© American College of Medical Genetics and Genomics Review

Hereditary ataxias: overview

Suman Jayadev, MD1 and Thomas D. Bird, MD1–3

The hereditary ataxias are a highly heterogeneous group of disor- (ataxia with vitamin E deficiency, cerebrotendinous xanthomato-
ders phenotypically characterized by gait ataxia, incoordination sis, Refsum, and coenzyme Q10 deficiency), whereas there are no
of eye movements, speech, and hand movements, and usually specific treatments for other ataxias. Diagnostic genetic testing is
associated with atrophy of the cerebellum. There are more than complicated because of the large number of relatively uncommon
35 autosomal dominant types frequently termed spinocerebellar subtypes with extensive phenotypic overlap. However, the best test-
ataxia and typically having adult onset. The most common sub- ing strategy is based on assessing relative frequencies, ethnic predi-
types are spinocerebellar ataxia 1, 2, 3, 6, and 7, all of which are lections, and recognition of associated phenotypic features such as
nucleotide repeat expansion disorders. Autosomal recessive ataxias seizures, visual loss, or associated movement abnormalities.
usually have onset in childhood; the most common subtypes are
­Friedreich, ataxia-telangiectasia, ataxia with oculomotor apraxia Genet Med advance online publication 28 March 2013
type 1, and ataxia with oculomotor apraxia type 2. Four autosomal
recessive types have dietary or biochemical treatment modalities Key Words: ataxia; cerebellum; neurogenetics

HEREDITARY ATAXIA Establishing the diagnosis

The hereditary ataxias are a clinically and genetically het- Establishing the diagnosis of hereditary ataxia requires:
erogeneous group of disorders characterized by slowly pro-
gressive incoordination of gait and often associated with 1. Detection on neurological examination of typical clinical
poor coordination of hands, speech, and eye movements. signs including poorly coordinated gait and finger/hand
Frequently, atrophy of the cerebellum occurs (Figure 1). movements, dysarthria (incoordination of speech), and
In this review, the hereditary ataxias are categorized by eye movement abnormalities such as nystagmus, abnor-
mode of inheritance and gene in which causative mutations mal saccade movements, and ophthalmoplegia.
occur, or chromosomal locus. The hereditary ataxias can be 2. Exclusion of nongenetic causes of ataxia (see Differential
inherited in an autosomal dominant, autosomal recessive, Diagnosis below).
X-linked manner or through maternal inheritance if part 3. Documentation of the hereditary nature of the disease
of a mitochondrial genetic syndrome. The genetic forms of by finding a positive family history of ataxia, identi-
ataxia are diagnosed by family history, physical examination, fying an ataxia-causing mutation, or recognizing a
­neuroimaging, and molecular genetic testing. The clinical clinical phenotype characteristic of a genetic form of
manifestations may result from one or a combination of dys- ataxia.
function of the cerebellar systems, lesions in the spinal cord,
and peripheral sensory loss. Differential diagnosis
Differential diagnosis of hereditary ataxia includes acquired,
Clinical manifestations nongenetic causes of ataxia, such as alcoholism, vitamin defi-
The clinical manifestations of the hereditary ataxias are pro- ciencies, multiple sclerosis, vascular disease, primary or met-
gressive incoordination of movement and speech, and a wide- astatic tumors, and paraneoplastic diseases associated with
based, uncoordinated, unsteady gait. In addition, patients occult carcinoma of the ovary, breast, or lung, and the idiopathic
may develop ophthalmoplegia (limitations of eye movement), degenerative disease multiple system atrophy (spinal muscular
spasticity, neuropathy, and cognitive/behavioral difficulties. atrophy). The possibility of an acquired cause of ataxia needs to
Particular signs beyond ataxia may guide the clinician in pur- be considered in each individual with ataxia because a specific
suit of directed genetic testing when investigating the cause of treatment may be available.
ataxia. For instance, cone–rod retinal dystrophy in conjunction
with familial ataxia may suggest spinocerebellar ataxia (SCA)7; TYPES OF HEREDITARY ATAXIA
Native American origin or co-occurrence of epilepsy would As discussed above, the hereditary ataxias can be subdivided
raise the possibility of SCA10. by mode of inheritance, (i.e., autosomal dominant, autosomal

Department of Neurology, University of Washington, Seattle, Washington, USA; 2Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA;
1

Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington, USA. Correspondence: Thomas D. Bird (tomnroz@uw.edu)
3

Submitted 8 November 2012; accepted 7 February 2013; advance online publication 28 March 2013. doi:10.1038/gim.2013.28

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Review JAYADEV and BIRD | Hereditary ataxias: overview

