Clinical Diagnosis

Ataxia with oculomotor apraxia type 1 (AOA1) is suspected in individuals with the following combination:

• Cerebellar ataxia, oculomotor apraxia, and areflexia followed by signs of severe peripheral neuropathy
• Childhood onset
• Slow progression leading to severe motor handicap
• Long survival [Barbot et al 2001]
• Absence of extraneurologic findings common in ataxia-telangiectasia (telangiectasias and immunodeficiency).
• Family history consistent with autosomal recessive inheritance

MRI. Cerebellar atrophy is present in all affected individuals. A very few individuals also have brain stem atrophy.

EMG. Signs of axonal neuropathy are found in 100% of individuals with AOA1.

Note: Normal EMG results may be observed only in those investigated in the very early stages of the disease.

Testing

Laboratory findings that can be used to confirm the diagnosis of AOA1 in a symptomatic person include [Barbot et al 2001, Le Ber et al 2003]:

• Serum concentration of albumin. Serum concentration of albumin is decreased (<3.8 g/L) in 83% of individuals with disease duration of more than ten to 15 years.
• Serum concentration of total cholesterol. Serum concentration of total cholesterol is increased (>5.6 mmol) in 68% of individuals with disease duration of more than ten to 15 years.
• Normal serum concentration of alpha-fetoprotein
• Neuropathology. Nerve biopsy confirms axonal neuropathy.

Molecular Genetic Testing

Gene. APTX is the only gene known to be associated with AOA1 [Date et al 2001, Moreira et al 2001b]. It encodes the protein aprataxin, which plays a role in DNA-single-strand break repair [Hirano et al 2007]. All Portuguese families with AOA1 share the same mutation (p.Trp279X), while Japanese families first described by Uekawa et al [1992] shared another mutation (c.689dupT), associated with a higher incidence of cognitive impairment .

Clinical testing

• Sequence analysis. Mutation detection rates have not yet been reported for sequence analysis; however, mutation scanning identified mutations diagnostic for either AOA1 or AOA2 in only 20 of the 43 (46.5%) individuals with the ataxia with oculomotor apraxia phenotype. In other words, almost half of Portuguese families with AOA do not appear to have AOA1 or AOA2 using mutation scanning; thus, mutations in other genes or mutations not detectable by this test method (such as exonic or whole-gene deletions) may be causative.
• Deletion/duplication analysis. Deletion of the entire APTX gene has been reported [Amouri et al 2004]. The frequency of alleles with partial- or whole-gene deletions is not known, but many would not be detected by sequence analysis of genomic DNA.

Table 1. Summary of Molecular Genetic Testing Used in AOA1

View in own window

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

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. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

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.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Molecular genetic testing of APTX is the next step in individuals with an autosomal recessive cerebellar ataxia that began around age four years and is associated with oculomotor apraxia and arreflexia (the beginning of the neuropathy), normal immune function, and normal serum concentration of alphafetoprotein.
• If APTX mutations are not identified, the next step is molecular genetic testing of SETX, the gene associated with AOA2.

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

No other phenotypes are known to be associated with mutations in APTX.

Natural History

Ataxia is the main cause of disability in ataxia with oculomotor apraxia type 1 in the first stages of the disease. Later, peripheral axonal motor neuropathy dominates the clinical picture.

Cerebellar ataxia. Symptoms are first noticed between ages two and ten years (mean: 4.3 years). In about 50% of affected individuals, onset is before age seven years. Two Italian adults with cerebellar ataxia were reported having disease onset at ages 28 and 29 years [Criscuolo et al 2004].

After initial normal motor development, all individuals develop cerebellar ataxia. The first manifestations of AOA1 are slowly progressive gait imbalance followed by dysarthria, then upper-limb dysmetria with mild intention tremor.

Oculomotor apraxia. Oculomotor apraxia is present in all individuals with AOA1. It is usually noticed a few years after the onset of ataxia. Oculomotor apraxia is the most striking feature in this disorder, but can be missed on routine neurologic examination. Individuals with oculomotor apraxia do not fixate normally on objects. When asked to look to one side, they turn their heads first, with eye contraversion, after which their eyes follow to the same side in several slow saccades with head thrusts.

