The Clinical Spectrum of Ataxia with Oculomotor Apraxia Type 2

Florian Brugger, MD,1 Michael Sch€upbach, MD,2 Michel Koenig, MD, PhD,3,4 Ren�e M€uri, MD, PhD,5 Stephan Bohlhalter, MD,5,6

Alain Kaelin-Lang, MD, PhD,2 Christian P. Kamm, MD,5 Georg K€agi, MD1,*

Abstract: Ataxia with oculomotor apraxia type 2 (AOA2) is an inherited disorder caused by mutations withinboth alleles of the senataxin gene. First symptoms are usually recognized before the age of 30. Unlikeseveral other autosomal recessive cerebellar ataxia syndromes, levels of alpha-fetoprotein are nearly alwayselevated in AOA2 and thus narrowing down the differential diagnosis list. We present 3 video casesillustrating and expanding the clinical spectrum of AOA2, with 1 case bearing a novel mutation with cervicaldystonia as the first symptom, the absence of neuropathy, and a disease onset beyond the age of 40.Furthermore, all patients were assessed by oculographic analysis, which revealed distinct patterns ofoculomotor abnormalities. The clinical spectrum of AOA2 might be even broader than previously described inlarger series. Oculography might be a useful tool to detect subclinical oculomotor apraxia in this disorder.

With a prevalence of ~8%, ataxia with oculomotor apraxia type 2

(AOA2) may be the third-most common non-Friedreich autoso-

mal recessive cerebellar ataxia in the European population.1,2 Dis-

ease-causing mutations lie in the SETX gene (9q34) coding for

senataxin, which is thought to be involved as a helicase in DNA

transcription and RNA processing.3,4 The clinical spectrum of

AOA2 includes cerebellar ataxia, sensorimotor neuropathy, ocu-

lomotor apraxia, pyramidal signs, mild cognitive impairment,

skeletal deformities, and hyperkinetic movement disorders,

including head tremor, dystonia, chorea, and myoclonus. Cere-

bellar atrophy and elevated alpha-fetoprotein (AFP; 99%) are usu-

ally present from early on.5,6 The absence of both peripheral

neuropathy and cerebellar atrophy is nearly exclusive for AOA2.5

Clinically, oculomotor apraxia is characterized by an initial

head thrust, which is followed by eye movements to the

intended side. The name of the disease can be misleading

because oculomotor apraxia is absent in half of the patients with

AOA2. The term “apraxia” is also considered to be a misnomer

in this context because it usually refers to the inability to pro-

perly execute skilled voluntary movements, despite normal

elementary sensorimotor function.

We report on 3 illustrative video cases of genetically con-

firmed AOA2, which show the wide clinical spectrum of the

disease and describe new clinical features and a new mutation.

Illustrative Cases: ClinicalPresentation

Case 1

This 24-year-old Macedonian female with known Sturge-

Weber syndrome first complained about unsteadiness at the age

of 11. At initial evaluation, she presented with gait ataxia,

increased left-sided muscle tone, reduced tendon reflexes, and

oculomotor apraxia. Family history was unremarkable, and the

brain MRI was normal. However, cerebellar atrophy was

observed on a subsequent scan 5 years later. At the age of 16,

the AFP was slightly elevated (6.7 ng/mL; N < 5.8 ng/mL).

Over the next 8 years, the disease progressed to an advanced

cerebellar syndrome with sensorimotor polyneuropathy, scolio-

sis, and pes cavus. Oculomotor examination revealed conver-

gent strabismus, gaze-evoked nystagmus, and slowing of

1Movement Disorders Center of Eastern Switzerland, Department of Neurology, Kantonsspital St.Gallen, St.Gallen, Switzerland; 2Movement DisordersCenter, Department of Neurology, University Hospital Berne, University of Berne, Berne, Switzerland; 3Laboratoire de Diagnostic G�en�etique, NouvelHopital Civil, Strasbourg, France; 4Institut de G�en�etique et de Biologie Mol�eculaire et Cellulaire, CNRS/Universit�e de Strasbourg/INSERM, Illkirch,France; 5Perception and Eye Movement Laboratory, Departments of Neurology and Clinical Research, Inselspital, University Hospital Berne, Berne,Switzerland; 6Neurology and Neurorehabilitation Center, Department of Internal Medicine, Luzerner Kantonsspital, Lucerne, Switzerland

