Ataxia

What is Ataxia?

Ataxia is derived from the Greek word meaning “irregularity” or “disorderliness”, but when used medically, the term describes a condition characterized by poor motor coordination. Ataxia causes incoordination of hands, staggering gait, and slurred speech, which may make the person, appear “drunk”. Ataxic patients are unable to walk in a straight line and tend to bump into things; in advanced stages they may need a walker or even a wheel chair. Patients also may have blurring of vision due to eye movement abnormalities. In addition to these motor incoordination due to problems with the cerebellum (the posterior portion of the brain responsible for coordination), ataxia can also occur as a result of problems with disturbance of the sensory system (abnormal perception of a position of a body part in space) and vestibular system (abnormal balance). A neurologist can usually differentiate between the two types of ataxia: motor and sensory.

There are about 150,000 patients affected with some form of ataxia in the USA. There are many causes of ataxia, but most can be categorized as sporadic (no specific cause), genetic or secondary to some injury to the brain. Congenital ataxias occur in children and they are due to structural abnormalities in the brain that occur before or during birth. These include cerebral palsy (often associated with injury to the brain at birth due to lack of oxygen or blood supply), hydrocephalus (increased pressure caused by blockage or build up of cerebrospinal fluid) or brain tumors, and other injuries to the brain.

Ataxia can be acute (sudden) or subacute (within a week). In acute cases the most common cause is either stroke or hemorrhage in the area of the cerebellum. Patients usually have headache, vomiting, neck stiffness or loss of consciousness. In children, bacterial or viral infections can cause acute ataxia and this usually improves with time. Patients develop fever, problems with walking and slurred speech over a period of hours to days and recover in a few weeks. MRI and spinal fluid analysis are helpful in diagnosis. Subacute onset of ataxia is usually seen in paraneoplastic cerebellar degeneration. This is a condition in which cancer in the breast, lungs, ovaries or other areas in the body can cause ataxia.

Episodic ataxia is a disorder with intermittent spells of ataxia with complete recovery between episodes. This is classified into types 1 and 2. These are dominantly inherited cerebellar ataxias. They are caused by genetic mutations within a voltage gated potassium channel (KCNA1) gene and the cerebral P/Q type calcium channel gene (CACNL1A4) respectively. Patients have spells of gait difficulty, dysarthria and nystagmus with complete recovery between episodes. Genetic episodic ataxias are responsive to medical treatment. Drug ingestion, multiple sclerosis and other causes can also lead to episodic ataxia in some cases.

Patients with chronic progressive ataxia have long standing difficulties over several years. These include several disorders like degeneration of cerebellum due to alcohol, hereditary cerebellar ataxias, brain tumors in children, and vitamin E deficiency. Vitamin B12 deficiency causes sensory ataxia in addition to muscle weakness.

Spinocerebellar ataxias (SCA) represent the most common form of chronic progressive ataxia in adults. They result from degeneration of pathways between the spinal cord and cerebellum. There are at least 25 types (SCA 1 to 25 see table for reference) and the number is increasing based on new research. Most of these disorders are genetic and have a 50% chance of transmission to children (autosomal dominant pattern of inheritance). All patients with these disorders must undergo genetic counseling.

SCA-2 is most common in the US and SCA3 is most common in Japan, Germany, Portugal and France. Typical age of onset of these syndromes is 4-60 years with average of 40 years. Although the type of SCA varies patients can become disabled by 5 years, bedridden by 10 years and death occurs any where between 10‑20 years after onset of disease.

The common clinical problems in SCA are gait ataxia, eye movement abnormalities (nystagmus or jerkiness and double vision), and dysarthria (speech difficulty). Some of the SCAs (SCA1,2,3,4,7 and 8) also cause peripheral neuropathy (damage to the peripheral nerves which causes the patient to have numbness or tingling in the hands and feet). SCA’s result in blindness and cause damage to the retina and the macula in the eye (SCA 7).

In addition to SCAs there are other inherited disorders that can cause ataxia, including DRPLA (dentatorubropallidoluysian atrophy). This is a rare neurodegenerative disorder that causes difficulties with walking (ataxia), problems with speech, dementia, chorea (involuntary writhing type of movements) and jerkiness of muscles (myoclonus). Some of the younger patients have seizures.