Blinking is exaggerated in most individuals.

Ocular movements on command are usually slightly limited; the eyes stop before reaching extreme positions of gaze. These slow eye movements appear equally on lateral and vertical gaze.

When the head is immobilized, movement of the eyes is impossible.

Oculocephalic reflexes are spared until advanced stages of the disease. When standing and turning their heads, affected individuals lose their balance and tend to move the whole body to compensate.

Ocular pursuit movements remain normal during the first years after the appearance of oculomotor apraxia. Later, oculomotor apraxia is followed by progressive external ophthalmoplegia (beginning with upward gaze).

Neuropathy. All individuals with AOA1 have an axonal peripheral neuropathy, with early areflexia that dominates the clinical picture in advanced phases of the disease and is the major cause of motor disability with severe weakness and wasting. Loss of independent walking happens about seven to ten years after onset; most individuals become wheelchair bound by adolescence.

Hands and feet are short and atrophic. Pes cavus is present in 30% of individuals and scoliosis in a few.

Vibration and postural sense are impaired only in older individuals with very long disease duration. Pain and light touch sensation are preserved.

Chorea. About 45% of affected individuals have chorea even after a long disease duration (up to 51 years) [Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Tranchant et al 2003, Criscuolo et al 2004, Habeck et al 2004]. At onset, the percentage may be as high as 80%, but in almost 50% of affected individuals, chorea disappears over the course of the disease [Le Ber et al 2003].

Dystonia. Upper-limb dystonia occurs in about 50% of individuals, sometimes sufficiently pronounced to justify diagnostic consideration of extrapyramidal disorders.

Intellect. Different degrees of cognitive impairment are observed, largely independent of ethnic origin [Tachi et al 2000, Moreira et al 2001a, Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Criscuolo et al 2004, Quinzii et al 2005]. Severe cognitive disability was reported in a single family [Moreira et al 2001b].

Life span. In the Portuguese kindreds, the age at last examination ranged from 17 to 68 years, corresponding to a disease duration of 12 to 58 years (mean: 27.5 years); two individuals died, one of an unknown cause and the other, an 11-year-old girl with AOA1 who had been symptomatic for eight years, from a thalamic tumor. One Japanese individual died at age 71 years. In the cohort reported by Le Ber et al [2003], disease duration was 51 years.

Other. No signs of extraneurologic involvement are evident.

Genotype-Phenotype Correlations

Missense mutations of APTX may be associated with a later onset (age ~9 years). All other individuals with AOA1 with homozygous truncating mutations (nonsense or frameshift) had onset ranging between ages two and 12 years (mean: 4.6 years) [Moreira et al 2001b, Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Amouri et al 2004, Habeck et al 2004, Quinzii et al 2005].

Cognitive impairment was reported in several families of different ethnic origins who had a range of mutation types, including nonsense, frameshift, splice site, and missense [Tachi et al 2000, Barbot et al 2001, Moreira et al 2001a, Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Criscuolo et al 2004, Quinzii et al 2005].

• The p.Trp279X nonsense mutation can be associated with cognitive impairment [Le Ber et al 2003] or normal cognitive development [Moreira et al 2001a, Le Ber et al 2003, Tranchant et al 2003].
• The presence of severe cognitive impairment in p.[Glu232GlyfsX38]+[Pro206Leu] compound heterozygotes and the presence of mild cognitive impairment/borderline intelligence in the respective homozygotes is unexplained.

Two compound heterozygotes for the p.Arg199His missense mutation and an unidentified second mutation had an atypical presentation with marked dystonia and mask-like faces in addition to the AOA1 clinical picture.

The pathologic variant p.Ala198Val is associated with predominant, more severe and persistent chorea [Le Ber et al 2003].

In two Italian adults, homozygous p.Pro206Leu and p.His201Gln pathologic allelic variants were associated with late-onset AOA1 (ages 28 and 29 years). In contrast, in Japanese individuals with AOA1, the p.Pro206Leu mutation is associated with earlier onset (age 10 years).

