Hereditary Ataxia Overview

Clinical Manifestations of Hereditary Ataxia

Clinical manifestations of hereditary ataxia are poor coordination of movement and a wide-based, uncoordinated, unsteady gait. Poor coordination of the limbs and of speech is often present.

Ataxia may result from dysfunction of the cerebellum and its associated systems, lesions in the spinal cord, peripheral sensory loss, or any combination of these three conditions.

Establishing the Diagnosis of Hereditary Ataxia

Establishing the diagnosis of hereditary ataxia requires the following:

• Detection on neurologic examination of typical clinical symptoms and signs including poorly coordinated gait and finger/hand movements, often associated with dysarthria and nystagmus

• Exclusion of non-genetic causes of ataxia (see Differential Diagnosis)

• Documenting the hereditary nature by finding a positive family history of ataxia, identifying an ataxia-causing gene mutation, or recognizing a clinical phenotype characteristic of a genetic form of ataxia.
  
  Note: In some individuals with no family history of ataxia it may not be possible to establish a genetic cause if all available genetic tests are normal.

Differential Diagnosis of Hereditary Ataxia

Differential diagnosis of hereditary ataxia includes acquired, non-genetic causes of ataxia, such as alcoholism, vitamin deficiencies, multiple sclerosis, vascular disease, primary or metastatic tumors, or paraneoplastic diseases associated with occult carcinoma of the ovary, breast, or lung. The possibility of an acquired cause of ataxia needs to be considered in each individual with ataxia because a specific treatment may be available.

Prevalence of Hereditary Ataxia

Prevalence of the autosomal dominant cerebellar ataxias (ADCAs) in the Netherlands is estimated to be at least 3:100,000 population [van de Warrenburg et al 2002].

Autosomal Dominant Cerebellar Ataxias (ADCA)

Synonyms for ADCA used prior to the identification of the molecular genetic basis of these disorders were Marie's ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term, spinocerebellar degeneration.

Molecular Genetics of ADCA

The autosomal dominant cerebellar ataxias for which specific genetic information is available are summarized in Table 1. Most are spinocerebellar ataxias (SCA), one is a complex form (DRPLA), two are episodic ataxias, and one is a spastic ataxia.