Besides autosomal dominant forms of ataxia, there are also autosomal recessive ataxias, in which each offspring has 25%, rather than 50%, risk of inheritance from the affected parent to children. Friedrich’s ataxia is an example of autosomal recessive ataxia. It is a disorder due to excessive repeats of nucleotides GAA in the DNA. Patients have ataxia along with spasticity, speech problems, nystagmus, weakness of lower extremities, and sensory problems. Patients with Friedreich’s ataxia also may develop scoliosis (curvature of spine), cardiomyopathy (enlargement of the heart), and diabetes and bowel and bladder dysfunction. This is a slow progressive disorder, but most patients become wheelchair bound within 10‑20 years after onset. There is, however, a marked variability in the presentation and progress of the disease. Other recessively inherited ataxias include vitamin-E deficiency (due to alpha tocopherol transfer protein deficiency or abetalipoproteinemia), ataxia telangiectasia, and infantile onset spinocerebellar ataxia among several others.

Can ataxia be treated?

Of all the movement disorders ataxia is among the most resistant to medical therapy. Clonazepam may help tremor and balance problems. It has side effects such as sedation, fatigue loss of libido etc. Other medications such as buspirone or 5 hydroxytryptophan have been studied but they have not been shown to be very beneficial. Phenytoin, an anticonvulsant, is useful for some episodic ataxias. Acetazolamide is useful in some of the rare forms of episodic ataxias such as episodic ataxia with paroxysmal choreoathetosis and spasticity (episodes of ataxia with stiffness and writhing type of abnormal movements).

Cerebellar ataxias including the genetic ataxias however do not have any definitive treatments. Some of the disorders have been reported to be slowed by taking antioxidants such as vitamins A, E, B12, idebenone, and Coenzyme Q10. Vitamin E is the treatment of choice in ataxia caused by vitamin E deficiency. When associated with parkinsonism, such as seen in the cerebellar form of multiple system atrophy (previous referred to as olivopontocerebellar atrophy), levodopa may be helpful.

Weakness, and spasticity contribute to the difficulties the patient may experience in ataxia. Physical therapy to maximize strength, conditioning and flexibility are helpful. General physical therapy and regular exercise are highly recommended. Early therapy may help patients with spasticity from developing contractures. Patients with ataxia can be helped with gait training during the earlier stages of the disease. Adaptations such as wheel chair and home adjustments can be discussed with the occupational therapist. Speech therapy can be helpful for patients with dysarthria.

Care of the bed-ridden patient in advanced stages of the progressive ataxia is very important. Skin care and eventual placement of PEG tube (feeding tube) in patients with swallowing difficulties will help prevent lung infections.

Selected References

Abele M, Burk K, Schols L, et al. The aetiology of sporadic adult-onset ataxia. Brain 2002;125:961-968.
Bürk K, Bösch S, Müller CA, et al. Sporadic cerebellar ataxia associated with gluten sensitivity. Brain 2001; 124:1013-1019.
Cagnoli C, Mariotti C, Taroni F, et al. SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. Brain 2006;129:235-42.
Criscuolo C, Chessa L, Di Giandomenico S, et al. Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology 2006;66:1207-10.
Di Prospero NA, Sumner CJ, Penzak SR, Ravina B, Fischbeck KH, Taylor JP. Safety, tolerability, and pharmacokinetics of high-dose idebenone in patients with Friedreich ataxia. Arch Neurol 2007;64:803-8.
Everett CM, Wood NW. Trinucleotide repeats and neurodegenerative disease. Brain. 2004; 127:2385-405
Fahn S, Jankovic J. Principles and Practice of Movement Disorders, Churchill Livingstone, Elsevier, Philadelphia, PA, 2007:1-652. (Accompanied by a DVD of movement disorders).
Furtado S, Payami H, Lockhart PJ, et al. Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2). Mov Disord 2004;19:622-9.
Hadjivassiliou M, Grunewald R, Sharrack B, et al. Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain 2003;126:685-91.
Hou J-G, Jankovic J. Movement disorders in Friedreich’s ataxia. J Neurol Sci 2003; 206:59-64.
Ito H, Kawakami H, Wate R, Matsumoto S, Imai T, Hirano A, Kusaka H. Clinicopathologic investigation of a family with expanded SCA8 CTA/CTG repeats. Neurology 2006;67:1479-81.
Jankovic J, Tolosa E, eds. Parkinson's Disease and Movement Disorders, 5th edition, Lippincott Williams and Wilkins, Philadelphia, PA, 2007:1-720. (Accompanied by a CD video atlas).
Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW; CINCH investigators. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 2007;130:2484-93.
Le Ber I, Bouslam N, Rivaud-Pechoux S, et al. Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain 2004;127:759-67.
Lock RJ, Tengah DP, Williams AJ, et al. Cerebellar ataxia, peripheral neuropathy, "gluten sensitivity" and anti-neuronal autoantibodies. Clin Lab 2006;52:589-92.
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Appendix