The missense mutation p.Pro206Leu is associated with a later onset [Date et al 2001] and the mutations p.Val263Gly and p.Lys197Gln with an even later onset: age 15 years [Tranchant et al 2003] and 25 years [Date et al 2001]

To the authors' knowledge, no correlation exists between the specific mutation and the affected individual's survival.

Nomenclature

In Japan, AOA1 is called early-onset ataxia with oculomotor apraxia and hypoalbuminemia [Date et al 2001, Shimazaki et al 2002, Sekijima et al 2003].

Prevalence

Through a systematic population-based survey of hereditary ataxias being conducted in Portugal since 1993 [Silva et al 1997], Friedreich ataxia, as expected, was found to be the most frequent autosomal recessive ataxia (32.8%), followed by AOA (12.6%). In Portugal there are now 42 individuals with AOA in 20 different families (AOA1= 3.6% of all autosomal recessive ataxias; AOA2= 3.3%). AOA prevalence in Portugal is estimated at .41 per 100,000 inhabitants. However, 20 of these individuals with AOA from 13 different families do not have either AOA1 or AOA2; thus, genetic heterogeneity remains a possible explanation.

In Japan, AOA1 seems to be the most frequent cause of autosomal recessive ataxia [Uekawa et al 1992, Fukuhara et al 1995, Hanihara et al 1995, Kubota et al 1995, Sekijima et al 1998, Tachi et al 2000, Moreira et al 2001a, Shimazaki et al 2002, Sekijima et al 2003].

In the entire cohort studied by Le Ber et al [2003] — mostly individuals of French origin with progressive cerebellar ataxia in whom Friedreich ataxia had been excluded — the frequency of AOA1 was 5.7%; among the subset of individuals with onset before age 25 years, the frequency of AOA1 was 9.1%.

Affected individuals with mutations in APTX have been identified worldwide:

• Thirteen individuals from three unrelated Tunisian families [Amouri et al 2004]
• Two unrelated individuals from Germany [Habeck et al 2004]
• Three unrelated Italian individuals [Criscuolo et al 2004]
• Two American children [Tsao & Paulson 2005]
• Four individuals of northern European heritage with ataxia and CoQ₁₀ deficiency [Quinzii et al 2005]

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ataxia with oculomotor apraxia type 1 (AOA1), the following evaluations are recommended:

• Examination of cognitive function
• Examination of cranial nerve function
• Extended neurologic examination of the limbs: initial inspection; tone; strength testing; reflexes; coordination; sensory testing
• Ophthalmologic examination

Treatment of Manifestations

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

A wheelchair is usually necessary for mobility by age 15-20 years.

Educational support should be provided to compensate for difficulties in speaking (dysarthria), in reading (oculomotor apraxia), and in writing (upper-limb ataxia and weakness).

Prevention of Secondary Complications

High-protein diet to restore serum albumin concentration is indicated to prevent edema secondary to hypoalbuminemia.

Low-cholesterol diet is advised.

Surveillance

Routine visits to the neurologist are appropriate.

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.

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

AOA1 is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• Both parents of an affected child are obligate carriers of an AOA1-causing mutation in APTX.
• 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. All the offspring of an individual with AOA1 are obligate heterozygotes (carriers) for a disease-causing mutation in APTX.

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 family members is possible if the disease-causing mutations in the family have been identified.

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 affected, 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 for AOA1 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified 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).

Molecular Genetic Pathogenesis

Data suggest that AOA1 is a novel type of DNA damage response-defective disease in which aprataxin may be associated with both the DNA single-strand and double-strand break repair machinery [Clements et al 2004].

Normal allelic variants. APTX consists of seven exons. Normal allelic variants have been reported (see Table 3).

Pathologic allelic variants. To date, 16 different mutations have been found in 37 families from different countries on three continents (Table 3).

