Journal of the Neurological Sciences 278 (2009) 77–81

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Journal of the Neurological Sciences

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Ataxia with oculomotor apraxia type 2: A clinical and genetic study of 19 patients

M. Tazir a,⁎, L. Ali-Pacha a, A. M'Zahem b, J.P. Delaunoy c, M. Fritsch c, S. Nouioua a, T. Benhassine d, S. Assami a,D. Grid e, J.M. Vallat f, A. Hamri b, M. Koenig c,g

a Laboratoire de Neurosciences, Université d'Alger, Service de Neurologie, Centre Hospitalier Universitaire Mustapha, Alger, Algeriab Service de Neurologie, Centre Hospitalier Universitaire, Constantine, Algeriac Laboratoire de Diagnostic Génétique, Hôpital Civil, 67091 Strasbourg cedex, Franced Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, USTHB, Bab Ezzouar, Alger, Algeriae Genethon, Evry, Francef Service et Laboratoire de Neurologie, Centre de Référence des Neuropathies Périphériques Rares, CHU de Limoges, Limoges, Franceg Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France

⁎ Corresponding author. Service de Neurologie, CeMustapha, 1, place du 1er Mai Algiers, 16000, Algeria. Te

E-mail address: meriemtazir@yahoo.com (M. Tazir).

0022-510X/$ – see front matter © 2008 Elsevier B.V. Aldoi:10.1016/j.jns.2008.12.004

a b s t r a c t

a r t i c l e i n f o

Article history:

Ataxia with oculo-motor ap Received 18 August 2008Received in revised form 21 November 2008Accepted 2 December 2008Available online 11 January 2009

Keywords:Ataxia with oculo-motor apraxia type 2Senataxin geneClinical phenotypeCerebellar atrophyAxonal polyneuropathyAlpha-fetoprotein

raxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia(ARCA) caused by mutations in the senataxin gene (SETX).We analysed the phenotypic spectrum of 19 AOA2 patients with mutations in SETX, which seems to be thethird most frequent form of ARCA in Algeria after Freidreich ataxia and Ataxia with vitamin E deficiency. InAOA2 patients, the mean age at onset for all families was in the second decade. Cerebellar ataxia wasprogressive, slowly leading to disability which was aggravated by axonal polyneuropathy present in almostall the patients. Mean disease duration until wheelchair was around 20 years. Oculo-motor apraxia (OMA)was present in 32% of the patients while convergent strabismus was present in 37%. Strabismus is thereforealso very suggestive of AOA2 when associated with ataxia and polyneuropathy even in the absence of OMA.Cerebellar atrophy was more severe in the eldest patients; however it may also be an early sign since it waspresent in the youngest and paucisymptomatic patients. The initial sign was gait ataxia in all but two patientswho presented with head tremor and writer cramp, respectively. Serum alpha-fetoprotein, which waselevated in all tested patients, was a good marker to suggest molecular studies of the SETX gene.

© 2008 Elsevier B.V. All rights reserved.

1. Introduction

Ataxia with oculo-motor apraxia type 2 (AOA2) belongs to the vastgroup of neurological conditions known as autosomal recessivecerebellar ataxia (ARCA), which are characterized by degeneration ofthe cerebellum, the spinal cord and often the peripheral nerves, and inmost cases by an early onset occurring before 20 years. Autosomalrecessive cerebellar ataxia comprises a large number of rare diseases,the most frequent in Mediterranean populations being Friedreichataxia (FRDA) and ataxiawith vitamin E deficiency (AVED) [1,2]. Ataxiawith oculo-motor apraxia type 1 (AOA1) and AOA2 are some of themost recent entities described in the group of ARCA. AOA2 ischaracterized by spinocerebellar ataxia with onset between 12 and22 years, which is significantly later than AOA1, defined by early onset(between age 2 and 5 years) [3,4]. Ataxia is the most frequentpresenting sign, whereas oculo-motor apraxia may be absent.Abnormal movement such as chorea or dystonic posturing with

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walking are described occasionally. Elevated serum alpha-fetoproteinis almost always found and cerebellar atrophy and absence of sensorypotentials are observed in a majority of patients [5]. Linkage analysisand homozygosity mapping allowed localisation of AOA2 on chromo-some 9q34 [5,6]. The causative gene encodes senataxin (SETX), a2677-aminoacid protein. Senataxin which contains a classic 7-motifdomain found in the superfamily 1 of helicases, may act in DNA repairor RNA metabolism [7,8].

In the present study we describe the clinical, electrophysiologicaland neuropathological features in 19 AOA2 patients (7 families) withmutations in SETX in order to analyse the phenotypic spectrum of thisdisorder which appeared to be the third most frequent form of ARCAin Algeria, after FRDA and AVED.

