Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia (Moreira et al., 2001).
Aicardi et al. (1988) described an autosomal recessive syndrome that closely resembled ataxia-telangiectasia (AT; 208900) but differed in important respects. They reported 14 patients in 10 families with a neurologic syndrome of oculomotor apraxia, ataxia, and choreoathetosis who ... Aicardi et al. (1988) described an autosomal recessive syndrome that closely resembled ataxia-telangiectasia (AT; 208900) but differed in important respects. They reported 14 patients in 10 families with a neurologic syndrome of oculomotor apraxia, ataxia, and choreoathetosis who had none of the extraneurologic features of AT. Although the neurologic signs were indistinguishable from those of AT, the onset tended to be later and none of the patients had a tendency to frequent infections; further, immunoglobulins, alpha-fetoprotein, T- and B-lymphocyte markers, and chromosomes 7 and 14 were normal in all patients tested. Barbot et al. (2001) reported 22 Portuguese patients with autosomal recessive cerebellar ataxia, ocular apraxia, and peripheral neuropathy with a mean age of onset of 4.7 years. There was no associated mental retardation, telangiectasia, or immunodeficiency. Barbot et al. (2001) concluded that ataxia with oculomotor apraxia may be more frequent than previously believed. Koeppen (2002) suggested that the patients reported by Barbot et al. (2001) may have exhibited supranuclear pseudoophthalmoplegia, which may be due to lesions in the nucleus pontis centralis caudalis of the paramedian pontine reticular formation. Shimazaki et al. (2002) reported 5 Japanese patients with autosomal recessive EAOH from 3 families and 1 sporadic case. Clinical features included age of onset from 3 to 12 years, cerebellar ataxia, peripheral neuropathy, oculomotor apraxia and external ophthalmoplegia, choreiform movements of the limbs, facial grimacing, mental deterioration, cerebellar atrophy, hypoalbuminemia, and hypercholesterolemia. Amouri et al. (2004) reported 3 unrelated Tunisian families with AOA, confirmed by mutation in the APTX gene (606350.0007; 606350.0008). The mean age at onset was 5 years with gait ataxia as the presenting symptom. Cerebellar ataxia affecting all 4 limbs and the trunk developed soon thereafter. Other features included dysarthria, ocular apraxia, distal sensory axonal neuropathy, and marked cerebellar atrophy by brain imaging. Hypoalbuminemia and hypercholesterolemia were also present. Affected members of 1 of the families had a somewhat atypical phenotype with absence of oculomotor apraxia, except in 1 patient, and preservation of knee reflexes. None of the patients had mental impairment. Criscuolo et al. (2004) reported 3 unrelated Italian patients with AOA confirmed by genetic analysis. Two of the patients had adult onset at ages 28 and 29, respectively. Criscuolo et al. (2005) reported a patient with adult-onset AOA confirmed by genetic analysis (606350.0009). The patient had onset of gait ataxia and dysarthria at age 40 years. Physical examination showed normal ocular movements, tongue and limb fasciculations, areflexia, and decreased vibration sense at the external malleoli. MRI showed cerebellar atrophy. Serum albumin was normal. Criscuolo et al. (2005) emphasized that milder phenotypes of AOA may occur in adults. Castellotti et al. (2011) identified APTX mutations in 13 (6.4%) of 204 Italian patients with progressive cerebellar ataxia. The patients had onset between ages 3 and 7 years, but most were examined as adults. The phenotype was homogeneous, characterized mainly by gait and limb ataxia, dysarthria, nystagmus, lower limb areflexia, sensory neuropathy, cognitive decline, dysarthria, and oculomotor deficits. Some had choreic movements of the upper limbs and face, and many had distal muscle weakness and atrophy affecting both upper and lower limbs. Six patients were wheelchair-bound in young adulthood. Six patients had mental retardation since early childhood, whereas 5 showed cognitive decline later in life. Hypoalbuminemia was found in 58%, and hypercholesterolemia in 69%. Three patients had increased alpha-fetoprotein (AFP; 104150). Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in 5 of 6 patients. There were no genotype/phenotype correlations.
Quinzii et al. (2005) found that 3 sibs originally reported by Musumeci et al. (2001) as having familial cerebellar ataxia with muscle coenzyme Q10 (CoQ10) deficiency (see, e.g., COQ10D1, 607426) actually had AOA1 due to a homozygous mutation ... Quinzii et al. (2005) found that 3 sibs originally reported by Musumeci et al. (2001) as having familial cerebellar ataxia with muscle coenzyme Q10 (CoQ10) deficiency (see, e.g., COQ10D1, 607426) actually had AOA1 due to a homozygous mutation in the APTX gene (W279X; 606350.0006). All 3 patients responded well to CoQ10 supplementation. Thirteen additional patients with coenzyme Q deficiency did not have APTX mutations. Quinzii et al. (2005) noted that CoQ10 deficiency has been associated with 3 major clinical phenotypes and remarked that the finding of mutation in the APTX gene in these sibs supports the hypothesis that the ataxic form of CoQ10 deficiency is a genetically heterogeneous entity in which deficiency of CoQ10 can be secondary. Le Ber et al. (2007) found decreased muscle CoQ10 in 5 of 6 patients with AOA1. Three patients who were homozygous for the W279X mutation had the lowest values. The CoQ10 deficiency did not correlate with disease duration, severity, or other blood parameters, and mitochondrial morphology and respiratory function were normal.
