Neuroacanthocytosis
Encyclopedia
Neuroacanthocytosis is a term that refers to a group of genetically diverse conditions complicated by movement disorders, neurological problems and spiculated
(misshapen) red blood cells. These syndromes, which include chorea acanthocytosis
, McLeod syndrome
, Huntington’s disease–like 2 (HDL2), and
pantothenate kinase-associated neurodegeneration
(PKAN), primarily affect the brain and the basal ganglia
. The conditions are caused by genetic mutations of several different genes including, VPS13A
, XK, JPH3
and PANK2. The mutations are inherited through various genetic mechanisms.
Specific neurologic symptoms characterize these diseases. These symptoms may include: involuntary or slow movement; posture and skeletal related abnormalities; weakness; cognitive impairment; psychiatric symptoms; and other symptoms related to brain degeneration and movement difficulties. The disorders all have in common the presence of spiculated red blood cells, also known as spur cells, which are formally called acanthocytes.
The diseases are hereditary, but rare, and in some cases extremely rare, with insufficient data to draw conclusions about frequency of the mutation. Huntington's disease-like 2 has slightly higher ethnic prevalence in South Africans and there is gender prevalence in McLeod Syndrome with males being more susceptible to the disease than females. The other two do not show any ethnic or gender bias.
Four syndromes are classified as neuroacanthocytosis. These syndromes are caused by different genetic mutations, but the signs and symptoms are usually similar, leading to the unified classification as forms of neuroacanthocytosis.
, involuntary dance-like movement, is another very common symptom of neuroacanthocytosis. Affected individuals may also suffer from involuntary face and tongue movements, which can cause difficulties with speech and eating. These movements are usually abrupt and irregular and present during both rest and sleep.
Individuals with neuroacanthocytosis also usually suffer from parkinsonism
, the uncontrolled slowness of movements, and dystonia
, abnormal body postures. Patients may have difficulty walking due to muscle weakness and the involuntary and uncontrollable movement complications caused by parkinsonism and chorea. Most affected individuals also have cognitive (intellectual) impairment and psychiatric symptoms such as anxiety
, paranoia
, depression
, obsessive behavior, and pronounced emotional instability. Seizures may also be a symptom of neuroacanthocytosis.
in neuroacanthocytosis disorders. Medication may be administered to decreases the involuntary movements produced by these syndromes. Antipsychotics are used to block dopamine
, anticonvulsants treat seizures and botulinum toxin
injections may control dystonia. Patients usually receive speech, occupational
and physical
therapies to help with the complications associated with movement. Sometimes, physicians will prescribe antidepressant
s for the psychological problems that accompany neuroacanthocytosis.
that aggravate symptoms. Death usually occurs within five to ten years after the onset of severe symptoms. Cardiac and neurologic complications are the usual cause of death, but if patients do not develop such problems, their lifespan may be longer. The disease may worsen with poor nutrition and complications of movement disorders or associated psychological disorders.
The mutation that causes chorea acanthocytosis is passed in an autosomal recessive manner, meaning that both alleles of the gene must be mutated for the person to have the disease. If both parents are affected by chorea acanthocytosis, all of the children will also acquire the disease. However, both parents may remain unaffected and be carriers of the mutated gene (heterozygous for the trait, carrying one defective allele) and produce an affected child. The likelihood of this occurring is 25%.
The gene that determines whether or not a person has chorea acanthocytosis is known as VPS13A (CHAC gene) and is located on chromosome 9q21. When mutated, this gene causes chorea acanthocytosis in the affected individual. This mutation causes a small, nonfunctional form of the protein chorein to be produced. Many researchers believe that chorein is responsible for cell movement, but the actual function of this protein remains unknown.
There are about 500–1,000 cases of chorea acanthocytosis worldwide and it is not specific to any particular ethnic group.
and experience problems with vision loss. There is a classical version of PKAN and an atypical version in which onset occurs much later and is less severe. Pantothenate kinase-associated neurodegeneration was formerly known as Hallervorden-Spatz syndrome after two German neuropathologists but the term is no longer used because of the unethical activities these men participated in both before and during World War II.