2. Patients and methods

2.1. Patients

Between 2001 and 2007 we analysed 188 Algerian families with aclinical presentation of autosomal recessive cerebellar ataxia (ARCA).Our aimwas to identify non-FRDA and non-AVED informative familieswith the purpose to unravel ARCA genetic heterogeneity and search

78 M. Tazir et al. / Journal of the Neurological Sciences 278 (2009) 77–81

for new ARCA loci. We identified 35 FRDA, 21 AVED, 8 AOA2, 4 ataxia-telangiectasia (A-T), 3 AOA1 and 2 ataxia of the Charlevoix-Saguenay(ARSACS) families. Two families were found to have ARCA2 due tomutations in a new ataxia gene named ADCK3 [9] and as much as 113ARCA families (60%) were not associated with mutation of the mainARCA genes. The aim of the present study is to review the phenotypicspectrum of AOA2 families and compare it to previous series. Allsubjects, exceptmembers of one family, gave informed consent to takepart in the study which was approved by the Ministry of Health,Health Ethic Committee in Algiers. Here we review the clinical andgenetic aspects of 19 patients from the 7 families which gave informedconsent.

2.2. Clinical assessment

Nineteen patients from 7 unrelated families from different regionsin Algeria, their parents and most of their healthy siblings wereassessed. All the patients received a complete neurological examina-tion. Motor disability was assessed by a seven-stage functional scale:0=normal; 1=mild modifications at examination; 2=mild functionaldisability, able to walk and run; 3=able to walk without help up to500 m, unable to run; 4=needs unilateral help to walk; 5=needsbilateral help to walk; 6=wheelchair-bound; 7=bedridden. Cognitiveassessment was performed with mini mental state examination(MMSE). Ophthalmologic and auditory examination, cardiological,ECG examination and echocardiography were performed on all thepropositi and most of the secondary patients.

The propositi and some secondary patients had also albuminemia,lipid electrophoresis, creatine kinase, hexosaminidase, aryl-sulfataseand alpha-fetoprotein blood testing and CSF immunoelectrophoresis

Table 1Clinical and molecular data

Patients Sex Age atonset

Diseaseduration

Funct.score

Initial signs OMA Other ocular signs

F1 P1 M 9 15 4 Head tremor + Unilateralstrabism

F1 P2 M 10 13 4 Gait ataxiaDysarthria

+ Unilateralstrabism

F1 P3 F 12 8 3 Gait ataxia + Unilateralstrabism

F1 P4 F 11 2 1 − − Unilateralstrabism

F1 P5 M 8 2 2 Mild ataxia − −F2 P1 F 14 25 5 Gait ataxia − Nystagm

F2 P2 M 14 23 5 Gait ataxia − NystagmF2 P3 F 14 20 5 Gait ataxia − −F2 P4 M 15 12 3 Writer cramp

gait ataxia− −

F3 P1 F 14 15 5 Gait ataxiadysarthria

− Unilateralstrabism nystagm

F3 P2 F 13 17 6 Gait ataxiadysarthria

− Nystagm

F4 P1 F 17 15 4 Gait ataxiadysarthria

− Nystagm

F4 P2 F 18 12 4 Gait ataxiadysarthria

+ −

F4 P3 F 19 3 3 Gait ataxia + −F4 P4 F 17 1 3 Gait ataxia − Unilateral

strabismF5 P1 F 16 6 3 Gait ataxia − −

F5 P2 M 18 6 2 Gait ataxia − NystagmF6 P M 17 11 6 Gait ataxia

dysarthria+ Nystagm

F7 P M 15 5 3 Gait ataxia − Unilateralstrabism nystagm

F=Family, P=Patient; +=present; −=absent; A=abolished; D=diminished; LL=Lower limbavailable; AFP: normal=0–6 μg/l; Cerebellar atrophy: +=mild; ++=moderate; +++=severe.

analysis. In 2 families the association of cerebellar ataxia andprominent peripheral neuropathy lead us to suspect giant axonalneuropathy and to perform a nerve biopsy to the propositus of eachfamily. (Methodology for analysis of nerve biopsy is exposed in ref[10]).

2.3. Electrophysiological analysis

Nerve conduction studies were performed with surface stimula-tion and recording electrodes. Motor nerve conduction velocity(MNCV) and compound motor action potentials (CMAP) amplitudeof the median and the peroneal nerves were recorded. Antidromicsensory compound action potential was recorded from the medianand sural nerves. Electromyography of the tibialis anterior and thefirst dorsalis interosseous muscle was performed with a concentricneedle electrode. Only the propositi were available for electroneuro-graphic studies in families 2 and 4. Electroencephalograms and visual,somesthesic and brainstem evoked potentials were performed in allthe propositi.