See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Reference sequences are those of the long isoform: NP_778243.1 and NM_175073.1

Normal gene product. APTX encodes a ubiquitously expressed protein, aprataxin. Alternative splicing on exon 3 generates two distinct isoforms. The longer transcript (NM_175073.1) is the major form found in human cell lines, with the shorter, frame-shifted form being present in lower amount [Date et al 2001, Moreira et al 2001b]. The longer transcript codes for a 342-amino acid protein (NP_778243.1), while the shorter one encodes a 168-amino acid protein. The longer transcript is composed of three domains:

• The PANT domain (PNKP-AOA1 N-terminal domain), also known as putative forkhead-associated (FHA) domain [Caldecott 2003] corresponding to the N-terminal region of aprataxin that shares 41% identity only with the N-terminus of animal polynucleotide kinase 3' phosphatase (PNKP) [Jilani et al 1999, Karimi-Busheri et al 1999, Moreira et al 2001b]. This domain facilitates binding to phosphorylated proteins [Kijas et al 2006]. The PNKP (dual 5' kinase 3' phosphatase) interacts with DNA polymerase b, DNA ligase III, and XRCC1 protein, forming the single-strand break repair (SSBR) complex, following exposure to ionizing radiation and reactive oxygen species [Whitehouse et al 2001].
• The HIT domain (middle domain), defined by the HIT motif, for nucleotide binding and hydrolysis. Members of the HIT super family (histidine triad) of nucleotide hydrolases/transferases [Brenner 2002] can be divided into two main groups:
  • The Hint (histidine triad nucleotide binding)-related proteins, binding nucleotides and displaying adenosine 5'-monophosphoramidase activity [Brenner et al 1997]
  • The Fhit (fragile histidine triad)-related proteins, cleaving diadenosine tetraphosphate (Ap₄A), which is potentially produced during activation of the SSBR complex [McLennan 2000]
• The C-terminal domain, containing a divergent zinc-finger motif [Moreira et al 2001b], which could allow binding to DNA and/or RNA [Kijas et al 2006]

The presence of these three domains has suggested that aprataxin is a nuclear protein with a role in DNA repair, reminiscent of the function of the protein defective in ataxia-telangiectasia, which would cause a phenotype restricted to neurologic signs when mutated. Subcellular localization studies showed that aprataxin is a nuclear protein, present in both the nucleoplasm and the nucleolus [Gueven et al 2004, Sano et al 2004]. Recent experimental studies indicate that aprataxin has dual DNA binding and nucleotide hydrolase activities. Aprataxin binds to double-stranded DNA with high affinity but is also capable of binding to double-stranded RNA and to single-stranded DNA, with increased affinity for hairpin structures. Aprataxin also hydrolyses, with similar efficiency, the model histidine triad nucleotide-binding protein substrate (AMPNH₂) and the fragile histidine triad protein substrate (Ap₄A) [Kijas et al 2006].

Several in vitro and in vivo studies have shown that aprataxin (long isoform) interacts with XRCC1 [Caldecott 2003, Clements et al 2004, Gueven et al 2004, Sano et al 2004] and XRCC4 [Clements et al 2004], proteins implicated in single-strand and double-strand repair mechanisms, respectively. The interaction with C-terminal region of XRCC1 is made through the 20 N-terminal amino acids of aprataxin FHA domain [Date et al 2004]. This interaction is important in maintaining the steady-state protein level of XRCC1 [Luo et al 2004]. Interaction with another single-strand break repair protein, PARP-1, was also reported [Date et al 2004].

Abnormal gene product. Gueven et al [2004] demonstrated that mutations (even missense ones) in APTX destabilize aprataxin and that cells from individuals with AOA1 are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA; however, no gross defect in single-strand break repair is apparent, even though the long isoform of aprataxin interacts with XRCC1 [Caldecott 2003, Clements et al 2004, Gueven et al 2004, Sano et al 2004].

Even when in vitro and in vivo studies show that aprataxin interacts with XRCC4, AOA1 cell lines exhibit neither radio-resistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of ataxia-telangiectasia [Clements et al 2004]. Recently, cells of an individual with AOA1 homozygous for a stop mutation showed marked, dose-related increases in induced chromosomal aberrations but did not show hypersensitivity to ionizing radiation, indicating direct involvement of aprataxin in the DNA single-strand break repair mechanisms [Mosesso et al 2005].

