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Hereditary Ataxia Overview

, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: November 26, 2014.

Summary

Disease characteristics. The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosomal locus) in which pathogenic variants occur.

Diagnosis/testing. Inherited (genetic) forms of ataxia must be distinguished from the many acquired (non-genetic) causes of ataxia. The genetic forms of ataxia are diagnosed by family history, physical examination, neuroimaging, and molecular genetic testing.

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

Management. Treatment of manifestations: Canes, walkers, and wheelchairs for gait ataxia; use of special devices to assist with handwriting, buttoning, and use of eating utensils; speech therapy and/or computer-based devices for those with dysarthria and severe speech deficits.

Prevention of primary manifestations: With the exception of vitamin E therapy for ataxia with vitamin E deficiency (AVED), no specific treatments exist for hereditary ataxia.

Definition

Clinical Manifestations of Hereditary Ataxia

Clinical manifestations of hereditary ataxia are poor coordination of movement and a wide-based, uncoordinated, unsteady gait. Poor coordination of the limbs and of speech (dysarthria) are 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
  • Documenting the hereditary nature by the presence of:
    • A positive family history of ataxia;
    • A causative (i.e., pathogenic) allelic variant or variants one of the many genes associated with hereditary ataxia;
    • 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 [Shakkottai & Fogel 2013].

Prevalence of Hereditary Ataxia

Prevalence of the autosomal dominant cerebellar ataxias (ADCAs) is estimated to be approximately 1-5:100,000 population [van de Warrenburg et al 2002, Ruano et al 2014].

Of the autosomal dominant ataxias, SCA3 is the most common worldwide, followed by SCA1, 2, 6, and 7 (see Figure 1).

Figure 1

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...)

Autosomal recessive types of hereditary ataxia account for approximately 3:100,000 [Ruano et al 2014] with Friedreich ataxia, ataxia-telangiectasia, and ataxia oculomotor apraxia being most common (see AOA1, AOA2).

The prevalance of genetic childhood ataxia varies from 0.1 to 10 cases per 100,000 population [Musselman et al 2014].

Causes

The hereditary ataxias can be subdivided first by mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, and mitochondrial) and secondarily by the gene in which pathogenic variants occur or chromosomal locus to which the phenotype has been mapped.

The nomenclature for the hereditary ataxias is a work in progress because of the large number of subtypes and their extensive phenotypic overlap.

  • Spinocerebellar ataxia (SCA) is a historical term first used in the 1950s based on Friedreich ataxia as a model. SCA now refers to autosomal dominant hereditary ataxia, and the numbers are assigned in the order in which the disease was identified (initially by linkage analysis and more recently by gene discovery). In some SCAs ataxia is the only phenotypic finding (e.g., SCA6), whereas other SCAs may have a complicated phenotype (e.g., SCA3). Some SCAs have spinal cord involvement, but many do not. Some of the complicated forms have not been given an SCA number (e.g., DRPLA).
  • SCAR refers to autosomal recessive spinocerebellar ataxias.
  • EA refers to episodic ataxias.
  • SPAX refers to ataxias that often have a prominent component of spasticity.

The hereditary ataxias have also been summarized by Duenas et al [2006], Finsterer [2009a], Paulson [2009] and Durr [2010]. The phenotypic overlap within the hereditary ataxias is also reflexed in the extensive range of neuropathologic features that have been detailed by Seidel et al [2012] and Rüb et al [2013].

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.

The autosomal dominant cerebellar ataxias for which specific genetic information is available are summarized in Table 1. Most are spinocerebellar ataxias (SCA); one is a complex form (DRPLA). See Table 2 for the episodic ataxias, all of which are inherited in an autosomal dominant manner, and Table 5 for the spastic ataxias, all but one of which are inherited in an autosomal recessive manner.

No specific treatments can prevent, delay, or reverse the major clinical features of the dominant SCAs. Some manifestations such as seizures can be treated; certain rehabilitative measures can be of benefit.

Often, one autosomal dominant ataxia cannot be differentiated from another because: (1) the most frequent manifestations of all of AD ataxias are progressive adult-onset gait ataxia (often with hand dysmetria) and dysarthria associated with cerebellar atrophy on brain imaging; (2) the ages of onset often overlap.