The gene responsible for Pantothenate kinase-associated neurodegeneration is known as PANK2. This gene aids in producing the enzyme
pantothenate kinase 2 which is active in the mitochondria of cells. When active, pantothenate kinase 2 codes for coenzyme A
which is essential for production of energy inside the organism from carbohydrates, fats and amino acids. When PANK2 is mutated, pantothenate kinase 2 does not function properly and therefore does not produce a working version of coenzyme A, allowing dangerous materials (like iron) to build up inside the brain instead of being converted into energy. This causes the symptoms that are present in Pantothenate kinase-associated neurodegeneration to occur.
and idebenone
were shown to have worsened the symptoms of PKAN and should be avoided.
PKAN is very rare and is thought to be present in one to three people per one million worldwide and is not specific to any particular ethnic group.
(enlarged heart) are also commonly seen in individuals with this disease. Behaviorial changes are also an early indicator of McLeod syndrome.
McLeod syndrome is unique in that it is inherited in an X-linked recessive
manner. The mutated gene that causes McLeod syndrome is located on the X chromosome
. Males (only have one X-chromosome) who have the mutation will pass their affected X chromosome to all of their daughters and to none of their sons. Males only need one mutated copy of the gene to acquire McLeod syndrome. Women (have two X-chromosomes) on the other hand, need both copies of their X-chromosomes to contain the mutated gene to be affected by the disease. Therefore, women who are carriers (heterozygous) pass their mutated X-chromosome to their offspring 50% of the time. When their sons receive the mutated chromosome, they will be affected by McLeod syndrome because they only have one X chromosome. For the daughters to become affected, they must receive a mutated chromosome from both parents. Because of this, McLeod syndrome is much more prevalent in males than it is in females.
The mutated gene that causes McLeod syndrome is the XK gene located on the X-chromosome. This gene is responsible for producing the XK protein which carries the blood antigen Kx (Kell antigen). Mutations of this gene result in an abnormally short, nonfunctional form of the protein XK which leads to an absence of Kx antigens on red blood cells. This absence of the Kx antigen leads to the blood phenotype known as the “McLeod phenotype”. While the absence of the Kx antigen potentially causes many blood problems for the affected individual, such as potential blood transfusions, it remains unknown how the mutation of the XK gene leads to the other problems present in individuals with McLeod syndrome.
McLeod syndrome is very rare. There are approximately 150 cases of McLeod syndrome worldwide and it is much more prevalent in males due to its mode of inheritance.
The gene responsible for this disease is JPH3 which is located on chromosome 16q24.3. JPH3 is responsible for making the protein junctophilin-3. This protein is found in the brain and is thought to help form the junctional membrane complex. This complex is thought to be involved in the release of charged calcium ions, which is crucial in cell-cell signaling
, in this case specifically, neuron
signaling within the brain. The mutation of this gene is a series of CTG/CAG trinucleotide repeats causing a malfunctioning gene. A normal individual usually has between 6 and 27 of these repeats in the JPH3 gene. However, an individual affected with Huntington's disease-like 2 has between 41 and 58 trinucleotide repeats.
.
(becoming progressively worse as it is passed from generation to generation) is expected. An affected individual may live 10–20 years after onset of symptoms.
Huntington’s disease-like 2 is very rare, fewer than 25 pedigrees
and 40 affected individuals have been discovered. The syndrome is most prevalent in South Africans for unknown reasons.
, or Bassen-Kornzweig Syndrome, a rare congenital disorder in which the body failed to produce chylomicron
s, a low density lipoprotein
(LDL) and very low density lipoprotein (VLDL). Individuals with this condition are unable to properly digest fats. Symptoms include ataxia
, peripheral neuropathy
and other forms of nerve dysfunction. It was first noted by the North American physician
Frank Bassen
, who later partnered with the ophthalmologist Abraham Kornzweig
to identify and describe causes and symptoms of the disease.
Characteristics of the syndrome includes the presence of acanthocytes (burr-cell malformation of the erythrocytes), and the reduction or even absence of B-lipoproteins. Complications include retinitis pigmentosa
, degenerative changes in the central nervous system involving the cerebellum and long tracts, fatty diarrhea
, ataxia
, areflexia, demyelination, defective intestinal lipid absorption with low serum cholesterol level, intestinal malabsorption, amaurosis
, retarded growth, and steatorrhea
. Intellectual development may also be slightly retarded. Many afflicted with the syndrome are unable to walk. The syndrome appears in infancy. Affected children appear normal at birth but usually fail to thrive during their first year. The syndrome predominates in males (71%). Most cases occur in children of Jewish descent, especially among Ashkenazi Jews. The disease is transmitted in an autosomal recessive manner. It is also commonly recognized as abetalipoprotein deficiency or abetalipoproteinemia.
