Author: Thomas D Bird, MD
Last update: 25 October 1999
Summary Disease characteristics.
The hereditary ataxias are a group of genetic disorders producing slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs.
Genetic forms of ataxia must be carefully distinguished from the many acquired (non-genetic) causes of ataxia. The genetic forms of ataxia are diagnosed by family history, physical examination, and ancillary clinical tests such as neuro-imaging. DNA-based genetic tests are available for the diagnosis of many of the hereditary ataxias including spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6, SCA7), dentatorubral-pallidoluysian atrophy (DRPLA), and Friedreich ataxia (FRDA).
Genetic counseling. The hereditary ataxias can be inherited in an autosomal dominant (such as SCA1-12 and DRPLA), an autosomal recessive (such as Friedreich ataxia and ataxia-telangiectasia) and, less commonly, an X-linked manner. Genetic counseling and risk assessment depend on accurate determination of the specific ataxia subtype.
Definition of Ataxia
The term ataxia refers to poor coordination of movement and is frequently used to describe a wide-based, uncoordinated, unsteady gait. Poor coordination of the limbs and 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.
Categories Acquired, Non-Genetic Ataxias Acquired, non-genetic causes of ataxia include alcoholism, vitamin deficiencies, multiple sclerosis, vascular disease, primary or metastatic tumors, or a paraneoplastic syndrome associated with occult carcinoma of the ovary, breast, or lung. The possibility of an acquired cause of ataxia needs to be considered in each patient because a specific treatment may be available.
Hereditary Ataxias Hereditary ataxias (HA) are usually slowly progressive and often associated with cerebellar atrophy, as seen from brain imaging studies.
The clinical features and molecular genetics of the hereditary ataxias are summarized in the following sections. Links are provided to the hereditary ataxias that are profiled in GeneClinics.
Autosomal Dominant Cerebellar Ataxias (ADCA) Before the evolution of a genotypic classification, many patients with dominant ataxias were given diagnoses such as Marie's ataxia or inherited olivopontocerebellar atrophy or cerebello-olivary atrophy, or the more generic term "spinocerebellar degeneration."
Fourteen major types of autosomal dominant hereditary ataxias are now known for which specific genetic information is available. Eleven are spinocerebellar ataxias (SCA), one is a complex form (DRPLA), and two are episodic ataxias (the category SCA9 has been reserved, but no clinical or genetic information regarding this type has been published). The frequency of the occurrence of each disease within the autosomal dominant cerebellar ataxia (ADCA) population. These data are based on the comprehensive study in the USA by Moseley et al 1998. The frequencies may vary between different regions and ethnic groups. For example, SCA2 is common in Korea and SCA3 is much more common in Japan and Germany than in the United Kingdom [Watanabe et al 1998, Leggo et al 1997, Schols et al 1997]. SCA3 was originally described in Portuguese families from the Azores and called Machado-Joseph Disease (MJD). Dentatorubral-pallidoluysian atrophy (DRPLA) is rare in North America but common in Japan.
Great overlap is present in the clinical characteristics of the eleven ataxias (SCA1 - SCA12) both in terms of age of onset and physical findings. All have gait ataxia. Often they cannot be differentiated by clinical or neuro-imaging studies. For example, the presence of early slow saccadic eye movements suggests SCA2; sensory axonal neuropathy is common in SCA4; early-onset ataxia with a slow, prolonged course is characteristic of SCA5; later onset of an isolated ataxia with a slow prolonged course suggests SCA6; and visual loss with retinopathy suggests SCA7. SCA8 is a slowly progressive ataxia with cerebellar atrophy and sometimes brisk reflexes and a normal lifespan [Koob et al 1999]. SCA10 may be associated with seizures. SCA11 is a relatively mild ataxia with normal lifespan reported in two families and linked to 15q [Worth et al 1999]. SCA12 begins with a tremor and may eventually be associated with dementia [Holmes et al 1999]. In addition to ataxia, DRPLA is often associated with chorea, seizures, and dementia [Ikeuchi et al 1995], and is often confused with Huntington disease.
SCA1, 2, 3, 6, and 7 and DRPLA are caused by CAG trinucleotide repeat expansions within the coding sequences of their respective genes. SCA8 has a CTG expansion [Koob et al 1999]. All these disorders are considered trinucleotide expansion disorders [Paulson & Fischbeck 1996]. Since the CAG tract codes for glutamine, such disorders have also been called "polyglutamine disorders." DNA-based mutation analysis of CAG trinucleotide repeat length is a highly specific and highly sensitive diagnostic test for SCA1, 2, 3, 6, and 7 and DRPLA. The sizes of the normal CAG repeat allele and the sizes of the disease-causing CAG allele. In some disorders, "intermediate alleles," in which the CAG repeat number overlaps between the upper range of normal and the lower range of abnormal, are present. These intermediate alleles may result either from difficulty in the laboratory in precise measurement of allele size or represent a true biologic "gray zone" in which the allele may or may not be associated with phenotypic abnormalities. Diagnosis and genetic counseling of individuals with allele sizes in the intermediate range require the support of an experienced laboratory, medical geneticist, and genetic counselor.
