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Neuroacanthocytosis is a general term that refers to a group of genetically similar conditions complicated by movement disorders, neurological problems and acanthocytes. These include Chorea Acanthocytosis, McLeod Syndrome, Huntington’s Disease–like 2 (HDL2), and Pantothenate kinase-associated neurodegeneration (PKAN). The conditions are caused by various genetic mutations of several different genes including, VPS13A, XK, JPH3 and PANK2.

Specific neurologic symptoms characterize these diseases, although these symptoms may vary, including involuntary or slow movement, posture and skeletal related abnormalities, weakness, cognitive impairment, and psychiatric symptoms, as well as other related symptoms. The disorders all have in common the presence of Acanthocytes, also known as spur cells, which are are spiculated red blood cells.

Neuroacanthocytosis was first discovered in the form of Bassen-Kornsweig disease in 1950. A second form of neuroacanthocytosis was then discovered by Levine in 1960 and Critchley in 1968 and resembled Huntington's Disease. The diseases are hereditary, but rare, and in some cases extremely rare, with insufficient data to draw conclusions about frequency. Huntington's disease-like 2 has slight ethnic prevalence favoring South Africans and there is gender prevalence in McLeod Syndrome with males being more susceptible to the disease over females.

History

Although there are four main disease that are considered to be forms of neuroacanthocytosis, there are many other syndromes that resemble neuroacanthocytosis, making it difficult to classify these diseases. Because of gradually accumulating knowledge of neuroacanthocytosis and similar diseases, the general subset of neuroacanthocytosis has been frequently changed over time. The first believed form of neuroacanthocytosis was discovered in 1950 and was entitled Bassen-Kornsweig syndrome, after its founders, Frank Bassen and Abraham Kornzweig, also known as abetalipoproteinemia. The disease is very similar to the subset of diseases known as neuroacanthocytosis because it also has symptoms of acanthocytes. However, the disease was later better understood and described as a form of Friedreich ataxia because it is very similar to this disease except for having acanthocytes.

The second disease that was found and considered neuroacanthocytosis is known as Levine- Critchley Syndrome. It first was discovered by Levine in 1960 and then again by Critchley in 1986. Neuroacanthocytosis is sometimes referred to as Levine-Critchley syndrome because the subset of four diseases that make up neuroacanthocytosis are very similar phenotypically to Levine-Critchley syndrome. They are characterized by movement and neurological disorders and acanthocytes.

General Symptoms & Complications

Signs and symptoms of a neuroacanthocytosis diseases may slightly vary from case to case but usually include several predominant symptoms. The hallmark feature of a neuroacanthocytosis disease is the presence of Acanthocytosis. Acanthocytosis is 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. Chorea is another very common symptom of neuroacanthocytosis. Chorea is involuntary dance-like movements that patients who suffer from neuroacanthocytosis cannot control. Affected individuals may also suffer from involuntary face and tongue movements as well which can cause difficulties with speech and eating. These movements are usually abrupt and irregular and present during rest and sleep. Individuals with neuroacanthocytosis also usually suffer from parkinsonism which is uncontrolled slowness of movements and dystonia which is 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 impairment and psychiatric symptoms. Seizures may also be a symptom of neuroacanthocytosis.

Prognosis

Neuroacanthocytosis is progressive and often fatal, with death usually occurring 5-10 years after a severe onset. However, if affected individuals do not develop significant cardiac or neurologic complications, the lifespan may be longer. The disease may become more complicated with poor nutrition and pneumonia.

Onset

The onset of a neuroacanthocytosis disease is usually between ages 20 and 40 and the average age of onset is 32. However, onset may occur as early as age 10. Affected individuals usually live for 10-20 years after onset.

Treatment

There is currently no treatment to slow the neurodegeneration in neuroacanthocytosis disorders. However, medication may be given to decreases the involuntary movements produced by these syndromes. These medications, like many antipsychotics, work by blocking dopamine. Anticonvulsants are used to treat seizures and Botulinium toxin injections are used to control dystonia. Therapy (speech, occupational, and physical) and antidepressants may be beneficial for these individuals as well.

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. The role of basal ganglia with respect to the chorea symptoms is also being researched.

Neuroacanthocytosis Diseases

Four syndromes are classified as neuroacanthocytosis. These syndromes are referred to as:

• Chorea Acanthocytosis
• McLeod Syndrome
• Huntington’s Disease–like 2 (HDL2)
• Pantothenate kinase-associated neurodegeneration (PKAN)

These syndromes are caused by different genetic mutations but the signs and symptoms are usually very similar.

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, plus many people with Chorea acanthocytosis uncontrollably bite their tongue, lips, and the inside of the mouth. Behavorial changes are also an early indicator of Chorea acanthocytosis.