*Correspondence to: Dr. Georg K€agi, Kantonsspital St. Gallen, Department of Neurology, Rorschacherstrasse 95, St. Gallen CH-9007, Switzerland;E-mail: georg.kaegi@kssg.ch

Keywords: AOA2, oculomotor apraxia, ataxia, senataxin.Relevant disclosures and conflicts of interest are listed at the end of this article.Received 18 December 2013; revised 10 March 2014; accepted 12 March 2014.Published online 27 May 2014 in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/mdc3.12021

© 2014 International Parkinson and Movement Disorder Society106

doi:10.1002/mdc3.12021

CASE SERIES

CLINICAL PRACTICE

saccades, but without clear-cut oculomotor apraxia (see Video,

Segment 1). The AFP level at this time was normal (11.3 ng/

mL; N < 13 ng/mL). Subsequent genetic testing revealed com-

pound heterozygous mutations of the SETX gene (Table 1).

Case 2

This 56-year-old Macedonian female first came to medical atten-

tion at the age of 42 because of involuntary head movements

with impaired oculomotor control that occurred only a few

months before. Family history was unremarkable and without

evidence of parental consanguinity. At that time, the CT scan of

the brain was normal and she was diagnosed with “cervical dys-

tonia.” After another 14 years, she was referred again because

her gait and “eye movements” had further deteriorated, making

her wheelchair bound shortly before referral. On clinical exami-

nation, she displayed severe gait ataxia, right-sided hemidystonia,

gaze-evoked nystagmus, and severe oculomotor apraxia. Vestib-

ulo-ocular reflex (VOR) suppression was absent (see Video, Seg-

ment 2). There was no evidence (neither clinically nor

electrophysiologically) of polyneuropathy. The brain MRI

showed vermis atrophy. Laboratory testing showed elevated AFP

levels (44.1 ng/mL; N < 13.9 ng/mL). Genetic testing revealed

a novel homozygous missense mutation of the SETX gene,

leading to a p.Ile1942Thr change (Table 1). This mutation is

predicted to be pathogenic with a score of 0.993 (range, 0–1) by

the PolyPhen-2 program and from sequence conservation

analysis (position homologous to p.Ile1942 is always an isoleu-

cine or valine, in any investigated eukaryotic species).7

Case 3

This 35-year-old Swiss male was referred because of progressive

gait problems. During early adolescence, he experienced some

“clumsiness.” In the third decade, he gradually developed

impairment of gait and mild dysarthria; however, these symp-

toms remained mild upon referral. Family history was negative,

and parental consanguinity was denied by the patient. At first

referral, he showed mild gait ataxia, square wave jerks, nystag-

mus, dysmetric saccades, right-sided brady-/hypokinesia, and

slightly increased muscle tone (see Video, Segment 3). Electro-

physiological testing detected subclinical sensory axonal poly-

neuropathy. The brain MRI showed vermis atrophy, and AFP

was elevated (35.6 ng/mL; N < 8.0 ng/mL). A dopaminergic

deficit was suspected because of the akinetic-rigid signs, but a

DaTSCAN was normal. Subsequent genetic testing revealed a

compound heterozygous mutation in the SETX gene (Table 1).

The patient engages in regular coordinative physical therapy

and, until present, remains physically independent.

Video OculographyVideo oculography was performed using a head-mounted, video-

based monocular eye tracker (Eyelink II). Subjects were seated in

TABLE 1 Case synopsis

Case 1 Case 2 Case 3

Age at onset 11 years ~40 years Early adolescence

Age at referral 24 years 56 years 35 years

Origin Macedonian Macedonian Swiss

Mutation Compound heterozygousc5591_5592delAA(frameshift mutation ? p.Gln1864ArgfsX34)c.6948T>A(missense mutation ? p.Asn2316Lys)

Homozygousc.5825T>C(missense mutation ? p.Ile1942Thr)

Compound heterozygousc.6860G>A(missense mutation ?p.Arg2287Gln)c.7331G>A(missense mutation ?p.Arg2444His)

Clinical featuresAtaxia ++ ++ +Neuropathy ++ � � (subclinical sensory)Oculomotorapraxia