Literature Cited

1. Amouri R, Moreira MC, Zouari M, El Euch G, Barhoumi C, Kefi M, Belal S, Koenig M, Hentati F. Aprataxin gene mutations in Tunisian families. Neurology. 2004;63:928–9. [PubMed: 15365154]
2. Barbot C, Coutinho P, Chorao R, Ferreira C, Barros J, Fineza I, Dias K, Monteiro J, Guimaraes A, Mendonca P, do Ceu Moreira M, Sequeiros J. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch Neurol. 2001;58:201–5. [PubMed: 11176957]
3. Bomont P, Watanabe M, Gershoni-Barush R, Shizuka M, Tanaka M, Sugano J, Guiraud-Chaumeil C, Koenig M. Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33-34, and with hearing impairment and optic atrophy to 6p21-23. Eur J Hum Genet. 2000;8:986–90. [PubMed: 11175288]
4. Brenner C. Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Biochemistry. 2002;41:9003–14. [PMC free article: PMC2571077] [PubMed: 12119013]
5. Brenner C, Garrison P, Gilmour J, Peisach D, Ringe D, Petsko GA, Lowenstein JM. Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins. Nat Struct Biol. 1997;4:231–8. [PMC free article: PMC2571075] [PubMed: 9164465]
6. Caldecott KW. DNA single-strand break repair and spinocerebellar ataxia. Cell. 2003;112:7–10. [PubMed: 12526788]
7. Clements PM, Breslin C, Deeks ED, Byrd PJ, Ju L, Bieganowski P, Brenner C, Moreira MC, Taylor AM, Caldecott KW. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. DNA Repair (Amst). 2004;3:1493–502. [PubMed: 15380105]
8. Criscuolo C, Mancini P, Sacca F, De Michele G, Monticelli A, Santoro L, Scarano V, Banfi S, Filla A. Ataxia with oculomotor apraxia type 1 in Southern Italy: late onset and variable phenotype. Neurology. 2004;63:2173–5. [PubMed: 15596775]
9. Date H, Igarashi S, Sano Y, Takahashi T, Takahashi T, Takano H, Tsuji S, Nishizawa M, Onodera O. The FHA domain of aprataxin interacts with the C-terminal region of XRCC1. Biochem Biophys Res Commun. 2004;325:1279–85. [PubMed: 15555565]
10. Date H, Onodera O, Tanaka H, Iwabuchi K, Uekawa K, Igarashi S, Koike R, Hiroi T, Yuasa T, Awaya Y, Sakai T, Takahashi T, Nagatomo H, Sekijima Y, Kawachi I, Takiyama Y, Nishizawa M, Fukuhara N, Saito K, Sugano S, Tsuji S. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat Genet. 2001;29:184–8. [PubMed: 11586299]
11. Fukuhara N, Nakajima T, Sakajiri K, Matsubara N, Fujita M. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): a new disease. J Neurol Sci. 1995;133:140–51. [PubMed: 8583217]
12. Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH, Gatti R, Date H, Onodera O, Taucher-Scholz G, Lavin MF. Aprataxin, a novel protein that protects against genotoxic stress. Hum Mol Genet. 2004;13:1081–93. [PubMed: 15044383]
13. Habeck M, Zuhlke C, Bentele KH, Unkelbach S, Kress W, Burk K, Schwinger E, Hellenbroich Y. Aprataxin mutations are a rare cause of early onset ataxia in Germany. J Neurol. 2004;251:591–4. [PubMed: 15164193]
14. Hanihara T, Kubota H, Amano N, Iwamoto H, Iwabuchi K. Rinsho Shinkeigaku. 1995;35:83–6. [PubMed: 7781224]
15. Hirano M, Yamamoto A, Mori T, Lan L, Iwamoto TA, Aoki M, Shimada K, Furiya Y, Kariya S, Asai H, Yasui A, Nishiwaki T, Imoto K, Kobayashi N, Kiriyama T, Nagata T, Konishi N, Itoyama Y, Ueno S. DNA single-strand break repair is impaired in aprataxin-related ataxia. Ann Neurol. 2007;61:162–74. [PubMed: 17315206]