Table 1. Molecular Genetics of Autosomal Dominant Cerebellar Ataxias

Disease Name	Gene Symbol	Chromosomal Locus	Protein Name	Type of Mutation	Reference / Testing
SCA1	ATXN1	6p23	Ataxin-1	CAG repeat
SCA2	ATXN2	12q24	Ataxin-2	CAG repeat
SCA3	ATXN3	14q24.3-q31	Ataxin-3	CAG repeat
SCA4	---	16q22.1	---	---	[Flanigan et al 1996]
SCA, 16q22-linked 1	PLEKHG4	16q22	Puratrophin-1	---	[Ishikawa et al 2005]
SCA5	SPTBN2	11p13	Spectrin beta chain, brain 2	Non-repeat mutations	[Ikeda et al 2006]
SCA6	CACNA1A	19p13	Voltage-dependent P/Q-type calcium channel alpha-1A subunit	CAG repeat
SCA7	ATXN7	3p21.1-p12	Ataxin-7	CAG repeat
SCA8	ATXN80S	13q21	---	CAG·CTG
SCA9 2	---	---	---	---	---
SCA10	ATXN10	22q13	Ataxin-10	ATTCT repeat
SCA11	TTBK2	15q14-q15.3	Tau-tubulin kinase 2	Non-repeat mutations	[Houlden et al 2007]
SCA12	PPP2R2B	5q31-q33	Serine/threonine protein phosphatase 2A 55-kd regulatory subunit B beta isoform	Non-repeat mutations	[Holmes et al 1999, Fujigasaki et al 2001]
SCA13	KCNC3	19q13.3-q13.4	Potassium voltage-gated channel subfamily C member 3	Non-repeat mutations	[Waters et al 2006]
SCA14	PRKCG	19q13.4	Protein kinase C gamma type	Non-repeat mutations	[Yamashita et al 2000, Brkanac et al 2002a, Chen et al 2003a, Chen et al 2003b, Yabe et al 2003]
SCA15	ITPR1	3p26-p25	Inositol 1,4,5-trisphosphate receptor type 1	Deletion of the 5' part of the gene	[van de Leemput et al 2007]
SCA16	SCA16	3p26.2-pter	Contactin-4	---	[Miura et al 2006]
Disease Name	Gene Symbol	Chromosomal Locus	Protein Name	Type of Mutation	Reference / Testing
SCA17	TBP	6q27	TATA-box binding protein	CAA/CAG repeat mutation	[Nakamura et al 2001]
SCA18	SCA18	7q22-q32	---	---	---
SCA19	SCA19	1p21-q21	---	---	[Verbeek et al 2002, Chung & Soong 2004, Schelhaas et al 2004]
SCA20		11q12.2-11q12.3	---	260-kb duplication	[Knight et al 2004, Knight et al 2008]
SCA21	SCA21	7p21-p15.1	---	---	[Vuillaume et al 2002]
SCA22	---	1p21-q21	---	---	[Chung et al 2003, Chung & Soong 2004, Schelhaas et al 2004]
SCA23	---	20p13-p12.3	---	---	[Verbeek et al 2004]
SCA25	SCA25	2p21-p13	---	---	---
SCA26	---	19p13.3	---	---	[Yu et al 2005]
SCA27	FGF14	13q34	Fibroblast growth factor 14	---	[van Swieten et al 2003]
SCA28	AFG3L2	18p11	AFG3-like protein 2	---	[Cagnoli et al 2005, Mariotti et al 2008]
DRPLA	ATN	12p13.3	Atrophin-1	CAG repeat
EA1	KCNA1	12p13	Potassium voltage-gated channel subfamily A member 1	---
EA23	CACNA1A	19p13	Voltage-dependent P/Q-type calcium channel alpha-1A subunit	Non-repeat mutations
	CACNB4	2q22-q23	Voltage-dependent L-type calcium beta-4 subunit	---	---
EA3 4	---	---	---	---	[Damji et al 1996]
EA4 5	---	---	---	---	[Steckley et al 2001]
ADSA 6	SAX1	12p13	---	---	[Meijer et al 2002]

1. Japanese families linked to the 16q22 region have a single-nucleotide substitution (-16C>T) in the 5' UTR of the PLEKHG4 gene and often share a common haplotype [Ishikawa et al 2005, Ohata et al 2006]. It is not yet certain whether the nucleotide substitution is itself pathogenic or whether all families with ataxia linked to this region have the same DNA change.

2. Although SCA9 has been reserved, no clinical or genetic information regarding this type has been published.

3. EA2, SCA6, and one type of familial hemiplegic migraine all represent allelic mutations in CACNA1A.

4. A single family with EA3 (periodic vestibulocerebellar ataxia with defective smooth pursuit)

5. A single family with EA4 (episodic ataxia with vertigo and tinnitus)

6. ADSA = autosomal dominant spastic ataxia

Other autosomal dominant cerebellar ataxias not included in Table 1

• Ataxia with early sensory/motor neuropathy (linked to 7q22-q32) [Brkanac et al 2002b]

• Cerebellar ataxia, deafness, narcolepsy, and optic atrophy (linked to 6p21-p23 in one family) [Melberg et al 1999]

• A heterozygous mutation in EAAT1, encoding a glutamate transporter (reported in a single individual with episodic ataxia, seizures, and hemiplegic migraine) [Jen et al 2005]

• Ataxia, cerebellar atrophy, mental retardation, and possible attention deficit/hyperactivity disorder (ADHD) (associated with a heterozygous mutation in SCA8, encoding a sodium channel [Trudeau et al 2005]

• Late-onset (40s-60s) cerebellar ataxia preceded by many years of spasmodic coughing. One individual had calcification of the dentate nuclei on MRI [Coutinho et al 2006].

Molecular genetic testing

• CAG trinucleotide expansion disorders. SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, and DRPLA are caused by CAG trinucleotide repeat expansions within the coding sequences of their respective genes. (Because the CAG tract codes for glutamine, such disorders have also been called polyglutamine disorders.)
  