recessive, X-linked, and mitochondrial), gene in which caus- is also variable, although generally the disease progresses over
ative mutations occur, or chromosomal locus.1–3 decades. Life span may be shortened in SCA1, -2, -3, and -7
or normal in SCA5, -6, and -14.5 The most common form of
Autosomal dominant cerebellar ataxias episodic ataxia is EA2, caused by a variety of point mutations
Synonyms for autosomal dominant cerebellar ataxias (ADCAs) in the same calcium channel gene (CACNA1A) associated with
used prior to the identification of the molecular genetic basis SCA6 and familial hemiplegic migraine.12
of these disorders were Marie’s ataxia, inherited olivopontocer-
ebellar atrophy, cerebello-olivary atrophy, or the more generic Genetics. The ADCAs for which specific genetic information
term, spinocerebellar degeneration. is available are summarized in Table 1. Most are SCAs; one is a
complex form with additional phenotypic features in addition
Clinical features of ADCA. The age of onset and physical to ataxia; four are episodic ataxias; and one is a spastic ataxia.
findings in the autosomal dominant ataxias overlap. Table  1 In addition to ADCAs described in Table 1, ADCAs include:
indicates a few distinguishing clinical features for each type.4–8
Scales for rating symptoms and signs of ataxia have been 1. Ataxia with early sensory/motor neuropathy (linked to
published.9 Often the autosomal dominant ataxias cannot be 7q22–q32); caused by mutations in IFRD1.13,14
differentiated by clinical or neuroimaging studies; they are 2. Cerebellar ataxia, deafness, narcolepsy, and optic atrophy
usually slowly progressive and often associated with cerebellar (linked to 6p21–p23 in one family).15
atrophy, as seen from brain imaging studies (Figure  1). 3. Ataxia, cerebellar atrophy, intellectual disability, and pos-
The frequency of the occurrence of each disease within the sible attention deficit/hyperactivity disorder (associated
autosomal dominant cerebellar ataxia (ADCA) population with a heterozygous mutation in SCN8A, encoding a
is noted in Table 1. Pyramidal signs (hyperreflexia and sodium channel).16
spasticity) are commonly found in patients with SCA1 and 4. Late-onset (40s–60s) cerebellar ataxia preceded by many
SCA3; cognitive impairment has been reported in association years of spasmodic coughing. One individual had calcifi-
with SCA2, SCA12, SCA13, SCA17; chorea may manifest in cation of the dentate nuclei on magnetic resonance imag-
patients with SCA17 or dentatorubral-pallidoluysian atrophy ing (MRI).17
(DRPLA). Many of the ADCAs in addition to limb and truncal
ataxia cause dysarthria, dysphagia, and neuropathy. The clinical Molecular genetic testing. Mutations associated with the
syndrome associated with SCA2 may include parkinsonism or ADCAs include nucleotide expansions occurring in either
motor neuron disease (amyotrophic lateral sclerosis)10,11 Age of expressed or nonexpression regions of the gene, point
onset is quite variable and usually in adulthood. Disease course mutations, duplications, and deletions.
Some of the earliest identified and most common ADCAs
result from CAG trinucleotide expansions. SCA1, SCA2, SCA3,
SCA6, SCA7, SCA12, SCA17, and DRPLA are all caused by
CAG repeats within the coding region of the respective genes
translating into an elongated polyglutamine tract in the protein.
Molecular genetic testing for CAG repeat length is a highly spe-
cific and sensitive diagnostic test. The sizes of the normal CAG
repeat allele and of the full-penetrance disease-causing CAG
expansion vary among the disorders (for individual reviews of
each disorder see GeneReviews.org).
Although ordering molecular testing for the polyglutamine
ataxia disorders listed above is straightforward and tests are
commercially available, there are two notes of caution in the
interpretation of results:

1. 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 on transmission to a reduced
or fully penetrant allele. Therefore, children of an indi-
Figure 1 Coronal brain MRI showing atrophy of both cerebellar
vidual carrying a mutable normal allele are at increased
hemispheres (arrows) in a 28-year-old woman with SCA2. MRI,
magnetic resonance imaging; SCA, spinocerebellar ataxia. risk of inheriting a disease-causing allele. In addition,

