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Ataxia with Oculomotor Apraxia Type 2

Synonym: AOA2

, MS, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: December 8, 2011.


Clinical characteristics.

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age three and 30 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of alpha-fetoprotein (AFP).


The diagnosis of AOA2 is based on clinical and biochemical findings, family history, and exclusion of the diagnosis of ataxia-telangiectasia and AOA1. AOA2 is associated with pathogenic variants in SETX, the gene that encodes the protein senataxin.


Treatment of manifestations: Physical therapy for disabilities resulting from peripheral neuropathy; wheelchair for mobility as needed; educational support (e.g., computer with speech recognition and special keyboard for typing) to compensate for difficulties in reading (caused by oculomotor apraxia) and in writing (caused by upper-limb ataxia).

Surveillance: Routine follow-up with a neurologist.

Genetic counseling.

AOA2 is inherited in an autosomal recessive manner. Each sib of an affected individual 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. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.


Clinical Diagnosis

Ataxia with oculomotor apraxia type 2 (AOA2) is suspected in individuals with the following findings [Moreira et al 2004, Anheim et al 2009]:

  • Cerebellar ataxia
  • Oculomotor apraxia (in ~51% of individuals)
  • Areflexia and later a peripheral axonal sensorimotor neuropathy (>90% of individuals)
  • Onset between age three and 30 years
  • Slow progression
  • Absence of cardiac involvement, cancer predisposition, or immunodeficiency, and rare or absent telangiectasia
  • Family history consistent with autosomal recessive inheritance

Pyramidal signs and dystonia are important features of AOA2 and may also be observed in affected individuals.

MRI. Marked cerebellar atrophy on head MRI was detected in all individuals undergoing this examination [Moreira et al 2004, Duquette et al 2005, Asaka et al 2006, Criscuolo et al 2006, Fogel & Perlman 2006, Lynch et al 2007, Anheim et al 2008, Nicolaou et al 2008, Schöls et al 2008, Fogel et al 2009, Tazir et al 2009, Bohlega et al 2011, H'mida-Ben Brahim et al 2011]. In the case described by Chen et al [2006], head MRI at age 40 years showed mild cerebellar hemispheric and moderate vermian hypoplasia/atrophy. In a study of 90 affected individuals, cerebellar atrophy was found in 96% [Anheim et al 2009].

EMG. Signs of axonal neuropathy are found in 90%-100% of individuals with AOA2 [Moreira et al 2004, Duquette et al 2005, Asaka et al 2006, Criscuolo et al 2006, Anheim et al 2008, Schöls et al 2008, Anheim et al 2009, Fogel et al 2009, Gazulla et al 2009, Nakamura et al 2009, Tazir et al 2009, Gazulla et al 2010, Bohlega et al 2011, H'mida-Ben Brahim et al 2011].


Laboratory findings that can be used to establish the diagnosis of AOA2 in a symptomatic individual include the following:

Neurochemical patterns study. Short-echo, single-voxel proton ((1)H) magnetic resonance spectroscopy performed in nine individuals with AOA2 showed total N-acetylaspartate levels in the cerebellum strongly correlated with the Friedreich Ataxia Rating Scale (FARS), which may be used as a measure of impairment in those with ataxia [Iltis et al 2010].

Neuropathology. Nerve biopsy confirms axonal neuropathy.

Molecular Genetic Testing

Gene. SETX is the only gene in which pathogenic variants are known to cause AOA2 [Moreira et al 2004].

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Ataxia with Oculomotor Apraxia Type 2

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
SETXSequence analysis 4Sequence variantsUnknown
Deletion/duplication analysis 5Exon or whole-gene deletions and duplications

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband. When the clinical findings are characteristic of AOA2, sequence analysis of the SETX full coding sequence and intronic flanking sequences is performed. If neither or only one pathogenic variant is identified, deletion/duplication analysis may be considered.

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

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variants in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Ataxia is the first sign of ataxia with oculomotor apraxia type 2 (AOA2) and is the major cause of disability early in the disease course. Later, peripheral sensorimotor neuropathy, particularly of the lower limbs, plays a significant role in disease progression.

