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Absence of aprataxin gene mutations in a Greek cohort with sporadic early onset ataxia and normal GAA triplets in frataxin gene

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Absence of aprataxin gene mutations in a Greek cohort with sporadic early onset ataxia and normal GAA triplets in frataxin gene
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  BRIEF COMMUNICATION Absence of aprataxin gene mutations in a Greek cohortwith sporadic early onset ataxia and normal GAA tripletsin frataxin gene C. Daiou  • K. Christodoulou  • G. Xiromerisiou  • M. Panas  • E. Dardiotis  • A. Kladi  • M. Speletas  • G. Ntaios  • A. Papadimitriou  • A. Germenis  • Georgios M. Hadjigeorgiou Received: 8 February 2009/Accepted: 17 November 2009   Springer-Verlag 2009 Abstract  Phenotype of patients with the aprataxin genemutation varies and according to previous studies,screening of aprataxin gene could be useful, once frataxingene mutation is excluded in patients with normal GAAexpansion in frataxin gene. In the present study, we soughtto determine possible causative mutations in aprataxin gene(all exons and flanking intronic sequences) in 14 Greek patients with sporadic cerebellar ataxia all but one withoutGAA expansion in frataxin gene (1 patient was heterozy-gous). No detectable point mutation or deletion was foundin the aprataxin gene of all the patients. Our results do notconfirm the previous studies. This difference may beattributed to the different populations studied and possibledifferent genetic background. It is still questionable whe-ther the screening for aprataxin mutation in Greek patients’Friedreich ataxia phenotype is of clinical importance; lar-ger, multicenter studies are necessary to clarify this issue. Keywords  Friedreich ataxia    Autosomal recessivecerebellar ataxias    Ataxia with oculomotor apraxia I   Aprataxin Introduction Autosomal recessive cerebellar ataxias (ARCA) encompassa large number of rare disorders known as inherited ataxias[1–3]. The two commonest ARCAs are Friedreich ataxia (FRDA) and ataxia telangiectasia (AT). Another form isataxia with oculomotor apraxia (AOA) which shows strongsimilarities with AT such as ataxia, oculomotor apraxia andcerebellar atrophy, although extra-neurological featuresthat are usually associated with AT, such as telangiectasias,immune deficiency, and susceptibility to cancer have notbeen reported for AOA. AOA is distinguished in two types:AOA1 and AOA2. Alpha-fetoprotein is raised in both ATand AOA2, usually at concentrations two to three times thenormal values. Other rarer forms of ataxia with a pheno-type very close to FRDA include spinocerebellar degen-eration caused by primary vitamin E deficiency andabetalipoproteinemia, which are characterized by mixedcerebellar and sensory features; also, ataxia with peripheralnerve involvement (SCAN1), and the spastic forms of recessive ataxia, ARSACS, and spataxin deficiency havebeen described in the European population [4].FRDA is the most frequent ARCA with an estimatedprevalence of 1:29,000–1:50,000 [4–9]. The incidence is C. Daiou    G. Xiromerisiou    A. Papadimitriou   G. M. Hadjigeorgiou ( & )Laboratory of Neurogenetics, Neuroscience Unit,Department of Neurology, Faculty of Medicine,University of Thessalia, Larissa, Greecee-mail: gmhadji@med.uth.grK. ChristodoulouCyprus Institute of Neurology and Genetics,Nicosia, CyprusM. Panas    A. KladiDepartment of Neurology, Faculty of Medicine,Kapodistrian University of Athens, Athens, GreeceE. Dardiotis    G. M. HadjigeorgiouInstitute of Biomedical Research and Technology,CERETETH, Larissa, GreeceM. Speletas    A. GermenisDepartment of Immunology and Histocompatibility,School of Medicine, University Hospital of Thessaly,Larissa, GreeceG. NtaiosFirst Propaedeutic Department of Internal Medicine,AHEPA Hospital, Aristotle University, Thessaloniki, Greece  1 3 Neurol SciDOI 