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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].