Table 1. Autosomal Dominant Cerebellar Ataxias: Molecular Genetics & Clinical Features

DiseaseGene / Locus 1Distinguishing Clinical Features 2OtherReferences 3
/ Selected OMIM Links
SCA1ATXN1
  • Pyramidal signs
  • Peripheral neuropathy
Occasional cognitive decline164400
SCA2ATXN2
  • Slow saccadic eye movements
  • Peripheral neuropathy
  • Decreased DTRs
  • Dementia
Large Cuban founder population183090
SCA3ATXN3
  • Pyramidal and extrapyramidal signs
  • Lid retraction, nystagmus, and decreased saccade velocity
  • Amyotrophy fasciculations, sensory loss
Large Portugese founder population; known as Machado-Joseph disease; shortens life span109150
SCA4 416q22.1
  • Sensory axonal neuropathy
  • Deafness
Flanigan et al [1996], Hellenbroich et al [2003], Edener et al [2011]
/ 600223
SCA5SPTBN2
  • Early onset
  • Slow course
Sometimes called Lincoln ataxia; normal life spanRanum et al [1994], Stevanin et al [1999], Burk et al [2004], Ikeda et al [2006]
/ 600224
SCA6 5CACNA1A
  • Sometimes episodic ataxia
  • Very slow progression
Often adult onset; normal life span183086
SCA7ATXN7
  • Visual loss with retinopathy
Often rapidly progressive; shortens life span164500
SCA8ATXN8
  • Slowly progressive
  • Sometimes brisk DTRs, decreased vibration sense
  • Rarely, cognitive impairment
608768
SCA9Not assigned
SCA10ATXN10
  • Occasional seizures
Large Mexican founder population603516
SCA11TTBK2
  • Mild
  • Remain ambulatory
604432
SCA12PPP2R2B
  • Slowly progressive ataxia
  • Action tremor in the 30s
  • Hyperreflexia
  • Subtle parkinsonism possible
  • Cognitive/psychiatric disorders incl dementia
604326
SCA13KCNC3
  • Mild intellectual disability
  • Short stature
605259
SCA14PRKCG
  • Early axial myoclonus
605361
SCA15ITPR1
  • Pure ataxia
  • Very slow progression
606658
SCA16Not assigned
  • Head tremor
Miyoshi et al [2001], Miura et al [2006]
SCA17TBP
  • Mental deterioration
  • Occasional chorea, dystonia, myoclonus, epilepsy
607136
SCA187q22-q32
  • Ataxia with early sensory/motor neuropathy
  • Nystagmus
  • Dysarthria
  • Decreased tendon reflexes
Brkanac et al [2002], Brkanac et al [2009]
/ 607458
SCA19/22KCND3
  • Slowly progressive
  • Rare cognitive impairment
  • Myoclonus
  • Hyperreflexia
Schelhaas et al [2001], Verbeek et al [2002], Chung et al [2003], Chung & Soong [2004], Schelhaas et al [2004], Duarri et al [2012], Lee et al [2012]
/ 607346
SCA2011q12
  • Early dysarthria
  • Spasmodic dysphonia
  • Hyperreflexia
  • Bradykinesia
608687
SCA21TMEM240
  • Mild to severe early-onset cognitive impairment
Devos et al [2001], Vuillaume et al [2002], Delplanque et al [2014]
/ 607454
SCA23PDYN
  • Dysarthria
  • Abnormal eye movements
  • Reduced vibration and position sense
Verbeek et al [2004], Bakalkin et al [2010]
/ 610245
SCA25SCA25
  • Sensory neuropathy
Stevanin et al [2003]
/ 608703
SCA26EEF2
  • Dysarthria
  • Irregular visual pursuits
Yu et al [2005], Hekman et al [2012]
/ 609306
SCA27FGF14
  • Early-onset tremor
  • Dyskinesia
  • Cognitive deficits
van Swieten et al [2003], Brusse et al [2006]
/ 609307
SCA28 6AFG3L2
  • Nystagmus
  • Ophthalmoparesis
  • Ptosis
  • Increased tendon reflexes
610246
SCA29ITPR1
  • Learning deficits
Dudding et al [2004]
/ 117360
SCA304q34.3-q35.1
  • Hyperreflexia
Storey et al [2009]
/ 613371
SCA31 4BEAN1
  • Normal sensation
Common in JapanNagaoka et al [2000], Sato et al [2009], Sakai et al [2010], Edener et al [2011]
/ 117210
SCA34ELOVL4
  • Skin changes disappear in adulthood
Cadieux-Dion et al [2014]
/ 133190
SCA35TGM6
  • Hyperreflexia
  • Babinski responses
Wang et al [2010]
/ 613908
SCA36NOP56
  • Muscle fasiculations
  • Tongue atrophy
  • Hyperreflexia
614153
SCA371p32
  • Abnormal vertical eye movements
Serrano-Munuera et al [2013]
SCA38ELOVL5
  • Adult onset
  • Axonal neuropathy
Di Gregorio et al [2014]
SCA40CCDC88C
  • Adult onset
  • Brisk reflexes
  • Spasticity
Tsoi et al [2014]
/ 616053
DRPLA ATN1
  • Chorea
  • Seizures
  • Dementia
  • Myoclonus
Mimics Huntington disease; more common in Japan125370
ADCADNDNMT1
  • Deafness
  • Sensory loss
  • Narcolepsy
Klein et al [2011], Klein et al [2013]
Hypomyelinating leukoencephalopathyTUBB4A
  • Hypomyelination
  • Basal ganglia atrophy
  • Rigidity
  • Dystonia
  • Chorea
Hamilton et al [2014], Miyatake et al [2014]
/ 612438