2.4. Mutation analysis

Patients with a clinical presentation reminiscent of AOA2 werescreened for SETX mutations. We sequenced all exons of the SETXgene from both the forward and reverse strands after purification ofthe polymerase chain reaction (PCR) products with the NucleoSpin"Extract 2 in 1 kit (Macherey-Nagel GmbH & Co). Flanking primersequences and PCR conditions are available upon request. In order toexclude PCR failure, homozygous exon deletions were confirmed byduplex PCR in which the second PCR fragment is an internal control

Tend.reflex LL

Headtremor

Deepsensoryloss

Cerebellaratrophy

AFPµg/l

Family mutations

A + + +++ 56 c.915GNT (exon 6) p.W305C

A − + +++ 46.7

A − − ++ 53.5

D − − ++ 26

D + − + 14.5A − − NA NA Deletion of exons 17 & 18

in-frame deletionA − − +++ NAA − − NA NAA − − ++ 18

A − + ++ 44 c.2602CNT (exon 8) p.Q868X

A − + NA 18

A ++ + ++ 15 c.915GNT (exon 6) p.W305C

A ++ + ++ 12

A − + NA 39A − + NA 33.5

A + + ++ 20 c.6546+5GNT skipping ofexon 17 (in frame)

A − + NA 46A − + ++ 54 deletion of exon 5 In-frame

deletionA − − ++ 21.5 6848−6851delCAGA

(exon 20) p.T2283KfsX32

s; OMA=oculomotor apraxia; Strabism=Strabismus; Nystagm=Nystagmus; NA=Not

Fig. 1. AOA2 families' pedigrees.

79M. Tazir et al. / Journal of the Neurological Sciences 278 (2009) 77–81

from chromosome 9q13 (frataxin exon 4). In addition, in order toexclude a variant in the sequence corresponding to the PCR primers,homozygous exon deletions were confirmed with a second set ofprimers not overlapping with the first set. Sequencing was done usinga Taq cycle sequencing kit (Applied Biosystems). Reaction productswere run on an automated DNA sequencer (model 3100 from AppliedBiosystems) and sequences were analysed with the SeqPilot softwareversion 2.0 (JSI medisys, Kippenheim, Germany). The mutations offamilies 3 and 4 were previously reported [7].

3. Results

3.1. Clinical data

The overall clinical and paraclinical findings are summarized inTable 1. Known consanguinity was found in families 2, 3, 4, 5 and 6

Fig. 2. Age at onset in sibling

(Fig. 1). The first signs described by the parents were abnormal falls,poor balance on walking and/or dysarthria. For the propositus offamily 1, head tremor was noticed two years before gait ataxia. Writercramp, demonstrated by right hand and fingers sustained musclecontraction at writing, was the presenting sign for the propositus offamily 2. The writer cramp was not relieved by anticholinergictreatment but was partly improved with physiotherapy. The mean ageat onset for all families was 14±3 years with a range from8 to 19 years.Differences of age at onset were greater between families than withinfamilies (Fig. 2). The mean duration of the disease, defined as timebetween age at onset and age at last clinical examination, was 11±7with a range from 8 to 25 years. The sex ratio (male: female) of thepatients was 0.73. Almost all patients had ataxia of gait which wasmore disabling in the eldest ones, and mild ataxia of the limbs andtrunk. Cerebellar dysarthria was present in almost 80% of the patients.Oculo-motor apraxia (OMA), defined as eye-head dissociation during

s from 7 AOA2 families.

Fig. 3. Nerve biopsy of patient F4 P1: Loss of large myelinated fibers. No clusters areseen. Semithin section. (Original magnification X 20).

Table 2AOA2 published series

AOA2 Le Ber et al. Duquette et al. Criscuolo et al. Present series

Number of patients 18 24 10 19Age at onset, years

(mean, range)15±4 (9–25) 14.8 (2–20) 20.3 (3–30) 14±3 (8–19)

Duration untilwheelchair (years)