A second form of neuroacanthocytosis, Levine-Critchley syndrome, was discovered by the American internist Irvine M. Levine
in 1960. He described in Neurology in 1964, and again in 1968. Subsequently, similar symptoms were identified and described by the British neurologist MacDonald Critchley
in 1968. In both cases, the physicians described a hereditary syndrome that combined acanthocytosis with neurological peculiarities but normal serum lipoprotein. Various patterns of neurologic conditions were similar to Gille de la Tourette’s syndrome
, Huntington’s and chorea syndromes
, Friedreich’s syndrome
, and parkinsonism
. Specific symptoms included tics, grimacing, movement disorders, difficulty swallowing, poor coordination, hyporeflexia
, chorea, and seizures. Patients often mutilated their tongues, lips, and cheeks. The diseases appeared in both sexes, and were usually diagnosed in infancy.
may play a role in the symptoms of chorea.
The Advocacy for neuroacanthocytosis patients and leading medical schools co-sponsor international symposia annually to also aid in furthering the research that is being done. These symposiums are all endorsed by the Movement Disorder Society
and various other sponsors. The first symposium was held in 2002 and organized by a specialist in neuroacanthocytosis, Professor Adrian Danek in Seeon, Bavaria
.
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....
(misshapen) red blood cells. These syndromes, which include chorea acanthocytosis
Chorea acanthocytosis
Chorea-acanthocytosis , is a rare hereditary disease caused by a mutation of the gene that directs structural proteins in red blood cells. It belongs to a group of four diseases characterized under the name Neuroacanthocytosis. When a patient's blood is viewed under a microscope, some of the red...
, McLeod syndrome
McLeod syndrome
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...
, Huntington’s disease–like 2 (HDL2), and
pantothenate kinase-associated neurodegeneration
Pantothenate kinase-associated neurodegeneration
Pantothenate kinase-associated neurodegeneration , also known as neurodegeneration with brain iron accumulation 1 and formerly called Hallervorden-Spatz syndrome Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and...
(PKAN), primarily affect the brain and the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
. The conditions are caused by genetic mutations of several different genes including, VPS13A
VPS13A
Vacuolar protein sorting-associated protein 13A is a protein that in humans is encoded by the VPS13A gene.-External links:*...
, XK, JPH3
JPH3
Junctophilin-3 is a protein that in humans is encoded by the JPH3 gene.-External links:* -Further reading:...
and PANK2. The mutations are inherited through various genetic mechanisms.
Specific neurologic symptoms characterize these diseases. These symptoms may include: involuntary or slow movement; posture and skeletal related abnormalities; weakness; cognitive impairment; psychiatric symptoms; and other symptoms related to brain degeneration and movement difficulties. The disorders all have in common the presence of spiculated red blood cells, also known as spur cells, which are formally called acanthocytes.
The diseases are hereditary, but rare, and in some cases extremely rare, with insufficient data to draw conclusions about frequency of the mutation. Huntington's disease-like 2 has slightly higher ethnic prevalence in South Africans and there is gender prevalence in McLeod Syndrome with males being more susceptible to the disease than females. The other two do not show any ethnic or gender bias.
Classification
| Neuroacanthocytosis disease group | |||||
|---|---|---|---|---|---|
| Disease | Mutation | Inheritance | |||
| Chorea acanthocytosis Chorea acanthocytosis Chorea-acanthocytosis , is a rare hereditary disease caused by a mutation of the gene that directs structural proteins in red blood cells. It belongs to a group of four diseases characterized under the name Neuroacanthocytosis. When a patient's blood is viewed under a microscope, some of the red... |
VPS13A (CHAC gene) | autosomal recessive | |||
| McLeod syndrome McLeod syndrome 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... |
XK gene on X-chromosome | X-linked recessive | |||
| Huntington’s disease–like 2 | JPH3 | autosomal dominant |- |
Pantothenate kinase-associated neurodegeneration Pantothenate kinase-associated neurodegeneration Pantothenate kinase-associated neurodegeneration , also known as neurodegeneration with brain iron accumulation 1 and formerly called Hallervorden-Spatz syndrome Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and... |
PANK2 | autosomal recessive |
Four syndromes are classified as neuroacanthocytosis. These syndromes are caused by different genetic mutations, but the signs and symptoms are usually similar, leading to the unified classification as forms of neuroacanthocytosis.