See Spinocerebellar ataxia: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

1. Chromosomal locus is given only when the gene is unknown.

2. All have gait ataxia.

3. References included when there is no GeneReview

4. SCA31 is caused by a complex pentanucleotide (TGGAA) n repeat insertion in the introns of TK2 and BEAN appeared crucial for SCA31 pathogenesis [Sato et al 2009]. SCA31 is not allelic to SCA4 which is in the same region (16q22.1) [Edener et al 2011].

5. SCA 6 is allelic to EA2 (see Table 2) and familial hemiplegic migraine type 1.

6. Allelic to SPAX5

The prevalence of individual subtypes of ADCA may vary from region to region, frequently because of founder effects. For example,

Nucleotide repeat disorders. Anticipation can be observed in the autosomal dominant ataxias in which CAG trinucleotide repeats occur (Table 1). Anticipation refers to earlier onset and increasing severity of disease in subsequent generations of a family. In the trinucleotide repeat diseases, anticipation results from expansion in the number of CAG repeats that occurs with transmission of the gene to subsequent generations. ATN1 (DRPLA) and ATXN7 (SCA7) have particularly unstable CAG repeats [La Spada 1997, Nance 1997]. In SCA7, anticipation may be so extreme that children with early-onset, severe disease die of disease complications long before the affected parent or grandparent is symptomatic. (See also Genetic Counseling.)

While attention has been focused on the phenomena of anticipation and trinucleotide repeat expansion, it is important to note that the number of trinucleotide repeats can also remain stable or even contract on transmission to subsequent generations.

Episodic Ataxias

The episodic ataxias are characterized by periods (i.e., minutes to hours) of unsteady gait often associated with nystagmus or dysarthria [Jen et al 2007]. Myokymia, vertigo, or hearing loss may occur in some of the subtypes. Permanent ataxia and even cerebellar atrophy may result late in the disease course.

Table 2. Episodic Ataxias: Molecular Genetics & Clinical Features

DiseaseGene / Locus 1Distinguishing Clinical FeaturesReferences 2
/ Selected OMIM Links
EA1KCNA1
  • Gait ataxia
  • Myokymia
  • Attacks lasting seconds to minutes; startle or exercise induced
  • No vertigo
160120
EA2 3CACNA1A
  • Gait ataxia
  • Nystagmus
  • Attacks lasting minutes to hours; posture change induced
  • Vertigo
  • Later, permanent ataxia
108500
EA3 41q42
  • Adult onset
  • Vertigo
  • Tinnitus
Cader et al [2005]
/ 606554
EA4 5--
  • Adult onset
Steckley et al [2001], Jen et al [2007]
/ 606552
EA5CACNB4
  • Childhood to adolescent onset
Escayg et al [2000], Jen et al [2007]
/ 613855
EA6SLC1A3
  • Seizures
  • Migraine
  • Childhood onset
de Vries et al [2009], Winter et al [2012]
/ 612656
EA719q13
  • Vertigo
  • Weakness
  • ? seizures
  • Childhood to adolescent onset
Kerber et al [2007]
/ 611907