  Molecular genetic testing for CAG repeat length is a highly specific and highly sensitive diagnostic test. The sizes of the normal CAG repeat allele and of the disease-causing (full penetrance) CAG repeat expansion vary among the disorders (see individual GeneReview for each disorder; links in Table 1).
  
  Two notes of caution in interpretation of CAG repeat length:

  • Some disorders are associated with alleles for which overlap exists between the upper range of normal and the lower range of abnormal CAG repeat size. Typically, such alleles are categorized as mutable normal or reduced penetrance.
    
    Mutable normal alleles (previously referred to as intermediate alleles) do not cause disease in the individual but can expand upon transmission to a reduced or full penetrance allele. Therefore, children of an individual with a mutable normal allele are at increased risk of inheriting a disease-causing allele.
    
    Reduced penetrance alleles may or may not cause disease; the probability of disease in persons with such alleles is typically unknown.
    
    Interpretation of test results in which the CAG repeat length is at the interface between the allele categories mutable normal/reduced penetrance or reduced penetrance/disease-causing can be difficult. In such cases, a consultation with the testing laboratory may be helpful to determine the precision of the CAG repeat length measurement.

  • In some instances SCA2, SCA7, SCA8, and SCA10 result from extremely large CAG expansion lengths that may only be detected with Southern blot analysis. For these disorders, a test result of apparent homozygosity (detection of a single allele size by PCR analysis) must be interpreted in the context of multiple factors including clinical findings, family history, and age of onset of symptoms to determine whether Southern blot analysis to test for the presence of a large CAG expansion mutation is appropriate.

• Other. SCA8 has a CTG trinucleotide repeat expansion in ATXN8OS [Koob et al 1999]. Extremely large repeats (~800) in ATXN8OS may be associated with an absence of clinical symptoms [Ranum et al 1999].
  
  SCA10 has a large expansion of an ATTCT pentanucleotide repeat in ATXN10, with the abnormal expansion range being much larger than that seen in the CAG repeat disorders [Matsuura et al 2000].

• Anticipation is observed in the autosomal dominant ataxias in which CAG trinucleotide repeats occur. Anticipation refers to earlier onset and increasing severity of disease in subsequent generations of a family. In the trinucleotide repeat diseases, anticipation results from expansion in the number of CAG repeats that occurs with transmission of the gene to subsequent generations. ATN1 (DRPLA) and ATXN7 (SCA7) have particularly unstable CAG repeats [La Spada 1997, Nance 1997]. In SCA7, anticipation may be so extreme that children with early-onset, severe disease die of disease complications long before the affected parent or grandparent is symptomatic.
  
  Anticipation is a significant issue in the genetic counseling of asymptomatic at-risk family members and in prenatal testing. Although general correlations exist between earlier age of onset and more severe disease with increasing number of CAG repeats, the age of onset, severity of disease, specific symptoms, and rate of disease progression are variable and cannot be accurately predicted by the family history or molecular genetic testing. While attention has been focused on the phenomena of anticipation and trinucleotide repeat expansion, it is important to note that the number of trinucleotide repeats can also remain stable or even contract on transmission to subsequent generations.
  
  In the CAG repeat disorders, expansion of the repeat is more likely to occur with paternal than with maternal transmission of the expanded allele. In contrast, in SCA8 the majority of expansions of the CTG repeat occur during maternal transmission [Koob et al 1999].

Clinical Features of ADCA

Figure 1. Worldwide distribution of SCA subtypes [ (more...)

Figure 1. Worldwide distribution of SCA subtypes [Schöls et al 1997, Moseley et al 1998, Saleem et al 2000, Storey et al 2000, Tang et al 2000, Maruyama et al 2002, Silveira et al 2002, van de Warrenburg et al 2002, Dryer et al 2003, Brusco et al 2004, Schöls et al 2004, Shimizu et al 2004, Zortea et al 2004, Jiang et al 2005].
[For larger view, click here.]
Figure published courtesy of L Schöls, P Bauer, T Schmidt, T Schulte, O Reiss of University of Tübingen and Ruhr-University Bochum, Germany.

