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.

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 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 (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		Subramony & 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		Garden [2012]
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 [2012]
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 [2012]
SCA18	Adolescence (12-25)	Decades	Ataxia with early sensory/motor neuropathy, nystagmus, dysarthria, decreased tendon reflexes	Muscle weakness, atrophy, fasiculations, Babinski responses	Brkanac et al [2002], Brkanac et al [2009]
SCA19/22	4th decade (10-51)	Decades	Slowly progressive, rare cognitive impairment, myoclonus, hyper-reflexia	Nine families	Schelhaas et al [2001], Verbeek et al [2002], Chung et al [2003], Lee et al [2012]
SCA20	5th decade (19-64)	Decades	Early dysarthria, spasmodic dysphonia, hyperreflexia, bradykinesia	Calcification of the dentate nucleus	Storey [2012]
SCA21	(6-30)	Decades	Mild cognitive impairment		Devos et al [2001]
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], Hekman et al [2012]
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		D'Adamo et al [2012]
EA2	(2-32)	Lifelong	Nystagmus; attacks lasting minutes to hours; posture change induced; vertigo; later, permanent ataxia		Spacey [2011]
SPAX1	(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

SPAX1 = autosomal dominant spastic ataxia 1

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.

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].

Pfeffer et al [2012] report that missense mutations in MTATP6 can cause both childhood and adult-onset cerebellar ataxia sometimes associated with abnormal eye movements, dysarthria, weakness, axonal neuropathy and hyperreflexia.

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.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions 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.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at approximately 15 to 18 weeks’ gestation) or chorionic villus sampling (usually performed at approximately ten to 12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

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 an option for some families in which the disease-causing mutation has been identified.

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.

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 1-10-13. [PMC free article: PMC1801355] [PubMed: 7485175]
2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 1-10-13.

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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

• 17 January 2013 (tb) Revision: mutation in KCND3 found to cause SCA19 and SCA22 (SCA19/22)
• 3 January 2013 (tb) Revision: clinical testing available for SCA35
• 1 November 2012 (tb) Revision: mutations in EEF2 identified as causative for SCA26
• 11 October 2012 (tb) Revision: mutations in VAMP1 identified as causative for SPAX1; mutations in GRM1 identified as causative for ARCA
• 13 September 2012 (tb) Revision: addition of Emre Onat et al [2012]
• 31 May 2012 (tb) Revision: to include Pfeffer et al 2012 re: ataxia associated with missense mutations in MTATP6; SCA18 assigned by OMIM to ataxia phenotype described by Brkanac et al 2002 and 2009.
• 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