Classification of Spinocerebellar Ataxias

NAME	LOCUS	PHENOTYPE
SCA1 (autosomal dominant type1)	6p23 with > 40 CAG repeats (Exonic) Ataxin1	Ataxia with ophthalmoparesis, pyramidal and extrapyramidal findings, chorea, spasticity, neuropathy, ophthalmoplegia
SCA2 (autosomal dominant type 2)	12q24.1 with > 31CAG repeats (Exonic) Ataxin2	Ataxia with slow saccades, ophthalmoplegia, and minimal pyramidal and extrapyramidal findings, levodopa-responsive parkinsonism, tremor, chorea, myoclonus, seizures, areflexia, neuropathy, dementia
SCA3 (Machado-Joseph disease) (autosomal dominant type 3)	14q24.3-q31 with > 38 CAG repeats (Exonic) Allelic to Machado-Joseph disease (MJD) Ataxin3	Ataxia with ophthalmoparesis, diplopia and variable pyramidal, extrapyramidal, spasticity, muscle weakness, and amyotrophy, psychosis, dystonia, neuropathy
SCA4 (autosomal dominant type 4)	16q22.1	Ataxia with normal eye movements, sensory axonal neuropathy, and pyramidal signs
SCA5 (autosomal dominant type 5) Also called Lincoln ataxia	Centromeric region of chromosome 11, 11p11-q11	Ataxia and dysarthria, early onset, slow course
SCA6 (autosomal dominant type 6)	19p13 with > 20 CAG repeats in α1A-voltage-dependent calcium channel gene, CACNA1A (Exonic)	Ataxia, dysarthria, diplopia, nystagmus, mild proprioceptive sensory loss, dystonia, normal life span, may be episodic
SCA7 (autosomal dominant type 7)	3p21.1-p12 with > 30 CAG repeats (Exonic) Ataxin7	Ophthalmoparesis; visual loss; ataxia; dysarthria, extensor plantar response, spasticity, pigmentary retinal degeneration, dementia
SCA8 (autosomal dominant type 8)	13q21 with > 91 CTG repeats (untranslated) (10q23-q24)	Gait ataxia, dysarthria, seizures, diplopia, nystagmus, tremor; leg spasticity and reduced vibratory sensation, normal life span
SCA9	Not assigned
SCA10 (autosomal dominant type 10)	22q13, > 800 ATTCT, noncoding, Ataxin10	Gait ataxia, dysarthria; nystagmus; partial complex and generalized motor seizures, tremor, spasticity, Mexian families
SCA 11 (autosomal dominant type 11)	15q14-q21.3	Slowly progressive gait and extremity ataxia, dysarthria, vertical nystagmus, hyperreflexia, mild
SCA12 (autosomal dominant type 12)	5q31-q33, > 66 CAG repeats in the promotor region, coding for protein phosphatase 2A	Tremor, bradykinesia, parkinsonism, dementia, hyperreflexia
SCA13 (single French family)	19q13.3-q13.4 (6q27 with CAG repeats in the TATA binding protein gene)	Gait and extremity ataxia, hyperflexia, extensor plantar responses, dysarthria, dysphagia, mental retardation, dementia, short stature
SCA14 (autosomal dominant type 14)	19q13.4, Protein kinase C γ	Pure ataxia in late-onset (>39), myoclonus and ataxia in young-onset
SCA15 (one Australian family)	3p24.2-pter (6q27 with CAG repeats)	Pure ataxia, slowly progressive
SCA16 (one Japanese family)	8q22.1-24.1	Ataxia, head and hand tremor
SCA17	6q27 with > 42 CAG repeats, TATA-Box binding protein	Ataxia, chorea, dystonia, dementia, psychosis, seizures, HD-like phenotype
SCA18 (one Irish-American family)	7q22-q32	Neuropathy
SCA19 (one Dutch family)	1p21-q23	Dementia, myoclonus, Might be allelic with SCA22
SCA19
SCA20 (autosomal dominant)	11 (but awating differentiation from SCA5)	Palatal myoclonus (tremor) and dysphonia, dentate calcification [Knight et al, 2004]
SCA21 (One French Family)	7p21.3-p15.1	Ataxia, parkinsonism, tremor, hyporeflexia, dementia
SCA22 (One Chinese Family)	1q21-q23	Chinese family, age at onset 10-46, gait ataxia, dysarthria, hyporeflexia, slowly progressive pure cerebellar ataxia and atrophy, might be allelic with SCA19
SCA23		One Dutch Family
SCA24	Reserved
SCA25 (autosomal dominant) (One French Family)	2p15-21	French family with ataxia and sensory neuropathy, onset 17 months to 39 years, may be similar to Friedreich’s ataxia