Age of onset and physical findings in the autosomal dominant ataxias overlap. Table 2 indicates a few more or less distinguishing clinical features for each type [Hammans 1996, Nance 1997, Schöls et al 1997, Klockgether et al 1998, Kerber et al 2005, Kraft et al 2005, Maschke et al 2005]. Often the autosomal dominant ataxias cannot be differentiated by clinical or neuroimaging studies; they are usually slowly progressive and often associated with cerebellar atrophy, as seen from brain imaging studies. The frequency of the occurrence of each disease within the autosomal dominant cerebellar ataxia (ADCA) population is noted in Table 2. Refer to Figure 1 for reported prevalence of ADCA subtypes worldwide.

Data are based on a comprehensive study in the US by Moseley et al [1998]. The prevalence of individual subtypes of ADCA may vary from region to region, frequently because of founder effects. For example, DRPLA and SCA3 are more common in Japan and Portugal, respectively; SCA2 is common in Korea and SCA3 is much more common in Japan and Germany than in the United Kingdom [Leggo et al 1997, Schöls et al 1997, Watanabe et al 1998, Kim et al 2001, Silveira et al 2002]. SCA3 was originally described in Portuguese families from the Azores and called Machado-Joseph disease (MJD). DRPLA is rare in North America and common in Japan. A recent study found evidence of frequency variation between different regions in Japan [Matsumura et al 2003].