Findings by Le Ber et al [2004], Moreira et al [2004], Duquette et al [2005], Asaka et al [2006], Chen et al [2006], Criscuolo et al [2006], Fogel & Perlman [2006], Lynch et al [2007], Anheim et al [2008], Nicolaou et al [2008], Schöls et al [2008], Anheim et al [2009], Fogel et al [2009], Gazulla et al [2009], Nakamura et al [2009], Tazir et al [2009], Gazulla et al [2010], Al-Kaabi et al [2011], Bohlega et al [2011], H'mida-Ben Brahim et al [2011] showed the following.

Cerebellar ataxia. All affected individuals, after initial normal development, show cerebellar ataxia, with slowly progressive gait imbalance [Watanabe et al 1998, Németh et al 2000]. The first symptoms are recognized between age seven and 25 years (mean 14.6 years) [Anheim et al 2009]. In a study of ten affected individuals from Italy, age at onset ranged between three and 30 years (mean 20.3 years) [Criscuolo et al 2006].

Neuropathy. Ninety percent to 100% of the individuals with AOA2 have sensorimotor neuropathy (i.e., absent or diminished tendon reflexes and sensorimotor deficit).

Oculomotor apraxia. Oculomotor apraxia is present in about 51% of individuals [Anheim et al 2009]. It is characterized by a dissociation of eye-head movements in the "head-free" condition, in which the head reaches the lateral target before the eyes. In an Italian cohort, this feature was present in only 20% of individuals [Criscuolo et al 2006], while in a study of 19 affected Algerian individuals oculomotor apraxia was present in 32% [Tazir et al 2009].

Saccadic pursuit, gaze-evoked nystagmus, poor horizontal OKN (optokinetic nystagmus), and square-wave jerks have also been observed in several individuals [Németh et al 2000, Lynch et al 2007, Nicolaou et al 2008, Schöls et al 2008, Al-Kaabi et al 2011].

In an Algerian study, 37% of affected individuals presented with convergent strabismus [Tazir et al 2009] and in a study of 90 affected individuals worldwide, strabismus was found in 12.3% [Anheim et al 2009]. Unilateral strabismus combined with nystagmus was found in an affected Algerian individual [H'mida-Ben Brahim et al 2011].

Movement disorders. Dystonic posture of the hands, choreic movements, and head or postural tremor are observed in about 14% of individuals [Németh et al 2000, Le Ber et al 2004, Lynch et al 2007, Anheim et al 2008, Schöls et al 2008, Anheim et al 2009, Tazir et al 2009]. The severity of the movement disorders persists in individuals with AOA2 in contrast to the movement disorder in individuals with ataxia with oculomotor apraxia type 1 (AOA1), in which chorea tends to disappear with time [Le Ber et al 2003, Le Ber et al 2004]. In the Italian study, extrapyramidal symptoms (including choreiform head movements, truncal dystonia, and head tremor) were reported in 20% of individuals; however, they rapidly disappeared as the disease progressed [Criscuolo et al 2006]. In the French-Canadian group of individuals tremor was an inconsistent feature present in 57% [Duquette et al 2005].

Pyramidal signs were found in 20.5% of individuals with AOA2 [Anheim et al 2009].

Intellect. Mild cognitive impairment is present in some individuals [Le Ber et al 2004], but none have had severe intellectual disability or dementia, even after long disease duration [Le Ber et al 2004]. In the Criscuolo et al [2006] study, three out of ten persons presented with mild intellectual impairment with onset around age 50 years.

Other. Deep sensory loss [Le Ber et al 2004, Fogel et al 2009, H'mida-Ben Brahim et al 2011], extensor plantar reflexes, swallowing difficulties, and sphincter disturbances are observed in some individuals [Le Ber et al 2004]. Various signs of extraneurologic involvement have been reported: early-onset menopause [Le Ber et al 2004, Criscuolo et al 2006], ovarian failure [Lynch et al 2007, Gazulla et al 2009], dermatofibrosarcoma protuberans [Schöls et al 2008], polycystic ovarian syndrome [Fogel et al 2009], and amenorrhoea secondary to hypogonadotropic hypogonadism [Anheim et al 2009].

Neuropathology. Chronic axonal neuropathy with preferential loss of large (and to a lesser degree small) myelinated fibers is detected in sural nerve biopsies [Duquette et al 2005, Criscuolo et al 2006, Anheim et al 2008, Al-Kaabi et al 2011].

