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.

Hereditary ataxia may result from one or any combination of the following:

• Dysfunction of the cerebellum and its associated systems

• Lesions in the spinal cord

• Peripheral sensory loss

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 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 results of 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

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Disease Name	Gene Symbol or Chromosomal Locus 1	Type of Mutation	Reference	Test Availability
SCA1	ATXN1	CAG repeat	Lin & Ashizawa [2011]	Clinical
SCA2	ATXN2	CAG repeat	Pulst [2010]	Clinical
SCA3	ATXN3	CAG repeat	Paulson [2011]	Clinical
SCA4 2	16q22.1	---	Flanigan et al [1996], Hellenbroich et al [2003], Edener et al [2011]	Research only
SCA5	SPTBN2	Non-repeat mutations	Ikeda et al [2006]	Clinical
SCA6	CACNA1A	CAG repeat	Gomez [2008]	Clinical
SCA7	ATXN7	CAG repeat	Bird et al [2007]	Clinical
SCA8	ATXN8 / ATXN80S	CAG·CTG	Ikeda et al [2007]	Clinical
SCA9 3	---	---
SCA10	ATXN10	ATTCT repeat	Matsuura & Ashizawa [2010]	Clinical
SCA11	TTBK2	Non-repeat mutations	Houlden [2008]	Clinical
SCA12	PPP2R2B	CAG repeat	Margolis et al [2011]	Clinical
SCA13	KCNC3	Non-repeat mutations	Pulst [2012]	Clinical
SCA14	PRKCG	Non-repeat mutations	Chen et al [2010]	Clinical
SCA15	ITPR1	Deletion of the 5' part of the gene	Storey [2011]	Clinical
SCA16	SCA16	---	Miura et al [2006]	Research only
SCA17	TBP	CAA/CAG repeat mutation	Toyoshima et al [2007]	Clinical
SCA18	IFRD1	Non-repeat mutations		Clinical
SCA19	SCA19	---	Verbeek et al [2002], Chung & Soong [2004], Schelhaas et al [2004]	Research only
SCA20	11q12.2-11q12.3	260-kb duplication	Storey [2009]	Research only
SCA21	SCA21	---	Vuillaume et al [2002]	Research only
SCA22	1p21-q21	---	Chung et al [2003], Chung & Soong [2004], Schelhaas et al [2004]	Research only
SCA23	PDYN	---	Verbeek et al [2004], Bakalkin et al [2010]	Clinical
SCA25	SCA25	---		Research only
SCA26	19p13.3	---	Yu et al [2005]	Research only
SCA27	FGF14	---	van Swieten et al [2003]	Clinical
SCA28	AFG3L2	---	Cagnoli et al [2006], Mariotti et al [2008]	Clinical
SCA29	3p26	---	Dudding et al [2004]	Research only
SCA30	4q34.3-q35.1	---	Storey et al [2009]	Research only
SCA31 2	BEAN1		Sato et al [2009], Sakai et al [2010], Edener et al [2011]	Research only
SCA35	TGM6	Missense	Wang et al [2010]	Research only
SCA36	NOP56	GGCCTG Intronic repeat expansion	Kobayashi et al [2011]	Research only
DRPLA	ATN1	CAG repeat	Tsuji [2010]	Clinical
EA1	KCNA1	---	Pessia & Hanna [2010]	Clinical
EA2 4	CACNA1A	Non-repeat mutations	Spacey [2011]	Clinical
	CACNB4	---		Clinical
EA3 5	1q42	---	Damji et al [1996]	Research only
EA4 6	---	---	Steckley et al [2001]	Research only
EA5	CACNB4	---	Jen et al [2007]	Clinical
EA6	SLC1A3	---	Jen et al [2007]	Clinical
ADSA 7	SAX1	---	Meijer et al [2002]	Research only

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Chromosomal locus is given only when the gene is unknown.

2. Japanese families linked to the 16q22 region have a single-nucleotide substitution (-16C>T) in the 5' UTR of PLEKHG4 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 [Sakai et al 2010]. Edener et al [2011] provide evidence that SCA4 and SCA31 are caused by different mutations, possibly in different genes at the same locus (16q22).

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

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

5. A single family with EA3 (periodic vestibulocerebellar ataxia with defective smooth pursuit) [Jen et al 2007]

6. A single family with EA4 (episodic ataxia with vertigo and tinnitus) [Jen et al 2007]

7. 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); caused by mutations in IFRD1 [Brkanac et al 2002, Brkanac et al 2009]

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

• Ataxia, cerebellar atrophy, intellectual disability, and possible attention deficit/hyperactivity disorder (ADHD) (associated with a heterozygous mutation in SCN8A, encoding a sodium channel [Trudeau et al 2006]

• 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 to Literature Cited).
  
  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]. The pathogenesis of the SCA8 phenotype is complex and also involves a (CAG)_n repeat in a second overlapping gene, ATXN8.
  
  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

The 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.

