Information on the following diseases can be found in the Related Disorders section of this report:

• Olivopontocerebellar Atrophy (OPCA)
• Multiple System Atrophy (MSA)
• Charcot-Marie-Tooth Disease
• Friedreich’s Ataxia
• Ataxia Telangiectasia

Ataxia is most often associated with degeneration of the region of the brain known as the cerebellum where movement, posture, and balance are coordinated. Thus, many of the symptoms and signs are those expected from cerebellar dysfunction. Ataxia may also be associated with damage (lesions) to the spine. Symptoms and signs often include a characteristic wide-based and unsteady way of walking (gait) that may be accompanied by awkward eye-hand coordination and slow, weak, or imprecise speech.

Other symptoms and signs may include involuntary eye movement (nystagmus) or double vision (diplopia), sensory loss, and cognitive impairment.

Some types of ataxia may be complicated by vision disorders including optic atrophy, retinitis pigmentosa, and eye movement paralysis (ophthalmoplegia). Other types of hereditary ataxia may be associated with heart disease, breathing problems, bone abnormalities and diabetes.

Some clinical features that may be associated with specific forms of autosomal dominant hereditary ataxia are listed below. In this list, SCA refers to spinocerebellar ataxia; DRPLA refers to dentato-rubro-pallido-luysian atrophy; EA refers to episodic ataxia; and SAX refers to spastic ataxia.

SCA1: Tremors of the hands (Parkinson-like), numbness in fingers and toes (peripheral neuropathy)

SCA2: Involuntary, irregular eye movements that occur when changing focus from one point to another (saccade), numbness of fingers and toes (peripheral neuropathy), loss of deep tendon reflexes such as at the kneecap, sometimes dementia

SCA3 (Machado Joseph Disease): Hand tremors, some rigidity, slowness of movement (extrapyramidal signs), involuntary eye movement (nystagmus), drawn back eyelids (lid retraction), numbness (sensory loss), eye jerking (saccade), muscle weakness and wasting (amyotrophy) with muscle twitches

SCA4: Progressive painless clumsiness, muscle weakness and atrophy

SCA5: Early onset and slow progression

SCA6: Very slow course, usually adult onset

SCA7: Damage to the retina (retinopathy) with vision loss

SCA8: Decreased sense of vibrations

SCA10: Occasional seizures

SCA11: Mild signs, able to walk about

SCA12: Early tremor, late dementia

SCA13: Mild mental retardation, short stature

SCA14: Slow progression of disease

SCA15: Very slow worsening of the walk or gait

SCA16: Head tremor

SCA17: Mental function declines

SCA19: Mild ataxia, spasms (myoclonus), mental deterioration and tremor

SCA21: Mild mental deterioration

SCA22: Slow worsening of the walk or gait

SCA25: Associated sensory neuropathy

DRPLA: Rapid, sudden involuntary movements (chorea), seizures, dementia, shocklike spasms (myoclonus)

EA1: Involuntary, rippling, muscular motion (myokymia), startle- or exercise-induced,

EA2: Involuntary rapid eye movements (nystagmus), dizziness (vertigo)

EA3: Vertigo, spasticity, involuntary eye movements (vestibulo-ocular reflex), ringing in the ears (tinnitus), double vision (diplopia)

EA4: Vertigo, rippling of muscles (myokymia), ringing in ears (tinnitus), double vision, and blurred vision

SAX1: Progressive leg spasticity

As noted above, some forms of the hereditary ataxias are transmitted in a dominant mode, others are transmitted through a recessive mode, and still others are transmitted in an X-linked fashion. This report deals with the disorders transmitted in an autosomal dominant fashion.

For many of the ataxias, the site of the faulty gene is known. These are listed below for autosomal dominant hereditary ataxias.

