The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia

Aurélie Méneret, MD* Yara Ahmar-Beaugendre, MD* Guillaume Rieunier* Nizar Mahlaoui, MD, MSc, MPH* Bertrand Gaymard, MD, PhD Emmanuelle Apartis, MD, PhD Christine Tranchant, MD, PhD Sophie Rivaud-Péchoux, MD Bertrand Degos, MD, PhD Baya Benyahia, MD, PhD Felipe Suarez, MD, PhD Thierry Maisonobe, MD Michel Koenig, MD, PhD Alexandra Durr, MD, PhD Marc-Henri Stern, MD, PhD Catherine Dubois d’Enghien Alain Fischer, MD, PhD Marie Vidailhet, MD Dominique StoppaLyonnet, MD, PhD‡ David Grabli, MD, PhD‡ Mathieu Anheim, MD, PhD‡

Correspondence to Dr. Anheim: [email protected]

Supplemental data at Neurology.org

ABSTRACT

Objective: To assess the clinical spectrum of ataxia-telangiectasia (A-T) in adults, with a focus on movement disorders.

Methods: A total of 14 consecutive adults with A-T were included at 2 tertiary adult movement disorders centers and compared to 53 typical patients with A-T. Clinical evaluation, neurophysiologic and video-oculographic recording, imaging, laboratory investigations, and ATM analysis were performed. Results: In comparison with typical A-T cases, our patients demonstrated later mean age at onset (6.1 vs 2.5 years, p , 0.0001), later loss of walking ability (p 5 0.003), and longer survival (p 5 0.0039). The presenting feature was ataxia in 71% and dysarthria and dystonia in 14% each. All patients displayed movement disorders, among which dystonia and subcortical myoclonus were the most common (86%), followed by tremor (43%). Video-oculographic recordings revealed mostly dysmetric saccades and 46% of patients had normal latencies (i.e., no oculomotor apraxia) and velocities. The a-fetoprotein (AFP) level was normal in 7%, chromosomal instability was found in 29% (vs 100% of typical patients, p 5 0.0006), and immunoglobulin deficiency was found in 29% (vs 69%, p 5 0.057). All patients exhibited 2 ATM mutations, including at least 1 missense mutation in 79% of them (vs 36%, p 5 0.0067).

Conclusion: There is great variability of phenotype and severity in A-T, including a wide spectrum of movement disorders. Karyotype and repeated AFP level assessments should be performed in adults with unexplained movement disorders as valuable clues towards the diagnosis. In case of a compatible phenotype, A-T should be considered even if age at onset is late and progression is slow. Neurology® 2014;83:1087–1095 GLOSSARY A-T 5 ataxia-telangiectasia; AFP 5 a-fetoprotein; IgA 5 immunoglobulin A; IgG 5 immunoglobulin G; IgM 5 immunoglobulin M; NS 5 not significant; SARA 5 Scale for the Assessment and Rating of Ataxia; UL 5 upper limbs; WT 5 wild-type.

Ataxia-telangiectasia (A-T), due to mutations in the ATM gene, is the second most frequent recessive ataxia.1 Typical patients with A-T exhibit progressive cerebellar ataxia starting in early childhood, oculocutaneous telangiectasia, immunodeficiency leading to recurrent infections, endocrinopathy, and increased risk of cancer.2–4 Laboratory findings include elevated a-fetoprotein (AFP) serum levels, immunoglobulin A (IgA) or immunoglobulin G (IgG) deficiency, and somatic acquired chromosomal aberrations in lymphocytes such as t(7; 14) translocations.2 Patients are *These authors contributed equally to this work as first authors. ‡These authors contributed equally to this work as last authors. From INSERM, UMRS 975, CNRS 7225-CRICM (A.M., E.A., S.R.-P., A.D., M.V., D.G.), AP-HP, Fédération de Neurophysiologie Clinique (B.G., T.M.), AP-HP, Département des Maladies du Système Nerveux (B.D., M.V., D.G.), Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Chromosomique (B.B.), and Département de Génétique et Cytogénétique (A.D., M.A.), Hôpital Pitié-Salpêtrière, Paris; Université Pierre et Marie Curie-Paris-6 (A.M., B.G., E.A., S.R.-P., B.D., A.D., M.V., D.G.); AP-HP, Service de Physiologie (Y.A.-B., E.A.), Hôpital Saint-Antoine; INSERM U830 (G.R., M.-H.S., D.S.-L.), Paris; Unité d’Immuno-Hématologie et Rhumatologie Pédiatriques (N.M., A.F.), CEREDIH (French Reference Center for Primary Immunodeficiencies) (N.M., F.S., A.F.), and Service d’Hématologie Adultes (F.S.), Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP); Imagine Institute (N.M., F.S., A.F.), Sorbonne Paris Cité (D.S.-L.), Université Paris Descartes; Département de Neurologie (C.T., M.A.), Hôpital Civil de Strasbourg; Fédération de Médecine Translationnelle de Strasbourg (FMTS) (C.T., M.A.), Université de Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (C.T., M.K., M.A.), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch; Laboratoire de Diagnostic Génétique (M.K.), Nouvel Hôpital Civil, Strasbourg; Laboratoire de Génétique des Maladies Rares (M.K.), INSERM UMR_S 827, Institut Universitaire de Recherche Clinique, Montpellier; and Department of Tumour Biology (M.-H.S., C.D.E., D.S.-L.), Institut Curie, Paris, France. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology