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Hereditary ataxias: overview | JAYADEV and BIRD Review
there are reduced-penetrance alleles that may or may not the expanded allele. By contrast, in SCA8, the majority of expan-
cause the disease in an individual; the probability of dis- sions of the CTG repeat occur during maternal transmission.
ease in persons with such alleles is typically unknown.
Interpretation of test results in which the CAG repeat Prevalence. The prevalence of these rare diseases is not widely
length is at the interface between the allele categories known. The prevalence of the ADCAs in the Netherlands is
mutable normal/reduced penetrance and reduced pen- estimated to be at least 3:100,000.22 The prevalence of individual
etrance/disease-causing can be difficult. In such cases, subtypes of ADCA may vary from region to region, frequently
a consultation with the testing laboratory may be help- because of founder effects. For example, DRPLA is more
ful to determine the precision of the CAG repeat length common in Japan and SCA3 in Portugal; SCA2 is common in
measurement. Korea and SCA3 is much more common in Japan and Germany
2. In some instances, SCA2, SCA7, SCA8, and SCA10 result than in the United Kingdom.23–25 SCA3 was originally described
from extremely large CAG expansions in length that may in Portuguese families from the Azores and called Machado-
be detected only by Southern blot analysis. For these dis- Joseph disease. DRPLA is rare in North America and common
orders, a test result of apparent homozygosity (detection in Japan. A recent study found evidence of frequency variation
of a single allele by PCR analysis) must be interpreted in between different regions in Japan.26 Data are based on a
the context of multiple factors including clinical findings, comprehensive study in the United States by Moseley et al.27
family history, and age of onset of symptoms to deter-
mine whether Southern blot analysis to test for the pres- Autosomal recessive hereditary ataxias
ence of a large CAG expansion mutation is appropriate. Numerous recent reviews have detailed the clinical findings,
genetics, and pathogenesis of the autosomal recessive ataxias.28
Other repeat expansions. SCA8 has a CTG trinucleotide The autosomal recessive ataxias may present with additional
repeat expansion in ATXN8OS.18 Extremely large repeats extra–central nervous system signs and symptoms. Table 2
(~800) in ATXN8OS may be associated with an absence of summarizes information for 13 typical autosomal recessive dis-
clinical symptoms.19 The pathogenesis of the SCA8 phenotype orders in which ataxia is a prominent feature. The disorders are
is complex and also involves a (CAG)n repeat in a second selected to indicate the range of genetic understanding that cur-
overlapping gene, ATXN8. rently exists regarding recessive causes of ataxia.
SCA10 has a large expansion of an ATTCT pentanucleotide Friedreich ataxia (FRDA) is the most common autosomal
repeat in ATXN10, with the abnormal expansion range being recessive ataxia, with a population frequency of 1–2:50,000.
much larger than that seen in the CAG repeat disorders.20 FRDA is characterized by slowly progressive ataxia with onset
usually before 25 years of age and is typically associated with
Anticipation. Anticipation is observed in the autosomal depressed tendon reflexes, dysarthria, Babinski responses, and
dominant ataxias in which CAG trinucleotide repeats occur. loss of position and vibration senses.29 About 25% of affected
Anticipation refers to earlier onset of an increasing severity of individuals have an “atypical” presentation with later onset (age
disease in subsequent generations of a family. In the trinucleotide >25 years), retained tendon reflexes, or unusually slow progres-
repeat diseases, anticipation results from expansion in the sion of disease. The vast majority of individuals have a GAA
number of CAG repeats that occurs with transmission of the triplet-repeat expansion in FXN. Unlike the ADCAs caused
gene to the next generation. ATN1 (DRPLA) and ATXN7 by CAG trinucleotide repeats, FRDA is not associated with
(SCA7) have particularly unstable CAG repeats.21 In SCA7, anticipation.
anticipation may be so extreme that children with early-onset, Ataxia-telangiectasia (A-T) is characterized by progressive
severe disease die of the disorder long before the affected parent cerebellar ataxia beginning between 1 and 4 years of age, oculo-
or grandparent is symptomatic. motor apraxia, frequent infections, choreoathetosis, telangiec-
Anticipation is a significant issue in the genetic counsel- tasias of the conjunctivae, immunodeficiency, and an increased
ing of asymptomatic at-risk family members and in prenatal risk for malignancy, particularly leukemia and lymphoma.
testing. Although general correlations exist between earlier Testing that supports the diagnosis of individuals with A-T is
age of onset and more severe disease with increasing number identification of a 7;14 chromosome translocation on routine
of CAG repeats, the age of onset, severity of disease, specific karyotype of peripheral blood, the presence of immunodefi-
symptoms, and rate of disease progression are variable and can- ciency and elevated serum α-fetoprotein, and in vitro radio-
not be accurately predicted by the family history or molecular sensitivity assay. Molecular genetic testing of A-T is available
genetic testing. Attention has been focused on the phenomena clinically.
of anticipation and trinucleotide repeat expansion, but it is Ataxia with vitamin E deficiency (AVED) generally manifests
important to note that the number of trinucleotide repeats can in late childhood or early teens with dysarthria, poor balance
also remain stable or even contract on transmission to subse- when walking (especially in the dark), and progressive clum-
quent generations. siness resulting from early loss of proprioception. Some indi-
In the CAG repeat disorders, expansion of the repeat is more viduals experience dystonia, psychotic episodes (paranoia),
likely to occur with paternal than with maternal transmission of pigmentary retinopathy, and/or intellectual decline. Most

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Review JAYADEV and BIRD | Hereditary ataxias: overview