SCA1: 6p23
SCA2: 12q24
SCA3: 14q24.3-q31
SCA4: 16q22.1
SCA5: 11p11-q11
SCA6: 19p13
SCA7: 3p21.1-p12
SCA8: 13q21
SCA10: 22q13
SCA11: 15q14-q21.3
SCA12: 5q31-q33
SCA13: 19q13.3-q13.4
SCA14: 19q13.4-qter
SCA16: 8q22.1-q24.1
SCA17: 6q27
SCA21: 7p21-p15
SCA22: 1p21-q23
SCA25: 2p15-21

DRPLA: 12p13.31

EA1: 12p13
EA2: 19p13
2q22-q23

SAX1: 12p13

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p11-q11" refers to a region between band 11 on the short arm of chromosome 11 and band 11 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

All individuals carry a few abnormal genes but they cause no problems because they are only present in single copies. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Autosomal dominant hereditary ataxias have been further classified as trinucleotide repeat disorders. A trinucleotide repeat is a segment of DNA that is repeated. An abnormally large number of repeated segments of DNA can interfere with normal protein function. Trinucleotide repeats are unstable and can change in length when a gene containing them is passed to the next generation. An increased number of repeats often leads to an earlier age of onset and more severe disease.

Some forms of ataxia are not hereditary and can occur as a result of severe infections or side effects of drugs or alcohol. In many cases, ataxia is a symptom of another neurological disorder rather than a distinct and separate illness.

Hereditary ataxias affect males and females in equal numbers. It is estimated that 150,000 people in the United States are affected by, or at risk for, hereditary ataxia. There is variation among the specific forms of hereditary ataxia as to when they typically first appear.

Olivopontocerebellar atrophy (OPCA) refers to a group of ataxias characterized by progressive neurological degeneration affecting the cerebellum, the pons and the inferior olives. OPCA may be classified based on clinical, genetic, or neuropathological findings; thus, there are many classifications of the disorder. Among the different classifications, there is wide variation in severity and age of onset. The symptoms of OPCA differ from person to person. Most patients experience difficulty with balance and coordination of the legs and arms (ataxia) and slurred speech (dysarthria). Other symptoms may include muscle spasms or weakness and stiffness of the muscles; numbness or tingling of the hands or feet; shaking (tremor) of the hand or arm; reduction or slowness of movements; loss of thinking and/or memory skills; difficulty controlling the bladder or bowels; and feeling faint when standing up. Some patients also have fatigue and/or trouble with sleep. Generally, symptoms of OPCA begin in mid-adult life and progress slowly over the course of many years. (For more information on this disorder, choose "Olivopontocerebellar Atrophy, Hereditary" as your search term in the Rare Disease Database.)

Multiple system atrophy (MSA) refers to three slowly progressive related disorders that affect the central and autonomic nervous systems. The disorders are olivopontocerebellar atrophy (OPCA), which primarily affects balance, coordination, and speech; a parkinsonian form (striatonigral degeneration), which can resemble Parkinson’s disease because of slow movement and stiff muscles; and a form sometimes called Shy-Drager disease. In all three forms of MSA, the patient can have a drop in blood pressure when the patient stands up, which causes dizziness or momentary blackouts. Other symptoms may include stiffness and rigidity, loss of balance and coordination, impaired speech, breathing and swallowing difficulties, blurred vision, male impotence, constipation and urinary difficulties. Most patients develop dementia late in the course of the disease, which is usually diagnosed in persons over age 50. MSA is twice as common in men as in women. (For more information on this disorder, choose "Multiple System Atrophy" as your seach term in the Rare Disease Database.)

Charcot-Marie-Tooth disease is usually inherited as a dominant trait. However, in some families it can occur as a recessive trait or even as an X-linked trait. This hereditary form of peripheral nerve disease is characterized by weakness and atrophy, primarily in the legs. Disappearance of the fatty shield surrounding the nerves (segmental demyelination of peripheral nerves) and associated degeneration of part of the nerve cells (axons) characterize this disorder. When it is passed to offspring as an X-linked trait, it affects males more severely than females. (For more information on this disorder, choose "Charcot-Marie-Tooth disease" as your search term in the Rare Disease Database).