Signs and symptoms
Signs and symptoms of a neuroacanthocytosis diseases may vary slightly from case to case but usually include several predominant symptoms. The hallmark feature of a neuroacanthocytosis disease is the presence of Acanthocytes. Acanthocytosis originated from the Greek word acantha, meaning thorn. Acanthocytes are spiculated red blood cells and can be caused by altered distribution of membrane lipids or membrane protein/skeleton abnormalities. In neuroacanthocytosis, acanthocytes are caused by skeleton abnormalities in the membrane of the cells that are affected, causing them to take on a spiculated shape while the lipids in the cell membrane have no abnormalities. ChoreaChorea (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...
, involuntary dance-like movement, is another very common symptom of neuroacanthocytosis. Affected individuals may also suffer from involuntary face and tongue movements, which can cause difficulties with speech and eating. These movements are usually abrupt and irregular and present during both rest and sleep.
Individuals with neuroacanthocytosis also usually suffer from parkinsonism
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
, the uncontrolled slowness of movements, and dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
, abnormal body postures. Patients may have difficulty walking due to muscle weakness and the involuntary and uncontrollable movement complications caused by parkinsonism and chorea. Most affected individuals also have cognitive (intellectual) impairment and psychiatric symptoms such as anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, paranoia
Paranoia
Paranoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
, depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, obsessive behavior, and pronounced emotional instability. Seizures may also be a symptom of neuroacanthocytosis.
Onset
The onset of a neuroacanthocytosis disease is usually between ages 20 and 40 with an average onset of symptoms occurring at age 32. However, symptoms may occur as early as age ten in some individuals with atypical versions of the disease. Affected individuals usually live for 10–20 years after onset occurs but complications from other illnesses can reduce their lifespan even more.Management
Currently, no treatment slows the neurodegenerationNeurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
in neuroacanthocytosis disorders. Medication may be administered to decreases the involuntary movements produced by these syndromes. Antipsychotics are used to block dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, anticonvulsants treat seizures and botulinum toxin
Botulinum toxin
Botulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is considered the most powerful neurotoxin ever discovered. Botulinum toxin causes Botulism poisoning, a serious and life-threatening illness in humans and animals...
injections may control dystonia. Patients usually receive speech, occupational
Occupational therapy
Occupational therapy is a discipline that aims to promote health by enabling people to perform meaningful and purposeful activities. Occupational therapists work with individuals who suffer from a mentally, physically, developmentally, and/or emotionally disabling condition by utilizing treatments...
and physical
Physical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
therapies to help with the complications associated with movement. Sometimes, physicians will prescribe antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s for the psychological problems that accompany neuroacanthocytosis.
Prognosis
Neuroacanthocytosis is a progressive disease in which patients usually develop significant cardiac or neurologic complications. They also become prone to such ancillary illnesses as pneumoniaPneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
that aggravate symptoms. Death usually occurs within five to ten years after the onset of severe symptoms. Cardiac and neurologic complications are the usual cause of death, but if patients do not develop such problems, their lifespan may be longer. The disease may worsen with poor nutrition and complications of movement disorders or associated psychological disorders.
Chorea acanthocytosis
Chorea acanthocytosis is a disease that affects movement in many parts of the body. The symptoms are mostly consistent with the symptoms prevalent in neuroacanthocytosis disorders, also, many people with chorea acanthocytosis uncontrollably bite their tongue, lips, and the inside of the mouth. Behaviorial changes are an early indicator of chorea acanthocytosis.Characteristics
Chorea acanthocytosis is diagnosed in individuals with the following manifestations:- Progressive dystonia
- Tongue protrusion and tongue and lip biting
- Progressive cognitive and behavioral changes
- Progressive myopathyMyopathyIn 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...