Table 1  Autosomal dominant hereditary ataxias

Disease Average onset Average duration
Namea Gene (range in years) (range in years) Distinguishing featuresb
SCA1 ATXN1 3rd–4th decade (<10 to >60) 15 years (10–28) Pyramidal signs, peripheral neuropathy
SCA2 ATXN2 3rd–4th decade (<10 to >60) 10 years (1–30) Slow saccadic eye movements, peripheral neuropathy, decreased
DTRs, dementia
SCA3 ATXN3 4th decade (10–70) 10 years (1–20) Pyramidal and extrapyramidal signs; lid retraction, nystagmus,
decreased saccade velocity; amyotrophy fasciculations, sensory
loss
SCA4 16q22.1 4th–7th decade (19–72) Decades Sensory axonal neuropathy, deafness; may be allelic with 16q22-
linked SCA
SCA5 SPTBN2 3rd–4th decade (10–68) >25 years Early onset, slow course; first reported in descendants of Abraham
Lincoln
SCA6 CACNA1A 5th–6th decade (19–71) >25 years Sometimes episodic ataxia, very slow progression
SCA7 ATXN7 3rd–4th decade (0.5–60) 20 years (1–45; early Visual loss with retinopathy
onset correlates with
shorter duration)
SCA8 ATXN8/ 4th decade (1–65) Normal life span Slowly progressive, sometimes brisk DTRs, decreased vibration
ATXN80S sense; rarely, cognitive impairment
SCA10 ATXN10 4th decade (12–48) 9 years Occasional seizures; most families are of Native American
background
SCA11 TTBK2 Age 30 years (15–70) Normal life span Mild, remain ambulatory
SCA12 PPP2R2B 4th decade (8–62) Slowly progressive ataxia; action tremor in the 30s; hyperreflexia;
subtle Parkinsonism possible; cognitive/psychiatric disorders
including dementia
SCA13 KCNC3 Childhood or adulthood Unknown Mild intellectual disability, short stature
SCA14 PRKCG 3rd–4th decade (3–70) Decades (1–30) Early axial myoclonus
SCA15 ITPR1 4th decade (7–66) Decades Pure ataxia, very slow progression
SCA16 SCA16 Age 39 years (20–66) 1–40 years Head tremor; one Japanese family
SCA17 TBP 4th decade (3–55) >8 years Mental deterioration; occasional chorea, dystonia, myoclonus,
epilepsy; Purkinje cell loss, intranuclear inclusions with expanded
polyglutamine
SCA18 7q22–q32 Adolescence (12–25) Decades Ataxia with early sensory/motor neuropathy, nystagmus,
dysarthria, decreased tendon reflexes, muscle weakness, atrophy,
fasiculations, Babinski responses
SCA19/22 KCND3 4th decade (10–51) Decades Slowly progressive, rare cognitive impairment, myoclonus,
hyperreflexia
SCA20 11q12.2– 5th decade (19–64) Decades Early dysarthria, spasmodic dysphonia, hyperreflexia, bradykinesia;
11q12.3 calcification of the dentate nucleus
SCA21 SCA21 6–30 Decades Mild cognitive impairment
SCA23 PDYN 5th–6th decade >10 years Dysarthria, abnormal eye movements, reduced vibration and
position sense; one Dutch family; neuropathologyc
SCA25 SCA25 (1.5–39) Unknown Sensory neuropathy; one French family
SCA26 EEF2 (26–60) Unknown Dysarthria, irregular visual pursuits; one Norwegian-American
family; MRI: cerebellar atrophy
SCA27 FGF14 Age 11 years (7–20) Decades Early-onset tremor; dyskinesia, cognitive deficits; one Dutch family
SCA28 AFG3L2 Age 19.5 years (12–36) Decades Nystagmus, ophthalmoparesis, ptosis, increased tendon reflexes;
two Italian families
SCA29 3p26 Early childhood Lifelong Learning deficits
SCA30 4q34.3– (45–76) Lifelong Hyperreflexia
q35.1
ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; DRPLA, dentatorubral-pallidoluysian atrophy; DTR, deep tendon reflex; EA, episodic ataxia; MRI,
magnetic resonance imaging; SCA, spinocerebellar ataxia; SPAX1, autosomal dominant spastic ataxia 1.
a
SCA9 has not been assigned. bAll have gait ataxia. cPurkinje cell loss, demyelination of the posterior and lateral columns of the spinal cord, and neuronal intranuclear
inclusions in the substantia nigra.

Table 1  Continued on next page

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Hereditary ataxias: overview | JAYADEV and BIRD Review
Table 1 Continued
Disease Average onset Average duration
Namea Gene (range in years) (range in years) Distinguishing featuresb
SCA31 BEAN1 5th–6th decade Lifelong Normal sensation
SCA35 TGM6 43.7 ± 2.9 (40–48) years 15.9 ± 8.8 (5–31) Hyperreflexia, Babinski responses; spasmodic torticollis
years
SCA36 NOP56 52.8 ± 4.3 years Decades Muscle fasiculations, tongue atrophy, hyperreflexia
DRPLA ATN1 3rd–4th decade Early onset correlates Chorea, seizures, dementia, myoclonus; often confused with
(8–20 or 40–60s) with shorter duration Huntington disease
EA1 KCNA1 1st–2nd decade (2–15) Attenuates after 20 Myokymia; attacks lasting seconds to minutes; startle or exercise
years induced; no vertigo
EA2 CACNA1A; 2–32 Lifelong Nystagmus; attacks lasting minutes to hours; posture-change
CACNB4 induced; vertigo; later, permanent ataxia
EA5 CACNB4 20–30 Lifelong Nystagmus; acetazolamide helpful
EA6 SLC1A3 Childhood Lifelong Headache; nausea; photophobia; rare alternating hemiplegia/
seizures
SPAX1 VAMP1 10–20 Normal life span Initial progressive leg spasticity; similar to ARSACS
ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; DRPLA, dentatorubral-pallidoluysian atrophy; DTR, deep tendon reflex; EA, episodic ataxia; MRI,
magnetic resonance imaging; SCA, spinocerebellar ataxia; SPAX1, autosomal dominant spastic ataxia 1.
a
SCA9 has not been assigned. bAll have gait ataxia. cPurkinje cell loss, demyelination of the posterior and lateral columns of the spinal cord, and neuronal intranuclear
inclusions in the substantia nigra.

