Goal 1.

Briefly describe the clinical characteristics of hereditary ataxias (sometimes referred to as "primary hereditary ataxias") for which an adult with ataxia or the caregivers of a child with ataxia would seek diagnosis and management from a neurologist as part of a multidisciplinary team.

Goal 2.

Review common and notable genetic causes of hereditary ataxia.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of hereditary ataxia in a proband.

Goal 4.

Inform genetic counseling of family members of an individual with hereditary ataxia.

Goal 5.

Review management of hereditary ataxia.

Excluded Categories

For the purposes of this overview the following categories of hereditary disorders in which ataxia may occur are not considered primary hereditary ataxias:

• Infantile-onset multisystem disorder
• Epileptic encephalopathy
• Presence of distinctive MRI findings:
  • Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in Joubert syndrome and related disorders)
  • Leukodystrophy
• Developmental delay / intellectual disability
• An inborn error of metabolism (e.g., peroxisomal biogenesis disorders, Zellweger spectrum disorders, disorders of glycosylation)
• Primary mitochondrial disorders (See Primary Mitochondrial Disorders Overview.)
• Other complex multisystem disorders such as Niemann-Pick disease type C and late-onset Tay-Sachs disease (see HEXA Disorders), which can on occasion present with ataxia

Manifestations

The manifestations of many of the more common primary hereditary ataxias discussed in Section 2 of this overview become evident between ages 30 and 50 years, although manifestations of other ataxias are evident before age 25 years (e.g., ataxia with oculomotor apraxia, Friedreich ataxia) or before age five years (e.g., ataxia-telangiectasia).

The first manifestation of ataxia can include:

• Most commonly, a slowly progressive gait disorder that appears unsteady and predisposes to unexpected falls;
• Disequilibrium ("dizziness"), which may lead to an evaluation for peripheral vestibular dysfunction;
• Hand and finger clumsiness or tremor, which may raise the possibility of essential tremor or even parkinsonism;
• Slurring of speech or unexpected choking, which could lead to an evaluation for amyotrophic lateral sclerosis (ALS);
• Rarely, double vision, which could lead to an evaluation by an optometrist or ophthalmologist.

At disease onset, these manifestations may be intermittent or evident only at certain times (e.g., later in the day, when tired, after consuming alcohol). The manifestations typically become constant and slowly worsen.

Typical cerebellar features on neurologic examination include:

• Wide-based, staggering walk with difficulty performing tandem gait;
• Truncal instability when sitting unsupported;
• Difficulty with target maneuvers of the upper extremities (dysmetria, terminal tremor);
• Slowed rapid alternating movements (dysdiadochokinesis);
• Dysarthria (slowed or slurred articulation, variable pitch and loudness, monotonous or "scanning" speech);
• Abnormal eye movements (saccade intrusions in primary gaze, nystagmus in horizontal or vertical gaze, saccade hypermetria).

Non-cerebellar findings that can mimic or exacerbate the cerebellar ataxia (which can be identified by examination or testing) include:

• Alterations in descending frontal or parietal motor pathways (e.g., in normal pressure hydrocephalus);
• Brain stem changes that disrupt cerebellar pathways (e.g., in central vestibular dysfunction);
• Sensory pathway dysfunctions that alter input to the cerebellum (visual, peripheral vestibular, posterior column, peripheral sensory);
• Other sources of motor change, especially as they affect gait (weakness, rigidity, spasticity);
• Non-neurologic disorders (e.g., joint disease).

Brain imaging (MRI, MRS, PET) confirms the presence of cerebellar atrophy or hypoplasia.

Electronystagmography can document dysfunction in cerebellar, vestibular, or oculomotor pathways.

Progression of a hereditary ataxia usually leads to:

• Use of assistive devices for ambulation five to ten years after onset and ultimately to wheelchair dependence;
• Choking or falls resulting in, for example, head injury or hip fracture, which are common causes of morbidity and mortality;
• Infection and sepsis (from aspiration or other pneumonia, urinary tract infection, decubiti), especially prominent in the later stages of disease;
• Decline in self-care ability, increasing risk of falls, dependence on a feeding tube, and/or incontinence;
• The family or caregiver's need to consider more in-home care assistance or out-of-home placement.