Date et al. (2001) characterized 7 families from various regions of Japan with clinical manifestations like those of the ataxia-oculomotor apraxia syndrome and again showed mapping to 9p13 as in Europeans and people of European descent. They narrowed ... Date et al. (2001) characterized 7 families from various regions of Japan with clinical manifestations like those of the ataxia-oculomotor apraxia syndrome and again showed mapping to 9p13 as in Europeans and people of European descent. They narrowed the candidate region and identified a novel gene encoding a member of the histidine triad (HIT, e.g., 601153, 601314) superfamily as the causative gene. They called its product aprataxin and assigned the gene symbol APTX (606350); this was the first member of the HIT superfamily to be linked to a distinct phenotype. Moreira et al. (2001) and Date et al. (2001) demonstrated mutations in the APTX gene as the cause of AOA in their Portuguese and Japanese populations (606350.0001-606350.0004). Castellotti et al. (2011) identified recessive APTX mutations in 13 (6.4%) of 204 Italian probands with progressive cerebellar ataxia. The most common mutation was W279X (606350.0006), which was found in homozygous state in 7 patients and in compound heterozygosity with another pathogenic APTX mutation in 1 patient. Three additional novel mutations were identified. Western blot analysis of patient lymphocytes showed severely decreased levels of APTX protein, consistent with loss of function as a disease mechanism. There were no genotype/phenotype correlations.
By 2001, the ongoing survey initiated in 1993 of hereditary ataxias and spastic paraplegias in Portugal, a country of 9.8 million persons, had identified 107 patients with autosomal recessive ataxia (Barbot et al., 2001). Friedreich ataxia (FRDA; 229300) ... By 2001, the ongoing survey initiated in 1993 of hereditary ataxias and spastic paraplegias in Portugal, a country of 9.8 million persons, had identified 107 patients with autosomal recessive ataxia (Barbot et al., 2001). Friedreich ataxia (FRDA; 229300) accounted for 38% of the cases. The next most common recessive ataxia in the survey, accounting for 21% of the cases, was ataxia with oculomotor apraxia. Anheim et al. (2010) found that AOA1 was the fourth most common form of autosomal recessive cerebellar ataxia in a cohort of 102 patients from Alsace, France. Of 57 patients for whom a molecular diagnosis could be determined, 3 were affected with AOA1. FRDA was the most common diagnosis, found in 36 of 57 patients, AOA2 (606002) was the second most common diagnosis, found in 7 patients, and ataxia-telangiectasia (AT; 208900) was the third most common diagnosis, found in 4 patients. Marinesco-Sjogren syndrome (MSS; 248800) was also found in 3 patients.
Ataxia with oculomotor apraxia type 1 (AOA1) is suspected in individuals with the following combination:...
DiagnosisClinical DiagnosisAtaxia 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.TestingLaboratory 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-fetoproteinNeuropathology. Nerve biopsy confirms axonal neuropathy. Molecular Genetic TestingGene. 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 testingSequence 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 (e.g., 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 AOA1View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAPTXSequence analysisSequence variants 2UnknownClinicalDeletion / duplication analysis 3Partial- or whole-gene deletionsUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.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 probandMolecular 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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in APTX.
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. ...
Natural HistoryAtaxia 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.
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]. ...
Genotype-Phenotype CorrelationsMissense 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.[Glu232Glyfs*38]+[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.
The diagnosis of AOA1 is ruled out whenever the clinical picture includes non-progressive ataxia, microcephaly, or seizures. The differential diagnosis varies by age group. ...