(muscle damage) characterized by muscle wasting (inability to properly use muscles) and weakness - Eye movement abnormalities
- Acanthocytosis
- Since chorea acanthocytosis is an autosomal recessive disorder, positive family history for chorea acanthocytosis will confirm the diagnosis.
Genetics
The gene that determines whether or not a person has chorea acanthocytosis is known as VPS13A (CHAC gene) and is located on chromosome 9q21. When mutated, this gene causes chorea acanthocytosis in the affected individual. This mutation causes a small, nonfunctional form of the protein chorein to be produced. Many researchers believe that chorein is responsible for cell movement, but the actual function of this protein remains unknown.
Management
- Botulinum toxinBotulinum toxinBotulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is considered the most powerful neurotoxin ever discovered. Botulinum toxin causes Botulism poisoning, a serious and life-threatening illness in humans and animals...
injections (Botox) to reduce dystonia - Mechanical protective devices (such as mouth guards) for tongue and lips
- AnticonvulsantAnticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
drugs for seizure control - Antipsychotics are prescribed for psychiatric problems
- Dopamine antagonists are prescribed (but should be heavily monitored) to patients to suppress involuntary movement
Epidemiology
The appearance of symptoms in chorea acanthocytosis usually appear in early to mid-adulthood. The first sign of chorea acanthocytosis is often behavioral changes that result in personality changes, obsessive compulsive disorder (OCD), and the inability to take care of oneself. These continue on throughout the individual's life and movement complications beginning in early-adulthood worsen with age.There are about 500–1,000 cases of chorea acanthocytosis worldwide and it is not specific to any particular ethnic group.
Pantothenate kinase-associated neurodegeneration
Pantothenate kinase-associated neurodegeneration (PKAN) is a disease characterized by brain iron accumulation and progressive difficulty with movement. The symptoms of this disease are mostly consistent with the general symptoms of neuroacanthocytosis disorders. The affected individual may develop dementiaDementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
and experience problems with vision loss. There is a classical version of PKAN and an atypical version in which onset occurs much later and is less severe. Pantothenate kinase-associated neurodegeneration was formerly known as Hallervorden-Spatz syndrome after two German neuropathologists but the term is no longer used because of the unethical activities these men participated in both before and during World War II.
Characteristics
Individuals are diagnosed with Pantothenate kinase-associated neurodegeneration when they have the following manifestations:- Dystonia and rigidity of movements
- Loss of ambulation (occurring within 15 years after onset)
- Eye of the tiger’s sign seen on an MRI caused by excess iron deposition in the globus pallidusGlobus pallidusThe 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...
(spherical section of the brain) - Retinal degeneration
- Corticospinal tractCorticospinal tractThe corticospinal or pyramidal tract is a collection of axons that travel between the cerebral cortex of the brain and the spinal cord....
damage - Acanthocytosis
- Family history of PKAN
Genetics
Pantothenate kinase-associated neurodegeneration is inherited in an autosomal recessive pattern meaning that both copies of the gene in an individual must be mutated for the person to be affected by the disease. This means that if both parents are affected, all of the children will acquire the disease as well. However, if both parents are carriers of the disease (heterozygous for the trait, have one mutated copy) and are not affected by PKAN, there is a 25% chance that their child will acquire the disease.The gene responsible for Pantothenate kinase-associated neurodegeneration is known as PANK2. This gene aids in producing the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
pantothenate kinase 2 which is active in the mitochondria of cells. When active, pantothenate kinase 2 codes for coenzyme A
Coenzyme A
Coenzyme A is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...
which is essential for production of energy inside the organism from carbohydrates, fats and amino acids. When PANK2 is mutated, pantothenate kinase 2 does not function properly and therefore does not produce a working version of coenzyme A, allowing dangerous materials (like iron) to build up inside the brain instead of being converted into energy. This causes the symptoms that are present in Pantothenate kinase-associated neurodegeneration to occur.
Prevention
There are no known prevention methods for Pantothenate kinase-associated neurodegeneration but certain drugs such as alpha-tocopherolAlpha-tocopherol
α-Tocopherol is a type of tocopherol with formula C29H50O2. It has E number "E307".α-Tocopherol is a form of vitamin E that is preferentially absorbed and accumulated in humans...
and idebenone
Idebenone
Idebenone is an experimental drug, initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of...
were shown to have worsened the symptoms of PKAN and should be avoided.