(+) ++ �Strabismus + � �Pyramidalsigns

� � �Dystonia + + +Chorea � � �Myoclonus � � �Pes cavus + � �

Diseaseprogression

Rapid Slow Very slow

Time onset towheelchair

~5 years ~15 years Not applicable

MR findingsVermis atrophy + + ++Hemisphereatrophy

� � �

Elevated AFPlevels

� + +

DaTSCAN Not done Not done Normal

Formaloculographictesting

Reduced number of saccades; markedlyreduced amplitude of horizontalsaccades; decreased velocity of upwardsaccades

Markedly reduced number of saccades(vertical > horizontal); severelydecreased amplitude of saccades ofall axes; saccade velocity cannotreliably be evaluated as a result ofthe paucity of generated saccades.

Initial testing: rare and slowed downwardsaccadesFollow-up (+2 years): further decreaseof saccade velocity downward

Electrophysiology Axonal sensorimotor neuropathy No evidence of neuropathy Axonal sensory neuropathy(subclinical)

MOVEMENT DISORDERS CLINICAL PRACTICE 107doi:10.1002/mdc3.12021

Brugger et al. CASE SERIES

front of a monitor in an optically and acoustically shielded room

with their heads stabilized by a chin rest. Four sessions with 15

pictures each were presented on a monitor. The patients were

instructed to freely and actively explore the pictures. In case 1,

only a few saccades were recorded. The horizontal saccades

showed reduced amplitudes, whereas the saccade velocity was

decreased for vertical saccades. In case 2, the paucity of generated

saccades with reduced amplitudes was the most prominent find-

ing. In case 3, video oculography revealed a decreased number

of downward saccades with reduced velocity. The horizontal

saccades were, however, largely normal.

DiscussionDuring diagnostic workup of autosomal recessive ataxias with

oculomotor apraxia and/or sensorimotor neuropathy, the assess-

ment of serum AFP might be useful because, if elevated, it nar-

rows down the differential diagnosis list to AOA2 and ataxia

telangiectasia. Elevated AFP levels, the absence of telangiectasia,

the absence of recurrent infections and susceptibility for neo-

plasms as well as disease onset after the age of 10 should favor

genetic testing for AOA2.8 However, normal AFP is not strictly

exclusive for AOA2, especially if measured just once. AFP usu-

ally remains stable throughout the disease, but the level can

change as the disease progresses. It has been shown that the

AFP level has an inverse correlation with the occurrence of

strabismus, and that strabismus is associated with faster disease

progression, which is in line with case 1.5 Another interesting

point of case 1 is that oculomotor apraxia was described at ini-

tial clinical workup and had disappeared by the age of 24,

which fits to the description of one Algerian family.9

Case 2 presented with an unusual late disease onset beyond

the age of 40 years, with a rather slow progression over two

decades to a severe phenotype. Of all our cases, oculomotor

apraxia was most prominent in this case. This individual obser-

vation underpins what Anheim et al. found on the basis of a lar-

ger population, showing that disease progression has an inverse

correlation with age of onset and with the occurrence of oculo-

motor apraxia.5 Notably, torticollis was the first symptom recog-

nized by the patient. Usually, disease starts with slowly

progressive gait ataxia, but head tremor, dysarthria, or even wri-

ter’s cramp may also be the presenting symptoms.9,10 Because

the vast majority of AOA2 cases display signs of polyneuropathy,

the absence of neuropathy in this case is unusual. These atypical

features of case 2 may be related to a new homozygous missense

mutation (p.Ile1942Thr), which affects an amino acid upstream

of the helicase domain. Isoleucine, at this position, is highly con-

served through evolution because there is always an isoleucine

or a valine, another short hydrophobic amino acid, at the equiv-

alent position of any eukaryotic SETX ortholog. Nevertheless,

some caution must be paid to the fact that genotyping of parents

and other siblings was not performed. Therefore, the possibility

of compound heterozygosity (exon or gene deletion on the

other allele) has not been ruled out.

Case 3 represents a rather classical phenotype of AOA2, but

without evidence of oculomotor apraxia. The mutation,

c.7331G>A (p.Arg2444His), has been described by Anheim

et al. and by Gazulla et al., who reported neuropathy in patients

carrying this mutation homozygously.11,12 Whereas Anheim

et al. found mild sensorimotor axonal neuropathy in their

patients, Gazulla et al. found a clinically progressive pure

sensory neuropathy with preserved motor fibers, which is in

contrast with previous reports of a sensorimotor pattern. In our

case, with the aforementioned mutation on one allele, subclini-

cal pure sensory neuropathy was found.