Dentatorubropallidoluysian atrophy (DRPLA) (autosomal dominant)	12p13.31, > 36 CAG repeats, Atrophin-1, c-Jun NH(2)-terminal kinase (JNK)	Ataxia, choreoathetosis, dystonia, seizures, myoclonus, dementia parkinsonism, hyporeflexia
Friedreich’s ataxia (autosomal recessive)	9q13-q21.1 with intronic GAA repeats, Frataxin	Ataxia, areflexia, extensor plantar responses, position sense deficits, cardiomyopathy, diabetes mellitus, scoliosis, foot deformities; defective iron transport from mitochondria
Friedreich's ataxia (autosomal recessive)	9p13 (intron 1), GAA repeats, Frataxin	Same as phenotype with maps to 9q but associated with vitamin E deficiency
Kearns-Sayre syndrome (sporadic)	MtDNA deletion and duplication mutations	Ptosis, ophthalmoplegia, pigmentary retinal degeneration, cardiomyopathy, diabetes mellitus, deafness, heart block, increased CSF protein, ataxia
Recessive ataxia with ocular motor Araxia (Aicardi syndrome) [Barbot et al, 2001]		Childhood onset, late neuropathy, long survival
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay	SACS 13q11-12	Childhood-onset, Ataxia, spasticity, retinal striations, dysarthria, axonal peripheral neuropathy, distal astrophy, atrophy of upper cerebellar vermis
Myoclonus epilepsy and ragged red fiber syndrome (MERRF) (maternal inheritance)	Mutation in mtDNA of the tRNAlys at 8344: also mutation at 8356	Myoclonic epilepsy, ragged red fiber myopathy, ataxia
Mitochondrial encephalopathy, lactic acidosis, and stroke syndrome (MELAS) (maternal inheritance)	TRNAleu mutation at 3243; also at 3271 and 3252	Headache, stroke, lactic acidosis, ataxia
Leigh's disease; subacute necrotizing encephalopathy ) maternal inheritance or autosomal recessive)	MtDNA complex V defect (ATPase gene at 8993) or mitochondrial protein synthesis defect (both maternally inherited); or complex IV defect (autosomal recessive)	Obtundatin, hypotonia, cranial nerve defects, respiratory failure, hyperintense signals on T2-weighted magnetic reonance images in basal ganglia, cerebellum, or braintem; ataxia
Episodic ataxic, type I (EA-1) (autosomal dominant)	12p; potassium channel gene KCNA-1	Episodic ataxia for minutes; provoked by startle or exercise; with facial and hand myokymia; cerebellar signs are not progressive; responds to phenytoin
Episodic ataxic, type II (EA-2) (autosomal dominant)	19p-13(CACNA1A) (allelic with SCA6) á1A-voltage dependent calcium channel subunit)	Episodic ataxia for days: provoked by stress, fatigue; with down-gaze nystagmus; cerebellar atrophy; progressive cerebellar signs; responds to acetazolamide.
Ataxia telangiectasia (autosomal recessive)	11q22-23; ATM gene for regulation of cell cycle. Mitogenic signal tansduction, and meiotic recombination	Telangiectasia, ataxia, slow saccades, dysarthria, pulmonary infections, neoplasms of lymphatic system; IgA and IgG deficiencies; diabetes mellitus, breast cancer.
Infantile-onset spinocerebellar ataxia of Nikali et at. (autosomal recessive)	10q23.3-q24.1	Infantile ataxia, sensory neuropathy; athetosis, hearing deficit, ophthalmoplegia, optic atrophy; primary hypogonadism in females.
Early-onset ataxia with oculomotor apraxia and hypoalbuminemia (EAOH); Shimazaki et al, 2002	APTX, Aprataxin
Ataxia with oculomotor apraxia type 2 (AOA2) (autosomal recessive); Le Ber et al 2004.	Linked to 9q34

There are many ataxias that are yet to be classified and further research into treatment and cause of these disorders is awaited. The following organizations can provide further information for specific disorders.

National Ataxia Foundation
2600 Fernbrook Lane, Suite 119
Minneapolis, MN 55447-4752
Tel: 763-553-0020
Fax: 763-553-0167
Email: naf@ataxia.org or naf@mr.net
http://www.ataxia.org

Friedreich’s Ataxia Research Alliance
2001 Jefferson Davis Highway, Suite 209
Arlington, VA 22202
Tel: 703-413-4468
Fax: 703-413-4467
Email: fara@frda.org
http://www.frda.org/