16. Jilani A, Ramotar D, Slack C, Ong C, Yang XM, Scherer SW, Lasko DD. Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3'-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage. J Biol Chem. 1999;274:24176–86. [PubMed: 10446192]
17. Karimi-Busheri F, Daly G, Robins P, Canas B, Pappin DJ, Sgouros J, Miller GG, Fakhrai H, Davis EM, Le Beau MM, Weinfeld M. Molecular characterization of a human DNA kinase. J Biol Chem. 1999;274:24187–94. [PubMed: 10446193]
18. Kijas AW, Harris JL, Harris JM, Lavin MF. Aprataxin Forms a Discrete Branch in the HIT (Histidine Triad) Superfamily of Proteins with Both DNA/RNA Binding and Nucleotide Hydrolase Activities. J Biol Chem. 2006;281:13939–48. [PubMed: 16547001]
19. Kubota H, Sunohara N, Iwabuchi K, Hanihara A, Nagatomo H, Amano N, Kosaka K. No To Shinkei. 1995;47:289–94. [PubMed: 7669433]
20. Le Ber I, Bouslam N, Rivaud-Pechoux S, Guimaraes J, Benomar A, Chamayou C, Goizet C, Moreira MC, Klur S, Yahyaoui M, Agid Y, Koenig M, Stevanin G, Brice A, Durr A. Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. Brain. 2004;127:759–67. [PubMed: 14736755]
21. Le Ber I, Moreira MC, Rivaud-Pechoux S, Chamayou C, Ochsner F, Kuntzer T, Tardieu M, Said G, Habert MO, Demarquay G, Tannier C, Beis JM, Brice A, Koenig M, Durr A. Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. Brain. 2003;126:2761–72. [PubMed: 14506070]
22. Luo H, Chan DW, Yang T, Rodriguez M, Chen BP, Leng M, Mu JJ, Chen D, Songyang Z, Wang Y, Qin J. A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment. Mol Cell Biol. 2004;24:8356–65. [PMC free article: PMC516742] [PubMed: 15367657]
23. Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol. 1999;14:583–90. [PubMed: 10488903]
24. McLennan AG. Dinucleoside polyphosphates-friend or foe? Pharmacol Ther. 2000;87:73–89. [PubMed: 11007992]
25. Merritt L. Recognition of the clinical signs and symptoms of Joubert syndrome. Adv Neonatal Care. 2003;3:178–86. [PubMed: 14502525]
26. Moreira MC, Barbot C, Tachi N, Kozuka N, Mendonca P, Barros J, Coutinho P, Sequeiros J, Koenig M. Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. Am J Hum Genet. 2001a;68:501–8. [PMC free article: PMC1235299] [PubMed: 11170899]
27. Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, Gibson T, Mendonca P, Costa M, Barros J, Yanagisawa T, Watanabe M, Ikeda Y, Aoki M, Nagata T, Coutinho P, Sequeiros J, Koenig M. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn- finger protein aprataxin. Nat Genet. 2001b;29:189–93. [PubMed: 11586300]
28. Moreira MC, Klur S, Watanabe M, Nemeth AH, Le Ber I, Moniz JC, Tranchant C, Aubourg P, Tazir M, Schols L, Pandolfo M, Schulz JB, Pouget J, Calvas P, Shizuka-Ikeda M, Shoji M, Tanaka M, Izatt L, Shaw CE, M'Zahem A, Dunne E, Bomont P, Benhassine T, Bouslam N, Stevanin G, Brice A, Guimaraes J, Mendonca P, Barbot C, Coutinho P, Sequeiros J, Durr A, Warter JM, Koenig M. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet. 2004;36:225–7. [PubMed: 14770181]
29. Mosesso P, Piane M, Palitti F, Pepe G, Penna S, Chessa L. The novel human gene aprataxin is directly involved in DNA single-strand-break repair. Cell Mol Life Sci. 2005;62:485–91. [PubMed: 15719174]
30. Musumeci O, Naini A, Slonim AE, Skavin N, Hadjigeorgiou GL, Krawiecki N, Weissman BM, Tsao CY, Mendell JR, Shanske S, De Vivo DC, Hirano M, DiMauro S. Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology. 2001;56:849–55. [PubMed: 11294920]