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usually wheelchair-bound by age 10 years, and die around age 20 years due to malignancies or respiratory failure.5 Whereas the typical picture of patients with A-T is well-described, little is known about the rare patients with A-T who are referred as adults to movement disorders centers, either because of slow progression6–8 or misleading clinical or laboratory findings responsible for undiagnosed A-T. In such cases, although various presentations such as resting tremor, myoclonus, dystonia, and choreoathetosis have been described, the phenomenology of movement disorders has not been studied systematically.6,9–13 To assess the clinical spectrum of A-T in adults, and to better characterize the related movement disorders, we retrospectively studied the phenotypes of 14 consecutive A-T cases referred to 2 tertiary adult movement disorders centers, compared to a group of 53 typical patients with A-T. METHODS Recruitment of patients with A-T. Patients with genetically proven A-T followed at 2 French tertiary adult movement disorders centers (Pitié-Salpêtrière Hospital, Paris, and University Hospital of Strasbourg, France) were recruited for this study. Over a 4-year period (2008–2012), 14 consecutive cases were identified in 9 unrelated families. Nine adult patients were diagnosed de novo, whereas the remaining 5 had previously been diagnosed in pediatric centers. All patients had a standardized interview and a detailed clinical examination by a movement disorders expert (D.G., C.T., A.D., B.D., M.V., or M.A.). Scale for the Assessment and Rating of Ataxia (SARA, from 0 to 40)14 was used to quantify the severity of ataxia. Dystonia severity was assessed with the motor score of Burke-Fahn-Marsden Dystonia Rating Scale (from 0 to 120).15 We also reviewed the patients’ medical history for infections during childhood or malignancies, and carefully looked for telangiectasias. Neurophysiologic polymyographic and video-oculographic recordings, EMG, imaging, and laboratory and genetic analyses were performed (see appendices e-1 and e-2 on the Neurology® Web site at Neurology.org).

Control group. To compare our adult patients with typical patients with A-T, we collected the records of 53 consecutive patients from the French Center of Reference for Primary Immunodeficiencies (CEREDIH). Data included demographic features, age at onset and age at death, biological findings (immunoglobulin levels, karyotype), ATM mutations, and, when available, clinical information regarding ataxia (n 5 37/53), abnormal movements (n 5 18/53), telangiectasia (n 5 40/53), pyramidal syndrome (n 5 8/53), ocular movements abnormalities (n 5 31/ 53), and AFP (n 5 33/53). Statistical analyses were performed using Student t test, Fisher exact test, and log-rank test using GraphPad software. Standard protocol approvals, registrations, and patient consents. Written informed consent was obtained from the patients (or the parents of minors) before blood sampling and genetic analyses. A local ethics committee approved the study. 1088

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RESULTS Demographics, clinical features, molecular findings, and neurophysiologic data of the 14 adult patients with A-T are summarized in tables 1 and 2.

