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Hereditary Ataxia Overview

Summary

Disease characteristics. The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. The hereditary ataxias are categorized by mode of       inheritance and causative gene or chromosomal locus.

Diagnosis/testing. Genetic forms of ataxia must be distinguished from the many acquired (non-genetic) causes of ataxia. The genetic forms of ataxia are diagnosed by family history, physical examination, and neuroimaging. Molecular genetic tests are available in clinical laboratories for the diagnosis of SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8, SCA10, SCA12, SCA13, SCA14, SCA17, SCA27, 16q22-linked SCA, ataxia with vitamin E deficiency (AVED), ataxia with oculomotor apraxia type 1 (AOA1), DRPLA, Friedreich ataxia (FRDA), infantile-onset spinocerebellar ataxia (IOSCA), and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).

Management.  Treatment of manifestations: Canes, walkers, and wheelchairs for gait ataxia; use of special devices to assist with handwriting, buttoning, and use of eating utensils; speech therapy and/or computer-based devices for those with dysarthria and severe speech deficits. Prevention of primary manifestations: No specific treatments exist for hereditary ataxia, except vitamin E therapy for ataxia with vitamin E deficiency (AVED).

Genetic counseling. The hereditary ataxias can be inherited in an autosomal dominant, autosomal       recessive , or X-linked manner. Genetic counseling and risk assessment depend on determination of the specific ataxia subtype in an individual.

Definition

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 are 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].

Causes

Single-gene causes.  The hereditary ataxias can be subdivided by mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, and mitochondrial) and causative gene or chromosomal locus. The hereditary ataxias have also been summarized by Evidente et al (2000), Pulst (2002), Rosa & Ashizawa (2002), and Duenas et al (2006).

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, Bylenok et al 2002 ; Chen, Brkanac et al 2003 ; Chen, Cimino et al 2003 ; 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 SCA20 11p13-q11 --- --- Knight et al 2004 SCA21 SCA21 7p21-p15.1 --- --- Vuillaume et al 2002 SCA22 --- 1p21-q21 --- --- --- SCA23 --- 20p13-p12.3 --- --- Verbeek et al 2002 , Chung et al 2003 , Chung & Soong 2004 , Schelhaas 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 --- 18p11.22-q11.2 --- --- Cagnoli et al 2005 DRPLA ATN 12p13.3 Atrophin-1 CAG repeat EA1 KCNA1 12p13 Potassium voltage-gated channel subfamily A member 1 --- EA2  3 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, Fernandez et al 2002]
• 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

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.

[For larger view, click here.]

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].

Figure published courtesy of L Schöls, P Bauer, T Schmidt, T Schulte, O Reiss of University of Tübingen and Ruhr-University Bochum, Germany.

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].

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

Clinical Features of Autosomal Recessive Hereditary Ataxias

Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses [Lynch et al 2006]. About 25% of affected individuals have an "atypical" presentation with later onset (after age 25 years), retained tendon reflexes, or unusually slow progression of disease. The vast majority of individuals have a GAA triplet-repeat expansion in the FXN gene. Unlike the autosomal dominant cerebellar ataxias caused by CAG trinucleotide repeats, FRDA is not associated with anticipation [Durr et al 1996].

Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Testing that supports the diagnosis of individuals with A-T is identification of a 7;14 chromosome translocation on routine karyotype of peripheral blood; the presence of immunodeficiency; and in vitro radiosensitivity assay. Molecular genetic testing of the ATM gene is available clinically.

Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens with dysarthria, poor balance when walking (especially in the dark), and progressive clumsiness resulting from early loss of proprioception. Some individuals experience dystonia, psychotic episodes (paranoia), pigmentary retinopathy and/or intellectual decline. Most individuals become wheelchair bound as a result of ataxia and/or leg weakness between ages 11 and 50 years. Although phenotypically similar to FRDA, AVED is more likely to be associated with head titubation or dystonia and less likely to be associated with cardiomyopathy. It is important to consider the diagnosis of AVED (which can be made by measuring serum concentration of vitamin E) because it is treatable with vitamin E supplementation [Yokota et al 1997 , Cavalier et al 1998].

An individual with both SCA8 and recessive ataxia with vitamin E deficiency (AVED) did not respond to vitamin E replacement [Cellini et al 2002].

A different autosomal recessive ataxia occurring on Grand Cayman Island is caused by mutations in a gene encoding a protein that may also be involved in vitamin E metabolism [Bomar et al 2003].

Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia (mean age of onset about seven years), followed in a few years by oculomotor apraxia that progresses to external ophthalmoplegia. All affected individuals have a severe primary motor peripheral neuropathy leading to quadriplegia with loss of ambulation about seven to ten years after onset. Intellect remains normal in affected individuals of Portuguese ancestry but mental deterioration has been seen in affected individuals of Japanese ancestry. The diagnosis of AOA1 is based on clinical findings [Barbot et al 2001 , Date et al 2001 , Moreira et al 2001 , Le Ber et al 2003 , Onodera 2006].

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between ages ten and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of alpha-fetoprotein (AFP) [Moreira et al 2003 , Asaka et al 2006]. The diagnosis of AOA2 is based on clinical and biochemical findings, family history, and exclusion of the diagnosis of ataxia-telangiectasia and AOA1.

Infantile-onset SCA (IOSCA) is a rare disorder reported from Finland with degeneration of the cerebellum, spinal cord, and brain stem and sensory axonal neuropathy [Nikali et al 2005].

Marinesco-Sjögren syndrome is a rare disorder in which ataxia is associated with mental retardation, cataract, short stature, and hypotonia [Zimmer et al 1992 , Anttonen et al 2005 , Senderek et al 2005].

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by early-onset (age 12-18 months) difficulty in walking and gait unsteadiness. Ataxia, dysarthria, spasticity, extensor plantar reflexes, distal muscle wasting, a distal sensorimotor neuropathy predominantly in the legs, and horizontal gaze nystagmus constitute the major neurologic signs, which are most often progressive. Yellow streaks of hypermyelinated fibers radiate from the edges of the optic fundi in the retina of Quebec-born individuals with ARSACS [Bouchard et al 1998]; the retinal changes are uncommon in French, Tunisian, and Turkish individuals with ARSACS [Mrissa et al 2000 , Pulst & Filla 2000]. Individuals with ARSACS become wheelchair bound at the average age of 41 years; cognitive skills are preserved long term and individuals are able to accomplish activities of daily living late into adulthood. Death commonly occurs in the sixth decade.

Other autosomal recessive cerebellar ataxias not included in Tables 3 and 4

• Ataxia with mental retardation, peripheral neuropathy, and marked cerebellar atrophy, reported in Japan [Tachi et al 2000]
• A family from Saudi Arabia with cerebellar atrophy, ataxia, and axonal sensorimotor neuropathy (linked to chromosome 14q31-q32; associated with mutations in TDP1, encoding topoisomerase 1-dependent DNA damage repair enzyme) [Takashima et al 2002]
• Ataxia with posterior column degeneration of the spinal cord and retinitis pigmentosa [Higgins et al 1997]
• Ataxia with hypogonadotrophic hypogonadism. A similar sibship has shown a deficiency of coenzyme Q10 [Gironi et al 2003].
• Ataxia with mental retardation, optic atrophy, and skin abnormalities in an inbred Lebanese family (linked to 15q24-q26) [Megarbane et al 2001 , Delague et al 2002]
• Ataxia with deafness and optic atrophy (linked to 6p21-p23) [Bomont et al 2000]
• A single Slovenian family in which five of 14 siblings have ataxia with saccadic intrusions, sensory neuropathy, and myoclonus [Swartz et al 2002]
• A large inbred Norwegian family with infantile-onset non-progressive ataxia (linked to 20q11-q13) [Tranebjaerg et al 2003]
• Ataxia and developmental delay, frequently seen in older children with biotinidase deficiency
• A Palestinian family with MR and cerebellar atrophy (linked to 22q11) [Baris et al 2005]
• Mutations in VLDLR, encoding the very low-density lipoprotein receptor, in Hutterite families with non-progressive cerebellar ataxia and mental retardation with inferior cerebellar hypoplasia and mild cerebral gyral simplification [Boycott et al 2005]
• A Dutch family with childhood-onset ataxia with pyramidal signs, postural tremor, and posterior column sensory loss (linked to 11p15) [Breedveld et al 2004]
• Several French Canadian families in the Beauce region of Quebec with a late-onset cerebellar ataxia associated with mutations in SYNE1 [Gros-Louis et al 2007] (see SYNE1-Related Disorders)
• Disorders associated with congenital cerebellar agenesis of varying degrees:
  • Joubert syndrome [Dixon-Salazar et al 2004 , Ferland et al 2004]
  • Cerebellar agenesis with neonatal diabetes mellitus [Sellick et al 2004]
  • Congenital disorders of glycosylation [Grunewald et al 2002]

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.