11 ≈10 15.8±7.4 18.5±5

Cerebellar ataxia 100% 100% 100% 94%Deep Sensory deficit 83% 100% 90% 61%Neuropathy 78% 96% 100% 90%OMA 56% 0% 20% 32%Strabismus 11% 29% – 37%Dystonia and/or

chorea, tremor44% 57% 20% 32%

Pyramidal signs 17% 0% 0% 11%Elevated serum AFP 100% 100% 67% 100%

80 M. Tazir et al. / Journal of the Neurological Sciences 278 (2009) 77–81

voluntary lateral head movements (head turns first, then eyes follow),was observed in 32% of the patients while convergent strabismus waspresent in 37% and nystagmus in 42% of the patients. Moderate motorand sensory neuropathy with distal weakness and amyotrophypredominating in the lower limbs was observed in 90% of the patients.In patients of families 3 and 6, motor deficit was important, andworsened gait difficulties. Skeletal deformities, such as pes cavusoccurring in 63% and scoliosis in 21% of the patients, were associatedwith polyneuropathy. Pyramidal signs were rare, with a Babinski signobserved in only 2 patients. There was no cranial nerve involvementother than strabismus. The functional disability was severe in 32% ofpatients (stages 5–6), moderate in 53% (stages 3–4), and mild (stages1–2) in 16% (Table 1). Patients at stage 5 remained ambulant for shortdistances with bilateral support but had to use awheelchair for longerdistances. Functional disability seemed to correlate with diseaseduration in all cases except for the patient of family 6 who waswheelchair-bound after only 5 years of evolution. Otherwise, meandisease duration until stage 5 (severely disabled) and 6 (wheelchair-bound) was 18.5±5 years. Cognitive assessment in all the propositiand the evaluated secondary patients was in the normal range. Theauditory and cardiac systems were normal in all assessed patients.Median MNCV was in the normal range in all examined patients, butCMAP amplitudes were moderately reduced in the eldest patients.Peroneal MNCV was in the normal range in 4 patients, reduced in 6patients, not recorded in 1 patient whereas amplitudes were reducedin the assessed patients. Sural action potential was absent in all theexamined patients. Nerve biopsy in 2 patients (from families 4 and 7)showed homogeneous and significant loss of myelinated fibers,mainly the large diameter ones, without signs of axonal regeneration(Fig. 3). Alpha-fetoprotein (AFP) blood levels were elevated in allassessed patients (Table 1). Albuminemia, lipid electrophoresis,creatine kinase, hexosaminidase, aryl-sulfatase blood testing andCSF immunoelectrophoresis analysis were in the normal range. EEGand evoked potentials were without abnormality. Evolution of thedisease is illustrated with family 1 which has 5 patients at differentstages of the disease. The initial symptom in patient 1, was headtremor at age 9 followed by slurred speech and gait imbalance at age14. When first seen at 17 years, he had OMA and strabismus. Thestriking features of the two eldest brothers (patients 1 and 2), whenseen at age 25 and 23, respectively, were: marked ataxic gait with pescavus, areflexia of the four limbs, dysarthria and bilateral convergentstrabismuswith limitation of ocular abduction. OMAwas not observedanymore presumably masked by external oculo-motor paresis. Patient3, a 20 years old sister was first seen at the age of 15. She had OMA andunilateral strabismus, was ataxic and could walk without help but shestopped attending school at the age of 14 because of her difficulties inwriting.When seen at the age of 18, her unsteadiness had increased to

the point that she could not walk without unilateral help. The twoyoungest sibs (patients 4 and 5), 13 and 10 years old respectively, hadminor neurological signs and no deep sensory impairment. Patient 5had mild gait clumsiness with sluggish reflexes, whereas patient 4,who had no complaints, had only areflexia in the lower limbs andslight strabismus. On EMG examination, motor potentials werenormal in the two youngest patients, whereas sensory potentialswere absent, and CMAP amplitudes were reduced in the 3 eldestpatients. Thus, distal motor axonal polyneuropathy occurred late inthe course of the disease, in this family.

3.2. Mutation findings

Mutations of families 3 and 4 were previously reported (Alg5 andAlg13, respectively, in ref. [10]. Table 1). Family 1 appeared to have thesame homozygous missense mutation as family 4. The mutationsidentified in the remaining families are novel and consist of twohomozygous exon deletions, a homozygous 4 nucleotide deletion anda homozygous splice site mutation (Table 1). The splice site mutationin family 5 changes the G at position +5 of exon 17 donor splice siteinto a T. This position is highly conserved, being a G in 84% of the casesand a purine in 91%. The nucleotide change presumably results inskipping of exon 17. No cell line from the patients was available to testthis prediction. No other nucleotide change was observed in the DNAof family 5 patients. Albeit the exon deletions and predicted exon-skipping result in in-frame deletions, they are predicted to bepathogenic as they affect highly conserved regions of senataxin. Thedeletion of exon 5 results in deletion of part of the highly conserved N-terminal domain and the absence of exons 17 and 18 results in thedeletion of motifs II and III, respectively, of the helicase domain [7].The 4 nucleotide deletion results in a frameshift after motif V of thehelicase domain.