Onset

The appearance of symptoms of Chorea acanthocytosis usually appear in early to mid-adulthood. The first sign of Chorea acanthocytosis is most often behavioral changes that may result in personality changes, obsessive compulsive disorder (OCD), and the inability to take care of oneself. They continue on throughout the individual's life and the movement complications worsen with age.

Incidence

There are about 500–1,000 cases of Chorea acanthocytosis worldwide and it is not specific to any particular ethnic group.

Genetics

This mutation is autosomal recessive, meaning that both alleles of the gene must be mutated for the person to have Chorea acanthocytosis. If both parents are affected by Chorea acanthocytosis, all of the children will also acquire the disease. However, both parents may remain unaffected but both are carriers of the mutated gene (heterozygous for the trait) 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 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.

Clinical Diagnosis

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 myopathy characterized by muscle wasting and weakness
• Eye movement abnormalities
• Acanthocytosis
• Since Chorea acanthocytosis is an autosomal recessive disorder, positive family history for Chorea acanthocytosis will confirm it to be the diagnosis.

Treatment

• Botulinum toxin to reduce dystonia
• Mechanical protective devices (for tongue and lips)
• Anti-epileptics for seizure control
• Antipsychotics are prescribed for psychiatric problems
• Dopamine antagonists are prescribed (but should be heavily monitored) to patients to suppress involuntary movement

McLeod Syndrome

McLeod Syndrome is a neurodegenerative syndrome 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 cardiomyopathy (enlarged heart) are also commonly seen in individuals with this disease. Behavorial changes are also an early indicator of McLeod Syndrome.

Onset

The appearance of symptoms of McLeod Syndrome usually appear in early to mid- adulthood beginning with behavioral changes and movement difficulties worsening with age.

Incidence and genetics

McLeod syndrome is very rare. There are approximately 150 cases of McLeod Syndrome worldwide and is much more prevalent in males.

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 McLeod syndrome 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 McLeod Syndrome. Therefore, women who are carriers (heterogeneous) pass their mutated X-chromosome 50% of the time. When their sons receive the mutated chromosome, they will be affected by McLeod syndrome. 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. 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 “McLeod phenotype.” While the absence of the Kx antigen potentially causes many blood problems for the affected individual, such as transfusions, it remains unknown how the mutation of the XK gene leads to the other problems present in individuals with McLeod syndrome.

Clinical Diagnosis

McLeod syndrome is diagnosed in individuals with the following manifestations:

• McLeod blood group phenotype
• Family history of McLeod syndrome
• Central Nervous system manifestations such as seizures
• Neuromuscular manifestations such as myopathy
• Dilated cardiomyopathy and arrhythmias
• Acanthocytosis
• Family history

Treatment

• Dopamine antagonists are prescribed to patients to suppress involuntary movement
• Antipsychotics are prescribed for psychiatric problems
• Anti-epileptic drugs for treating seizures

Huntington's Disease-like 2

Huntington’s disease-like 2 syndrome is a disease that resembles Huntington’s disease 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.

Onset

Huntington’s disease-like 2 usually appears around midlife but anticipation is expected. An affected individual may live 10-20 years after onset.

Incidence

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.

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. Atleast 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, in this case, neuron signaling within the brain. The mutation of this gene is a series of trinucleotide repeats. To be considered Huntington’s disease-like 2, the gene must have atleast 41 CTG repeats. Normal alleles have six- 28 CTG repeats and questionable alleles have 29-39 repeats.

Clinical Diagnosis

Molecular genetic testing must be done to diagnose a person with Huntington’s disease-like 2, 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.

Treatment

Because Huntington’s disease-like 2 is very rare, treatment is solely based on the treatments for Huntington’s disease and other neurodegenerative disorders.

• 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

Prevention

There are no known prevention methods to slow the progression. Certain measures should be taken to prevent falls and other injuries for the affected individual. Examples of this are removing loose rugs and clutter and monitoring nutrition and swallowing to prevent aspiration.

Pantothenate Kinase-Associated Neurodegeneration

Patothenate 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 plus the affected individual may develop dementia and experience problems with vision loss. There is a classical version of PKAN and an atypical version where onset occurs much later and is less severe. Pantothenate kinase-associated neurodegeneration was formerly known as Hallervorden-Spatz syndrome after two German neuropathologists but is no longer used because of the unethical activities of these men before and during World War II.

Onset

Usually appears before the age of ten but about 25% of affected individuals have an onset that is atypical and after the age of ten with a more gradual progression of the disease.

Incidence

Patothenate kinase-associated neurodegeneration is very rare and is thought to be present in one to three people per one million people worldwide and is not specific to any particular ethnic group.

Genetics

Patothenate kinase-associated neurodegeneration is inherited in the 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) and are not affected by Pantothenate kinase-associated neurodegeneration, then 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 pantothenate kinase 2 which is active in the mitochondria of cells. When active, pantothenate kinase 2 helps 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.