Anticipation is observed in all the autosomal dominant ataxias in which CAG trinucleotide repeats occur except SCA6. Anticipation refers to earlier age of onset and increasing severity of disease in subsequent generations of a family. In these trinucleotide repeat diseases, anticipation results from expansion in the number of CAG repeats that occurs with transmission of the gene to subsequent generations. DRPLA and SCA7 have particularly unstable CAG repeats [LaSpada 1997, Nance 1997]. In SCA7, anticipation may be so extreme that children with early-onset, severe disease may die of disease complications long before the affected parent or grandparent is symptomatic. In all the autosomal dominant cerebellar ataxias (except SCA8), expansion of the CAG repeat is more likely to occur with paternal transmission of the expanded allele. 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 DNA-based 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 when transmitted to subsequent generations.
SCA8 differs from those disorders with CAG repeats in that the majority of expansions of the CTG repeat occur during maternal transmission [Koob et al 1999]. Extremely large repeats (such as 800) may be associated with no clinical symptoms for presently unknown reasons [Ranum et al 1999].
Two forms of autosomal dominant episodic ataxia (EA) are the result of ion channel mutations. EA1 is caused by mutations in a potassium channel gene [Browne et al 1994] and EA2 by mutations in a voltage-dependent calcium channel [Ophoff et al 1996]. EA2, SCA6, and one type of familial hemiplegic migraine all represent allelic mutations in the same calcium channel gene on chromosome 19p13 [Elliott 1997]. EA1 and EA2 do not have clinically available DNA-based testing Autosomal Recessive Hereditary Ataxias The differential diagnosis of autosomal recessive disorders that include ataxia is extensive and the reader is referred to detailed reviews [Harding 1993, Ylitalo & Hagberg 1988].
Five typical autosomal recessive disorders in which ataxia is a prominent feature. These disorders are selected to indicate the range of genetic understanding that presently exists regarding recessive causes of ataxia. Friedreich ataxia (FRDA), ataxia-telangiectasia (A-T), and ataxia with vitamin E deficiency (AVED) represent disorders for which disease-causing mutations have been identified in specific genes. Ataxia with vitamin E deficiency (AVED) is phenotypically similar to FRDA. Compared with FRDA, patients with AVED are more likely to have head titubation or dystonia and less likely to have cardiomyopathy. It is especially important to make the diagnosis of AVED (through measurement of blood levels of vitamin E) because the disorder can be treated with vitamin E supplementation [Cavalier et al 1998, Yokota et al 1997]. Marinesco-Sjögren syndrome is a rare disorder in which ataxia is associated with mental retardation, cataract, and neuromuscular hypotonia.
X-Linked Hereditary Ataxias Numerous single families have been described with ataxia inherited in an X-linked pattern. Most have other associated clinical findings such as spasticity [Apak et al 1989], mental retardation [Bertini et al 1992], deafness [Arts et al 1993], dementia [Farlow et al 1987], or sideroblastic anemia [Raskind et al 1991]. A few families with ataxia inherited in an X-linked pattern have uncomplicated ataxia [Spira et al 1979, Lutz et al 1989].
Ataxia with Mitochondrial Disorders
A progressive ataxia is sometimes associated with mitochondrial diseases such as MERRF (myoclonic epilepsy with ragged red fibers and NARP (neuropathy, ataxia, and retinitis pigmentosa) [DiMauro & Bonilla 1997]. Mitochondrial disorders are often associated with additional clinical manifestations, such as seizures, deafness, diabetes, cardiomyopathy, retinopathy, and short stature.
The term sporadic refers to the instance in which only one family member has a disorder. Sporadic cases of progressive ataxia are a relatively common occurrence. A small proportion of such cases (2-5%) prove to be one of the autosomal dominant cerebellar ataxias on the basis of a new mutation, false paternity, or decreased penetrance [Moseley et al 1998]. Other cases prove to have atypical instances of autosomal recessive Friedreich ataxia or an undiagnosed X-linked hereditary ataxia. Other autosomal recessive causes of ataxia, such as ataxia-telangiectasia, ataxia with vitamin E deficiency, and metabolic and lipid storage disorders such as the chronic and adult-onset forms of GM2 gangliosidoses, should also be considered. Some sporadic cases of ataxia prove to have an acquired, non-genetic cause.
Diagnosis of the Hereditary Ataxias
Establishing the correct diagnosis for a given patient usually involves a medical history, physical examination, and neurologic examination, as well as detailed family history and use of DNA-based testing.
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 DNA-based testing, neuro-imaging studies, and the results of autopsy examinations.
Because of extensive clinical overlap between all of the forms of SCA, it is very difficult in any given patient with ataxia and a family history consistent with autosomal dominant inheritance to establish a diagnosis without DNA-based testing.
