients usually begin to notice symptoms in their 50s and the course is usually slowly progressive. Common features include peripheral neuropathy,

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

, 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.

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 In cellular biology, membrane transport refers to the collection of mechanisms that regulate the passage of solutes such as ions and small molecules through biological membranes, which are lipid bilayers that contain proteins embedded in them. Th ...

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, an individual with one relatively small deletion may have both diseases. The phenotype may be present without the syndrome presenting.

Diagnosis

Laboratory features

McLeod syndrome is one of only a few 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 medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...

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 pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rod ...

. Similar changes may also be seen in the thalamus,

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...

, and putamen. The

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...

and cerebral cortex are generally spared.

Treatment

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

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.

Epidemiology

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 X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into ...

. Some individuals with McLeod phenotype develop

neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...

, 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.

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:

Harvard Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher le ...

dental student Hugh McLeod, whose red blood cells were observed to have weak expression of Kell system antigens during

blood donation A blood donation occurs when a person voluntarily has blood drawn and used for blood transfusion, transfusions and/or made into biopharmaceutical medications by a process called Blood fractionation, fractionation (separation of whole blood com ...

, and found to be acanthocytic (spiky) under the microscope. The wives of King Henry VIII of England show a pattern of pregnancies and infant deaths, which with his mental deterioration suggest that the king may have been Kell positive and have had McLeod syndrome.

References

External links

GeneReview/NIH/UW entry on McLeod Neuroacanthocytosis Syndrome
{{DEFAULTSORT:Mcleod Syndrome Red blood cell disorders Syndromes affecting the nervous system X-linked recessive disorders Cardiogenetic disorders Neurogenetic disorders Syndromes affecting the heart Syndromes affecting blood Rare syndromes