10.1007/s10072-009-0201-0  much lower in Asians and those of African descent [7]while the carrier rate has been estimated at 1:60–1:120 [6,10–12]. FRDA is characterized by an early onset progres- sive gait and limb ataxia, dysarthria, lack of tendon reflexesin the legs, loss of position sense, weakness of the legs andhypertrophic cardiomyopathy [13, 14]. The FRDA locus was mapped to chromosome 9q13–21.1 [15] and the gene (frataxin; MIM: 606829) wasrevealed in 1996 [6]. In FRDA patients, homozygosity foran abnormal GAA repeat expansion and compound heter-ozygosity for the expansion and a point mutation of thefrataxin gene, have been identified [6, 14]. Approximately, 96% of the typical FRDA patients are homozygous for theGAA expansion in intron 1, whereas the remaining 4% arecompound heterozygous for a GAA expansion and a pointmutation within the coding region of the gene [6, 16]. Recently, another subgroup of ARCA associated withoculomotor apraxia (AOA) has been distinguished with twodifferent geneticentities:(1)AOAtype 1and (2)ataxiawithocular apraxia type 2 [17]. AOA type 1 (AOA1) is the mostfrequent cause of autosomal recessive ataxia in Japan andsecond to FRDA in Portugal [18]. The relative frequency of AOA1 was 5.7% in a mixed European series of non-FRDApatients with progressive cerebellar ataxias [17], 7.5% in aPortuguese series of patients with a possible AOA1 pheno-type[19]and11.1%inastudybyCriscuoloetal.onpatientswithprogressivenon-FRDAandperipheralneuropathy[20].AOA1 is characterized by early onset gait ataxia(between 2 and 6 years of age), dysarthria, limb dysmetria,oculomotor apraxia, distal and symmetric muscle weaknessand wasting, mild loss of vibration and joint position senseand slow progression. Laboratory studies show a motor andsensory axonal neuropathy, mild loss of large myelinatedaxons, cerebellar and brainstem atrophy on MRI, hypoal-buminemia and hypercholesterolemia [4, 17, 21]. AOA1 is caused by mutation of the aprataxin gene(aprataxin), on chromosome 9q13 [19, 22, 23]. The protein was reported to influence DNA repair, particularly single-strand DNA breaks [24, 25], albeit other additional roles have been proposed, such as in RNA processing [26].Up til now, different mutations have been found inaprataxin gene in patients with AOA1 [27].The presence of chorea, sensorimotor neuropathy withtypical sensory involvement, oculomotor anomalies, andareflexia (absence of the Babinski sign) can help in dis-tinguishing AOA1 from FRDA on a clinical basis [17].Moreover, patients with FRDA have typically spinal atro-phy at MRI, when compared with AOA1 patients that showmore cerebellar involvement [17].However, the phenotype of patients with the aprataxingene mutation varies and according to previous studies [17,21, 28–30], the screening of aprataxin could be useful once FRDA is excluded.In the present study, we searched for aprataxin muta-tions in Greek patients with sporadic cerebellar ataxiawhere GAA expansion in frataxin gene has been excluded. Patients and methods Fourteen Greek patients were selected with ARCA wheretest for GAA expansion in frataxin gene has been negativewere studied (Table 1). All cases were sporadic and therewas no consanguinity between them. Patients with ahomozygous expansion in intron 1 of the frataxin genewere excluded. The mean age at onset was 16.57  ± 6.9 years (range 5–30). All patients presented gait ataxia,dysmetria and dysarthria. Thirteen of the 14 patients hadnystagmus and 10 of them had ophthalmoplegia, while 8had saccadic ocular pursuit. Two of the patients presentedoptic atrophy and reduced visual acuity. Motor weaknessexisted in 10 patients and 3 of them had muscle atrophy.The neurological examination revealed areflexia for 9 of them, whereas 11 had positive Babinski sign. Ten haddisturbances in deep tendon reflexes and only one patientpresented hearing loss. Scoliosis existed in half of thepatients and pes cavus in