Differential DiagnosisThe diagnosis of AOA1 is ruled out whenever the clinical picture includes non-progressive ataxia, microcephaly, or seizures. The differential diagnosis varies by age group. Ataxia with oculomotor apraxia type 2 (AOA2), the disorder most likely to be confused with AOA1, is characterized by mean age at onset of 15.6 years, sensory motor neuropathy (93%), oculomotor apraxia (47%), and chorea or dystonia (44%). Serum concentration of alpha fetoprotein (AFP) is increased in 86% of individuals [Moreira et al 2004]. See Table 2.AOA2 maps to chromosomal locus 9q34 [Bomont et al 2000, Nemeth et al 2000]; SETX has been identified as the gene in which mutation is causative [Moreira et al 2004]. In one study, AOA2 accounted for 8% of all autosomal recessive cerebellar ataxia, making it second only to Friedreich ataxia in prevalence among adults with autosomal recessive ataxia [Le Ber et al 2004]. Table 2. Comparison of AOA1 and AOA2View in own windowAOA1 (p.Trp279X mutation)AOA2 (p.Arg1368X mutation)Mean age at onset (range)4.3 years (2-10)13 years (10-14)EvolutionMore severeMore benignOculomotor apraxiaEarly and severeMild to moderateDistoniaMarked, early in the disease, disappearing with ageLess markedNeuropathyEarly and severeLess severe and beginning later in the diseaseBiochemical findingsLate-onset low serum albumin and high cholesterol; normal alpha-fetoprotein at all stagesEarly elevation of alpha-fetoproteinOther. Several families with ataxia and oculomotor apraxia do not demonstrate linkage to either 9p13 or 9q34, a finding that suggests the existence of another locus or loci [Moreira et al 2001a, Moreira et al 2001b].Early childhood. The diagnosis of AOA1 can be difficult to establish in very young children because all features of the disorder are not yet apparent. When oculomotor apraxia is present, ataxia-telangiectasia should be excluded. Joubert syndrome is a rare, autosomal recessive disorder that affects the cerebellum and brain stem. It is characterized by the presence of a distinct respiratory pattern and profound tachypnea in the newborn period. Nonspecific features such as hypotonia, ataxia, developmental delay, and oculomotor apraxia can occur. The diagnosis of Joubert syndrome is based on the presence of these characteristic clinical features and is confirmed with cranial magnetic resonance imaging (MRI), which reveals the "molar tooth sign" resulting from hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities [Maria et al 1999, Merritt 2003]. Adolescence Friedreich ataxia (FRDA) can be excluded on clinical grounds. In FRDA, oculomotor apraxia is not observed and the cerebellum is normal on MRI. Molecular genetic testing of FRDA detects mutations in almost 100% of affected individuals. Ataxia with vitamin E deficiency (AVED) should be considered because it is one of two treatable disorders in this group, the other being coenzyme Q10 deficiency [Musumeci et al 2001, Quinzii et al 2005]. Peripheral neuropathy with areflexia and pes cavus may be confused with Charcot-Marie-Tooth syndrome. (See Charcot-Marie-Tooth Hereditary Neuropathy Overview.) Adulthood. In apparent simplex cases (individuals with no family history of AOA1), SCA2, which also associates cerebellar ataxia with slow eye movements, can be excluded by molecular genetic testing of ATXN2, the gene in which mutation causes SCA2 [Pulst et al 1996]. See also Ataxia Overview.
To establish the extent of disease in an individual diagnosed with ataxia with oculomotor apraxia type 1 (AOA1), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 functionExamination of cranial nerve functionExtended neurologic examination of the limbs: initial inspection; tone; strength testing; reflexes; coordination; sensory testingOphthalmologic examination Treatment of ManifestationsPhysical 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 ComplicationsHigh-protein diet to restore serum albumin concentration is indicated to prevent edema secondary to hypoalbuminemia.Low-cholesterol diet is advised. SurveillanceRoutine 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 InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDAPTX9p21.1AprataxinAPTX homepage - Mendelian genesAPTXData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Ataxia with Oculomotor Apraxia Type 1 (View All in OMIM) View in own window 208920ATAXIA, EARLY-ONSET, WITH OCULOMOTOR APRAXIA AND HYPOALBUMINEMIA; EAOH 606350APRATAXIN; APTXMolecular Genetic PathogenesisData 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). Table 3. Selected APTX Allelic VariantsView in own windowClass of Variant AlleleExon / IntronDNA Nucleotide Change (Alias 1) Protein Amino Acid Change 1Predicted Effect on AprataxinReferenceNormalIntron 1c.134-12A>C---None--Exon 3c.431C>A p.S144Y--PathologicExon 5c.589A>Cp.Lys197GlnMissense; aberrant processing Tranchant et al [2003]c.593C>Tp.Ala198ValLe Ber et al [2003], Criscuolo et al [2004]c.596G>Ap.Arg199HisMoreira et al [2001b] c.602A>Gp.His201ArgShimazaki et al [2002] c.603T>Ap.His201GlnCriscuolo et al [2004] c.617C>Tp.Pro206LeuDate et al [2001], Moreira et al [2001b], Shimazaki et al [2002], Criscuolo et al [2004] c.689dupT (689insT) (689-690insT)p.Glu232Glyfs*38Frameshift; truncation Date et al [2001], Moreira et al [2001b], Shimazaki et al [2002], Sekijima et al [2003] c.739 C>Tp.Arg247XStop; truncationMosesso et al [2005] c.770+1G>A--Splice; truncationLe Ber et al [2003] Exon 6c.788T>Gp.Val263GlyMissense; aberrant processingDate et al [2001] c.800A>Gp.Asp267GlyLe Ber et al [2003] c.835T>Cp. Trp279Argc.837 G>Ap.Trp279XStop; truncationMoreira et al [2001b], Le Ber et al [2003], Tranchant et al [2003], Habeck et al [2004], Quinzii et al [2005] c.841delTp.Ser281Leufs*8Frameshift; truncationDate et al [2001] Exon 7c.875-1G>A--Splice; truncationAmouri et al [2004]Total deletion of gene--No productSee 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_175073.1Normal 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].