Demographic features. Age at onset ranged from 1 to 14

years and was on average significantly higher than in typical patients with A-T (6.1 vs 2.5 years, p , 0.0001). Diagnostic delay was also significantly longer in our patients (15.6 vs 3.5 years, p , 0.0001), particularly in those with onset before 3 years of age (patients 1, 6, 12, and 13). Milestones of disease evolution. Among our 14 patients,

the presenting feature was ataxia in 10 and dysarthria and dystonia each in 2. Two patients reported walking difficulties and falls in early childhood, which spontaneously improved before the occurrence of new symptoms (tremor in patient 6 and dystonia in patient 13). Patient 13 also had dysarthria since he started talking. Strikingly, he did not have limb cerebellar ataxia at age 20 years. Seven patients (including the 5 patients diagnosed in childhood or adolescence) became wheelchair-bound between ages 9 and 25 years. Seven out of 9 patients diagnosed in adulthood could still walk at the time of last examination, aged 20 to 31 years. Kaplan-Meier curves showed significantly longer survival and later wheelchair confinement in our patients compared to typical patients with A-T (p 5 0.004 and p 5 0.003, respectively) (figure 1). Movement disorders. At the time of examination, cerebellar ataxia was present in 13 of our 14 patients (93% vs 97% in the typical patients with A-T, not significant [NS]), but was not the prominent feature in 6 of them (patients 6, 8–11, and 14). SARA scores ranged from 7 to 28 (maximum score 40). All patients displayed movement disorders (100% vs 44% of the typical patients with A-T, p 5 0.0013). Dystonia, observed in 12 out of 14 patients (86%), was characterized based on clinical analysis and polygraphic recording (except for patient 14). The patients exhibited various combinations of abnormal postures, dystonic spasms, tonic activity, co-contraction, and overflow at the recorded sites. Dystonia was focal or segmental, mainly involving the upper limbs (UL) or the neck in 8 patients, and was multifocal but mildly severe in the remainder. Levodopa slightly alleviated dystonia in 3 of the 6 patients who had tried it. Ten patients had myoclonic jerks superimposed in dystonic body segments and 2 had multifocal myoclonus without dystonia, involving the UL, trunk, and neck. Myoclonus was systematically recorded in 11 of these 12 patients. Myoclonus had no peculiar temporospatial organization and was not stimulus-sensitive. In most cases (9/11), the burst durations of myoclonic jerks (upper limit) were longer than expected for cortical myoclonus (.50 ms). No

Table 1

Demographic, clinical, biological, and molecular features of the patients

Age at Patient onset, y

Age at diagnosis, y

Age at last examination, y

Presenting feature

Wheelchair, y

Movement SARA BFMRS Ataxia disorders

1

18

26

Ataxia

9

28

2

21

1

1

Ocular motor abnormalities

Neuropathy

1

1

2

9

17

24

Ataxia

14

27

21

1

1

1

1

3

7

7

21

Ataxia

11

24

ND

1

1

1

1

4

8

9

25

Ataxia

14

26

10

1

1

1

1

5

5

7

36

Ataxia

12

26.5

10

1

1

1

ND

6

1

30

31

Ataxia

NA

11

14

1

1

1

2

7

14

37

36

Ataxia

25

19.5

2

1

1

1

1

8

6

23

25

Dysarthria

NA

20.5

9.5

1

1

1

2

9

6

26

27

Dysarthria

NA

20

9

1

1

1

1

10

8

29

30

Dystonia

NA

7.5

6

1

1

1

2

11

6

30

31

Dystonia

NA

11

16.5

1

1

1

2

12

1

23

23

Ataxia

NA

13.5

6

1

1

1

1

13

2

20

20

Ataxia

NA

7

ND

2

1

2

2

14

10

27

28

Ataxia

18

25

16

1

1

1

1

Elevated Telangiectasia AFP

Karyotype abnormalities

Immunoglobulin deficiency

Cerebellar atrophy (MRI)

