McLeod syndrome
Encyclopedia
McLeod syndrome 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.
, 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.
s 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.
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
. Similar changes may also be seen in the thalamus
, substantia nigra
and putamen. The cerebellum
and cerebral cortex
are generally spared.
, was named after the first patient in which it was found: a Harvard dental student Hugh McLeod, whose red blood cell
s were observed to have weak expression of Kell system antigens during blood donation
, and his red cells were found to be acanthocytic
(spiky) under the microscope.
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.
The phenotype may be present without the syndrome presenting.
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.
, the main patient of the Season 7 episode "You Must Remember This
" is ultimately diagnosed with this condition.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that may affect the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, peripheral nerves, muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
and heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
. It is caused by a variety of recessively-inherited mutations in the XK gene
XK (protein)
XK is a protein found on human red blood cells and other tissues which is responsible for the Kx antigen which helps determine a person's blood type.-Clinical significance:...
on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
. The gene is responsible for producing a specific protein (Kell antigen) on the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
surface.
Clinical features
Patients usually begin to notice symptoms in their 50s and the course is usually slowly progressive. Common features include peripheral neuropathyPeripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
and hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
. Other features include limb chorea
Chorea (disease)
Choreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία , see choreia , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term...
, facial tics, other oral movements (lip and tongue biting), seizures, a late-onset dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
and behavioral changes.
Laboratory features
McLeod syndrome is one of only a few disorders in which acanthocyteAcanthocyte
Acanthocyte, in human biology and medicine, refers to a form of red blood cell that are spiked, or possess various abnormal thorny projections. Acanthocytosis is the condition with acanthocyte-like red blood cells....
s may be found on the peripheral blood smear
Blood film
A blood film or peripheral blood smear is a thin layer of blood smeared on a microscope slide and then stained in such a way to allow the various blood cells to be examined microscopically...
. Blood evaluation may show signs of hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
. Elevated creatine kinase
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
can be seen with myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
in McLeod syndrome.
Radiologic and pathologic features
MRI shows increased T2Thoracic spinal nerve 2
The thoracic spinal nerve 2 is a spinal nerve of the thoracic segment..It originates from the spinal column from below the thoracic vertebra 2 ....
signal in the lateral putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
with caudate
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
atrophy and secondary lateral ventricular
Lateral ventricles
The lateral ventricles are part of the ventricular system of the brain. Classified as part of the telencephalon, they are the largest of the ventricles....
dilation. Necropsy shows loss of neurons and gliosis
Gliosis
Gliosis is a proliferation of astrocytes in damaged areas of the central nervous system . This proliferation usually leads to the formation of a glial scar....
in the caudate and globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
. Similar changes may also be seen in the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
and putamen. The cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
and cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
are generally spared.
History
McLeod syndrome was discovered in 1961 and, as with the Kell antigen systemKell antigen system
The Kell antigen system 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 alloimmune diseases which destroy red blood cells. Kell can be noted as K, k, or Kp...
, was named after the first patient in which it was found: a Harvard dental student Hugh McLeod, whose red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s were observed to have weak expression of Kell system antigens during blood donation
Blood donation
A blood donation occurs when a person voluntarily has blood drawn and used for transfusions or made into medications by a process called fractionation....
, and his red cells were found to be acanthocytic
Acanthocyte
Acanthocyte, in human biology and medicine, refers to a form of red blood cell that are spiked, or possess various abnormal thorny projections. Acanthocytosis is the condition with acanthocyte-like red blood cells....
(spiky) under the microscope.
Genetics
The McLeod phenotype is a recessive mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of the Kell blood group system
Kell antigen system
The Kell antigen system 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 alloimmune diseases which destroy red blood cells. Kell can be noted as K, k, or Kp...
. The McLeod gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encodes the XK protein
XK (protein)
XK is a protein found on human red blood cells and other tissues which is responsible for the Kx antigen which helps determine a person's blood type.-Clinical significance:...
, which is located on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, and has the structural characteristics of a membrane transport
Membrane transport
In cellular biology the term membrane transport refers to the collection of mechanisms that regulate the passage of solutes such as ions and small molecules through biological membranes namely lipid bilayers that contain proteins embedded in them...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
but an unknown function. Absence of the XK protein is an X-linked disease
Sex linkage
Sex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance...
.
Mutational variants result in McLeod syndrome either with or without neuroacanthocytosis
Neuroacanthocytosis
Neuroacanthocytosis is a term that refers to a group of genetically diverse conditions complicated by movement disorders, neurological problems and spiculated red blood cells...
: the gene on the X chromosome for McLeod syndrome is physically close to the gene for chronic granulomatous disease
Chronic granulomatous disease
Chronic granulomatous disease is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens...
. As a result, individuals with one disease may have both.
The phenotype may be present without the syndrome presenting.
Epidemiology and disease associations
McLeod syndrome is present in 0.5 to 1 per 100,000 of the population. McLeod males have variable acanthocytosisAcanthocyte
Acanthocyte, in human biology and medicine, refers to a form of red blood cell that are spiked, or possess various abnormal thorny projections. Acanthocytosis is the condition with acanthocyte-like red blood cells....
due to a defect in the inner leaflet bilayer of the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
, as well as mild hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
. McLeod females have only occasional acanthocytes and very mild hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
; the lesser severity is thought to be due to X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
inactivation via the Lyon effect. Some individuals with McLeod phenotype develop myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
, neuropathy or psychiatric symptoms, producing a syndrome that may mimic chorea
Chorea (disease)
Choreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία , see choreia , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term...
.
McLeod syndrome can cause an increase in the enzymes creatine kinase
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
(CK) and lactate dehydrogenase
Lactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
(LDH) found in routine blood screening.
Treatment
There is no cure for McLeod syndrome, the 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.Pop culture
In the episode of popular TV series HouseHouse (TV series)
House is an American television medical drama that debuted on the Fox network on November 16, 2004. The show's central character is Dr. Gregory House , an unconventional and misanthropic medical genius who heads a team of diagnosticians at the fictional Princeton-Plainsboro Teaching Hospital in...
, the main patient of the Season 7 episode "You Must Remember This
You Must Remember This (House)
"You Must Remember This" is the twelfth episode of the seventh season of the American medical drama House. It aired on February 14, 2011.-Plot:...
" is ultimately diagnosed with this condition.