Table 2. Autosomal Dominant Cerebellar Ataxias: Clinical Features

Disease Name 1	Average Onset (Range in Years)	Average Duration (Range in Years)	Distinguishing Features (All Have Gait Ataxia)	Other	References
SCA1	4th decade (<10 to >60)	15 years (10-28)	Pyramidal signs, peripheral neuropathy
SCA2	3rd - 4th decade (<10 to >60)	10 years (1-30)	Slow saccadic eye movements, peripheral neuropathy, decreased DTRs, dementia
SCA3	4th decade (10-70)	10 years (1-20)	Pyramidal and extrapyramidal signs; lid retraction, nystagmus, decreased saccade velocity; amyotrophy fasciculations, sensory loss
SCA4	4th - 7th decade (19-72)	Decades	Sensory axonal neuropathy, deafness	May be allelic with 16q22-linked SCA	[Flanigan et al 1996]
SCA, 16q22-linked	(55)		Late-onset hearing loss	May be allelic with SCA4	[Nagaoka et al 2000, Wieczorek et al 2006]
SCA5	3rd - 4th decade (10-68)	>25 years	Early onset, slow course	1st reported in descendants of Abraham Lincoln	[Ranum et al 1994, Ikeda et al 2006, Stevanin et al 1999, Burk et al 2004]
SCA6	5th - 6th decade (19-71)	>25 years	Sometimes episodic ataxia, very slow progression
SCA7	3rd - 4th decade (0.5 - 60)	20 years (1-45; early onset correlates with shorter duration)	Visual loss with retinopathy
SCA8	39 yrs (18-65)	Normal lifespan	Slowly progressive, sometimes brisk DTRs, decreased vibration sense; rarely, cognitive impairment		[Day et al 2000, Juvonen et al 2000, Ito et al 2006]
Disease Name	Average Onset (Range in Years)	Average Duration (Range in Years)	Distinguishing Features (All Have Gait Ataxia)	Other	References
SCA10	36 yrs	9 years	Occasional seizures	Most families are of Mexican background	[Grewal et al 1998, Matsuura et al 1999]
SCA11	30 yrs (15-70)	Normal lifespan	Mild, remain ambulatory		[Worth et al 1999, Houlden et al 2007]
SCA12	33 yrs (8-55)		Slowly progressive ataxia; action tremor in the 30s; hyperreflexia; subtle Parkinsonism possible; cognitive/psychiatric disorders incl dementia		[Holmes et al 1999, Fujigasaki et al 2001, O'Hearn et al 2001, Bahl et al 2005]
SCA13	Childhood	Unknown	Mild mental retardation, short stature		[Durr et al 2000, Herman-Bert et al 2000, Waters et al 2005]
SCA14	28 yrs (12-42)	Decades (1-30)	Early axial myoclonus		[Yamashita et al 2000, Brkanac et al 2002a, Chen et al 2003a, van de Warrenburg et al 2003, Yabe et al 2003, Stevanin et al 2004]
SCA15	Unknown	Decades	Pure ataxia, very slow progression		[Knight et al 2001, Storey et al 2001, Knight et al 2003]
SCA16	39 yrs (20-66)	1-40 years	Head tremor	One Japanese family	[Miyoshi et al 2001, Miura et al 2006]
SCA17	6-34 yrs	>8 years	Mental deterioration; occasional chorea, dystonia, myoclonus, epilepsy	Purkinje cell loss, intranuclear inclusions with expanded polyglutamine	[Koide et al 1999, Fujigasaki et al 2001, Nakamura et al 2001, De Michele et al 2003, Lasek et al 2006]
Disease Name	Average Onset (Range in Years)	Average Duration (Range in Years)	Distinguishing Features (All Have Gait Ataxia)	Other	References
SCA19	34 years (20-45)	Decades	Cognitive impairment, myoclonus, tremor	One Dutch family	[Schelhaas et al 2001, Verbeek et al 2002]
SCA20	46 years (19-64)	Decades	Early dysarthria, spasmodic dysphonia, hyperreflexia, bradykinesia	Calcification of the dentate nucleus	[Knight et al 2004]
SCA21	6-30 yrs	Decades	Mild cognitive impairment		[Devos et al 2001]
SCA22	10-46 yrs	Decades	Slowly progressive ataxia	One Taiwanese family	[Chung et al 2003]
SCA23	5th-6th decade	>10 years	Dysarthria, abnormal eye movements, reduced vibration and position sense	One Dutch family; neuropathology 2	[Verbeek et al 2004]
SCA25	1.5-39 yrs	Unknown	Sensory neuropathy	One French family	[Stevanin et al 2003]
SCA26	26-60 yrs	Unknown	Dysarthria, irregular visual pursuits	One Norwegian-American family; MRI: cerebellar atrophy	[Yu et al 2005]
SCA27	11 yrs (7-20)	Decades	Early-onset tremor; dyskinesia, cognitive deficits	One Dutch family	[van Swieten et al 2003, Brusse et al 2006]
SCA28	19.5 yrs (12-36)	Decades	Nystagmus, ophthalmoparesis, ptosis, increased tendon reflexes	Two Italian families	[Cagnoli et al 2005, Mariotti et al 2008]
DRPLA	8-20 yrs or 40-60s	Early onset correlates with shorter duration	Chorea, seizures, dementia, myoclonus	Often confused with Huntington disease
EA1	1st decade (2-15)	Attenuates after 20 years	Myokymia; attacks lasting seconds to minutes; startle or exercise induced; no vertigo
EA2	3-52 yrs	Lifelong	Nystagmus; attacks lasting minutes to hours; posture change induced; vertigo; later, permanent ataxia
ADSA	10-20 yrs	Normal lifespan	Initial progressive leg spasticity	Similar to ARSACS

ADCA = autosomal dominant cerebellar ataxias

SCA = spinocerebellar ataxia

DRPLA = dentatorubral-pallidoluysian atrophy

SAX = spastic ataxia

EA = episodic ataxia

DTRs = deep tendon reflexes

ADSA = autosomal dominant spastic ataxia

1. SCA9 has not been assigned.

2. Purkinje cell loss, demyelination of the posterior and lateral columns of the spinal cord, and neuronal intranuclear inclusions in the substantia nigra

Autosomal Recessive Hereditary Ataxias

Autosomal recessive disorders that include ataxia have been reviewed (see review: Breedveld et al 2004).

Table 3 and Table 4 summarize information for eight typical autosomal recessive disorders in which ataxia is a prominent feature. The disorders are selected to indicate the range of genetic understanding that presently exists regarding recessive causes of ataxia. Other rare autosomal recessive hereditary ataxias are described briefly.