individuals become wheelchair bound as a result of ataxia and/ Marinesco–Sjögren syndrome is a rare disorder in which
or leg weakness between the ages 11 and 50 years. Although ataxia is associated with intellectual disability, cataract, short
phenotypically similar to FRDA, AVED is more likely to be stature, and hypotonia.39,40
associated with head titubation or dystonia, and less likely to be
associated with cardiomyopathy. It is important to consider the Polymerase γ-1-associated hereditary ataxias. Mutations in
diagnosis of AVED (which can be made by measuring serum mitochondrial genes can result in an ataxia phenotype (see
concentration of vitamin E) because it is treatable with vitamin below). In addition, nuclear genes regulating mitochondrial
E supplementation.30,31 processes can also result in a hereditary ataxia. Autosomal
A different autosomal recessive ataxia occurring on Grand recessive mutations in polymerase γ-1 are associated with
Cayman Island is caused by mutations in ATCAY, the gene a broad spectrum of central nervous system and systemic
encoding the protein CRAL-TRIO, which may also be involved phenotypes, but two in particular manifest with ataxia as a
in vitamin E metabolism.32 prominent feature.
Ataxia with oculomotor apraxia type 1 (AOA1) is character-
ized by childhood onset of slowly progressive cerebellar ataxia 1. Mitochondrial recessive ataxic syndrome: This is caused
(mean onset age ~7 years), followed in a few years by oculo- by autosomal recessive mutations in polymerase γ-1 and
motor apraxia that progresses to external ophthalmoplegia. is characterized by cerebellar ataxia, nystagmus, dysar-
All affected individuals have a severe primary motor periph- thria ophthalmoplegia, and frequently epilepsy; it is rela-
eral neuropathy leading to quadriplegia with loss of ambula- tively common in Scandinavia. Age of onset ranges from
tion about 7–10 years after onset. Intellect remains normal in childhood to mid-adulthood. Brain MRI may reveal cer-
affected individuals of Portuguese ancestry, but mental deterio- ebellar atrophy.41
ration has been seen in affected individuals of Japanese ances- 2. Sensory ataxia, neuropathy, dysarthria, and ophthalmo-
try. The diagnosis of AOA1 is based on clinical findings and plegia: As the name implies, a sensory neuropathy con-
confirmed by molecular genetic testing.33–35 tributes to the ataxia observed in patients with sensory
Ataxia with oculomotor apraxia type 2 (AOA2) is character- ataxia, neuropathy, dysarthria, and ophthalmoplegia.
ized by onset between ages 10 and 22 years, cerebellar atrophy, In addition, affected individuals may have eye move-
axonal sensorimotor neuropathy, oculomotor apraxia, and ele- ment abnormalities (ophthalmoplegia) and dysarthria.42
vated serum concentration of α-fetoprotein.36,37 The diagnosis Epilepsy, myopathy, MRI abnormalities, and ragged red
of AOA2 is based on clinical and biochemical findings, family fibers have all been reported in association with sensory
history, and exclusion of the diagnoses of A-T and AOA1; it is ataxia, neuropathy, dysarthria, and ophthalmoplegia.
confirmed by molecular genetic testing.
Infantile-onset SCA is a rare disorder reported in Finland Autosomal recessive spastic ataxia of Charlevoix-Saguenay
with degeneration of the cerebellum, spinal cord, and brain is characterized by early onset (age 12–18 months) difficulty
stem, and sensory axonal neuropathy.38 in walking and gait unsteadiness. Ataxia, dysarthria, spasticity,

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Review JAYADEV and BIRD | Hereditary ataxias: overview

Table 2  Autosomal recessive ataxias

Gene symbol/ Population Onset Duration in
Disease name protein name frequency (range in years) years Distinguishing features
Friedreich ataxia (FRDA) FXN/frataxin 1–2:50,000 1st–2nd decade 10–30 Hyporeflexia, Babinski responses, sensory
(4–40) loss, cardiomyopathy
Ataxia-telangiectasia ATM 1:40,000 to 1st decade 10–20 Telangiectasia, immune deficiency,
1:100,000 cancer, chromosomal instability, increased
α-fetoprotein
Ataxia with vitamin E TTPA Rare Age 2–52 years, Decades Similar to FRDA, head titubation (28%)
deficiency usually <20
Ataxia with oculomotor APTX/ Unknown Childhood Decades Oculomotor apraxia, choreoathetosis,
apraxia type 1 aprataxin mild intellectual disability,
hypoalbuminemia
Ataxia with oculomotor SETX Unknown Age 10–22 years Decades Cerebellar atrophy, axonal sensorimotor
apraxia type 2 neuropathy, oculomotor apraxia
IOSCA C10orf2/ Rare (Finland) Infancy Decades Peripheral neuropathy, athetosis, optic
twinkle or less atrophy, deafness, ophthalmoplegia,
seizures
Marinesco–Sjögren SIL1 Rare Infancy Decades Intellectual disability, cataract, hypotonia,
syndrome myopathy
Autosomal recessive SACS/sacsin Rare Childhood Decades Spasticity, peripheral neuropathy, retinal
spastic ataxia of striation
Charlevoix-Saguenay
Refsum disease PHYH; PEX7 Rare 1st–6th decade Decades Neuropathy, deafness, ichthyosis,
retinopathy
CoQ10 deficiency CABC1; Rare Childhood Decades Seizures, cognitive decline, pyramidial
COQ2; COQ9; signs, myopathy
PDSS1; PDSS2
MIRAS POLG1 Rare (Finland Childhood to Decades Nystagmus, dysarthria, epilepsy,
and Norway) young adulthood cerebellar atrophy on MRI
SANDO POLG1 Rare Childhood to Decades Abnormal eye movements, ragged red
young adulthood fibers, myopathy, dysphagia, neuropathy,
myopathy
Cerebrotendinous CYP27A1 1:50,000 Childhood to Decades Thick tendons, cognitive decline,
xanthomatosis young adulthood dystonia, white matter disease, cataract
CoQ10, coenzyme Q10; IOSCA, infantile-onset spinocerebellar ataxia; MIRAS, mitochondrial recessive ataxia syndrome; MRI, magnetic resonance imaging; SANDO,
sensory ataxia, neuropathy, dysarthria and ophthalmoplegia.