Postmortem brain examination in a 79-year-old Italian who died of heart failure revealed reduction in the overall size of the brain, including atrophy of the cerebellar folia and marked widening of the sulci [Criscuolo et al 2006]. Cerebellar atrophy was most evident at the level of the vermis and the anterior lobe. The brain stem and spinal cord were slightly reduced in size without other anomalies. The substantia nigra appeared normally pigmented. Atheromatous plaques were present in all the arteries of the circle of Willis. Histologic examination showed normal cortical neurons (both in number and shape), marked loss of Purkinje cells in the cerebellar cortex, and mild fibrous gliosis that was more severe in the vermis than in the hemispheres. No inclusions or torpedos were found. The neurons of the dentate nuclei were slightly reduced in number. Chromatolysis of the oculomotor and raphe nuclei was observed in the brain stem. The inferior and accessory olives appeared relatively spared. In the spinal cord severe demyelination of the gracilis and cuneatus funiculi and degeneration of Clarke's columns with gliosis were observed.

Life span. In individuals studied to date, disease duration ranged between two and 53 years, corresponding to the maximum age of last examination, which was at 79 years.

Genotype-Phenotype Correlations

A study of 90 individuals with AOA2 found that pathogenic missense variants in the helicase domain (HD) caused less severe AOA2 phenotypes than either missense variants outside of the HD or deletions and truncating variants of SETX. However, individuals with pathogenic truncating or missense variants outside of the helicase domain had a lower frequency of pyramidal signs — a finding that may reflect masking of the pyramidal signs by severe motor neuropathy [Anheim et al 2009].


AOA2 was first known as "ataxia with later onset and high level of alpha-fetoprotein."


The prevalence of p.Leu1976Arg and p.Glu65Lys pathogenic variants was studied by genotyping 154 samples from the Gaspésie region, including 82 French-Canadian and 72 Anglo-Norman control samples [Duquette et al 2005]. In this study, five individuals (3 of Anglo-Norman and 2 of French-Canadian backgrounds) were carriers of the p.Leu1976Arg common French-Canadian variant and none was a carrier of the rarer p.Glu65Lys variant. According to these results, the carrier rate for the p.Leu1976Arg variant is estimated to be 3.5% (1:28) for Québécois of Anglo-Norman origin and 2.1% (1:47) for the French-Canadian population of Gaspésie. No individuals homozygous for the pathogenic variants p.Leu1976Arg or p.Glu65Lys were identified.

A study of 102 individuals with suspected autosomal recessive cerebellar ataxia from eastern Europe (95 from Alsace, in eastern France) reported seven individuals with AOA2 (6.9%). AOA2 prevalence in Alsace was inferred to be slightly less than 1:400,000 [Anheim et al 2010].

Differential Diagnosis

Childhood. The diagnosis of ataxia with oculomotor apraxia type 2 (AOA2) can be difficult to establish in young children because not all features of the disease are present or apparent. AOA2 in childhood needs to be distinguished from the following disorders:


Adulthood. In simplex cases (i.e., a single occurrence in a family), the possibility of spinocerebellar ataxia type 2 (SCA2) (a dominant form of ataxia which also associates cerebellar ataxia with slow eye movements) can be excluded by molecular genetic testing of SCA2 [Pulst et al 1996].


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with oculomotor apraxia type 2 (AOA2), the following evaluations are recommended:

  • Assessment of cognitive function
  • Examination of cranial nerve function
  • Neurologic examination including assessment of gait and limb ataxia, coordination, tone, strength, reflexes, and sensory perception
  • Ophthalmologic examination
  • Clinical genetics consultation
  • Physical therapy and occupational therapy assessment of strength and balance
  • Serum alpha-fetoprotein (AFP) concentration, if not evaluated previously

Treatment of Manifestations

Physical therapy may be helpful, particularly for disabilities resulting from peripheral neuropathy.

A wheelchair is usually necessary for mobility by age 30 years.

Educational support (e.g., use of a computer with speech recognition and special keyboard for typing) should be provided to compensate for difficulties in reading (caused by oculomotor apraxia) and in writing (caused by upper-limb ataxia).

Prevention of Secondary Complications

A low-cholesterol diet is advised.


Routine visits to the attending neurologist are indicated.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

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

Ataxia with oculomotor apraxia type 2 (AOA2) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one SETX pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual 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 risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. No individuals with AOA2 have been known to reproduce.

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

Heterozygote (Carrier) Detection

Carrier testing for at-risk family members is possible on a clinical basis once the pathogenic variants have been identified in the proband.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

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 and Preimplantation Genetic Diagnosis

Once the SETX pathogenic variants have been identified or linkage has been established in the family, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for AOA2 are possible.