Management
Most of the treatment for Pantothenate kinase-associated neurodegeneration is aimed at suppressing dystonia. Measures taken to aid in this process are as follows:- Botulinum toxin
- Ablative pallidotomy or thalamotomyThalamotomyFirst introduced in the 1950s, thalamotomy is an invasive procedure, primarily effective for tremors such as those associated with Parkinson's Disease , where a selected portion of the thalamus is surgically destroyed...
which are both surgical procedures to help suppress symptoms - Deep brain stimulation
- Oral doses of drugs that help to relax muscles such as baclofenBaclofenBaclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
and trihexyphenidylTrihexyphenidylTrihexyphenidyl , also known as benzhexol, is an antiparkinsonian agent of the antimuscarinic class. It has been in clinical usage for decades...
Epidemiology
Pantothenate kinase-associated neurodegeneration usually appears before the age of ten but about 25% of affected individuals have an onset that is atypical (after the age of ten) with a more gradual progression of the disease.PKAN is very rare and is thought to be present in one to three people per one million worldwide and is not specific to any particular ethnic group.
McLeod syndrome
McLeod syndrome is a neurodegenerative disease characterized by movement disorder, cognitive impairment and psychiatric symptoms. Movement in many parts of the body is impaired by this syndrome. The symptoms are mostly consistent with the general symptoms for neuroacanthocytosis disorders. Heart problems such as arrhythmia and dilated cardiomyopathyDilated cardiomyopathy
Dilated cardiomyopathy or DCM is a condition in which the heart becomes weakened and enlarged and cannot pump blood efficiently. The decreased heart function can affect the lungs, liver, and other body systems....
(enlarged heart) are also commonly seen in individuals with this disease. Behaviorial changes are also an early indicator of McLeod syndrome.
Characteristics
McLeod syndrome is diagnosed in individuals with the following manifestations:- McLeod blood group phenotype
- Family history of McLeod syndrome
- Central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
manifestations such as seizures - Neuromuscular manifestations such as myopathy
- Dilated cardiomyopathy and arrhythmias
- Acanthocytosis
Genetics
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
manner. The mutated gene that causes McLeod syndrome 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...
. Males (only have one X-chromosome) who have the mutation will pass their affected X chromosome to all of their daughters and to none of their sons. Males only need one mutated copy of the gene to acquire McLeod syndrome. Women (have two X-chromosomes) on the other hand, need both copies of their X-chromosomes to contain the mutated gene to be affected by the disease. Therefore, women who are carriers (heterozygous) pass their mutated X-chromosome to their offspring 50% of the time. When their sons receive the mutated chromosome, they will be affected by McLeod syndrome because they only have one X chromosome. For the daughters to become affected, they must receive a mutated chromosome from both parents. Because of this, McLeod syndrome is much more prevalent in males than it is in females.
The mutated gene that causes McLeod syndrome is the XK gene located on the X-chromosome. This gene is responsible for producing the XK protein which carries the blood antigen Kx (Kell antigen). Mutations of this gene result in an abnormally short, nonfunctional form of the protein XK which leads to an absence of Kx antigens on red blood cells. This absence of the Kx antigen leads to the blood phenotype known as the “McLeod phenotype”. While the absence of the Kx antigen potentially causes many blood problems for the affected individual, such as potential blood transfusions, it remains unknown how the mutation of the XK gene leads to the other problems present in individuals with McLeod syndrome.
Management
Various medicines are prescribed to patients such as;- Dopamine antagonists are prescribed to patients to suppress involuntary movement
- Antipsychotics are prescribed for psychiatric problems
- Anti-epileptic drugs for treating seizures
Epidemiology
The appearance of symptoms in McLeod syndrome usually appear in early to mid-adulthood beginning with behavioral changes and movement difficulties that worsen with age.McLeod syndrome is very rare. There are approximately 150 cases of McLeod syndrome worldwide and it is much more prevalent in males due to its mode of inheritance.