Figure

Figure 1. Worldwide distribution of SCA subtypes [Schöls et al 1997Moseley et al 1998Saleem et al 2000Storey et al 2000Tang et al 2000Maruyama et al 2002Silveira et al 2002van de Warrenburg et al 2002Dryer et al 2003Brusco et al 2004Schöls (more...)

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 in 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

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Disease Name 1	Average Onset (range in yrs)	Average Duration (range in yrs)	Distinguishing Features 2	Other	References
SCA1	3rd - 4th decade (<10 to >60)	15 yrs (10-28)	Pyramidal signs, peripheral neuropathy		Lin & Ashizawa [2011]
SCA2	3rd - 4th decade (<10 to >60)	10 yrs (1-30)	Slow saccadic eye movements, peripheral neuropathy, decreased DTRs, dementia		Pulst [2010]
SCA3	4th decade (10-70)	10 yrs (1-20)	Pyramidal and extrapyramidal signs; lid retraction, nystagmus, decreased saccade velocity; amyotrophy fasciculations, sensory loss		Paulson [2011]
SCA4	4th - 7th decade (19-72)	Decades	Sensory axonal neuropathy, deafness	May be allelic with 16q22-linked SCA	Flanigan et al [1996]
SCA5	3rd - 4th decade (10-68)	>25 yrs	Early onset, slow course	1st reported in descendants of Abraham Lincoln	Ranum et al [1994], Stevanin et al [1999], Burk et al [2004], Ikeda et al [2006]
SCA6	5th - 6th decade (19-71)	>25 yrs	Sometimes episodic ataxia, very slow progression		Gomez [2008]
SCA7	3rd - 4th decade (0.5 - 60)	20 yrs (1-45; early onset correlates with shorter duration)	Visual loss with retinopathy		Bird et al [2007]
SCA8	4th decade (1-65)	Normal life span	Slowly progressive, sometimes brisk DTRs, decreased vibration sense; rarely, cognitive impairment		Ikeda et al [2007]
SCA10	4th decade (12-48)	9 yrs	Occasional seizures	Most families are of Mexican background	Matsuura & Ashizawa [2010]
SCA11	Age 30 yrs (15-70)	Normal life span	Mild, remain ambulatory		Houlden [2008]
SCA12	4th decade (8-62)		Slowly progressive ataxia; action tremor in the 30s; hyperreflexia; subtle Parkinsonism possible; cognitive/psychiatric disorders incl dementia		Margolis et al [2011]
SCA13	Childhood or adulthood	Unknown	Mild intellectual disability, short stature		Pulst [2012]
SCA14	3rd - 4th decade (3-70)	Decades (1-30)	Early axial myoclonus		Chen et al [2010]
SCA15	4th decade (7-66)	Decades	Pure ataxia, very slow progression		Storey [2011]
SCA16	Age 39 yrs (20-66)	1-40 yrs	Head tremor	One Japanese family	Miyoshi et al [2001], Miura et al [2006]
SCA17	4th decade (3-55)	>8 years	Mental deterioration; occasional chorea, dystonia, myoclonus, epilepsy	Purkinje cell loss, intranuclear inclusions with expanded polyglutamine	Toyoshima et al [2007]
SCA19	Age 34 yrs (20-45)	Decades	Cognitive impairment, myoclonus, tremor	One Dutch family	Schelhaas et al [2001], Verbeek et al [2002]
SCA20	5th decade (19-64)	Decades	Early dysarthria, spasmodic dysphonia, hyperreflexia, bradykinesia	Calcification of the dentate nucleus	Storey [2009]
SCA21	(6-30)	Decades	Mild cognitive impairment		Devos et al [2001]
SCA22	(10-46)	Decades	Slowly progressive ataxia	One Taiwanese family	Chung et al [2003]
SCA23	5th - 6th decade	>10 yrs	Dysarthria, abnormal eye movements, reduced vibration and position sense	One Dutch family; neuropathology 3	Verbeek et al [2004]
SCA25	(1.5-39)	Unknown	Sensory neuropathy	One French family	Stevanin et al [2003]
SCA26	(26-60)	Unknown	Dysarthria, irregular visual pursuits	One Norwegian-American family; MRI: cerebellar atrophy	Yu et al [2005]
SCA27	Age 11 yrs (7-20)	Decades	Early-onset tremor; dyskinesia, cognitive deficits	One Dutch family	van Swieten et al [2003], Brusse et al [2006]
SCA28	Age 19.5 yrs (12-36)	Decades	Nystagmus, ophthalmoparesis, ptosis, increased tendon reflexes	Two Italian families	Cagnoli et al [2006], Mariotti et al [2008], Edener et al [2010]
SCA29	Early childhood	Lifelong	Learning deficits		Dudding et al [2004]
SCA30	(45-76)	Lifelong	Hyperreflexia		Storey et al [2009]
SCA31	5th-6th decade	Lifelong	Normal sensation		Nagaoka et al [2000]
SCA35	43.7 +/-2.9 (40-48) yrs	15.9+/-8.8 (5-31) yrs	Hyperreflexia, Babinski responses	Spasmodic torticollis	Wang et al [2010]
SCA36	52.8 +/- 4.3 years	Decades	Muscle fasiculations, tongue atrophy, hyperreflexia		Kobayashi et al [2011]
DRPLA	3rd - 4th decade (8-20 or 40-60s)	Early onset correlates with shorter duration	Chorea, seizures, dementia, myoclonus	Often confused with Huntington disease	Tsuji [2010]
EA1	1st - 2nd decade (2-15)	Attenuates after 20 yrs	Myokymia; attacks lasting seconds to minutes; startle or exercise induced; no vertigo		Pessia & Hanna [2010]
EA2	(2-32)	Lifelong	Nystagmus; attacks lasting minutes to hours; posture change induced; vertigo; later, permanent ataxia		Spacey [2011]
ADSA	(10-20)	Normal life span	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. All have gait ataxia.