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.

  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Ataxia with Oculomotor Apraxia Type 2: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Ataxia with Oculomotor Apraxia Type 2 (View All in OMIM)


Gene structure. SETX is composed of 24 coding and two non-coding exons (NM_015046.5). For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. To date, several different benign variants have been identified [Moreira et al 2004, Fogel & Perlman 2006, Lynch et al 2007, Bohlega et al 2011].

Pathogenic variants. To date, 74 pathogenic variants have been found in families worldwide. See Table A, locus-specific databases and HGMD.

Normal gene product. SETX encodes the newly identified and ubiquitously expressed 2,677 amino-acid protein, probable helicase senataxin (NP_055861.3). Senataxin is composed of four regions: an N-terminal region that shares homologies with the fungal Sen1p proteins; a second region that is not conserved; a third region that contains a classic seven-motif domain found in the superfamily 1 of helicases; and a C-terminal region that is not conserved [Moreira et al 2004].

Studies in yeast show that it is involved in splicing and termination of tRNA and small nuclear and nucleolar RNAs, and has RNA helicase activity encoded by its C-terminal domain [Ursic et al 1997, Rasmussen & Culbertson 1998, Kim et al 1999]. Recent data suggest that senataxin indeed plays a role in coordinating transcriptional events [Suraweera et al 2009].

Senataxin could also play a role in neuronal differentiation through the fibroblast growth factor 8 signaling [Vantaggiato et al 2011].

Senataxin may play a role in both RNA and DNA helicase activity and act in a DNA repair pathway, like several other proteins mutated in autosomal recessive cerebellar ataxias, for example, ataxia-telangiectasia [Shiloh 2003], ataxia with oculomotor apraxia type 1 [Moreira et al 2001b], ataxia-telangiectasia-like disorder [Stewart et al 1999], and spinocerebellar ataxia with peripheral neuropathy 1 [Takashima et al 2002]. Results also suggest that senataxin may be a nuclear RNA helicase with a role in the splicing machinery, and that the molecular pathology of AOA2 may share features with spinal muscular atrophy and spinal muscular atrophy with respiratory distress.

Abnormal gene product. Importantly, the pathogenic missense variants to date cluster within the N-terminus and helicase domains (HD). Cell culture studies suggest that the N-terminus may be essential for correct senataxin localization to the cytoplasm [Chen et al 2006]. However, other studies showed senataxin being predominantly nuclear [Suraweera et al 2007]; in the same study AOA2 cells displayed a defect in DNA double-strand break repair (which was rescued with full-length SETX cDNA) but no evidence of a defect in DNA single-strand break repair [Suraweera et al 2007].

Sensitivity to oxidative DNA-damaging agents was also observed in lymphoblastoid cell lines harboring the p.Leu114del deletion [Airoldi et al 2010].

The IVS16+2insT homozygous variant resulted in aberrant splicing of the senataxin mRNA, affecting the DNA/RNA helicase domain [Fogel et al 2009].

Reduced telomere length was detected in lymphocytes from persons affected with AOA2, suggesting possible involvement of senataxin in telomere stability [De Amicis et al 2011].

The fact that pathogenic missense variants outside the HD cause more severe phenotypes than pathogenic missense variants located in the HD could be consistent with the existence of one or more additional functional domains in senataxin. This may include the N-terminal domain and a conserved domain located just before the HD [Anheim et al 2009].


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Chapter Notes


The authors wish to thank all patients and their families for their collaboration, as well as all the physicians involved in the clinical study of the families. Genetic studies were supported by funds from the Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science), the Portuguese Ministry of Health (projects STRDA/C/SAU/277/92 and PECS/C/SAU/219/95), the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpitaux Universitaires de Strasbourg (PHRC regional), and the GIS-Maladies Rares (SPATAX Research Network. Grant 4MR12FA004DS). M.C.M. had a post-graduate fellowship SFRH/BPD/11502/2002 from Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science).

Revision History

  • 8 December 2011 (me) Comprehensive update posted live
  • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for SETX
  • 5 March 2007 (me) Comprehensive update posted to live Web site
  • 31 May 2005 (mcm) Revision: Sequence analysis clinically available
  • 15 November 2004 (me) Review posted to live Web site
  • 23 June 2004 (mcm) Original submission
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