extensor plantar reflexes, distal muscle wasting, a distal senso- Coenzyme Q10 (CoQ10) deficiency is often associated with
rimotor neuropathy predominantly in the legs, and horizontal seizures, cognitive decline, pyramidal track signs, and myopa-
gaze nystagmus constitute the major neurologic signs, which thy but may also include prominent cerebellar ataxia.48,49 The
are most often progressive. Yellow streaks of hypermyelinated symptoms may respond to CoQ10 treatment.
fibers radiate from the edges of the optic fundi in the retina Cerebrotendinous xanthomatosis has characteristic thicken-
of Quebec-born individuals with autosomal recessive spastic ing of tendons often associated with cognitive decline, dystonia,
ataxia of Charlevoix-Saguenay,43 whereas the retinal changes are cataract, and white matter changes on brain MRI.
uncommon in French, Tunisian, and Turkish individuals with
the condition.44,45 Individuals with autosomal recessive spastic Other autosomal recessive ataxias
ataxia of Charlevoix-Saguenay become wheelchair bound at the 1. Members of a family from Saudi Arabia have cerebel-
average age of 41 years; cognitive skills are preserved long term, lar atrophy, ataxia, and axonal sensorimotor neuropa-
and individuals are able to accomplish activities of daily living thy (linked to chromosome 14q31–q32; associated with
late into adulthood. Death commonly occurs in the sixth decade. mutations in TDP1, encoding a topoisomerase 1-depen-
Refsum disease generally presents in childhood or young dent DNA damage repair enzyme, SCAN1).50,51
adulthood; in addition to ataxia, there may be peripheral neu- 2. Ataxia with hypogonadotrophic hypogonadism. A simi-
ropathy, deafness, ichthyosis, or retinitis pigmentosa.46 lar sibship has shown a deficiency of CoQ10.52
Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, 3. A single Slovenian family in which 5 of 14 siblings have
and cataract (PHARC), a syndrome similar to Refsum disease, ataxia with saccadic intrusions, sensory neuropathy, and
is caused by mutations in ABHD12.47 myoclonus.53

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Hereditary ataxias: overview | JAYADEV and BIRD Review
4. A large consanguineous Norwegian family with infantile- EVALUATION STRATEGY
onset nonprogressive ataxia (linked to 20q11–q13).54 Once a hereditary ataxia is considered in an individual, the fol-
5. A large consanguineous Saudi Arabian family has child- lowing approach can be used to determine the specific cause
hood-onset ataxia sometimes associated with epilepsy to aid in discussions of prognosis and genetic counseling.
and cognitive deficits with a frameshift mutation in Establishing the specific cause of hereditary ataxia for a given
K1AA0226, which encodes rundataxin.55 individual usually involves a medical history, physical exami-
6. Mutations in VLDLR, encoding the very low-density nation, neurologic examination, neuroimaging, detailed family
lipoprotein receptor, in Hutterite families with nonpro- history, and molecular genetic testing.
gressive cerebellar ataxia and intellectual disability with Because of extensive clinical overlap among all of the forms
inferior cerebellar hypoplasia and mild cerebral gyral of hereditary ataxia, it is difficult in any given individual with
simplification.56 ataxia and a family history consistent with autosomal dominant
7. Several French Canadian families in the Beauce region of inheritance to establish a diagnosis without molecular genetic
Quebec with a late-onset cerebellar ataxia associated with testing. Clinical findings may help distinguish among some of
mutations in SYNE1.57,58 the autosomal recessive ataxias.
8. Disorders associated with congenital cerebellar agenesis A three-generation family history with attention to other
or hypoplasia of varying degrees: relatives with neurologic signs and symptoms should be
­
• Joubert syndrome with pontine molar-tooth sign on obtained. Documentation of relevant findings in relatives can
MRI.59,60 be accomplished either through direct examination of those
• Cerebellar agenesis with neonatal diabetes mellitus.61 individuals or review of their medical records, including the
• Very low-density lipoprotein receptor–associated cer- results of molecular genetic testing, neuroimaging studies, and
ebellar hypoplasia. autopsy examinations.
• Congenital disorders of glycosylation.62
• Pontocerebellar hypoplasia.63,64 NonDNA testing. Plasma clinical tests are available that
9. Doi et al. (2011)65 have reported a single consanguine- suggest the presence of five autosomal recessive hereditary
ous Japanese sibship with childhood-onset psychomotor ataxias: elevated α-fetoprotein in A-T and AOA2, low serum
retardation followed by adult-onset gait ataxia associated vitamin E in AVED, elevated cholestenol in cerebrotendinous
with cerebellar vermis atrophy on MRI and a homozy- xanthomatosis, and hypoalbuminemia in AOA1. Normal
gous missense mutation in SYT14, the gene encoding values of these tests may sometimes represent false negatives
synaptotagmin-14. and do not exclude a specific type of ataxia.