ATM mutations

2

1

1

c.9022C.T/p.R3008Ca; c.9022C.T/p.R3008Ca

Pyramidal Patient syndrome 1

2

1

1

2

2

1

1

1

2

1

c.9022C.T/p.R3008C; c.9022C.T/p.R3008C

3

2

1

1

2

2

ND

c.7456C.T/p.R2486X; c.8161 G.A/p.D2721N

4

2

1

1

2

2

1

c.7456C.T/p.R2486X; c.8161 G.A/p.D2721N

5

2

2

2

2

2

ND

IVS2111 G.A; IVS5515delG

6

2

2

1

1

2

2

c.8147T.C/p.V2716A; c.6679C.T/p.R2227C

7

1

2

1

2

2

1

IVS28-1G.C; IVS34132insAlu

8

1

2

1

2

2

1

IVS1912T.G; c.8147T.C/p.V2716A

9

1

2

1

2

1

1

IVS1912T.G; c.8147T.C/p.V2716A

10

2

2

1

2

2

1

IVS1912T.G; c.8147T.C/p.V2716A

11

2

2

1

2

2

1

IVS1912T.G; c.8147T.C/p.V2716A

12

2

2

1

2

1

1

c.824delT/p.L275; c.3248A.G/p.H1083R

13

2

2

1

1

1

2

c.3383A.G/p.Q1128R; c.8122 G.A/p.D2708N; c.513C.T/p.Y171Y

14

2

1

1

1

2

1

DupEx64165; c.6108T.G/p.Y2036X

Abbreviations: AFP 5 a-fetoprotein; BFMRS 5 Burke-Fahn-Marsden Dystonia Rating Scale; NA 5 not applicable; ND 5 not determined; SARA 5 Scale for the Assessment and Rating of Ataxia. a Variant shown to be pathogenic.37

cortical transient potential preceding myoclonus or transcortical C-reflex was detected, including in subjects with the shorter myoclonus (patients 7, 9, and 10), suggesting myoclonus of subcortical origin (figure 2, A and B). Six patients (43%) had tremor: 3 had slow cerebellar action tremor at a frequency between 3 and 3.5 Hz; 1 presented with mixed rest and action tremor at a frequency between 3.2 and 4 Hz (figure 2, C and D, patient 6); 2 had dystonic tremor in body segments affected by dystonia. We did not observe chorea. One patient exhibited mild parkinsonism that was markedly improved with levodopa (patient 6, by 50%). Five patients, including

patient 6, underwent 123I-FP-CIT (DaTSCAN, GE Healthcare, London, UK) SPECT imaging. None had dopaminergic denervation. Other features. Lower limbs pyramidal syndrome, characterized by diffused deep tendon reflexes or extensor plantar reflexes, was present in 3 of the 14 patients (21% vs 30% in the typical A-T cohort, NS). All lower limbs or ankle deep tendon reflexes were abolished in 9 patients. Ocular or cutaneous telangiectasias were present in 5 of the 14 patients (36% vs 98% in typical patients with A-T, p , 0.0001). Recurrent infections Neurology 83

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1090 Table 2

Movement disorders in our series Dystonia

Myoclonus

Tremor

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Dystonic Patient Location signsa