See Episodic ataxia: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

1. Chromosomal locus is given only when the gene is unknown.

2. References included when there is no GeneReview

3. EA2 is allelic to SCA6 (see Table 1) and familial hemiplegic migraine type 1.

4. A single family with EA3 (periodic vestibulocerebellar ataxia with defective smooth pursuit)

5. A single family with EA4 (episodic ataxia with vertigo and tinnitus)

Autosomal Recessive Hereditary Ataxias

The autosomal recessive hereditary ataxias are listed in Table 3:

  • The first part of the table lists those autosomal recessive ataxias that are relatively common (i.e., reported in >5 families; e.g., FRDA, AOA1, AOA2, and ATM) or treatable (e.g., CTX, Refsum syndrome, and AVED) or found more often in a specific ethnic group (e.g., ARSACS in French-Canadians).
  • The second part of the table lists autosomal recessive ataxias that are relatively uncommon (i.e. reported in 1-5 families) [Musselman et al 2014].

An overall review of these conditions can be found in Embirucu et al [2009].

Note that autosomal recessive disorders associated with ataxia and/or cerebellar hypoplasia that are caused by biallelic pathogenic variants in one of many related genes are not included in this discussion or in Table 3. Examples include the following:

Table 3. Autosomal Recessive Cerebellar Ataxias: Single Gene Disorders

Gene / Locus 1DiseaseDistinguishing Clinical FeaturesOtherReferences 2
/ Selected OMIM Links
More common and/or treatable 3
ANO10Autosomal recessive spinocerebellar ataxia 10 (SCAR10)
  • Downbeat nystagmus
  • Fasciculations
  • Spasticity
Vermeer et al [2010], Renaud et al [2014]
/ 613728
APTXAtaxia with oculomotor apraxia type 1 (AOA1)
  • Oculomotor apraxia
  • Cchoreoathetosis
  • Mild intellectual disability
  • Hypoalbuminemia
208920
ATMAtaxia-telangiectasia
  • Telangiectasia
  • Immune deficiency
  • Cancer
  • Chromosomal instability
  • Increased alpha-fetoprotein
208900
C10orf2Infantile-onset spinocerebellar ataxia (IOSCA)
  • Peripheral neuropathy
  • Athetosis
  • Optic atrophy
  • Deafness
  • Ophthalmoplegia
271245
CYP27A1Cerebrotendinous xanthomatosis (CTX)
  • Thick tendons
  • Cognitive decline
  • Dystonia
  • White matter disease
  • Cataract
Treat with chenodeoxycholic acid606530
FXNFriedreich ataxia (FRDA)
  • Hyporeflexia
  • Babinski responses
  • Sensory loss
  • Cardiomyopathy
229300
PHYH
PEX7
Refsum disease
  • Neuropathy
  • Deafness
  • Ichthyosis
  • Retinopathy
Treat with dietary phytanic acid266500
PNPLA6Boucher-Neuhäuser syndrome
  • Vision loss
  • Delayed puberty
  • Spasticity
Tarnutzer et al [2014]
/ 215470
SACSAutosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
  • Spasticity
  • Peripheral neuropathy
  • Retinal striation
270550
SETXAtaxia with oculomotor apraxia type 2 (AOA2)
  • Cerebellar atrophy
  • Axonal sensorimotor neuropathy
  • Oculomotor apraxia
606002
SIL1Marinesco-Sjögren syndrome
  • Intellectual disability
  • Cataract
  • Hypotonia
  • Myopathy
248800
SLC52A2Brown-Vialetto-Van Laere syndrome 2
  • Optic atrophy
  • Hearing loss
Treat with riboflavinFogel et al [2014], Foley et al [2014]
/ 614707
TTPAAtaxia with vitamin E deficiency (AVED)
  • Similar to FRDA
  • Head titubation (28%)
Treat with vitamin E277460
WFS1Wolfram syndrome
  • Juvenile diabetes
  • Optic atrophy
  • Hearing loss
Chaussenot et al [2011], Fogel et al [2014]
/ 222300
Less common 4
ABHD12Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC)
  • Polyneuropathy
  • Hearing loss
  • Ataxia
  • Retinopathy
  • Cataract
Similar to RefsumFiskerstrand et al [2010], Chen et al [2013]
/ 612674
ACO2Infantile cerebellar- retinal degeneration (ICRD)
  • Infant onset
  • Hypotonia
  • Seizures