X-linked hereditary ataxias Testing strategy when family history suggests autosomal
X-linked sideroblastic anemia and ataxia are characterized by dominant inheritance. There has been much progress in our
early-onset ataxia, dysmetria, and dysdiadochokinesis. The ability to identify causative genes for a significant proportion
ataxia is either nonprogressive or slowly progressive. Upper of autosomal dominantly inherited ataxias. An estimated 50–
motor neuron signs (brisk deep tendon reflexes, unsustained 60% of the dominant hereditary ataxias (see Table 1) can be
ankle clonus, and equivocal or extensor plantar responses) are identified with highly accurate and specific molecular genetic
present in some males. Mild learning disability is seen. Anemia testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10,
is mild without symptoms. Carrier females have a normal neu- SCA12, SCA17, and DRPLA; all have nucleotide repeat
rologic examination. Causative mutations are present in ABC7, expansions in the pertinent genes. Of note, the interpretation
encoding a protein involved with mitochondrial iron transport, of test results can be complex because (i) the exact range for
suggesting a common pathogenesis with FRDA.66 the abnormal repeat expansion has not been fully established
Adult-onset ataxia, especially in men, may be part of the frag- for many of these disorders; and (ii) only a few families have
ile X-associated tremor/ataxia syndrome.67,68 been reported with SCA8 and thus penetrance and gender
effects have not been completely resolved.71 Thus, diagnosis
Ataxias with mitochondrial gene mutations and genetic counseling of individuals undergoing such testing
A progressive ataxia is sometimes associated with mitochon- require the support of an experienced laboratory, medical
drial disorders including myoclonic epilepsy with ragged geneticist, and genetic counselor.
red fibers; neuropathy, ataxia, and retinitis pigmentosa;1 and Because of the broad clinical overlap, most laboratories that
Kearns–Sayre syndrome. Mitochondrial disorders are often test for the hereditary ataxias have a battery of tests including
associated with additional clinical manifestations, such as sei- testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA12,
zures, deafness, diabetes mellitus, cardiomyopathy, retinopathy, SCA14, and SCA17. Many laboratories offer them as two groups
and short stature.69 Pfeffer et al.70 report that missense mutations in stepwise fashion based on population frequency, testing first
in MTATP6 can cause both childhood- and adult-onset cerebel- for the more common ataxias, SCA1, SCA2, SCA3, SCA6, and
lar ataxia sometimes associated with abnormal eye movements, SCA7. Although pursuing multiple genes simultaneously may
dysarthria, weakness, axonal neuropathy, and hyperreflexia. seem less optimal than serial genetic testing, it is important

Genetics in medicine | Volume 15 | Number 9 | September 2013 679

Review JAYADEV and BIRD | Hereditary ataxias: overview

to recognize that the cost of the battery of ataxia tests often is history is negative. For instance, family history may not be
equivalent to that of an MRI. Positive results from the molecu- obvious because of early death of a parent, failure to recognize
lar genetic testing are more specific than MRI findings in the autosomal dominant ataxia in family members, late onset in a
hereditary ataxias. Guidelines for genetic testing of hereditary parent, reduced penetrance of the mutant allele in an asymp-
ataxia have been published.72 tomatic parent, or a de novo mutation. The risk to siblings
Testing is also available for some autosomal dominant forms depends on the genetic status of the proband’s parents. If one of
of SCA that are not associated with repeat expansions, namely the proband’s parents has a mutant allele, the risk to the sibs of
SCA5, SCA13, SCA14, SCA15, SCA27, SCA28, and 16q22- inheriting the mutant allele is 50%. Individuals with autosomal
linked SCA. dominant ataxia have a 50% chance of transmitting the mutant
Testing for the less common hereditary ataxias should be allele to each child.
individualized and may depend on factors such as ethnic back-
ground (SCA3 in the Portuguese, SCA10 in the Native American Risk to family members: autosomal recessive hereditary
population with some exceptions73); seizures (SCA10); pres- ataxia
ence of tremor (SCA12, fragile X-associated tremor/ataxia The parents of an individual affected with an autosomal reces-
syndrome); presence of psychiatric disease or chorea (SCA17); sive ataxia are obligate heterozygotes and therefore carry a
or uncomplicated ataxia with long duration (SCA6, SCA8, and single copy of a disease-causing mutation. In general, the het-
SCA14). Dysphonia and palatal myoclonus are associated with erozygotes are asymptomatic. Siblings of a proband have a 25%
calcification of the dentate nucleus of cerebellum (SCA20). chance of being affected, a 50% chance of being a heterozygote
If a strong clinical indication of a specific diagnosis exists carrier, and a 25% chance of being unaffected and not a carrier.
based on the affected individual’s examination (e.g., the pres- Once it is established that an at-risk sib is unaffected, the chance
ence of retinopathy, which suggests SCA7) or if family history is of his/her being a carrier is two-thirds. All offspring of affected
positive for a known type, testing can be performed for a single patients are obligate carriers.
disease.
Risk to family members: X-linked hereditary ataxia
Testing strategy when the family history suggests autosomal The father of an affected male will not have the disease nor will
recessive inheritance. A family history in which only sibs are he be a carrier of the mutation. However, women with an affected
affected and/or when the parents are consanguineous suggests son and another affected male relative are obligate heterozygotes.
autosomal recessive inheritance. Because of their frequency The risk to siblings depends on the carrier status of the mother.
and/or treatment potential, FRDA, A-T, AOA1, AOA2, AVED, If the mother of the proband has a disease-causing mutation, the
and metabolic or lipid storage disorders such as Refsum disease chance of transmitting it in each pregnancy is 50%. Male siblings
and mitochondrial diseases should be considered. who inherit the mutation will be affected whereas female siblings
inheriting the mutation will be carriers and usually not affected.
Testing simplex cases. A simplex case is a single occurrence If the proband with an X-linked disease represents a simplex
of a disorder in a family, sometimes incorrectly referred to as a (single occurrence in the family) and if the disease-causing muta-
“sporadic” case. If no acquired cause of the ataxia is identified, tion cannot be detected in the leukocyte DNA of the mother, the
the probability is ~13% that the affected individual has SCA1, risk to siblings is low but greater than that of the general popula-
SCA2, SCA3, SCA6, SCA8, SCA17, or FRDA,74 and mutations tion because of the possibility of maternal germline mosaicism.
in rare ataxia genes are even less common.75 Other possibilities The daughters of an affected male are all carriers whereas none of
to consider are a de novo mutation in a different autosomal his sons will be affected or be carriers.
dominant ataxia, decreased penetrance, alternative paternity,
or a single occurrence of an autosomal recessive or X-linked Related genetic counseling issues
disorder in a family such as fragile X-associated tremor/ataxia Testing of at-risk asymptomatic adult relatives of individu-
syndrome. Although the probability of a positive result from als with autosomal dominant cerebellar ataxia is possible after
molecular genetic testing is low in an individual with ataxia molecular genetic testing has identified the specific disorder
who has no family history of ataxia, such testing is usually and mutation in the family. Such testing should be performed
justified to establish a specific diagnosis for the individual’s in the context of formal genetic counseling. This testing is not
medical evaluation and for genetic counseling. Always consider useful in predicting age of onset, severity, type of symptoms,
a possible nongenetic cause such as multiple system atrophy, or rate of progression in asymptomatic individuals. Testing of
cerebellar type in simplex cases.76 asymptomatic at-risk individuals with nonspecific or equivo-
cal symptoms is predictive testing, not diagnostic testing. When
GENETIC COUNSELING testing at-risk individuals, an affected family member should be
Risk to family members: autosomal dominant hereditary tested first to confirm that the mutation is identifiable by cur-
ataxia rently available techniques. Results of testing of 29 asymptom-
Most individuals diagnosed as having autosomal dominant atic persons at risk for autosomal dominant ataxias have been
ataxia have an affected parent, although occasionally the family reported.77