Location/ severity

Burst duration, ms

Myoclonus on JLBA/C dystonic sites

Location

Frequency, Hz/burst duration, ms, Severity regularity

Activation mode, Rtr/P/ A/I/Ot

Nature

1

M

Ap, S, T, Co, O

UL, d, L . R/1

522330

2/2

Yes

UL, L, p

1

3/220, r

P, A

Cerebellar

2

M

Ap, S, T, Co, O

—

NA

NA

NA

UL, R 5 L, p

11

2/410, r

P, A

Dystonic

3

—

—

UL, R 5 L, p, neck/ 662215 1

ND/2

Nob

—

NA

NA

NA

NA

4

—

—

UL, R 5 L, p, trunk/1

ND/2

Nob

UL, R 5 L, pd

1

3, 5/150, r

A, I

Cerebellar

5

UL, N

Ap, S, T, Co

UL, R 5 L, p, neck/ 782285 1

ND/ND

Yes

—

NA

NA

NA

NA

6

M

Ap

—

NA

NA

NA

UL, LL, R 5 L, pd neck, trunk

111

3, 224/1502200, r

Rtr,c P, A, Ot

Parkinsonian

7

UL

Ap

UL, d, R 5 L/1

22235

2/2

Yes

—

NA

NA

NA

NA

8

UL/N

Ap, S, T

UL, R, pd/1

482145

ND/2

Yes

UL, R 5 L, pd

1

323, 5/280, r

P, A, I

Cerebellar

9

UL

Ap, S, T, Co, O

UL, L, pd/1

26275

2/2

Yes

UL, R 5 L, pd

1

6, 5/105, r

Rtr, P, A

Dystonic

10

UL

Ap, S

UL, R 5 L, d/1

22245

2/2

Yes

—

NA

NA

NA

NA

11

M

Ap, S, T, Co

UL, L, p/1

1102170

ND/2

Yes

—

NA

NA

NA

NA

752120

12

UL, N

Ap, S, T, O

UL, R 5 L, d/1

202140

ND/2

Yes

—

NA

NA

NA

NA

13

UL, N

Ap, S, T, Co

UL, l, neck, trunk/ 1

1102385

ND/2

Yes

—

NA

NA

NA

NA

14

UL/N

Apd

UL, neck/d

d

d

Yes

d

NA

NA

NA

NA

Abbreviations: 1 5 mild; 11 5 moderate; 111 5 severe; A 5 action tremor; Ap 5 abnormal posture; C 5 transcortical C reflex; Co 5 co-contraction; d 5 distal; I 5 action tremor increasing with intentional movements; JLBA 5 jerk-locked back-averaging; LL 5 lower limb; M 5 multifocal; N 5 neck; NA 5 not applicable; ND 5 not determined (unavailable data); O 5 overflow; Ot 5 orthostatic; P 5 postural tremor; p 5 proximal; r 5 regular; Rtr 5 rest tremor; S 5 spasms; T 5 tonic activity; UL 5 upper limb. a Clinical and neurophysiologic signs of dystonia, assessed on the recorded site: S, T, Co, O, and Ap were assessed on clinical analysis. b Pure myoclonus. c Tremor activated by mental calculation. d Missing neurophysiologic data.

Figure 1

Kaplan-Meier curves in our adult cohort vs typical patients with A-T

not have cerebellar atrophy at age 20 years but had a few hyperintense T2 lesions in the cerebral white matter, in particular in the genu of the internal capsule and in the left superior cerebellar peduncle. EMG. Data were available for 13 patients. A total of 8 (62%) had mild to severe axonal sensorimotor lengthdependent polyneuropathy, whereas EMG results were normal in 5 patients, all with disease duration of more than 15 years. AFP levels. All patients had AFP assessment at least once. AFP levels were elevated in 13 (93%) of them, with concentrations ranging from 17.0 to 454.8 ng/mL (reference value ,10 ng/mL). Patient 7 had normal AFP levels 4 years after disease onset, but elevated AFP levels thereafter (19 ng/mL after 9 years and 90 after 23 years’ disease duration). Patient 5 had normal AFP levels at age 25 years (3.0 ng/mL) and at age 34 years (4.5 ng/mL) after disease duration of 29 years. The mean AFP value in the adult patients with A-T was 159.3 6 38.8 vs 221.2 6 36.2 in typical patients with A-T (NS). Karyotype. Lymphocyte karyotype was performed in

all patients. A total of 4 (29%, vs 100% of the typical patients with A-T, p 5 0.0006) had chromosomal instability, manifesting mainly as breaks and reciprocal translocations between chromosomes 7 and 14, in 4%–33% of the analyzed cells.

(A) Survival. (B) Survival without being wheelchair-bound. A-T 5 ataxia-telangiectasia. **p , 0.01.

(otitis, bronchitis, Bartholin abscesses) were seen in only 1 patient (7% vs 45% in typical patients, p 5 0.0213), and neoplasia in none (vs 26%, p 5 0.0284). None of the patients had diabetes. Video-oculographic recordings. Video-oculographic re-

cordings (appendix e-3) were available in 13 patients. A total of 6 (46%) had the following characteristics in common: saccadic pursuit and hypometric or hypermetric saccades with normal latency and velocity. The 7 remaining patients had saccadic pursuit and dysmetric saccades with reduced velocity or prolonged latency. Criteria for the diagnosis of ocular motor apraxia were met in 5 patients. Nystagmus was present in 7 patients (gaze-evoked and asymmetrical in 3, gaze-evoked and symmetrical in 1, gaze-evoked and downbeat in 2, not determined in 1). Nine patients made significant antisaccades errors, suggesting frontal involvement. MRI. Brain MRI was available in 12 patients. A total

of 10 (83%) had very mild to severe isolated cerebellar atrophy. Patient 6 had normal brain MRI at age 25 years after disease duration of 24 years. Patient 13 did

Immunoglobulin plasma levels. Plasma IgG, IgA, and immunoglobulin M (IgM) level assessments were conducted in all patients. Immunoglobulin deficiency was detected in 4 of them (29% vs 69% in typical A-T, p 5 0.057). Three patients had low IgA plasma levels; one of them also had low plasma IgM levels. Another one had isolated low IgG plasma levels. The only patient presenting with recurrent infections (patient 5) had normal immunoglobulin plasma levels (but IgG subclasses and humoral immune responses were not assessed). Genetic analyses. All patients had biallelic homozygous or compound heterozygous mutations of the ATM gene (appendix e-2). Our patients had a higher probability to carry at least one ATM missense mutation than the A-T controls (79% vs 36%, p 5 0.007). Pathogenicity of the mutations was proved as described in the e-Methods in 13 patients. Strong arguments were in favor of pathogenicity in the remaining patient (patient 12): he had a truncating mutation and a missense mutation that has previously been described in a patient with A-T.5 Functional ATM analyses. Epstein-Barr virus–immor-

talized lymphoblastoid cell lines were obtained for 4 of the 14 adult patients with A-T and compared to 3 typical A-T and 3 wild-type (WT) cell lines. ATM protein expression was detected in 3 adult A-T cell lines (37%, 10%, and 19% of WT ATM content for Neurology 83