  • Intellectual disability
  • Retinopathy
Shortened life spanSpiegel et al [2012]
/ 614559
ADCK3 (CABC1)Autosomal recessive spinocerebellar ataxia 9 (SCAR9)
  • Mild psychomotor retardation
  • Seizures
  • Elevated plasma lactate
Treatment with CoQ10Lagier-Tourenne et al [2008], Mollet et al [2008]
/ 612016
ATCAYCayman ataxia
  • Grand Cayman Island
  • Psychomotor retardation
Bomar et al [2003]
/ 601238
ATP8A2Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 (CAMRQ4)
  • Turkish
  • Intellectual disability
  • Quadrupedal locomotor
Emre Onat et al [2012]
/ 615268
STUB1 (CHIP)Autosomal recessive spinocerebellar ataxia16 (SCAR16)
  • Adolescent-onset ataxia with cerebellar atrophy
  • abnormal EMG/NCV
  • Cognitive impairment
Shi et al [2013], Depondt et al [2014], Synofzik et al [2014]
/ 615768
CLCN2Leukoencephalopathy with ataxia (LKPAT)
  • Spasticity
  • Retinopathy
Depienne et al [2013]
/ 615651
CLN5Adult-onset autosomal recessive ataxia associated with neuronal ceriod-lipofuscinosis 5 (CLN5 disease)
  • Cognitive decline
  • Glaucoma
Mancini et al [2014] / 256731
CWF19L1Autosomal recessive ataxia (Turkish)
  • Turkish
  • Developmental delay
  • Cognitive impairment
Burns et al [2014]
FLVCR1Posterior column ataxia with rentinitis pigmentosa (AXPC1)
  • Spinal posterior column ataxia
  • Retinitis pigmentosa
Higgins et al [1999], Ishiura et al [2011]
/ 609033
GOSR2Ramsay Hunt syndrome
  • Myoclonus epilepsy
Corbett et al [2011]
/ 614018
GRID2
  • Delayed speech & cognitive development
  • Tonic upgaze
  • Retinopathy
Hills et al [2013], Van Schil et al [2014]
GRM1Autosomal recessive spinocerebellar ataxia 13 (SCAR13)
  • Roma
  • Developmental delays
  • Intellectual deficit
  • Small brain
Guergueltcheva et al [2012]
/ 614831
KCNJ10SeSAME syndrome
  • Deafness
  • Intellectual disability
  • Electrolyte imbalance
Scholl et al [2009]
/ 612780
KIAA0226Autosomal recessive spinocerebellar ataxia 15 (SCAR15)
  • Epilepsy
  • Cognitive deficits
Assoum et al [2013]
/ 615705
LAMA1Cerebellar dysplasia
  • Cerebellar cysts
  • Retinopathy
Aldinger et al [2014]
/ 150320
POLGMitochondrial recessive ataxia syndrome (MIRAS)
  • Neuropathy
  • Sensory ataxia
  • Myopathy
  • Progressive external opthalmoplegia
157640
203700
258450
607459
PTF1APancreatic and cerebellar agenesis (PACA)
  • Neonatal diabetes
  • Cerebellar hypoplasia/agenesis
  • Dysmorphic facial features
Sellick et al [2004]
/ 609069
SLC9A1Lichtenstein-Knorr syndrome
  • Severe sensorineural deafness
Turkish familyGuissart et al [2014] / 107310
SPTBN2Autosomal recessive spinocerebellar ataxia14 (SCAR14)
  • Cognitive deficits
Lise et al [2012], Elsayed et al [2013]
/ 615386
SYNE1SYNE1-related autosomal recessive cerebellar ataxia
  • French Canadian
610743
SYT14Autosomal recessive spinocerebellar ataxia 11 SCAR11
  • Japanese
  • Psychomotor retardation
Doi et al [2011]
/ 614229
TDP1Spinocerebellar ataxia with axonal neuropathy (SCAN1)
  • Axonal sensorimotor neuropathy
607250
TPP1Autosomal recessive spinocerebellar ataxia 7 (SCAR7)
  • Hyperreflexia
  • Diffuse cerebellar atrophy on MRI
Breedveld et al [2004], Sun et al [2013]
/ 609270
VLDLRVLDLR-associated cerebellar hypoplasia (CAMRQ1)
  • Hutterite
  • Intellectual disability
  • Cerebral gyral simplification
224050
WWOXAutosomal recessive spinocerebellar ataxia 12 (SCAR12)
  • Epilepsy
  • Intellectual disability
  • Spasticity
Mallaret et al [2014]
/ 614322
ZNF592Autosomal recessive spinocerebellar ataxia 5 (SCAR5)
  • Lebanese
  • Optic atrophy
  • Skin abnormalities
Mallaret et al [2014]
/ 606937
9q34-qterAutosomal recessive spinocerebellar ataxia 2 (SCAR2)
  • Mental deficiency
  • Microcephaly
  • Cataract
Cerebellar granule cell lossDelague et al [2001]
/ 213200