680 Volume 15 | Number 9 | September 2013 | Genetics in medicine

Hereditary ataxias: overview | JAYADEV and BIRD Review
Molecular genetic testing of asymptomatic individuals Prevention of primary manifestations
younger than 18 years who are at risk for adult-onset disorders Treatments are available for a few autosomal recessive ataxias:
for which no treatment exists is not considered appropriate, Vitamin E therapy for AVED, chenodeoxycholic acid for cere-
primarily because it negates the autonomy of the child with no brotendinous xanthomatosis, CoQ10 for CoQ10 deficiency, and
compelling benefit. Furthermore, concern exists regarding the dietary restriction of phytanic acid for Refsum disease. Idebenone
potential unhealthy adverse effects that such information may may ameliorate the cardiac and neurologic manifestations of
have on family dynamics, the risk of discrimination and stig- FRDA.78 No other specific treatments exist for hereditary ataxias.
matization in the future, and the anxiety that such information
may cause. Therapies under investigation
For more information, see also the National Society of Underwood and Rubinsztein79 review potential strategies for
Genetic Counselors resolution on genetic testing of children treating ataxias associated with trinucleotide repeat expansions.
and the American Society of Human Genetics and American RNA interference strategies have been suggested for some auto-
College of Medical Genetics points to consider: ethical, legal, somal dominant SCAs.80 For further and up-to-date information,
and psychosocial implications of genetic testing in children and readers may search ClinicalTrials.gov for access to information
adolescents. on clinical studies for a wide range of diseases and conditions.

DNA banking. DNA banking is the storage of DNA (typically Resource

extracted from white blood cells) for possible future use. Because National Ataxia Foundation, 2600 Fernbrook Lane Suite 119,
it is likely that testing methodology and our understanding Minneapolis, MN 55447; Phone: 763.553.0020; http://www.
of genes, mutations, and diseases will improve in the future, ataxia.org.
consideration should be given to banking DNA of affected
individuals. ACKNOWLEDGMENTS
This study was supported by funding from Veterans Affairs
Prenatal testing. Prenatal diagnosis for some of the hereditary Research and the National Center for Biotechnology Informa-
ataxias is possible by analyzing fetal DNA (extracted from tion. This overview represents a revised and updated version of
cells obtained by chorionic villus sampling at about 10–12 Thomas D. Bird’s Hereditary Ataxia in GeneReviews at GeneTests:
weeks’ gestation or amniocentesis, usually performed at about Medical Genetics Information Resource (online resource). Copy-
15–18 weeks’ gestation) for disease-causing mutations. The right U
­ niversity of Washington, Seattle, Washington, 1998–2012.
disease-causing allele(s) of an affected family member must be http://www.genetests.org.
identified before prenatal testing can be performed.
Requests for prenatal testing for (typically) adult-onset dis- DISCLOSURE
eases are not common. Differences in perspective may exist T.D.B. received licensing fees from and is on the speaker’s bureau
among medical professionals and within families regarding the of Athena Diagnostics. S.J. declares no conflict of interest.
use of prenatal testing, particularly if the testing is being con-
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