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Figure 2

Parkinsonian tremor and dystonia in ataxia-telangiectasia

Polymyographic recording of the upper limb obtained from patient 6 demonstrates a slow parkinsonian tremor, occurring at rest (A), enhanced with mental calculation (*) and suppressed with action (B, voluntary extension of the wrist**); tremor is composed of 150-ms-length regular bursts pacing at 3.2 Hz frequency in proximal and distal muscles. Polymyographic recordings of the upper limb obtained from patients 12 (C) at rest and 9 (D) during voluntary postural maintenance (shoulder abduction, elbow flexion, and wrist extension) demonstrate several EMG components of dystonia, namely spasms (s) and tonic activity (t, dotted line, flexor carpi radialis muscle [FCR]), mixed with brief disorganized dystonic myoclonus (m, burst length range: 26–140 ms; C, D) and with a bout of regular dystonic tremor (*, burst mean length 105 ms; frequency 6.5 Hz; D). Acc 5 accelerometer; ECR 5 extensor carpi radialis muscle; FDI 5 first dorsal interosseous.

patients 4, 12, and 13, respectively), whereas signal was barely detectable for patient 5. The level of signal for the ATM target phospho-KAP1 Ser824 as a marker of ATM kinase activity after 5-Gy irradiation was substantially reduced in all adult A-T cell lines compared to the WT cell lines. However, this level varied from minimal to intermediate (5%, 13%, 4%, and 57% of WT for patients 4, 5, 12, and 13, respectively; figure 3 and appendix e-4). DISCUSSION A-T is a pleiotropic disorder characterized by great variability both in natural history (including age at onset and kinetics of disease progression) and phenotypes. In comparison with typical patients with A-T, patients seen in adult neurology centers all have the common characteristic of prolonged survival and milder functional impairment (mainly for patients diagnosed during adulthood). Also, they greatly differ based on presenting and prominent clinical features and laboratory findings. 1092

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The spectrum of movement disorders associated with A-T is known to be broad,16 and the present study helps to better delineate their characteristics. As shown previously, A-T may appear as dystonia, especially of early onset, without frank cerebellar involvement.12,13,17–21 Recently, siblings presenting with dopa-responsive cervical dystonia were found to have ATM mutations.21 As such, focal dystonia was the presenting feature in 14% of the patients in our series, and focal, segmental, or multifocal dystonia was present in 86% of them at time of examination. Subcortical myoclonus, confirmed by strict criteria on the polygraphic recording, was very frequent (86% in our series), mainly associated with dystonia. Resting tremor, frequently described in mild A-T cases in the literature,6,11,22 was found in only 1 patient, in association with action tremor, whereas 2 patients had dystonic tremor and 3 others had action tremor of cerebellar origin. Chorea, previously reported to be present in 70% of mild A-T cases,6 was strikingly

Figure 3

Western blot analysis of ATM and ATM function

Each cell line is analyzed with (1) or without (2) exposure to 5-Gy gamma rays, 1 hour after irradiation. Wild-type (WT), typical ataxia-telangiectasia (A-T), and adult A-T cell lines are analyzed for ATM, phosphorylated KAP1 on ser824, and total KAP1. b-Actin is measured as a loading control.

not found in any of our patients. We hypothesize that many of the reported patients who were only assessed clinically could actually have myoclonic dystonia, which can easily be mistaken for chorea, especially in patients also exhibiting cerebellar hypotonia. Finally, 3 patients (21%) had 4 distinct types of movement disorders (ataxia, dystonia, myoclonus, or tremor), and 12 (86%) had at least 3 different movement disorders, reflecting the heterogeneity and complexity of A-T. Ocular motor recordings brought unexpected results. It is widely accepted that ocular motor apraxia is a hallmark of A-T, even in most mild cases, but diagnosis is usually only made clinically.6,9 Ocular motor apraxia is characterized clinically by the inability to initiate horizontal saccades, generally in addition to hypometric saccades, in the head-fixed condition, and in the recordings by increased latencies and decreased amplitudes of horizontal saccades.23,24 In our series, ocular motor apraxia as defined electrophysiologically was found in 5 patients, whereas all others had normal saccade latencies. A common unspecific pattern was found in 6 patients (46%) characterized by the association of saccadic pursuit, dysmetric saccades of normal velocity and latency, and occasional nystagmus. Three patients had both hypometric (mostly centrifugal) and hypermetric (mostly centripetal) saccades, reflecting the anarchy characteristic of the cerebellar syndrome. Whereas A-T is widely considered to be a cerebellar degeneration disorder, our results indicate it is in fact a multisystem neurodegenerative disease. In addition to cerebellar ataxia, we found subcortical involvement with dystonia and subcortical myoclonus, corticospinal tract signs, frontal involvement in the ocular motor recordings, periventricular white matter

