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discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/236934081

New Subtype of Spinocerebellar Ataxia With

Altered Vertical Eye Movements Mapping to
Chromosome 1p32

Article April 2013

DOI: 10.1001/jamaneurol.2013.2311 Source: PubMed

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 ORIGINAL CONTRIBUTION

ONLINE FIRST
New Subtype of Spinocerebellar Ataxia
With Altered Vertical Eye Movements
Mapping to Chromosome 1p32 Author Aff
Unit, Depar
Carmen Serrano-Munuera, MD; Marc Corral-Juan, BSc; Giovanni Stevanin, PhD; Hector San Nicolas, BSc; Medicine, H
Carles Roig, MD, PhD; Jordi Corral, BSc; Berta Campos, PhD; Laura de Jorge, BSc; Carlos Morcillo-Suarez, PhD; Deu, Marto
Serrano-Mu
Arcadi Navarro, PhD; Sylvie Forlani, MD, PhD; Alexandra Durr, MD, PhD; Jaime Kulisevsky, MD, PhD; Translation
Alexis Brice, MD, PhD; Ivelisse Sanchez, PhD; Victor Volpini, MD, PhD; Antoni Matilla-Duenas, PhD Neurogene
Neurodegen
Departmen
Health Scie
Institute Ge
Importance: To provide clinical and genetic diagnoses performed. Whole-exome sequencing was used for 2 af- Badalona (M
for patients conditions, it is important to identify and fected relatives. For most patients, the initial symptoms Drs Sanche
Matilla-Due
characterize the different subtypes of spinocerebellar ataxia included falls, dysarthria, or clumsiness followed by a Diagnostic
(SCA). complete cerebellar syndrome. For all 9 affected rela- Genetic-Mo
tives, we observed altered vertical eye movements, as ini- dInvestiga
Objective: To clinically and genetically characterize a tial ocular signs for 3 of them and for the 2 asymptom- Bellvitge, l
Spanish kindred with pure SCA presenting with altered atic family members, all having inherited the risk San Nicolas
vertical eye movements. haplotype. Neuroimaging showed isolated cerebellar Campos an
Jorge), Dep
atrophy.
Neurology,
Design: Family study of ambulatory patients. Electro- Creu i St Pa
oculographic and genetics studies were performed in 2 Results: Initial genome-wide linkage analysis revealed Institut de
referral university centers. suggestive linkage to chromosome 1p32. Multipoint analy- (UPF-CSIC
sis and haplotype reconstruction further traced this SCA Biomdica
Setting: Primary care institutional center in Spain. locus to a 0.66-cM interval flanked by D1S200 and Morcillo-Su
D1S2742 (zmax =6.539; P .0001). The causative muta- National In
Bioinforma
Participants: Thirty-six participants from a large Span- tion was unidentified by exome sequencing. Pompeu Fa
ish kindred were clinically examined, and 33 family mem- Morcillo-Su
bers were genetically examined. Detailed clinical data were Conclusions and Relevance: We report a new sub- Movement
obtained from 9 affected relatives. Two ataxic siblings and type of SCA presenting in patients as slow progressing Neurology
2 asymptomatic family members were examined using ataxia with altered vertical eye movements linked to a Pau Hospit
an enhanced clinical protocol for a follow-up period of 11-megabase interval on 1p32. The Human Genome No- Universitat
Barcelona a
7 years. menclature Committee has assigned this subtype of ataxia Investigacio
the designation SCA37. sobre Enfer
Main Outcomes and Measures: High-density genome- Neurodegen
wide single-nucleotide polymorphism arrays, along with JAMA Neurol. Published online April 29, 2013. Kulisevsky)
microsatellite analysis, and genetic linkage studies were doi:10.1001/jamaneurol.2013.2311 Medicine, U
Autonoma
Serrano-Mu

Author Affiliations are listed at
the end of this article.
A
Sanchez, an
UTOSOMAL DOMINANT increasing).3-6 Few mutations cause pure and Mr Cor
spinocerebellar ataxias cerebellar syndrome and isolated neuro- and Catalan
(SCAs) are a highly hetero- degeneration. In fact, most SCAs are mul- Research an
geneous group of move- tisystemic disorders presenting with clini- Catalonia (
ment disorders character- cal and neuropathological variabilities.7,8 and Institu
ized by progressive cerebellar ataxia of the The prognosis is variable, and drug treat- et de la Rec
U975, Univ
gait and limbs variably associated with ments have shown limited effectiveness. Pierre-et-M
ophthalmoplegia, pyramidal and extrapy- Several clinical scales have been Universite P
ramidal signs, dementia, pigmentary reti- developed to measure the severity of Recherche
nopathy, seizures, lower motor neuron SCAs. 9 The Scale for the Assessment Cerveau et
signs, or peripheral neuropathy.1,2 Genet- and Rating of Ataxia (SARA) is the most epiniere, EP
ics has a significant role to play in the eti- widely used. 10 Since its design, SARA national de
scientifique
ology, and actually 32 different loci have has demonstrated construct validity, recherche 7
been associated with SCA phenotypes with internal consistency, and interrater reli- Hospitalier
23 defective genes identified, although ability, together with favorable repro- Paris, Franc
these numbers are still in flux (ie, ducibility and responsiveness.11,12 Forlani, Du

