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].

Testing

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

• Serum alpha-fetoprotein (AFP) concentration greater than 20 ng/mL (in >95% of affected individuals) [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, Zühlke et al 2007, Anheim et al 2008, Nicolaou et al 2008, Schöls et al 2008, Anheim et al 2009, Fogel 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]. Although normal laboratory values for serum AFP concentration are highly variable, the majority range between 0 and 20 ng/mL. Serum AFP concentration varies over time and is lower than that usually observed in ataxia-telangiectasia [Le Ber et al 2004]. Interestingly, serum AFP concentration was increased in five of eight nonsymptomatic heterozygous study participants. In the remaining three carriers, the concentration of AFP, even though in the normal range, was higher than in the three non-carrier relatives [Anheim et al 2008].
• Serum total cholesterol concentration greater than 5.6 mmol/L (in ~50% of affected individuals) [Le Ber et al 2004]. Normal value: 3.5-5.8 mmol/L.
• Serum creatine kinase (CK) concentration is increased in some affected individuals and elevated immunoglobulin levels (IgG and IgA) have been found in several families [Watanabe et al 1998, Le Ber et al 2004, Anheim et al 2008, Schöls et al 2008, Gazulla et al 2010].

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 mutations are known to cause AOA2 [Moreira et al 2004].

Clinical testing

• Sequence analysis. Direct sequencing of the SETX coding sequence and intronic flanking sequences identified mutations in families from Algeria, Belgium, Canada, Cape Verde, Cyprus, England, France, Germany, Ireland, Italy, Japan, Norway, Pakistan, Portugal, Saudi Arabia, Spain, Sudan, Switzerland, Syria, Tunisia, Turkey, United Kingdom, United States, and Vietnam [Moreira et al 2004, Duquette et al 2005, Asaka et al 2006, Criscuolo et al 2006, Fogel & Perlman 2006, Lynch et al 2007, Zühlke et al 2007, Anheim et al 2008, Nicolaou et al 2008, Schöls et al 2008, Anheim et al 2009, Fogel et al 2009, Nakamura et al 2009, Bohlega et al 2011]. Mutation detection rates have not yet been reported.
• Deletion/duplication analysis. Both exonic/multiexonic deletions and duplications [Criscuolo et al 2006, Arning et al 2008, Anheim et al 2009] that disrupt SETX have been reported; typically, such rearrangements are not detectable by sequence analysis.

Table 1. Summary of Molecular Genetic Testing Used in Ataxia with Oculomotor Apraxia Type 2

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SETX	Sequence analysis	Sequence variants 2	Unknown	Clinical
	Deletion / duplication analysis 3	Exonic or whole-gene deletions and duplications

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Testing that identifies 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. See CMA.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

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 mutation is identified, deletion/duplication analysis may be considered.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations 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 disease-causing mutations in the family.

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

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Juvenile amyotrophic lateral sclerosis (ALS4) (also known as distal hereditary motor neuronopathy with pyramidal features, or dHMN) is associated with three different missense mutations (p.Thr3Ile, p.Leu389Ser, and p.Arg2136His) in SETX [Chen et al 2004]. ALS4 is a rare autosomal dominant form of amyotrophic lateral sclerosis (ALS) characterized by severe distal muscle weakness and atrophy, normal sensation, and pyramidal signs associated with degeneration of motor neurons in the brain and spinal cord. Individuals affected with ALS4 usually have onset before age 25 years, a slow rate of progression, sparing of bulbar and respiratory muscles, and a normal life span [Chance et al 1998, Rabin et al 1999, De Jonghe et al 2002, Chen et al 2004].

An autosomal dominant form of ataxia appears to be associated with two SETX missense mutations (p.Asn603Asp-p.Gln653Lys) shared in cis configuration by a mother and daughter [Bassuk et al 2007]. Both had cerebellar ataxia with atrophy of the cerebellum, dysarthria, oculomotor defects (saccadic pursuits and gaze-evoked nystagmus), and tremor. The mother had onset of cerebellar ataxia at age 13 years, the daughter at age three years. Mental status, reflexes, sensation, muscle tone, and levels of alpha-fetoprotein and serum creatine kinase were within normal range.

Natural History

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, Nemeth 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 [Nemeth 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 [Nemeth 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 hypogonadotrophic 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 missense mutations in the helicase domain (HD) caused less severe AOA2 phenotypes than either missense mutations outside of the HD or deletions and truncating mutations of SETX. However, in individuals with truncating or missense mutations 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].

Nomenclature

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

Prevalence

The prevalence of p.Leu1976Arg and p.Glu65Lys mutations 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 mutation and none was a carrier of the rarer p.Glu65Lys mutation. According to these results, the carrier rate for the p.Leu1976Arg mutation is estimated to be 3.5% (1:28) for Quebecois of Anglo-Norman origin and 2.1% (1:47) for the French-Canadian population of Gaspésie. No individuals homozygous for the mutations p.Leu1976Arg or p.Glu65Lys were identified.

A study of 102 individuals with suspected autosomal recessive cerebellar ataxia from Eastern Europe (95 from Alsace, Eastern France region) 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].

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
• 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 (such as 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.

Surveillance

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 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 and therefore carry one mutant allele.
• 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.

Carrier Detection

Carrier testing for at-risk family members is possible on a clinical basis once the mutations 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Acknowledgments

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