changes, and peripheral nerve abnormalities. As our patients were recruited through tertiary movement disorders centers, it is no surprise that movement disorders were in the forefront. This is consistent with previous reports of mild adult forms of A-T presenting as movement disorders.6,10,12,18,21 Our results and the previous literature also demonstrate that movement disorders are not the only gateway to the diagnosis of adult forms of A-T: diagnosis may also be evoked in front of nonspecific clinical signs and ocular motor abnormalities characterized by saccadic pursuit and dysmetric saccades with normal latency and velocity, or in cases of sensorimotor length-dependent axonal neuropathy, frequently with prominent distal motor involvement or even distal spinal muscular atrophy.11 Association of general clinical features such as telangiectasia, recurrent infections, endocrine abnormalities, and malignancies are evocative when present, but their absence in no way dismisses the diagnosis, especially in adults. Brain imaging may also be misleading as 2 patients did not have cerebellar atrophy, and one of them had T2 hyperintense white matter lesions. This is not an isolated finding, as the same type of lesion has been described in rare A-T cases before.25–27 The extreme variability of phenotypes of patients with A-T renders diagnosis difficult and laboratory tests may be helpful. In patients with classical A-T phenotypes and patients with unexplained movement disorders, laboratory workup comprising repeated karyotypes, AFP, and immunoglobulin level assessments should be conducted. Elevated AFP levels evoke either A-T or ataxia with ocular motor apraxia type 2.28 In our series, diagnosis of A-T was suspected in patient 13, who did not show any cerebellar signs, Neurology 83

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on the association of unexplained movement disorders and elevated AFP alone. AFP levels were also elevated in the 6 patients with the previously described primary-appearing dystonia A-T phenotype who were screened.12,13,18 Four patients with A-T presenting with adult-onset resting tremor and subsequent severe distal spinal muscular atrophy with only slight cerebellar ataxia all had elevated AFP levels.11 However, we showed, confirming scarce previous observations,8,9,29 that AFP levels might be normal in early stages or even stay normal in some patients with A-T. Thus, not only should AFP screenings be repeated, but normal AFP levels do not dismiss the diagnosis of A-T, especially if the phenotype is atypical. Karyotype abnormalities or immunoglobulin deficiency, in association with an evocative phenotype, may be enough to justify ATM screening. However, in contrast with the literature and our own typical A-T cohort, karyotype was rarely abnormal in our series, with only 4 patients showing chromosomal instability.6,8–10,17,30–33 This could be explained in part by examination of an insufficient number of mitoses in some of our patients. Immunoglobulin deficiency is relatively rare in mild A-T forms, but has been described before,10,33 and was present in 2 patients with otherwise mild phenotypes in our series. In clinical practice, an early-onset movement disorder with slow progression should be evocative of A-T. Disease onset is usually in childhood or early adolescence (age 1 to 14 years in our 14 patients), frequently as soon as walking is acquired (4 patients in our series), although on average significantly later than in typical patients with A-T (age 6.1 vs 2.5 years, p , 0.0001). The 5 patients diagnosed in childhood were all wheelchair-bound by age 14 years, but 7 others were not at last examination, despite disease duration of 18– 29 years, indicating unexpected slow progression. Detailed medical history in early childhood is also helpful, as 2 of our patients with an atypical movement disorder phenotype that seemed to appear in adolescence actually had spontaneously remittent gait instability in early childhood. The same observation was noted in 3 patients in 2 other studies.17,18 The phenotypic variability is, at least partially, explained by differences in ATM genotype. Most patients with the classic severe form of A-T have truncating mutations, whereas mild forms of A-T are usually caused by missense or splice site mutations that leave or are predicted to leave residual amounts of active ATM.5,9,34,35 Our results are in accordance with the literature, as 79% of our patients—characterized overall by slower progression or delayed onset as well as later confinement to wheelchair and longer survival—had at least one missense mutation, compared to 36% of the typical patients with A-T (p 5 0.0067). Moreover, siblings in 1094