Friedreich’s ataxia is a recessive type of hereditary neuromuscular syndrome characterized by slow degenerative changes of the spinal cord, peripheral nerves and the brain. Dysfunction of the central nervous system affects coordination of the muscles in the limbs. Speech can be affected and numbness or weakness of the arms and legs develop. Various transitional and overlapping forms of Friedreich’s ataxia can occur. This syndrome appears to be the most common of the many forms of hereditary ataxia. It usually begins during childhood or the teen years. (For more information on this disorder, choose "Ataxia, Friedreich" as your search term in the Rare Disease Database).

Ataxia telangiectasia, also known as Louis-Bar syndrome, is inherited as a recessive trait. It is a progressive cerebellar ataxia that usually begins during infancy. It involves progressive loss of coordination in the limbs, head and eyes with a below-normal immune response to infections. In later stages, dilated blood vessels (telangiectasias) appear in the eyes and skin. Individuals with this form of ataxia are more susceptible to sinus and lung infections, and are at higher risk for developing certain tumors (neoplasms). Ataxia telangiectasia may be misdiagnosed as Friedreich ataxia until dilated blood vessels appear in the skin (telangiectasias). (For more information on this disorder, choose "Ataxia Telangiectasia" as your search term in the Rare Disease Database).

Diagnosis
For a diagnosis of hereditary ataxia, there must be a neurological examination that shows poorly coordinated gait, often combined with uncoordinated finger/hand movements. Difficulty with speech (dysarthria) and uncontrolled eye movements (nystagmus) may also be present. In addition, non-genetic causes of ataxia must be excluded. The hereditary nature of the disorder may be established by a positive family history of ataxia or identifying an ataxia-causing gene mutation.

Molecular genetic testing is currently available for some autosomal dominant hereditary ataxias. To find out whether that is the case for specific ones, speak to your physician or a certified genetic counselor.

Treatment
Treatment of ataxia is symptomatic and supportive. Continuous medical supervision to avoid potential complications involving the heart, lungs spine, bones and muscles is recommended. Mental functions usually remain unaffected in most forms of hereditary ataxia but emotional strain can affect patients and their families. In such cases, psychological counseling may be helpful.

Physical therapy may be recommended by a physician. In addition, various aids may assist muscular movement. Some drugs may be useful in treating some symptoms of ataxia. Propanalol may be effective against static tremors, for instance. Dantrolene, Baclofen, or Tizanidine may help some patients with muscle spasms of the legs. Genetic counseling will be of benefit for patients and families affected by the hereditary ataxias.

Three clinical trials involving the hereditary ataxias are currently in progress, sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH).

Clinical and Molecular Correlation in Spinocerebellar Ataxia Type 10 (SCA10)
In this study, blood will be collected from members of families with autosomal dominant hereditary ataxias for detailed molecular genetic analysis. This trial is being conducted in cooperation with Baylor College of Medicine and will take place at the University of Texas Medical Branch at Galveston, Texas.

For further information please contact:

Tetsuo Ashizawa, MD
Baylor College of Medicine
Tel: 409-772-2466

Study ID Numbers are: 199/11796; BCM-H4499

Phenotype/Genotype Correlations in Movement Disorders
This observational study is designed to establish accurate clinical diagnosis of inherited movement disorders in families using the newest technological means in order to study the underlying molecular processes. Patients with good genealogical records are especially desired for this study. If a patient presents with disease about which the molecular basis is well known, then the clinical presentation (phenotype) will be correlated with known chromosomal and molecular characteristics (genotype).

For further information please contact:

Patient Recruitment and Public Liaison Office
National Institute of Neurological Disorders and Stroke (NINDS)
9000 Rockville Pike
Bethesda, MD 20892

Tel: 800-411-1222
e-mail: prpl@mail.cc.nih.gov

Study ID numbers are: 010206; 01-N-0206

Study of Inherited Neurological Disorders
This study is designed to learn more about the natural history of inherited neurological disorders and the role of hereditary in their development. Children and adults may be eligible for this study.