Affected individuals do not usually live longer than 25 years after manifestations emerge.

See Figure 1 for worldwide distribution of the most common primary hereditary ataxias.

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 (more...)

Nucleotide Repeat Disorders

The nucleotide repeat disorders (see Table 1), the most common cause of hereditary ataxia, are discussed separately because of their unique molecular mechanism and inheritance issues.

Other Common Hereditary Ataxias

Potentially Treatable Hereditary Ataxias

Medical History

Most of the common primary hereditary ataxias start similarly with an unsteady gait, imbalance or "dizziness," unexpected falls, clumsiness, and tremors.

Distinctive features of the medical history that could suggest a specific diagnosis (see Table 1 and Table 3) include the following:

• Age of onset:
  • After age 50 years: SCA6
  • Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2
  • Before age five years: ataxia-telangiectasia
  • Infantile: SCA2, SCA7
• Onset with episodic features: SCA6, the episodic ataxias
• Associated with:
  • Retinopathy: SCA7
  • Seizure disorder: SCA10, infantile-onset SCA7, DRPLA
  • Dementia: SCA2, SCA17, DRPLA
  • Severe dizziness or vertigo: SCA3, SCA6, RFC1 CANVAS / spectrum disorder
  • Muscle cramping: SCA2, SCA3
  • Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia
  • Immunodeficiency or cancer: ataxia-telangiectasia

Physical Examination

All the primary hereditary ataxias have cerebellar features, but some have specific cerebellar or extracerebellar changes on examination that can suggest a specific diagnosis (see Table 1 and Table 3). In addition to the information provided in the medical history above, the following may be observed:

• Early presence of slowed oculomotor saccades: SCA2, SCA7
• Ophthalmoplegia: SCA1, SCA2, SCA3
• Oculomotor apraxia: ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2
• Fixation instability (saccade intrusions) in primary gaze: Friedreich ataxia
• Ocular conjunctival and skin telangiectases: ataxia-telangiectasia
• Downbeat nystagmus: SCA6 and episodic ataxia type 2
• Central or peripheral vestibular involvement: SCA3, SCA6, RFC1 CANVAS / spectrum disorder
• Motor unit fasciculations: SCA2, SCA3
• Peripheral neuropathy: SCA3, RFC1 CANVAS / spectrum disorder
• Spasticity: SCA1, SCA3, SCA7
• Extrapyramidal signs: SCA1, SCA2, SCA3, SCA17, DRPLA
• Absent deep tendon reflexes and upgoing toes: Friedreich ataxia

Family History

A three-generation family history should be taken with attention to relatives with manifestations of hereditary ataxia and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing, neuroimaging studies, and autopsy examinations. Findings in the family that may assist in narrowing the scope of relevant hereditary ataxias include the following:

• Earlier onset and increasing severity of disease in subsequent generations suggest an autosomal dominant nucleotide repeat disorder associated with anticipation (see Table 1).
• An affected parent or grandparent suggests autosomal dominant inheritance.
• No male-to-male transmission of the disorder suggests X-linked inheritance.
• Affected sibs or consanguinity suggests autosomal recessive inheritance. Note: In communities with a high prevalence of an autosomal recessive ataxia (e.g., the ARSACS carrier frequency in the Saguenay–Lac-Saint-Jean region of Quebec is 1:21), affected individuals in two or more generations may be observed.
• Late-onset cerebellar ataxia in a grandfather who has a grandson with intellectual disability suggests fragile X-associated tremor/ataxia syndrome in the grandfather.
• Note: In the absence of a molecularly confirmed ataxia, reports of balance problems in a grandparent, parent, or sib do not necessarily indicate a shared genetic cause. Multifactorial and acquired cerebellar disorders, which are four to five times more common than inherited ataxias, can confuse a family history.

Molecular Genetic Testing

Nucleotide repeat disorders. Establishing the diagnosis in an individual with one of the nucleotide repeat disorders (see Table 1) requires identification of an expanded nucleotide repeat and determination of the nucleotide repeat size for each disorder (see Table 2).