Cerebellar oculomotor signs were observed in all patients.

Furthermore, video oculography showed saccadic abnormalities

in all cases; however, there were substantial differences regard-

ing generation and accuracy of saccadic movements. Increased

latencies and reduced range of saccades are the hallmark of

oculomotor apraxia.13 Clinically, oculomotor apraxia was

established in case 2, but only variably present in case 1. On

oculography, cases 1 and 2 generated only few saccades or sac-

cades with low amplitudes. A low number of acquired saccades

represents (1) the inability to perform saccades and (2) the very

slow velocity of these eye movements, which were not regis-

tered as saccades by the device. We consider that several

aspects of the oculography are likely explained by oculomotor

apraxia. Although we were aware of oculomotor abnormalities

in case 1, we were surprised about the extent of saccadic

abnormalities on oculography. We therefore suggest that video

oculography might be a useful tool to detect subclinical oculo-

motor apraxia.

In conclusion, case 2, with a novel SETX mutation, extends

the spectrum of AOA2 by three unusual features: (1) disease

onset beyond the age of 40; (2) cervical dystonia as the first

symptom; and (3) absence of neuropathy. This report suggests

that AFP testing should be recommended in patients with an

unexplained ataxia even beyond the age of 40. Additionally,

apparative assessments might be useful to detect subclinical

neuropathy or oculomotor apraxia in AOA2.

Author Roles(1) Research Project: A. Conception, B. Organization, C. Exe-

cution; (2) Statistical Analysis: A. Design, B. Execution,

C. Review and Critique; (3) Manuscript: A. Writing of the

First Draft, B. Review and Critique.

F.B.: 1C, 3A

M.S: 1C, 3B

M.K.: 1C, 3B

R.M.: 1C, 3B

S.B.: 1C, 3B

A.K.-L.: 1C, 3B

C.P.K.: 1C, 3B

G.K.: 1C, 3B

AcknowledgmentsThe authors acknowledge Dr. J.P. Delaunoy for his support

during genetic testing and Anna M€uller for her English proof-

reading of the manuscript.

108 MOVEMENT DISORDERS CLINICAL PRACTICEdoi:10.1002/mdc3.12021

The Clinical Spectrum of AOA2CASE SERIES

DisclosuresFunding Sources and Conflicts of Interest: The authors

report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: F.B. has

served on the advisory boards of Merck Serono and Biogen

Idec; has received honoraria from Merck Serono (travel

expenses); and has been employed by Kantonsspital St. Gallen.

M.S. has held consultancies with Medtronic and Lundbeck; has

received travel reimbursement and speaker’s honoraria from

Medtronic, Lundbeck, and Actelion; has been employed by

University Hospital Berne; and is the CEO of KGMed Ltd.

M.K. has been awarded grants from Agence Nationale

pour la Recherche-Maladies Rares and Maladies Neurologi-

ques et Psychiatriques (ANR-09-MNPS-001-01) and ANR/

E-rare JTC 2011 “Euro-SCAR” (2011-RARE-004-01) and

has been employed by University of Strasbourg (Faculty of

Medicine), University Hospital–Strasbourg. R.M. has been

awarded grants from the Swiss National Foundation and has

been employed by the Department of Neurology, University

Hospital Bern. S.B. has served on the advisory board of

UCB Pharma; has received honoraria from Abbott (travel

expenses); Has been awarded grants from the Swiss National

Foundation and Parkinson Switzerland; and has been

employed by Luzerner Kantonsspital. A. K.-L. has served on

the advisory boards of UCB Pharma and Boehringer Ingel-

heim; has received honoraria from Lundbeck and Allergan;

has been awarded grants from Parkinson Switzerland, the

Baasch-Medicus Foundation, and the Gloria and Jacques Gos-

sweiler Foundation; has been employed by the Department

of Neurology, University Hospital Bern; and has held con-

tracts with Novartis (clinical trial agreement). C.P.K. has held

consultancies with Bayer Schering, TEVA, Genzyme, Merck-

Serono, and Biogen Idec; has served on the advisory boards

of Bayer Schering, TEVA, Genzyme, Merck-Serono, and Bio-

gen Idec; and has been employed by the Department of

Neurology, University Hospital Bern. G.K. has served on the

advisory boards of Boehringer-Ingelheim and Lundbeck; has

received honoraria (to attend meetings) from Bayer and

Lundbeck; has been awarded grants from Parkinson Switzer-

land, Swiss Heart Foundation, Medical Research Center of

the Kantonsspital St. Gallen; and has been employed by Kan-

tonsspital St. Gallen.