DNA testing that is accurate and specific is clinically available for 6 types of autosomal dominant hereditary ataxia (SCA1, SCA2, SCA3, SCA6, SCA7, and DRPLA) and for one type of autosomal recessive hereditary ataxia [Friedreich ataxia (FRDA)]. About 50% of the dominant hereditary ataxias can be identified with DNA testing for these six disorders; all have trinucleotide repeat expansions in the pertinent genes. Other types of clinical tests are available for two types of autosomal recessive hereditary ataxias: ataxia telangiectasia (A-T) and ataxia with vitamin E deficiency (AVED).
Testing strategy when the family history suggests autosomal dominant inheritance
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 and SCA7. Many laboratories offer them as two groups in stepwise fashion based on population frequency, testing for SCA1, SCA2, and SCA3 first as they are more common and testing for SCA6 and SCA7 second as they are less common. This approach to testing is reasonable unless the clinician has a strong clinical indication of a specific diagnosis based on the patient's examination (e.g., the presence of retinopathy in a patient, which suggests SCA7) or if family history is positive for a known type; in these instances, testing can be performed for single diseases.
Note: The exact range for the abnormal CAG repeat expansion has not been fully established for many of these disorders. Expansions falling in an "intermediate" range require a review of the pertinent literature and consultation with a specialist. Also, penetrance of clinical phenotype varies with both CAG expansion size and patient age and differs with each type of ataxia.
Testing strategy when the family history is negative
Testing the patient with ataxia who has no family history of other individuals with similar findings presents a special problem. First, acquired non-genetic causes of ataxia should be considered. If no acquired cause is identified, then the probability is 2-5% [Moseley et al 1998] that a patient with sporadically occurring ataxia will have SCA1, SCA2, SCA3, SCA6, SCA7, or Friedreich ataxia (FRDA). At this point it is appropriate to consider testing for FRDA, even in patients with an atypical phenotype. Prior to the availability of molecular genetic testing, the diagnosis of FRDA was only considered in patients who met strict diagnostic criteria that included onset of symptoms less than 20 years of age and absence of deep tendon reflexes; however, based on the results of DNA-based testing, the phenotypic spectrum for FRDA has been broadened to include older age of onset (>20 years) and preservation of deep tendon reflexes [Durr et al 1996].
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 when the diagnosis is hereditary ataxia. Although the probability of a positive result from a molecular genetic test is low in a patient with sporadic ataxia, this approach is usually justified to establish a specific diagnosis for the patient's medical evaluation and for genetic counseling.
Family histories with affected sibs only
Family histories in which only affected sibs occur suggest autosomal recessive inheritance. The differential diagnosis in this situation includes a wide variety of recessive disorders, but of particular importance, 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's disease and Tay-Sachs GM2 gangliosidosis - should be considered.
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. This section deals with genetic risk assessment and the use of genetic testing to clarify genetic status. It is not meant to address all personal or cultural issues that individuals might face or to substitute for consultation with a genetics professional. —ED.
Once testing is completed, family members can be advised of the appropriate risk estimates based on the diagnosis in their family and their positions in the pedigree.
SCA 1, SCA2, SCA3, SCA6, SCA7 and DRPLA are autosomal dominant disorders. Each child of an affected person is at 50% risk of having the disease. FRDA, A-T, and AVED are autosomal recessive disorders. Each child of normal carrier parents is at 25% risk of having the disease. Testing asymptomatic at-risk adult relatives of individuals with autosomal dominant cerebellar ataxia is possible after direct DNA testing has identified the specific disorder in the proband. Such testing should be performed in the context of formal genetic counseling. Testing of asymptomatic at-risk children is strongly discouraged. Prenatal diagnosis is technically feasible; however, requests for this testing have not been reported. (See also the National Society of Genetic Counselors statement on genetic testing of children.)
Resources GeneClinics provides information about selected national organizations and resources for the benefit of the reader. GeneClinics is not responsible for information provided by other organizations.
National Ataxia Foundation 2600 Fernbrook Lane, Suite 119 Minneapolis, MN 55447 Phone: (612) 553-0020 Fax: (612) 553-0167 E-mail: email@example.com Web: http://www.ataxia.org References Statements and Guidelines Regarding Genetic Testing
The National Society of Genetic Counselors has published a resolution  on prenatal and childhood testing for adult-onset disorders. Literature Cited
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Profile History Author Thomas D Bird, MD [Medline Publications] University of Washington
Last Update/Review 25 October 1999
25 Oct 1999 (PB) Author updates 31 Aug 1999 (PB) Author updates 11 Mar 1999 (P Baskin) Author updates (SCA8) 5 Mar 1999 (P Baskin) Author updates (SCA10) 12 Oct 1998 (P Baskin) Author updates 24 Aug 1998 (P Baskin) Author updates 2 July 1998 (P Baskin) BP/TB edits added 23 June 1998 (P Baskin) T Bird edits added