3. 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: Embirucu et al [2009]).

Table 3 and Table 4 summarize information for eleven 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

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Disease Name	Gene Symbol / Protein Name	Reference	Test Availability
Friedreich ataxia (FRDA)	FXN / frataxin	Bidichandani & Delatycki [2012]	Clinical
Ataxia-telangiectasia (A-T)	ATM	Gatti [2010]	Clinical
Ataxia with vitamin E deficiency (AVED)	TTPA	Schuelke [2010]	Clinical
Ataxia with oculomotor apraxia type 1 (AOA1)	APTX / aprataxin	Coutinho & Barbot [2010]	Clinical
Ataxia with oculomotor apraxia type 2 (AOA2)	SETX	Moreira & Koenig [2011]	Clinical
IOSCA 1	C10orf2 / twinkle	Nikali & Lönnqvist [2010]	Clinical
Marinesco-Sjögren syndrome	SIL1	Anttonen & Lehesjoki [2010]	Clinical
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)	SACS / sacsin	Robitaille et al [2007]	Clinical
Refsum disease	PHYH PEX7	Wanders et al [2010]	Clinical
CoQ10 deficiency	CABC1 COQ2 COQ9 PDSS1 PDSS2	Montero et al [2007]	Clinical
Cerebrotendinous xanthomatosis (CTX)	CYP27A1	Federico et al [2011]	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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) [Berry-Kravis et al 2007, Leehey 2009] (see FMR1-Related Disorders).

Ataxias with Mitochondrial Disorders

A progressive ataxia is sometimes associated with mitochondrial disorders including MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa) [Finsterer 2009b], and Kearns-Sayre syndrome. Mitochondrial disorders are often associated with additional clinical manifestations, such as seizures, deafness, diabetes mellitus, cardiomyopathy, retinopathy, and short stature [Da Pozzo et al 2009].

Mode of Inheritance

Hereditary ataxias may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner. If a proband has a specific syndrome associated with ataxia (e.g., ataxia as a finding in a mitochondrial disorder or FXTAS), counseling for that condition is indicated.

Risk to Family Members — Autosomal Dominant Hereditary Ataxia

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.

Sibs of a proband

• The risk to sibs depends on 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 Ataxia

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 Hereditary Ataxia

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

• The risk to sibs depends on the carrier status of the mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.

• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the disease-causing mutation cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

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 family. 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].

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

For more information, 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.

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 to 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, discussion of these issues is appropriate.

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

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Treatment of Manifestations

Management of ataxias 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.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Underwood & Rubinsztein [2008] review potential strategies for treating ataxias associated with trinucleotide repeat expansions.

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

National Ataxia Registry
Phone: 352-273-9194
Fax: 352-392-8058
Email: NationalAtaxiaRegistry@neurology.ufl.edu
Web: www.nationalataxiaregistry.org

Other

Genetics clinics, staffed by genetics professionals, provide 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Published Guidelines/Consensus Statements

1. 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. Available online. 1995. Accessed 4-20-12.
2. National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available online. 1995. Accessed 4-20-12.

Literature Cited

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Suggested Reading

1. Rottnek M, Riggio S, Byne W, Sano M, Margolis RL, Walker RH. Schizophrenia in a patient with spinocerebellar ataxia 2: coincidence of two disorders or a neurodegenerative disease presenting with psychosis? Am J Psychiatry. 2008;165:964–7. [PubMed: 18676601]

Revision History

• 26 April 2012 (tb) Revision: autosomal recessive SCA caused by mutation in ANO10 added

• 16 February 2012 (tb) Revision: SCA35 added

• 26 January 2012 (tb) Revision: updated information on SCA with axonal neuropathy; SCAR9 added

• 15 September 2011 (tb) Revision: additional rare form of autosomal recessive ataxia

• 21 July 2011 (tb) Revision: addition of SCA36

• 17 February 2011 (me) Comprehensive update posted live

• 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