1. Chromosomal locus is given only when gene is unknown.

2. References included when there is no GeneReview

3. Reported in more than five families

4. “Less common” = reported in 1-5 families [Musselman et al 2014].

Friedreich ataxia (FRDA) is the most common of the autosomal recessive ataxias. It generally begins in childhood with slowly progressive ataxia associated with depressed tendon reflexes and posterior column sensory loss.

  • About 25% of affected individuals have an "atypical" presentation with later onset (age >25 years), retained tendon reflexes, or unusually slow progression of disease.
  • The vast majority of individuals have a GAA triplet-repeat expansion in FXN; however, FRDA is not associated with anticipation [Durr et al 1996]. Rare individuals have a missense mutation in one FXN allele with the GAA repeat in the other allele.

X-Linked Hereditary Ataxias

X-linked inheritance of cerebellar ataxia occurs (Table 4), but is quite uncommon except for fragile X tremor ataxia syndrome (FXTAS) [Zanni & Bertini 2011].

Table 4. X-linked Cerebellar Ataxias: Molecular Genetics & Clinical Features

Gene / Locus 1DiseaseDistinguishing Clinical FeaturesOtherReferences 2
/ Selected OMIM Links
ABCB7X-linked sideroblastic anemia and ataxia (XLSA/A)
  • Early childhood onset
  • Anemia is asymptomatic
Carrier females may have sideroblasts301310
CASKCASK-related disorders
  • Cognitive deficiency
  • Microcephaly
  • Hypotonia
  • Optic nerve hypoplasia
Growth retardation300749
FMR1FXTAS
  • Adult onset
Most common of the X-linked ataxias;
occurs in male and female premutation carriers
300623
OPHN1X-linked mental retardation with cerebellar hypoplasia and distinctive facial appearance
  • Infantile onset
  • Hypotonia
  • Developmental delay
  • Seizures
Zanni et al [2005]
/ 300486
SLC9A6Syndromic X-linked mental retardation, Christianson type
  • Infantile onset
  • Intellectual disablity
  • Seizures
MR in carrier females;
may resemble Angelman syndrome
Gilfillan et al [2008], Garbern et al [2010]
/ 300243
Xq25-q27.1X-linked spinocerebellar ataxia 5
  • Infantile onset
  • Cerebellar hypoplasia
Norwegian ancestryZanni et al [2008]
/ 300703

XLSA/A = X-linked sideroblastic anemia and ataxia

FXTAS = fragile X-associated tremor/ataxia syndrome

1. Chromosomal locus is given only when the gene is unknown.

2. References included when there is no GeneReview

Spastic Ataxias

The combination of spasticity with signs of cerebellar ataxia is relatively common and one or the other finding may predominate [de Bot et al 2012]. For example, ataxia and cerebellar atrophy both frequently occur in spastic paraplegia 7 (a form of hereditary spastic paraplegia), caused by pathogenic variants in SPG7 coding the protein paraplegin [van Gassen et al 2012].

Five disorders have specifically been designated spastic ataxia (SPAX) (Table 5). SPAX1 is inherited in an autosomal dominant manner and the other four are inherited in an autosomal recessive manner.

Table 5. Spastic Ataxias: Molecular Genetics & Clinical Features

Disease (MOI)GeneDistinguishing Clinical FeaturesOtherReferences
/ Selected OMIM Links
SPAX1 (AD)VAMP1
  • Initial progressive leg spasticity
  • Gait ataxia
Meijer et al [2002], Bourassa et al [2012]
/ 108600
SPAX2 (AR)KIF1C
  • Often w/childhood-onset tremor & dysmetria
Dor et al [2014]
/ 611302
SPAX3 (AR)MARS2
  • Periventricular white matter changes
Bayat et al [2012]
/ 611390
SPAX4 (AR)MTPAP
  • Optic atrophy
Amish familyCrosby et al [2010]
/ 613672
SPAX5 1 (AR)AFG3L2
  • Often w/peripheral neuropathy & epilepsy
Pierson et al [2011]
/ 614487

See Spastic ataxia: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

MOI = mode of inheritance

1. Allelic to SCA28 (see Table 1)

Ataxias with Mitochondrial Disorders

A progressive ataxia is sometimes associated with mutation of mitochondrial DNA (mtDNA) (see Mitochondrial Disorders Overview) including MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa) [Finsterer 2009b], and Kearns-Sayre syndrome. Disorders of mtDNA 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.