nine of them. Diabetes mellituswas present in one patient, cardiomyopathy in two anddysphagia in six persons. MRI showed cerebellar atrophyfor all the patients. Seven patients had sensory neuropathywhile five of them had sensory axonal neuropathy. None of the patients presented characteristic features of oculomotorapraxia AOA1, such as hypercholesterolemia, hypoalbu-minemia or oculomotor apraxia.Blood genomic DNA was extracted routinely from all 14patients. They were all examined for the GAA expansion inintron 1 with the technique of expand long PCR analysis.One of the patients (P9; Table 1) was found heterozygousfor the GAA expansion, and further investigation of thefrataxingenewasperformedbysequenceanalysis,forlikelycompound heterozygosity for the GAA expansion and apoint mutation within the coding region of the gene. Finally,all 14 patients were analyzed for nucleotide changes in theaprataxin gene, as a possible cause of the clinical presenta-tion of these cases. Testing for the aprataxin gene sequencewas performed according to the protocol of Moreira et al.[23]. Finally, analysis of all exons coding for the entire longform of the mature protein was carried out, by automateddirect sequencing, using the capillary array electrophoresissequencer of Beckman Coulter. Results Mutational analysis of 14 patients for the GAA expansionin intron 1 of the frataxin gene, revealed all but one with Neurol Sci  1 3  normal allele size. One of them was heterozygous for theexpansion. This patient was further examined for pointmutation in the frataxin gene, as a possible cause of theFRDA clinical presentation. It was found that this patientcarried a single nucleotide polymorphism (A ? G) atnucleotide 54 from the start codon of the frataxin gene (ref SNP ID: rs2481598).No detectable changes were found in the aprataxin genein all 13 patients with normal allele in frataxin intron 1, aswell as in the patient heterozygous for the GAA expansion.Moreover, a homozygous deletion of the aprataxin gene orany of the exons of the gene was excluded, since PCRproducts for all exons of the gene were amplified in allpatients. Discussion Autosomal recessive cerebellar ataxias are a heterogeneousgroup of neurodegenerative disorders, with different neu-rologic, ophthalmologic, or general signs. Owing to highphenotypic variability, classification in clinical subgroupsis not an easy task; this makes it difficult to distinguish theneurodegenerative disorders based on the clinical presen-tation of the patients. Molecular analysis is a strong tool forthe determination of a number of different subgroups of ARCA, such as FRDA [18].In our attempt to determine the source of the causativemutation for the FRDA phenotype in patients with normalGAA expansion in the frataxin gene, we sequenced allexons and flanking introns in the aprataxin gene and foundno detectable alterations.The rationale for the present study was based on theprevious reports. In particular, Tranchanat et al. [21]reported two patients with a very atypical clinical picturewith late onset and without ocular motor apraxia. Thesetwo patients were compound heterozygotes for a non-senseand a missense mutation of the aprataxin gene. Thesefindings encourage the investigation of the aprataxin genein early progressive ataxia even in the absence of oculo-motor apraxia. Moreover, Le Ber et al. reported on 14patients with different mutations of the aprataxin gene Table 1  Clinical features of our patientsClinical features P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 P14Age at onset (years) 15 15 28 7 19 14 22 5 12 30 15 14 19 17Gait ataxia  ? ? ? ? ? ? ? ? ? ? ? ? ? ? Nystagmus  ? ? ? - ? ? ? ? ? ? ? ? ? ? External Ophthalmoplegia  ? ? ? - - ? ? ? ? - ? - ? ? Saccadic ocular pursuit  ? ? ? - - - ? ? - - ? - ? ? Motor weakness  ? ? - ? - ? ? ? - - ? ? ? ? Muscle atrophy  ? ? - - - - - - - - ? - - - Pes cavus  - ? - ? ? ? ? - - ? ? - ? ? Areflexia  ? ? - - ? - ? - ? - ? ? ? ? Extensor plantar response  - ? - ? ? ? ? ? ? ? ? - ? ? Sensory neuropathy  ? ? - - ? ? ? - ? - - ? - - Hearing loss  - - - - - - - ? - - - - - - Cardiomyopathy  - - - - ? - - ? - - - - - - Diabetes mellitus  - - - - - - ? - - - - - - - Scoliosis  ? ? - - ? ? - - - - - ? ? ? Sensitive axonal neuropathy  ? ? - - - ? ? - ? - - - - - Disturbances in deep tendon reflexes  ? ? - ? - ? ? - ? - ? ? ? ? Dysarthria  ? ? ? ? ? ? ? ? ? ? ? ? ? ? Optic atrophy  - - - - - - - - - - - - ? ? Reduced visual acuity  - - - - - - - - - - - - ? ? Dysmetria  ? ? ? ? ? ? ? ? ? ? ? ? ? ? Dysphagia  - - - ? - ? ? - - - - ? ? ? Cerebellar atrophy on MRI  ? ? ? ? ? ? ? ? ? ? ? ? ? ? Hypercholesterolemia  - - - - - - - - - - - - - - Oculomotor apraxia  - - - - - - - - - - - - - - Hypoalbuminemia  - - - - - - - - - - - - - - Neurol Sci  1 3  where oculomotor apraxia was present only in 86%,hypoalbuminemia only in 83% and hypercholesterolemiaonly in 75% suggesting that characteristic features such asoculomotor apraxia or biological abnormalities are oftenlacking in patients with aprataxin mutations [17]. In addi-tion, Criscuolo et al. reported a patient with a homozygousmutation in the aprataxin gene [29]. The clinical presen-tation of the patient showed the onset of the disease at40 years, mild gait and limb ataxia, slurred speech, dys-phagia, normal ocular movements, tongue and limb fas-ciculations, brisk jaw jerk, areflexia and decreasedvibration sense at the external malleoli, normal serumcreatine kinase and albumin, mild familial hypercholes-terolemia and hypertriglyceridemia. This paper suggeststhe screening of aprataxin exons in sporadic or recessivepatients with cerebellar atrophy, after the exclusion of FRDA.In addition, Ferrarini et al. [30] described a patient witha homozygous mutation of the aprataxin gene. Ataxiaoculomotor apraxia with typical head eyes lag was absentin the patient. Moreover, the proband showed short-rapidmovements in her fingers, but was able to control them,challenging their choreic origin. Furthermore, someauthors consider the presence of Babinski sign a distinctivetrait of FRDA to AOA [17].The patient had involvement of central pathways as evidenced by abnormal plantarresponses and by MTS, thus pyramidal features should notbe considered a criterion of exclusion of the disease of AOA1. In conclusion, the proband of this paper emphasizesthe phenotypical variability of AOA1 and suggests thatonce FRDA is excluded, patients with sporadic or recessiveprogressive ataxias, even those lacking OMA or chorea orpresenting atypical features, such as Babinski sign, shouldundergo mutational screening of aprataxin.Finally, Amouri et al. reported the same splice mutationin two families with different phenotypes, as the first oneshowed a typical presentation of AOA1, while the otherone had atypical clinical features such as the absence of oculomotor apraxia, the most striking feature of AOA1[28]. This fact underlines the difficulty to establish agenotype–phenotype correlation in autosomal recessiveAOA1.Our study has several limitations, such as the lack of adequate MRI, biochemical, and neurophysiological hintsfor differential diagnosis of ARCAs, and the limitedgenetic testing, which could have included the  a -tocopheroltransfer protein ( a -TPP), AT, and SEXT genes [4]. Nev-ertheless, our study is the first and hitherto-only study toinvestigate the presence ofaprataxin mutations in GAAexpansion—negative, ARCA patients of Greek srcin.In conclusion, we did not find any mutation in apra-taxin gene in our cohort of patients; therefore, it isquestionable whether the screening for aprataxin mutationin such patients is of clinical importance in our area.Larger, multicenter studies are necessary to clarify thisissue. References 1. Klockgether T (2000) Handbook of ataxia disorders. MarcelDekker, Inc., New York 2. 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