For further information please contact:

Patient Recruitment and Public Liaison Office
National Institute of Neurological Disorders and Stroke (NINDS)
9000 Rockville Pike
Bethesda, MD 30892

Tel: 800-411-1222
e-mail: prpl@mail.cc.nih.gov

Study ID numbers are: 000043; 00-N-0043

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Spinocerebellar Ataxia 1; SCA1. Entry Number; 164400: Last Edit Date; 8/7/2002. Spinocerebellar Ataxia 2; SCA2. Entry Number; 183090: Last Edit Date 8/13/2002. Machado-Joseph Disease; MJD. (SCA3) Entry Number; 109150: Last Edit Date: 8/7/2003.
Spinocerebellar Ataxia 4; SCA4. Entry Number; 600223; Last Edit Date; 3/26/2003. Spinocerebellar Ataxia 5; SCA5. Entry Number; 600224; Last Edit Date; 6/21/2002. Spinocerebellar Ataxia 6; SCA6. Entry Number; 183086; Last Edit Date; 8/7/2003. Spinocerebellar Ataxia 7; SCA7. Entry Number; 164500; Last Edit Date; 7/9/2003. Spinocerebellar Ataxia 8; SCA8. Entry Number; 603680: Last Edit Date; 10/10/2003. Spinocerebellar Ataxia 10; SCA10. Entry Number; 603516; Last Edit Date; 10/2/2002. Spinocerebellar Ataxia 11; SCA11. Entry Number; 604432: Last Edit Date; 8/7/2002. Spinocerebellar Ataxia 12; SCA12. Entry Number; 604326; Last Edit Date; 1/24/2003. Spinocerebellar Ataxia 13; SCA13. Entry Number; 605259; Last Edit Date; 8/7/2002. Spinocerebellar Ataxia 14; SCA14. Entry Number; 605361: Last Edit Date; 4/23/2003. Spinocerebellar Ataxia 15; SCA15. Entry Number; 606658; Last Edit Date; 1/30/2002. Spinocerebellar Ataxia 16; SCA16. Entry Number; 606364: Last Edit Date; 10/8/2001. Spinocerebellar Ataxia 17; SCA17. Entry Number; 607136; Last Edit Date; 8/22/2002.
Spinocerebellar Ataxia 19; SCA19. Entry Number; 607346: Last Edit Date; 11/14/2002. Spinocerebellar Ataxia 21; SCA21. Entry Number; 607454: Last Edit Date; 1/7/2003. Spinocerebellar Ataxia 10; SCA10. Entry Number; 603516: Last Edit Date; 10/2/2002. Dentatorubral-Pallidoluysian Atrophy; DRPLA. Entry Number; 125370: Last Edit Date; 1/24/2003. Episodic Ataxia, Type 1; EA1. Entry Number; 160120: Last Edit Date; 4/7/2003. Episodic Ataxia, Type 2: EA2. Entry Number; 108500; Last Edit Date; 12/12/2001.
Ataxia, Spastic, Autosomal Dominant; SAX1. Entry Number; 108600: Last Edit Date; 4/11/2002.

TEXTBOOKS
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Burns RS. Episodic Ataxia Type II. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:601-02.

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Rowland LP, ed. Merritt’s Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA . 2000:645-55.

Adams RD, Victor M, Ropper AA, eds. Principles of Neurology. 6th ed. McGraw-Hill Companies. New York, NY, 1997:1080-89.

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Rosa AL, Ashizawa T. Genetic ataxia. Neurol Clin. 2002;20:727-57.

Margolis RL. The spinocerebellar ataxias: order emerges from chaos. Curr Neurol Neurosci Rep. 2002;2:447-56.

Thyagarajan D. Genetics of movement disorders: an abbreviated overview. Stereotact Funct Neurosurg. 2001;77:48-50.

Klockgether T, Wullner U, Spauschus A, et al. The Molecular biology of the autosomal-dominant cerebellar ataxias. Mov Disord. 2000;15:604-12.

Evidente VG, Gwinn-Hardy KA, Caviness JN, et al. Hereditary ataxias . Mayo Clin Proc. 2000;75:475-90.

StevainG, Durr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J. Hum Genet. 2000;8:4-18.

Klockgether T, Evert B. Genes involved in hereditary ataxias . Trends Neurosci. 1998;21:413-18.

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