Note that many nuclear genes regulate mitochondrial function and may be mutated in autosomal recessive ataxias (See Mitochondrial Disorders Overview and Table 3, POLG).

Evaluation Strategy

Once a hereditary ataxia is considered in a proband (i.e., the index case in a family), the following approach can be used to determine the specific genetic cause to aid in discussions of prognosis and genetic counseling. Establishing the specific genetic cause of hereditary ataxia for a given individual usually involves a medical history, physical examination, neurologic examination, neuroimaging, three-generation family history, and molecular genetic testing.

Clinical Findings

Gait ataxia is the common manifestation of these disorders. Other common findings include: nystagmus, dysarthria, and dysmetria. Brain imaging often shows cerebellar atrophy or hypoplasia. Age of onset varies widely, but is frequently in childhood in autosomal recessive ataxias. Intellectual disability, peripheral neuropathy, and retinal abnormalities may also occur.

Family History

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 molecular genetic testing, neuroimaging studies, and autopsy examinations.

Testing

Non-DNA-based clinical tests are usually nonspecific except for rare instances such as vitamin E deficiency in AVED.

Molecular Genetic Testing

The ordering of molecular genetic tests and interpretation of results is complex and may require the support of an experienced laboratory, medical geneticist, and genetic counselor.

Approaches to molecular genetic testing of a proband to consider are serial testing of single genes, multi-gene panel testing (simultaneous testing of multiple genes), and genomic testing (whole exome sequencing, whole genome sequencing, and whole mitochondrial sequencing).

Single gene and multi-gene panel testing. In contrast to genomic testing, serial testing of single genes and multi-gene panel testing rely on the clinician developing a hypothesis about which specific gene or set of genes to test.

Hypotheses may be based on one or more of the following:

  • Mode of inheritance
  • Distinguishing clinical features
  • Other discriminating features (listed in the Other column of the tables) including:
    • Apparent anticipation for a nucleotide repeat disorder;
    • Ethnicity (country/region of origin);
    • Distinctive age of onset;
    • Shortened life span;
    • Treatment available;
    • Specific neuropathologic findings.

Note when considering use of a multi-gene panel: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Nemeth et al [2013] studied the clinical utility of a multi-gene panel for diagnosis of neurologic disorders using the hereditary ataxias as a model. Using next-generation sequencing they searched for small, intragenic pathogenic variants in 58 known human ataxia genes in 50 individuals with ataxia and a wide range of findings whose testing for SCA1, 2, 3, 6, 7, and Friedreich ataxia had been normal.

  • Mutations were found in eight different genes: PRKCG PRKCG, TTBK2, SETX, SPTBN2, SACS, MRE11, KCNC3, and DARS2.
  • The overall detection rate was 18% and varied from 8.3% in those with adult-onset progressive disorders to 40% in those with childhood or adolescent onset progressive disorders.
  • The highest detection rate was in those with adolescent onset and a positive family history (75%).

This study demonstrated that this multi-gene panel was efficient, cost effective and enabled a molecular diagnosis in many refractory cases.

Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of a hereditary ataxia, genomic testing may be considered. Such testing may include whole exome sequencing (WES), whole genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations can not be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Mode of Inheritance

See the GeneReviews Illustrated Glossary for more discussion of clues on family history that may help in identifying an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance.

More than one affected family member

Simplex case

Distinguishing Clinical Features

Distinguishing clinical findings exist for a number of inherited ataxias:

  • Because of extensive clinical overlap between all forms of autosomal dominant hereditary ataxia, it is difficult in any given individual with ataxia and a family history consistent with autosomal dominant inheritance to establish a diagnosis without molecular genetic testing. Note that retinal disease suggests SCA7, Portugese ancestry suggests SCA3, seizures and Amerindian ancestry suggests SCA10, and chorea suggests SCA17 or DRPLA [Ashizawa et al 2013]. See Table 1.
  • Clinical findings such as intellectual disability, seizures, eye abnormalities, or peripheral neuropathy may help distinguish between some of the autosomal recessive ataxias. See Table 3.
  • Distinct brief (minutes to hours) episodes of ataxia separated by normal function strongly suggests an episodic ataxia. See Table 2.
  • Prominent spasticity suggests one of the spastic ataxias. See Table 5.