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our series had relatively similar phenotypes and disease courses: patients 1 and 2 had severe ataxia and dystonia, patients 3 and 4 had severe ataxia and myoclonus, and all were wheelchair-bound before age 15 years. Patients 8 to 11, 4 sisters, had prominent dystonia with mild ataxia and an overall milder phenotype. Patient 10, albeit with a similar age at onset and disease duration as her sisters, had a milder phenotype, consisting of mild focal myoclonic dystonia and dysarthria, with a SARA score of only 7 at age 29 years. Differences in ATM genotyping do not fully explain the phenotypic variability, but evaluating both protein function and the level of residual ATM protein can be helpful in variant forms of A-T.9,36 Finally, when facing a patient with ataxia or movement disorders of unknown etiology, A-T should be considered, and ATM sequencing performed, even if the phenotype is atypical. AUTHOR CONTRIBUTIONS A.M., E.A., D.S.-L., D.G., M.A., G.R., and M.-H.S. drafted/revised the manuscript for content, including medical writing for content. D.G. and M.A. designed the study. A.M., Y.A.-B., E.A., B.G., C.T., S.R.-P., B.D., B.B., F.S., T.M., M.K., A.D., N.M., G.R., M.-H.S., C.D.E., A.F., M.V., D.S.-L., D.G., and M.A. acquired and analyzed/interpreted data. D.G. and M.A. supervised the study.

STUDY FUNDING CEREDIH has received grants by the French AT-Europe Foundation.

DISCLOSURE A. Méneret received a research grant from AP-HP and travel funding from ANAINF, JNLF, and the European Federation of the Neurological Societies. Y. Ahmar-Beaugendre reports no disclosures relevant to the manuscript. G. Rieunier received research grants from the French Medical Research Foundation (grant FDT20130928274) and the AT Europe Association. N. Mahlaoui and B. Gaymard report no disclosures relevant to the manuscript. E. Apartis received a grant from the French Association for Essential Tremor (APTES). C. Tranchant and S. Rivaud-Péchoux report no disclosures relevant to the manuscript. B. Degos received travel grants from Novartis, Lundbeck, Teva, Merz, Ipsen, and Medtronics. B. Benyahia, F. Suarez, T. Maisonobe, M. Koenig, A. Durr, M. Stern, C. Dubois d’Enghien, and A. Fischer report no disclosures relevant to the manuscript. M. Vidailhet received research grants from Metz, UCB, Novartis, INSERM (Cossec), and ANR; from associations of patients, France Parkinson, and AMADYS; and travel grants from the Movement Disorders Society and Dystonia Coalition. D. Stoppa-Lyonnet reports no disclosures relevant to the manuscript. D. Grabli received lecture fees from Lundbeck, Teva, Novartis, and Boehringer-Ingelheim; travel grants from Novartis and Abbott Products; and grants from Direction Générale de l’Organisation des Soins (DGOS), Institut National de la Santé et de la Recherche Médicale (INSERM), MJ Fox Foundation for Parkinson Research, and the French Association for Essential Tremor (APTES). M. Anheim received lecture fees from Actelion, Teva, and Novartis; travel grants from Novartis and Actelion; honoraria from Abbvie; and a grant from the French Association for Essential Tremor (APTES). Go to Neurology.org for full disclosures.

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The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia Aurélie Méneret, Yara Ahmar-Beaugendre, Guillaume Rieunier, et al. Neurology 2014;83;1087-1095 Published Online before print August 13, 2014 DOI 10.1212/WNL.0000000000000794 This information is current as of August 13, 2014 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/83/12/1087.full.html

Supplementary Material

Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/13/WNL.0000000000 000794.DC1.html

References

This article cites 37 articles, 13 of which you can access for free at: http://www.neurology.org/content/83/12/1087.full.html##ref-list-1

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This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org//cgi/collection/all_clinical_neurology All Movement Disorders http://www.neurology.org//cgi/collection/all_movement_disorders Dystonia http://www.neurology.org//cgi/collection/dystonia Gait disorders/ataxia http://www.neurology.org//cgi/collection/gait_disorders_ataxia Myoclonus http://www.neurology.org//cgi/collection/myoclonus

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