Huntington's disease-like 2
Huntington’s disease-like 2 syndrome is a disease that resembles Huntington’s disease and that occurs in people with characteristic features of Huntington’s disease without the mutation in the gene associated with the disorder, HD. It belongs to a family of four Huntington’s disease-like syndromes. Huntington’s disease-like 2 is a neurodegenerative disease that effects movement, cognitive and emotional impairment. It is consistent with many of the general symptoms of neuroacanthocytosis.Characteristics
Molecular genetic testing (DNA tests) must be done to diagnose a person with Huntington’s disease-like 2 because clinical diagnosis is not enough. Individuals that are to be tested usually have symptoms that are similar to Huntington’s disease or who have a family history of Huntington’s disease-like syndromes.Genetics
Huntington’s disease-like 2 is inherited in an autosomal dominant manner. Because it is autosomal dominant, only one copy of the gene needs to be mutated for the individual to be affected by the disease. At least one parent must be affected to have an affected child.If both parents are heterozygous (each have one affected copy of the gene and one normal copy) then there is a 75% chance that their children will acquire the disease.The gene responsible for this disease is JPH3 which is located on chromosome 16q24.3. JPH3 is responsible for making the protein junctophilin-3. This protein is found in the brain and is thought to help form the junctional membrane complex. This complex is thought to be involved in the release of charged calcium ions, which is crucial in cell-cell signaling
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
, in this case specifically, neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
signaling within the brain. The mutation of this gene is a series of CTG/CAG trinucleotide repeats causing a malfunctioning gene. A normal individual usually has between 6 and 27 of these repeats in the JPH3 gene. However, an individual affected with Huntington's disease-like 2 has between 41 and 58 trinucleotide repeats.
Prevention
There are no known prevention methods to slow the progression of HDL2. Certain measures should be taken to prevent falls and other injuries that may be common due to the movement difficulties for the affected individual. Examples of this are removing items such as loose rugs and clutter from the individual's space and monitoring nutrition and swallowing to prevent aspirationPulmonary aspiration
Pulmonary aspiration is the entry of material from the oropharynx or gastrointestinal tract into the larynx and lower respiratory tract...
.
Management
Because Huntington’s disease-like 2 is very rare, treatment is solely based and built upon the treatments for Huntington’s disease and other neurodegenerative disorders. The main forms of treatment are;- Medications to suppress abnormal movements
- Antidepressants, antipsychotics, and mood stimulants are used to treat the psychiatric manifestations
- Education about the disease can reduce stress and guilt in the patient and family
Epidemiology
Huntington’s disease-like 2 usually appears around midlife but anticipationAnticipation (genetics)
In genetics, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders such as...
(becoming progressively worse as it is passed from generation to generation) is expected. An affected individual may live 10–20 years after onset of symptoms.
Huntington’s disease-like 2 is very rare, fewer than 25 pedigrees
Pedigree chart
A pedigree chart is a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next, most commonly humans, show dogs, and race horses....
and 40 affected individuals have been discovered. The syndrome is most prevalent in South Africans for unknown reasons.
History
Neuroacanthocytosis was first identified in 1950 as Bassen-Kornzweig diseaseAbetalipoproteinemia
Abetalipoproteinemia, or Bassen-Kornzweig syndrome, is a rare autosomal recessive disorder that interferes with the normal absorption of fat and fat-soluble vitamins from food. It is caused by a deficiency of apolipoprotein B-48 and B-100, which are used in the synthesis and exportation of...
, or Bassen-Kornzweig Syndrome, a rare congenital disorder in which the body failed to produce chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
s, a low density lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
(LDL) and very low density lipoprotein (VLDL). Individuals with this condition are unable to properly digest fats. Symptoms include ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, peripheral neuropathy
Peripheral 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....
and other forms of nerve dysfunction. It was first noted by the North American physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
Frank Bassen
Frank Bassen
Frank Albert Bassen, , practiced as a haematologist and internist in New York, 1933–1978, in affiliation with Mount Sinai Hospital. He was born 14 November 1903 in St. George, New Brunswick, Canada and graduated from McGill University. He emigrated to the United States via Vanceboro, Maine, in 1928...
, who later partnered with the ophthalmologist Abraham Kornzweig
Abraham Kornzweig
Abraham Leon Kornzweig, , born in New York, a physician and ophthalmologist specializing in geriatric ophthalmology. He opened a new field in investigative medicine, and founded the Society of Geriatric Ophthalmology. He was also widely known as the co-discoverer and namer of Bassen-Kornzweig...
to identify and describe causes and symptoms of the disease.