4. Discussion

Ataxia with oculo-motor apraxia type 2 is relatively frequent inAlgeria. Our study of 188 ARCA patients shows that AOA2 is the thirdmost frequent form of ARCA, after FRDA and AVED and before A-T. Thisreport describes a series of 19 AOA2 patients belonging to 7 families.Three important series have been reported to date (Table 2). The firstone includes 6 families from different Mediterranean areas and fromthe West Indies [11], the second is a single cluster of 10 French-Canadian families with ataxia and neuropathy, known as the Quebeccluster [12] and the third, describes 10 patients from 4 Italian families[13].

Known parental consanguinity, which favours occurrence ofautosomal recessive diseases, was present in all but 2 families forwhich the respective parents were born in the same village. Mean age

81M. Tazir et al. / Journal of the Neurological Sciences 278 (2009) 77–81

at onset was before 20 years, as reported in the others series. Althoughfamilies 1 and 4 had the same W305C mutation in the senataxinprotein, there was important variability of the age at onset (Fig. 2);however, the stage of disability was similar in the 2 families. Thisheterogeneity, which has been already described between familieswith identical mutations, is in favour of the interaction of the majorgene SETX with regulatory or modifying genes, for which fewexamples are available among human inherited diseases [14].Environmental factors may influence the phenotype too.

Disease severity was correlated with disease duration. Meandisease duration until wheelchair in the present series was similarto the Italian series [13]. Gait ataxia and dysarthria were the initialsigns in almost all patients. When examined, all patients had cere-bellar signs except patient 4 of family 1 who only had mild strabismusand areflexia in the lower limbs. Cerebellar ataxia was progressive,slowly leading to disability. In contrast to the Quebec series [12],areflexia or hyporeflexia was an early feature of our patients andalmost the only sign in the 2 youngest patients of family 1. Axonalsensory-motor polyneuropathy is the second cardinal sign aftercerebellar ataxia in AOA2 patients. It was present in our families asin Quebec patients and in the majority of the multiethnic and Italianpatients. It contributes, with cerebellar ataxia, to the progressivemotor disability of the patients. Although present in the diseaseacronym, oculo-motor apraxia is an inconstant sign of the disease. Asshown in family 1, OMA may disappear with disease evolution.Convergent strabismus was more frequent than OMA in our series(37%). Like OMA, strabismus may be very suggestive of AOA2 whenassociated with ataxia and polyneuropathy. In contrast to the Quebecseries, deep sensory impairment of the lower limbs, present in 58% ofour patients, was observed mostly in the eldest patients after severalyears of disease evolution. Movement disorders such as dystonia,chorea and head or postural tremor were relatively frequent in theinternational series (44% of patients, 11). Hand dystonia was observedonly in one patient of our series and head tremor in 5 patients. Tremorwas observed in only 1 person in the Italian series but in 57% of theQuebec cluster. Dystonia was not mentioned in this later series.Difficulties in swallowing, found in all the patients of the Italian series[13] and in 33% of the international series [11], were not observed inour patients. Cerebellar atrophy on MRI or CT-scan was present in allexplored patients, and was more severe in the eldest patients.However, it may be an early sign of the disease since it was presentin the youngest and paucisymptomatic patients. Serum AFP waselevated in all tested patients as in the majority of the patients in theother series. Recently, it has been reported that non-symptomaticheterozygous relatives could have moderately increased AFP serumlevels as well [15].

Thus, the clinical phenotype of this AOA2 series is similar to thepreviously reported series. Cerebellar ataxia is associated to axonalsensory-motor neuropathy, deep sensory deficit, OMA, and conver-gent strabismus which is more frequent than OMA in the presentseries. Cerebellar atrophy on MRI may be an early sign. Increasedserum AFP level is recognized as a good biological marker for AOA2,and in a context of ARCA without telangiectasia, it helps to orientate

molecular studies towards direct search for mutations in the SETXgene.

Acknowledgements

The authors are grateful to the families and to the clinicians whoreferred patients to us. We wish to thank S. Makri, M. Assoum, D.H'mida and N. Drouot for the study of the non-AOA2 families. Thiswork was supported by The University of Algiers and the Ministère dela Santé, de la Population et de la Réforme Hospitalière, Algeria.Genetic studies were supported by funds from the Ministère françaisde la santé, de la famille et des personnes handicapées (réseauneuromusculaire DHOS-OPRC number 2003-227), the Agence Natio-nale pour la Recherche (grant ANR-05-MRAR⁎013-01), the InstitutNational de la Santé et de la Recherche Médicale and the CentreNational de la Recherche Scientifique.

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