Molecular Genetics of Autosomal Recessive Hereditary Ataxias

Table 3. Examples of Autosomal Recessive Hereditary Ataxias: Molecular Genetics

Disease Name	Gene Symbol	Chromosomal Locus	Protein Name	Test Availability
Friedreich ataxia (FRDA)	FXN	9q13	Frataxin	Clinical
Ataxia-telangiectasia (A-T)	ATM	11q22.3	Serine-protein kinase ATM	Clinical
Ataxia with vitamin E deficiency (AVED)	TTPA	8q13.1-q13.3	Alpha-tocopherol transfer protein	Clinical
Ataxia with oculomotor apraxia type 1 (AOA1)	APTX	9p13.3	Aprataxin	Clinical
Ataxia with oculomotor apraxia type 2 (AOA2)	SETX	9q34	Probable helicase senataxin	Clinical
IOSCA 1	PEO1	10q24	Twinkle protein	Clinical
Marinesco-Sjögren	SIL1	5q31	Nucleotide exchange factor SIL1	Research only
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)	SACS	13q12	Sacsin	Clinical

1. IOSCA = infantile-onset spinocerebellar ataxia

X-Linked Hereditary Ataxias

X-linked sideroblastic anemia and ataxia (XLSA/A) is characterized by early-onset ataxia, dysmetria, and dysdiadochokinesis. The ataxia is either non-progressive or slowly progressive. Upper motor neuron (UMN) signs (brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses) are present in some males. Mild learning disability is seen. Anemia is mild without symptoms. Carrier females have a normal neurologic examination. Causative mutations are present in ABC7, encoding a protein involved with mitochondrial iron transport, suggesting a common pathogenesis with Friedreich ataxia [Allikmets et al 1999, Bekri et al 2000, Maguire et al 2001].

Adult-onset ataxia, especially in men, may be part of the fragile X-associated tremor/ataxia syndrome (FXTAS) [Hagerman & Hagerman 2004] (see FMR1-Related Disorders).

Ataxias with Mitochondrial Disorders

A progressive ataxia is sometimes associated with mitochondrial diseases (see Mitochondrial Disease Overview) such as MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa) [DiMauro & Bonilla 1997], and Kearns-Sayre syndrome. Mitochondrial disorders are often associated with additional clinical manifestations, such as seizures, deafness, diabetes mellitus, cardiomyopathy, retinopathy, and short stature.

A deficiency of coenzyme Q10 has been described in individuals with cerebellar ataxia, usually with childhood onset and often associated with seizures [Musumeci et al 2001, Lamperti et al 2003]. The symptoms may respond to coenzyme Q10 treatment.

Mode of Inheritance

Hereditary ataxias may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner.

Risk to Family Members — Autosomal Dominant Hereditary Ataxias

Parents of a proband

• Most individuals diagnosed as having autosomal dominant ataxia have an affected parent, although occasionally the family history is negative.

• Family history may appear to be negative because of early death of a parent, failure to recognize autosomal dominant ataxia in family members, late onset in a parent, reduced penetrance of the mutant allele in an asymptomatic parent, or a de novo mutation for autosomal dominant ataxia.

Sibs of a proband

• The risk to sibs depends upon the genetic status of the proband's parents.

• If one of the proband's parents has a mutant allele, the risk to the sibs of inheriting the mutant allele is 50%.

Offspring of a proband. Individuals with autosomal dominant ataxia have a 50% chance of transmitting the mutant allele to each child.

Risk to Family Members — Autosomal Recessive Hereditary Ataxias

Parents of a proband

• The parents are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation.

• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

Offspring of a proband. All offspring are obligate carriers.

Risk to Family Members — X-Linked Recessive Hereditary Ataxias

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• Women who have an affected son and another affected male relative are obligate heterozygotes.

Sibs of a proband. A female carrier has a 50% chance of transmitting the disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation are carriers and will be unaffected.

Offspring of a proband. All the daughters of an affected male are carriers; none of his sons will be affected.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with autosomal dominant cerebellar ataxia is possible after molecular genetic testing has identified the specific disorder and mutation in the proband. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. When testing at-risk individuals, an affected family member should be tested first to confirm that the mutation is identifiable by currently available techniques. Results of testing of 29 asymptomatic persons at risk for autosomal dominant ataxias have been reported [Goizet et al 2002].

Testing of asymptomatic individuals during childhood at risk for adult-onset disorders for which no treatment exists is not appropriate in the absence of symptoms. The principal arguments against testing asymptomatic individuals who are younger than age 18 years are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Individuals who are symptomatic during childhood usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents (Genetic Testing; pdf).