Clinical Diagnosis

Individuals are diagnosed with Pantothenate kinase-associated neurodegeneration when they have the following manifestations:

• Extrapyramidal disfunction (dystonia, rigidity, choreoathetosis)
• Loss of ambulation (occurring within 15 years after onset)
• Eye of the tiger’s sign seen on an MRI caused by iron deposition in the globus pallidus
• Retinal degeneration
• Acanthocytosis
• Corticospinal tract involvement
• Family history

Treatment

Most of the treatment for Pantothenate kinase-associated neurodegeneration is aimed at suppressing the dystonia. Measures taken to aid in this process are as follows:

• Botulinum toxin and intrathecal baclofen injections
• Ablative pallidotomy or thalmotomy
• Deep brain stimulation
• Oral doses of baclofen and trihexyphenidyl

Prevention

There are no known prevention methods for Pantothenate kinase-associated neurodegeneration but alpha-tocopherol and idebenone were shown to have worsened the symptoms of Pantothenate kinase-associated neurodegeneration and should be avoided.

References

Bibliography

• "Chorea Acanthocytosis." Genetics Home Reference. Genetics Home Reference, ::May 2008. Web. 07 Feb. 2010. ::<http://ghr.nlm.nih.gov/condition=choreaacanthocytosis>.
• "Choreoacanthocytosis -- GeneReviews -- NCBI Bookshelf." National Center for Biotechnology Information. Gene Reviews, 13 Oct. 2006. ::Web. 02 Mar. 2010. <http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=chac>.
• Dobsen-Stone, C. "Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis." European Journal of Human ::Genetics ::(2002): 773-81. Print.

<http://www.nefo.med.uni-muenchen.de/~adanek/dobson-stone_danek_2002.pdf>.

This is a good source because it is from a British Medical Journal.

• "Huntington Disease-Like 2." National Center for Biotechnology Information. Gene Reviews, 13 Aug. 2009. Web. 02 Mar. 2010. ::<http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hd-l2#hd-l2.Evaluations_Followin>.

Also part of government information.

• "Huntington Disease-like Syndrome." Genetics Home Reference. Aug. 2008. Web. 02 Mar. 2010. <http://ghr.nlm.nih.gov/condition=huntingtondiseaselikesyndrome>.
• "JPH3 - Junctophilin 3." Genetics Home Reference. Aug. 2008. Web. 02 Mar. 2010. <http://ghr.nlm.nih.gov/gene=jph3>.

Good source because it is from a government database.

• "McLeod Neuroacanthocytosis Syndrome -- GeneReviews -- NCBI Bookshelf." National Center for Biotechnology Information. 26 ::Mar. ::2007. Web. 07 Feb. 2010. <http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=mcleod>.
• "McLeod Neuroacanthocytosis Syndrome." Genetics Home Reference. May 2008. Web. 02 Mar. 2010. ::<http://ghr.nlm.nih.gov/condition=mcleodneuroacanthocytosissyndrome>.
• "Neuroacanthocytosis." Medpedia. Web. 03 Mar. 2010. <http://wiki.medpedia.com/Neuroacanthocytosis>.
• "Neuroacanthocytosis Information Page:." National Institute of Neurological Disorders and Stroke (NINDS). 16 Mar. 2009. Web. ::07 ::Feb. 2010. <http://www.ninds.nih.gov/disorders/neuroacanthocytosis/neuroacanthocytosis.htm>.

Also a good source because it is part of government information.

• "Pantothenate Kinase-associated Neurodegeneration." Genetics Home Reference. Oct. 2006. Web. 03 Mar. 2010. ::<http://ghr.nlm.nih.gov/condition=pantothenatekinaseassociatedneurodegeneration>.
• "Pantothenate Kinase-Associated Neurodegeneration." National Center for Biotechnology Information. Gene Reviews, 9 Jan. 2008. Web. ::02 Mar. 2010. <http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pkan>.
• Rauschkolb, Paula K., and Stephen A. Berman. "Neuroacanthocytosis." EMedicine (2010). WebMD. 20 Jan. 2010. Web. 08 Feb. 2010. ::<http://emedicine.medscape.com/article/1150817-overview>.
• Reiss, Ulrike M., Pedro A. De Alacron, and Frank E. Shafer. "Acanthocytosis: eMedicine Pediatrics: General Medicine." EMedicine - ::Medical Reference. 7 Aug. 2008. Web. 08 Feb. 2010. <http://emedicine.medscape.com/article/954356-overview>.
• Robertson Jr., William C., Ismeal Mohamed, and Bhagwan Moorjani. "Chorea In Children." EMedicine (2008). WebMD. 23 Sept. 2008. Web. ::08 Feb. 2010. <http://emedicine.medscape.com/article/1181993-overview>.