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2013 American Medical Association. All rights reserved.

 ? ?
I Markers
1 2
D1S319
D1S2661
II D1S417
1 2 3 4 5 6 D1S2652
D1S475
D1S200
D1S2742
III ?
1 2 3 4 5 6 7 8 9 10 11 12 D1S2690
D1S2867
4
2
2
1 rs151062149
2 1
1 2
1 2
3 1
6 6
2 2
2 1
1 2

IV
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

2 1 2 1 4 2 1 2 1 2 1 2 2 4 2 2 2 2 1 4 1 4 1 3 3 1 5 2 3 1 2 2 2 2 2 3
1 2 1 2 1 1 2 1 2 1 2 1 2 1 1 1 1 1 2 2 2 2 1 1 1 1 1 1 1 1 2 1 2 1 2 2
3 2 3 2 1 2 2 1 2 1 2 1 2 1 2 1 2 1 2 2 2 2 2 2 2 1 1 1 2 2 1 1 2 1 2 2
2 1 2 1 2 1 2 2 1 2 2 2 1 2 1 2 1 2 1 2 1 2 1 1 2 2 2 2 2 1 2 2 2 2 2 2
1 1 1 1 2 2 1 2 1 2 1 2 1 2 1 2 1 2 1 1 1 1 1 1 1 2 1 2 1 1 1 2 2 2 2 2
1 1 1 1 1 3 2 1 1 1 2 1 3 4 1 1 1 1 1 3 1 3 5 3 5 1 1 1 5 3 4 1 4 1 4 1
1 4 1 4 7 7 4 6 4 6 4 6 9 2 6 6 6 6 4 4 4 4 4 6 4 6 6 9 4 6 4 6 9 6 9 6
2 1 2 1 1 2 2 2 1 2 2 2 1 1 1 2 1 2 1 2 1 2 3 2 3 2 3 1 3 2 2 2 2 2 2 1
1 1 1 1 4 2 3 1 1 1 3 1 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 2 1 1 4 1 4 5
1 1 1 1 1 1 1 2 1 2 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 2 1 2 1 1

V 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

2 4 1 4 2 2 3 2 3 2 3 2 3 2 2 4 2 4 1 1 2 3 2 2
1 1 2 1 1 2 2 1 2 1 1 1 1 1 2 4 1 4 1 2 2 2 2 2
3 1 2 1 1 2 2 2 2 1 2 1 2 1 1 1 1 1 2 1 2 2 2 2
2 2 2 2 2 1 1 2 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
1 2 1 2 2 1 1 2 1 2 1 2 1 2 1 1 2 1 1 3 2 2 2 2
1 1 2 4 1 3 1 1 1 1 5 1 5 1 4 2 1 2 2 2 4 1 4 4
1 7 4 2 6 9 7 6 2 6 4 9 4 9 4 5 6 5 4 9 9 6 9 9
2 1 2 1 2 1 2 2 1 2 3 1 3 1 2 1 2 1 2 2 2 1 2 2
1 4 3 1 1 1 1 1 1 1 1 1 1 1 1 5 1 5 1 2 4 5 4 4
1 1 1 1 2 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 1 1

VI
1 2 3 4 5 6 7

4 1 2 1
4 2 1 1
1 1 1 2
2 2 2 2
1 3 2 1
1 2 1 2
5 9 6 4
1 2 2 2
5 1 1 1
2 1 1 1

Figure 1. Pedigree of the Spanish kindred (subtype SCA37 of spinocerebellar ataxia) showing the reconstructed haplotypes resulting from the analysis of
10 polymorphic markers spanning 20.38 cM on chromosome region 1p32.