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for some of the hereditary ataxias is possible by analyzing fetal DNA (extracted from cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation) for disease-causing mutations. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for (typically) adult-onset diseases are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) have been identified. For laboratories offering PGD, see .

Treatment of Manifestations

Management is usually directed at providing assistance for coordination problems through established methods of rehabilitation medicine and occupational and physical therapy.

• Canes, walkers, and wheelchairs are useful for gait ataxia.

• Special devices are available to assist with handwriting, buttoning, and use of eating utensils.

• Speech therapy may benefit persons with dysarthria. Computer devices are available to assist persons with severe speech deficits.

Prevention of Primary Manifestations

With the exception of vitamin E therapy for AVED, no specific treatments exist for hereditary ataxia.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Revision History

• 6 January 2009 (cd) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as probable cause of SCA20

• 25 September 2008 (tb) Revision: heterozygous mutations in AFG3L2 identified as the cause of SCA28

• 27 February 2008 (tb) Revision: deletion of part of ITPR1 identified as cause of SCA15

• 18 December 2007 (tb) Revision: mutations in TTBK2 associated with SCA11

• 27 June 2007 (me) Comprehensive update posted to live Web site

• 27 October 2006 (tb) Revision: SCA16 reassigned to 3p26.2-pter

• 31 August 2006 (tb) Revision: clinical testing available for infantile-onset spinocerebellar ataxia (IOSCA)

• 4 August 2006 (tb) Revision: clinical testing available for SCA5, SCA13, SCA27, and 16q22-linked SCA

• 27 April 2006 (tb) Revision: mutations in KCNC3 cause SCA13; additions to Causes- Autosomal Dominant Cerebellar Ataxias, References

• 1 February 2006 (tb) Revision: mutations in SPTBN2 cause SCA5

• 19 December 2005 (tb) Revision: Marinesco-Sjögren caused by mutations in SIL1

• 8 November 2005 (tb) Revision: SCA28

• 17 October 2005 (tb) Revision: SCA27

• 14 September 2005 (tb) Revision: author changes

• 12 July 2005 (tb) Revision: SCA4 gene and protein identified

• 4 April 2005 (tb) Revision: SCA26 added

• 8 February 2005 (me) Comprehensive update posted to live Web site

• 23 November 2004 (tb) Revision: author changes

• 14 October 2004 (tb/cd) Revision

• 30 June 2004 (tb) Revision: SCA20 added

• 11 June 2004 (tb) Revision: SCA12 gene identified

• 27 May 2004 (ca) Revision: addition of SCA world map (Figure 1)

• 23 January 2004 (tb) Revision: SCA19

• 30 December 2003 (tb) Revision: change in test availability

• 2 October 2003 (tb) Revision: X-linked sideroblastic anemia gene identified

• 17 July 2003 (tb) Revision: SCA22

• 20 May 2003 (tb) Revision

• 27 February 2003 (me) Comprehensive update posted to live Web site

• 9 January 2002 (tb) Revision: SCA18

• 8 November 2001 (tb) Revision: SCA15, SCA18

• 14 August 2001 (tb) Revision: SCA17

• 25 July 2001 (tb) Revision: SCA16

• 11 April 2001 (tb) Revision: SCA12

• 8 December 2000 (tb) Revision: SCA10

• 15 November 2000 (tb) Revision: AOA

• 8 November 2000 (tb) Revision: SCA10

• 25 September 2000 (tb) Revision: SCA8

• 25 August 2000 (tb) Revision: SCA14

• 7 August 2000 (tb) Revision: Hereditary Ataxias/Clinical Features & References

• 14 June 2000 (tb) Revision

• 22 May 2000 (tb) Revision

• 14 January 2000 (tb) Revision

• 25 October 1999 (tb) Revision

• 31 August 1999 (tb) Revision

• 11 March 1999 (tb) Revision: SCA8

• 5 March 1999 (tb) Revision: SCA10

• 28 October 1998 (me) Overview posted to live Web site

• 23 June 1998 (tb) Original submission