Note that commercially available multigene panels that rely on sequence analysis alone will not identify these nucleotide repeat expansions; thus, specific assays are required to analyze the nucleotide repeat in each gene of interest. Options offered by some laboratories:

• A multigene "repeat expansion" panel to specifically identify nucleotide repeat expansions
• A multigene ataxia panel that combines both repeat expansion testing and sequence-based testing analysis

Non-nucleotide repeat disorders. Establishing the diagnosis of one of the disorders listed in Table 3 requires detection of a sequence variant. Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

• A "sequence-based" ataxia multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (4) Sequencing-based tests including exome sequencing do not readily detect nucleotide repeat expansions.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing is an option that does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. Note that sequencing-based tests including exome sequencing do not readily detect nucleotide repeat expansions.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Mode of Inheritance

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

For hereditary ataxias that are nucleotide repeat disorders, select the relevant link to the GeneReview chapter (if available) in Table 1 for genetic counseling issues.

The genetic counseling issues for the other common hereditary ataxias (see Table 3) are discussed below.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant hereditary ataxia have an affected parent.
• Some individuals diagnosed with hereditary ataxia have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with autosomal dominant hereditary ataxia may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. (Note: Parental mosaicism has been reported in SCA29 [Ngo et al 2019] and other rarer ataxias.)
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for hereditary ataxia because of the possibility of age-related penetrance in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant hereditary ataxia has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an individual diagnosed with autosomal recessive hereditary ataxia are presumed to be heterozygous for a pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an ATM pathogenic variant are at increased risk for cancer and coronary artery disease; see Ataxia-Telangiectasia.)

Sibs of a proband

• If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an ATM pathogenic variant are at increased risk for cancer and coronary artery disease; see Ataxia-Telangiectasia.)

Offspring of a proband. The offspring of an individual with autosomal recessive hereditary ataxia are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the ataxia-related pathogenic variants in the family.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a hereditary ataxia, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The goals of supportive care are to maximize function and reduce complications. Depending on the clinical manifestations, affected individuals benefit from supportive care by a multidisciplinary team of specialists including neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech-language pathologists, pulmonologists, and mental health specialists.

Surveillance

There are no published surveillance guidelines for hereditary ataxias in general.

Author Notes

As a Clinical Professor of Neurology, Dr Perlman is involved in the diagnosis and treatment of cerebellar ataxia and other neurogenetic disorders. She conducts research on collaborative natural history, biomarker, and clinical trials in spinocerebellar ataxia, Friedreich ataxia, ataxia-telangiectasia, late-onset Tay-Sachs disease, and Huntington disease.

Dr Perlman can be reached at:

UCLA Neurology Services
300 UCLA Medical Plaza, Suite B200, Los Angeles, CA, 90095
Phone: 310-794-1195
Fax: 310-794-7491
Web page: www.uclahealth.org/neurology/neurogenetics

Acknowledgments

The author acknowledges the following organizations and people:

• National Ataxia Foundation, sponsor of grants for collaborative natural history and biomarker studies
• Friedreich's Ataxia Research Alliance, sponsor of grants for collaborative natural history and biomarker studies
• The Smith Family Foundation, the Lapin Family Fund, the Bettencourt Fund, the John Paul Jr. Fund, and the Wapner Fund
• Our patients and their families, for their willingness to work with us and to share with us their ideas and hopes

Author History

Thomas D Bird, MD; University of Washington (1998-2022)
Susan Perlman, MD (2022-present)

Revision History

• 16 November 2023 (bp) Revision: added FGF14 to Tables 1 and 2; deleted COQ6 and PDSS1 from Table 5
• 16 June 2022 (bp) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 17 February 2011 (me) Comprehensive update posted live
• 27 June 2007 (me) Comprehensive update posted live
• 8 February 2005 (me) Comprehensive update posted live
• 27 February 2003 (me) Comprehensive update posted live
• 28 October 1998 (me) Overview posted live
• 23 June 1998 (tb) Original submission