References1. Le Ber I, Bouslam N, Rivaud-Pechoux S, et al. Frequency and pheno-

typic spectrum of ataxia with oculomotor apraxia 2: a clinical andgenetic study in 18 patients. Brain 2004;127:759–767.

2. Anheim M, Fleury M, Monga B, et al. Epidemiological, clinical, para-clinical and molecular study of a cohort of 102 patients affected with

autosomal recessive progressive cerebellar ataxia from Alsace, EasternFrance: implications for clinical management. Neurogenetics 2010;11:1–12.

3. Skourti-Stathaki K, Proudfoot NJ, Gromak N. Human senataxinresolves RNA/DNA hybrids formed at transcriptional pause sites to pro-mote Xrn2-dependent termination. Mol Cell 2011;42:794–805.

4. Moreira MC, Klur S, Watanabe M, et al. Senataxin, the ortholog of ayeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet2004;36:225–227.

5. Anheim M, Monga B, Fleury M, et al. Ataxia with oculomotor apraxiatype 2: clinical, biological and genotype/phenotype correlation study ofa cohort of 90 patients. Brain 2009;132:2688–2698.

6. Fogel BL, Perlman S. Clinical features and molecular genetics of autoso-mal recessive cerebellar ataxias. Lancet Neurol 2007;6:245–257.

7. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for pre-dicting damaging missense mutations. Nat Methods 2010;7:248–249.

8. Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellarataxias. N Engl J Med 2012;366:636–646.

9. Tazir M, Ali-Pacha L, M’Zahem A, et al. Ataxia with oculomotorapraxia type 2: a clinical and genetic study of 19 patients. J Neurol Sci2009;278:77–81.

10. Criscuolo C, Chessa L, Di GS, et al. Ataxia with oculomotor apraxiatype 2: a clinical, pathologic, and genetic study. Neurology2006;66:1207–1210.

11. Gazulla J, Benavente I, Lopez-Fraile IP, Tordesillas C, Modrego P,Alonso I, Pinto-Basto J. Sensory neuronopathy in ataxia with oculomo-tor apraxia type 2. J Neurol Sci 2010;298:118–120.

12. Anheim M, Fleury MC, Franques J, et al. Clinical and molecular find-ings of ataxia with oculomotor apraxia type 2 in 4 families. Arch Neurol2008;65:958–962.

13. Clausi S, De Luca M, Chiricozzi FR, Tedesco AM, Casali C, MolinariM, Leggio MG. Oculomotor deficits affect neuropsychological perfor-mance in oculomotor apraxia type 2. Cortex 2013;49:691–701.

Supporting InformationA video accompanying this article is available in the supporting

information here:

Video. The video shows the clinical findings on oculomotor test-

ing. On segment 1 (case 1), the patient is asked to generate hori-

zontal saccades, first to the left and then to the right side.

Hypermetric saccades are the main findings without clear-cut

oculomotor apraxia. Furthermore, some head titubation is present.

Beside the neurological signs, stigmata of the known Sturge-

Weber syndrome, including facial naevus flammeus and an

increased size of the left eye bulb resulting from a glaucoma, can

be identified on the video segment. Segment 2 (case 2) shows the

full-blown picture of oculomotor apraxia. On the video, the

patient is asked to first look to the right side and back to the tar-

get in front of her. As soon as she moves her head, the lack of

VOR suppression leads to an eye deviation contralaterally to the

intended side, followed by a very slow saccade to the correct side.

On segment 3 (case 3), some dysmetric saccades can be observed;

however, saccade velocity and saccade initiation are normal.

There is no evidence of oculomotor apraxia.

MOVEMENT DISORDERS CLINICAL PRACTICE 109doi:10.1002/mdc3.12021

Brugger et al. CASE SERIES