31. Nemeth AH, Bochukova E, Dunne E, Huson SM, Elston J, Hannan MA, Jackson M, Chapman CJ, Taylor AM. Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34. Am J Hum Genet. 2000;67:1320–6. [PMC free article: PMC1288574] [PubMed: 11022012]
32. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14:269–76. [PubMed: 8896555]
33. Quinzii CM, Kattah AG, Naini A, Akman HO, Mootha VK, DiMauro S, Hirano M. Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology. 2005;64:539–41. [PubMed: 15699391]
34. Sano Y, Date H, Igarashi S, Onodera O, Oyake M, Takahashi T, Hayashi S, Morimatsu M, Takahashi H, Makifuchi T, Fukuhara N, Tsuji S. Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein. Ann Neurol. 2004;55:241–9. [PubMed: 14755728]
35. Sekijima Y, Hashimoto T, Onodera O, Date H, Okano T, Naito K, Tsuji S, Ikeda S. Severe generalized dystonia as a presentation of a patient with aprataxin gene mutation. Mov Disord. 2003;18:1198–200. [PubMed: 14534929]
36. Sekijima Y, Ohara S, Nakagawa S, Tabata K, Yoshida K, Ishigame H, Shimizu Y, Yanagisawa N. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): clinical and neuropathological features of a Japanese family. J Neurol Sci. 1998;158:30–7. [PubMed: 9667774]
37. Shimazaki H, Takiyama Y, Sakoe K, Ikeguchi K, Niijima K, Kaneko J, Namekawa M, Ogawa T, Date H, Tsuji S, Nakano I, Nishizawa M. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations. Neurology. 2002;59:590–5. [PubMed: 12196655]
38. Silva MC, Coutinho P, Pinheiro CD, Neves JM, Serrano P. Hereditary ataxias and spastic paraplegias: methodological aspects of a prevalence study in Portugal. J Clin Epidemiol. 1997;50:1377–84. [PubMed: 9449941]
39. Tachi N, Kozuka N, Ohya K, Chiba S, Sasaki K. Hereditary cerebellar ataxia with peripheral neuropathy and mental retardation. Eur Neurol. 2000;43:82–7. [PubMed: 10686465]
40. Tranchant C, Fleury M, Moreira MC, Koenig M, Warter JM. Phenotypic variability of aprataxin gene mutations. Neurology. 2003;60:868–70. [PubMed: 12629250]
41. Tsao CY, Paulson G. Type 1 ataxia with oculomotor apraxia with aprataxin gene mutations in two American children. J Child Neurol. 2005;20:619–20. [PubMed: 16159533]
42. Uekawa K, Yuasa T, Kawasaki S, Makibuchi T, Ideta T. Rinsho Shinkeigaku. 1992;32:1067–74. [PubMed: 1297549]
43. Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell. 2001;104:107–17. [PubMed: 11163244]

Suggested Reading

1. Le Ber I, Brice A, Durr A. New autosomal recessive cerebellar ataxias with oculomotor apraxia. Curr Neurol Neurosci Rep. 2005;5:411–7. [PubMed: 16131425]

Acknowledgments

The authors wish to express their gratitude to all patients and families for their collaboration and support, as well as to 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) and the Portuguese Ministry of Health (projects STRDA/C/SAU/277/92, PECS/C/SAU/219/95, POCI/SAU-ESP/59114/04).

Author History

Paula Coutinho, MD, PhD (2002-present)
Clara Barbot MD, PhD (2002-present)
Maria-Céu Moreira da Silva, MS, PhD; CNRS/INSERM/Université Louis-Pasteur (2002-2010)
Michel Koenig, MD, PhD; CNRS/INSERM/Université Louis-Pasteur (2002-2010)

Revision History

• 22 June 2010 (me) Comprehensive update posted live
• 5 June 2006 (me) Comprehensive update posted to live Web site
• 25 May 2004 (me) Comprehensive update posted to live Web site
• 28 January 2004 (pc) Revision: change in test availability
• 11 June 2002 (me) Review posted to live Web site
• 8 November 2001 (pc) Original submission