In the absence of distinguishing clinical features, multi-gene panel testing may be considered. Panels may be oriented around a specific, relatively small subset of hereditary ataxias (e.g., the most common autosomal dominant spinocerebellar ataxias) or may include a broad range of disorders (e.g., all known hereditary ataxias).

Other

Ethnicity. Singe-gene testing may be considered on the basis of an indvidual’s ethnic background

Prevalence. Prevalence of a disorder can be used to order in which a series of single gene testing is performed (i.e., test in order of most common to least common hereditary ataxia) or choice of a multi-gene panel (i.e., selecting a panel including only the five or six most common hereditary ataxias).

The most common adult-onset autosomal dominant ataxias are SCA1, SCA2, SCA3, SCA6, and SCA7, and the most common autosomal recessive ataxias (which are usually of childhood-onset) are Friedreich ataxia, AOA1, AOA2, and ataxia-telangiectasia.

Genetic Counseling

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. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

This GeneReview includes hereditary ataxias that may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner. (Hereditary ataxias caused by mutation of mitochondrial DNA are discussed in Mitochondrial Disorders Overview.)

If a proband has a specific syndrome associated with ataxia (e.g., Friedreich ataxia or FXTAS), counseling for that condition is indicated.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

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.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents are obligate heterozygotes and therefore carry a single copy of a pathogenic variant.
  • 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 heterozygotes (carriers) for a mutant allele.

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

Carrier Detection

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

Risk to Family Members — X-Linked Inheritance

Parents of a proband

  • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
  • 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 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant 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 pathogenic variant 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.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing for females at risk for an X-linked disorder requires prior identification of the pathogenic variant in the family.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with hereditary ataxia is possible after molecular genetic testing has identified the specific disorder and pathogenic variant(s) in the family. Such testing should be performed in the context of formal genetic counseling.

In general, molecular genetic test results are not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.

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.

For more information, 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant(s) has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing. However, in general, age of onset, severity of disease, specific symptoms, and rate of disease progression are variable and cannot be accurately predicted by the family history or molecular genetic testing. See Causes, ADCA, Nucleotide repeat disorders.

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 pathogenic variant(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
    Booklet providing information about Spinocerebellar Ataxia
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • NCBI Genes and Disease

Management

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 AVED, Refsum syndrome, CTX and CoQ10 deficiency, 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.

References

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 11-20-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 11-20-14.

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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]

Chapter Notes

Revision History

  • 26 November 2014 (tb) Revision: addition of PNPLA6, CLN5, and CWF19L1
  • 30 October 2014 (tb) Revision: addition of Brown-Vialetto-Van Laere syndrome 2 (caused by mutation of SLC52A2) and Wolfram syndrome (caused by mutation of WFS1)
  • 16 October 2014 (aa) Revision: addition of SCA40, caused by mutation of CCDC88C
  • 2 October 2014 (tb) Revision: SCA21, Lichtenstein-Knorr Syndrome added
  • 28 August 2014 (tb) Revision: addition of ELOVL5 and LAMA
  • 14 August 2014 (me) Comprehensive update posted live
  • 3 April 2014 (tb) Revision: to information on KIAA0226 [Assoum et al 2013]
  • 20 March 2014 (tb) Revision: SCA34; SPTBN2 associated with autosomal recessive cerebellar ataxia; update in prevalence information
  • 27 February 2014 (tb) Revision: addition of CLCN2, WWOX, and links to OMIM Phenotypic Series
  • 13 February 2014 (tb) Revision: review of spastic ataxia
  • 23 January 2014 (tb) Revision: edits to prevalence, clinical features of ADCA, AR single cases; added SCA37 to Tables 1&2; added SCA32 and SCA34 to Table 1.
  • 7 November 2013 (tb) Revision: autosomal recessive SCA with eye movement abnormalities (most notably tonic upgaze) caused by mutations in GRID2
  • 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
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