Evaluation Strategy

Once the diagnosis of ataxia has been established in an individual, the following approach can be used to determine the specific cause of ataxia to aid in discussions of prognosis and genetic counseling. Establishing the specific cause of hereditary ataxia for a given individual usually involves a medical history, physical examination, neurologic examination, and neuroimaging, as well as detailed family history and use of molecular genetic testing.

Clinical findings.  Because of extensive clinical overlap between all of the forms of hereditary ataxia, it is difficult in any given individual with ataxia and a family history consistent with autosomal dominant inheritance to establish a diagnosis without molecular genetic testing. Clinical findings may help distinguish between some of the autosomal recessive ataxias.

Family history.  A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records including the results of molecular genetic testing, neuroimaging studies, and autopsy examinations.

Testing.   Non-DNA-based clinical tests are available for two autosomal recessive hereditary ataxias: ataxia-telangiectasia (A-T) and ataxia with vitamin E deficiency (AVED).

Molecular genetic testing.  Tan & Ashizawa (2001), Rosa & Ashizawa (2002), and Maschke et al (2005) have discussed a clinical diagnosis testing strategy using DNA analysis.

Testing strategy when the family history suggests autosomal dominant inheritance

• An estimated 50%-60% of the dominant hereditary ataxias (see Table 1) can be identified with highly accurate and specific molecular genetic testing for SCA1 , SCA2 , SCA3 , SCA6 , SCA7 , SCA8 , SCA10 , SCA12 , SCA17 , and DRPLA ; all have trinucleotide repeat expansions in the pertinent genes.

• Because of the broad clinical overlap, most laboratories that test for the hereditary ataxias have a battery of tests including testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA12, SCA14 , and SCA17. Many laboratories offer them as two groups in stepwise fashion based on population frequency, testing first for the more common ataxias, SCA1, SCA2, SCA3, SCA6, and SCA7.

• Testing is also available for some autosomal dominant forms of SCA that are not associated with repeat expansions, namely SCA5, SCA13 , SCA14, SCA27, and 16q22-linked SCA.

• Testing for the less common hereditary ataxias should be individualized and may depend on such factors as ethnic background (SCA10 in the Mexican population, with some exceptions [Fujigasaki et al 2002 , Matsuura et al 2002]), presence of tremor (SCA12), presence of cognitive deficit or chorea (SCA17), or uncomplicated ataxia with long duration (SCA8 and SCA14).

• If a strong clinical indication of a specific diagnosis exists based on the affected individual's examination (e.g., the presence of retinopathy, which suggests SCA7) or if family history is positive for a known type, testing can be performed for a single disease.

• Of note, the interpretation of test results can be complex because (1) the exact range for the abnormal CAG repeat expansion has not been fully established for many of these disorders; (2) only a few families have been reported with mutations in ATXN8OS (the gene associated with SCA8) and thus penetrance and gender effects have not been completely resolved. Thus, diagnosis and genetic counseling of individuals undergoing such testing require the support of an experienced laboratory, medical geneticist, and genetic counselor.

• Of note, the cost of the battery of ataxia tests is equivalent to that of an MRI. Positive results from the molecular genetic testing are more specific than an MRI. Although the probability of a positive result from molecular genetic testing is low in an individual with ataxia who has no family history of ataxia, such testing is usually justified to establish a specific diagnosis for the individual's medical evaluation and for genetic counseling.

Testing strategy when the family history reveals affected sibs only.  A family history in which only sibs are affected suggests autosomal recessive inheritance. Because of their frequency and/or treatment potential, Friedreich ataxia , ataxia-telangiectasia , ataxia with vitamin E deficiency , and metabolic or lipid storage disorders including Refsum disease and chronic or adult-onset hexosaminidase A deficiency (GM2 gangliosidosis) should be considered.

Testing strategy for simplex cases (i.e., a single occurrence in a family, sometimes incorrectly referred to as a "sporadic" occurrence). If no acquired cause is identified, the probability is about 13% that the affected individual has SCA1, SCA2, SCA3, SCA6, SCA8, SCA17, or Friedreich ataxia [Abele et al 2002]. Other possibilities to consider are a de novo mutation in a different autosomal dominant ataxia, decreased penetrance, alternate paternity, or a single occurrence of an autosomal recessive or X-linked disorder in a family.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

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 (pdf; Genetic Testing).

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 DNA Banking for a list of laboratories offering this service.

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) has/have been identified. For laboratories offering PGD, see .

Management

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.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents (pdf; Genetic Testing).
  
  
• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders.

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