In our study, we report the clinical and genetic find- atic relatives, patients IV:3 and V:7, were also examined using
ings in a Spanish kindred presenting with a pure cer- the same enhanced clinical protocol for the same period of time.
ebellar phenotype consisting of ataxia with altered ver- All the studies were performed in the absence of medication
tical eye movements and with no evidence of anticipation. treatment. Eye movements were recorded using an auto-
mated, computerized electronystagmographic package (Nys-
The causative genetic defect for this disorder localizes to
tar; Nicolet Audiodiagnostics). Detailed methods for random
an 11-megabase interval on chromosome 1p32. The Hu- and fixed saccades tests, smooth pursuit tests, and optokinetic
man Genome Nomenclature Committee has assigned this nystagmus (ON) tests are described in the eAppendix
new ataxia subtype the designation SCA37. (jamaneuro.com).13 Oculographic data from 6 healthy con-
trols (ranging in age from 40 to 74 years) were registered.
METHODS
GENETICS STUDIES
CLINICAL STUDIES
Genomic DNA samples were isolated from blood leukocytes
Our study was approved by the local Human Subjects Protec- or fibroblasts expanded from skin biopsy samples using auto-
tion Committee (ie, Comites Eticos de Investigacion Clnica) mated DNA purification (Chemagen). DNA samples were ob-
of the University Hospital Germans Trias i Pujol in Badalona, tained from 23 unaffected and 10 affected relatives. Affected
Spain, and included patient consent forms for both genetic test- relatives were first tested for mutant CAG expansions within
ing and research for all relatives participating in the study. the SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA12, SCA17,
Figure 1 shows the genealogical tree of the Spanish family with and DRPLA genes. Relatives with linkage to the SCA4 locus and
68 members spanning 6 generations. A neurological examina- mutations in the KCND3 gene were excluded. Twelve rela-
tion was performed by the first author (C.S.M.) for 9 ataxic pa- tives, 6 healthy and 6 affected, were included in the initial ge-
tients (ie, patients IV:5, IV:6, IV:7, IV:10, IV:11, IV:16, IV:19, netic linkage study that used the Infinium HumanLinkage-12
IV:21, and V:15), 8 spouses, and 19 asymptomatic relatives. Data Genotyping BeadChip (Illumina Inc). The panel included 6609
on the medical histories of the remaining members of the fam- single-nucleotide polymorphism (SNP) markers with an aver-
ily were collected. The SARA scores10 were assessed for 8 ataxic age gap of 441 kilobases and 0.58 cM across the genome. Geno-
patients during the first visit, twice during a 5-year period for types were assigned using the Bead Studio genotyping module
1 affected patient (IV:10) and at least once a year during fol- software (Illumina Inc), and linkage was analyzed using Mer-
low-up visits for 7 years for 2 affected relatives (patients IV:5 lin.14 Penetrance was set to 80% for all participants. To con-
and IV:6). These 2 affected siblings were further investigated firm linkage and refine mapping, 10 affected and 23 healthy
using an enhanced clinical protocol, including electrocardio- relatives of the pedigree were further genotyped for microsat-
grams, echocardiograms, audiometric tests, nerve conduction ellite markers located on chromosome 1 and for SNPs using
studies, magnetic resonance imaging of the brain, evoked po- the Genome-Wide Human SNP Array 6.0 (Affymetrix), which
tentials, transcranial magnetic stimulation, and electro- contains 906 600 SNPs. Two-point and multipoint genetic link-
oculographic studies during follow-up visits. Two asymptom- age analyses were then performed with the MLINK and

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2013 American Medical Association. All rights reserved.

 A C
Target Position vs Time
20

40 Channel B: Eye Position vs Time

2s
B D

Target Position vs Time

32

40 Channel B: Eye Position vs Time

1s

Figure 2. A and B, Sagittal and coronal T1-weighted magnetic resonance imaging scans of the brain of patient IV:5. The eye movements during vertical fixed
saccades (C) (20 amplitude; top line, upward saccades; bottom line, downward saccades [arrows]) and smooth pursuit (D) (0.4 Hz; 16 amplitude; and peak
velocity, 40/s ) are shown for patient IV:6. The asterisks indicate saccadic intrusions.