Characteristics of the syndrome includes the presence of acanthocytes (burr-cell malformation of the erythrocytes), and the reduction or even absence of B-lipoproteins. Complications include retinitis pigmentosa
Retinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
, degenerative changes in the central nervous system involving the cerebellum and long tracts, fatty diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, areflexia, demyelination, defective intestinal lipid absorption with low serum cholesterol level, intestinal malabsorption, amaurosis
Amaurosis
Amaurosis is vision loss or weakness that occurs without an apparent lesion affecting the eye. It may result from either a medical condition or from excess acceleration, as in flight...
, retarded growth, and steatorrhea
Steatorrhea
Steatorrhea is the presence of excess fat in feces. Stools may also float due to excess lipid, have an oily appearance and be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may occur. There is increased fat excretion, which can be measured by determining the...
. Intellectual development may also be slightly retarded. Many afflicted with the syndrome are unable to walk. The syndrome appears in infancy. Affected children appear normal at birth but usually fail to thrive during their first year. The syndrome predominates in males (71%). Most cases occur in children of Jewish descent, especially among Ashkenazi Jews. The disease is transmitted in an autosomal recessive manner. It is also commonly recognized as abetalipoprotein deficiency or abetalipoproteinemia.
A second form of neuroacanthocytosis, Levine-Critchley syndrome, was discovered by the American internist Irvine M. Levine
Irvine M. Levine
Irvine M. Levine first discovered Levine-Critchley syndrome in 1960. He is an American physician and described his findings in Neurology in 1964 and again in 1968.-References:...
in 1960. He described in Neurology in 1964, and again in 1968. Subsequently, similar symptoms were identified and described by the British neurologist MacDonald Critchley
MacDonald Critchley
Macdonald Critchley CBE was a British neurologist. He was former president of the World Federation of Neurology, and the author of over 200 published articles on neurology and 20 books, including The Parietal Lobes , Aphasiology, and biographies of James Parkinson and Sir William Gowers.Macdonald...
in 1968. In both cases, the physicians described a hereditary syndrome that combined acanthocytosis with neurological peculiarities but normal serum lipoprotein. Various patterns of neurologic conditions were similar to Gille de la Tourette’s syndrome
Tourette syndrome
Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...
, Huntington’s and chorea syndromes
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
, Friedreich’s syndrome
Friedreich's ataxia
Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system, resulting in symptoms ranging from gait disturbance to speech problems; it can also lead to heart disease and diabetes....
, and parkinsonism
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
. Specific symptoms included tics, grimacing, movement disorders, difficulty swallowing, poor coordination, hyporeflexia
Hyporeflexia
Hyporeflexia is the condition of below normal or absent reflexes. It can be tested for by using a reflex hammer. It is the opposite of hyperreflexia....
, chorea, and seizures. Patients often mutilated their tongues, lips, and cheeks. The diseases appeared in both sexes, and were usually diagnosed in infancy.
Research
There is research being done by the NINDS to increase scientific understanding of these disorders as well to identify prevention and treatment methods. The genetic mutations of some of the diseases have been identified and are being studied as well. Researchers suspect that the basal gangliaBasal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
may play a role in the symptoms of chorea.
The Advocacy for neuroacanthocytosis patients and leading medical schools co-sponsor international symposia annually to also aid in furthering the research that is being done. These symposiums are all endorsed by the Movement Disorder Society
The Movement Disorder Society
The Movement Disorder Society is an international professional society of clinicians, scientists, and other healthcare professionals who are interested in Parkinson's disease, related neurodegenerative and neurodevelopmental disorders, hyperkinetic Movement Disorders and abnormalities in muscle...
and various other sponsors. The first symposium was held in 2002 and organized by a specialist in neuroacanthocytosis, Professor Adrian Danek in Seeon, Bavaria
Bavaria
Bavaria, formally the Free State of Bavaria is a state of Germany, located in the southeast of Germany. With an area of , it is the largest state by area, forming almost 20% of the total land area of Germany...
.
External links
- Neuroacanthocytosis information and research. Online Newsletter.
- Neurologic Disorders Index, National Institutes of Health.
- Healthwise. CIGNA.