LINKMAP modules (both version 5.10), respectively, from
FASTLINK (version 4.1P).15 For the multipoint analysis, we used
the framework maps from the Marshfield Medical Research
Foundation,16 deCODE Genetics,17 and Genethon.18 Whole-
exome sequencing was performed with DNA samples from 2
affected relatives. The method is described in the eAppendix.
Known variants were discarded from further analysis based on
the information from the Ensembl version 62 database, which
hosts data from the most important human variation re-
sources such as 1000 Genomes, dbSNP, and HapMap. Candi-
date genes were prioritized based on potentially damaging vari-
ants, as previously described.19
RESULTS
CLINICAL FEATURES
The index patient (IV:7) was evaluated for the first time
at the age of 54 years. He had a 2-year history of falls and
abnormal speech. A neurological examination disclosed
dysmetric vertical saccades and irregular vertical ocular
pursuit, whereas his horizontal eye movements ap-
peared to be normal. Additional clinical signs included
scanning speech, mild trunk ataxia, severe dysmetria in
both legs, and irregular fast alternating movements and
dysmetria with the left hand. His deep tendon reflexes
were normal, and further examination revealed no cog-
nitive impairment, long tract signs, myoclonus, tremor,
sensory loss, cogwheel rigidity, or other extrapyramidal
signs. Computed tomography revealed diffuse cerebel-
lar atrophy. No further clinical information is available
from this patient because he died of disseminated ad-
enocarcinoma 4 months after his first visit. Patient IV:5
was first seen at the age of 64 years. A neurological ex-
amination showed slight clumsy tandem walking. Ver-
tical saccades were remarkably inaccurate, and vertical
pursuit was irregular, with a cogwheel pattern revealed
during the eye movement examination. By contrast, his
horizontal eye movements were normal. Abnormal hori-
zontal pursuit and horizontal nystagmus appeared dur-
ing follow-up. Remarkably, horizontal saccades re-
mained normal. Clinical progression of the ataxia in
patient IV:5 outlines a more benign phenotype than that
in the index patient IV:7. After 7 years of disease pro-
gression, tandem walking is still possible for patient IV:5,
and he does not report falls and has no major difficul-
ties in activities of daily living. Magnetic resonance
imaging of the brain first showed cerebellar atrophy of
the vermis with normal brainstem (Figure 2A), evolv-
ing to generalized cerebellar atrophy after 2 years
(Figure 2B). His brainstem remained normal during fol-
low-up. The brainstem auditory evoked potentials de-
tected endocochlear mild and bilateral loss that per-
sisted unchanged in time. Patient IV:6 was examined for
the first time at 59 years of age. She complained of mild
unsteadiness while walking. A neurological examina-
tion revealed subtle difficulty in tandem walking, inac-
curate vertical saccades, and clumsy vertical pursuit. Her
horizontal eye movements were normal. She developed
cerebellar syndrome involving the trunk and lower limbs
and experienced frequent falls. Dysarthria became evi-

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2013 American Medical Association. All rights reserved.


30
Patient IV:5
Patient IV:6
25
Patient IV:10
Patient IV:11
20 Patient IV:16
SARA Score
Patient IV:19
Patient IV:21
15
Patient V:15
10
5 and 3) confirmed this clinical finding. Electrocardiog-
0
0 3 4 5 6 7 10 15
Years From Onset
Figure 3. Scale for the Assessment and Rating of Ataxia (SARA) scores of 8
affected patients.
dent 1 year later. Abnormal horizontal saccades and pur-
suit, as well as dysphagia, were clearly noted 5 years from
onset. She is currently 66 years of age and needs help in
activities of daily living. Baseline magnetic resonance
imaging of her brain revealed general cerebellar atrophy
with sparing of the brainstem. The brainstem auditory
evoked potentials yielded normal results. Electrocardiog-
raphy, echocardiography, transcranial magnetic stimu-
lation tests, and nerve conduction studies (eTables 1 and
2) all yielded normal results, and the results remained
normal during follow-up for both patient IV:5 and pa-
tient IV:6.
Clinical data were obtained from 6 additional pa-
tients with ataxia (ie, patients IV:10, IV:11, IV:16, IV:
19, IV:21, and V:15). They were first seen 10 to 38 years
after onset. Their initial symptoms included falls, dys-
arthria, or clumsiness. Clinical progressions were slow
albeit variable. Four patients who were still alive (ie, pa-
tients IV:10, IV:11, IV:19, and IV:21) became wheelchair-
bound 10 to 33 years from onset. All 6 patients had ab-
normal eye movements in both vertical and horizontal
planes, with mainly hypometric saccades and cogwheel
pursuit. Of these 6 patients, 4 had dysphagia (patients
IV:16, IV:19, IV:21, and V:15), 3 had cerebellar tremor
(patients IV:10, IV:11, and IV:21), and 1 had nystagmus
(patient IV:10). None of them presented with motor or
sensory deficits, extensor plantar reflexes, fascicula-
tions, epileptic seizures, or cognitive impairment. Com-
puted tomographic or magnetic resonance imaging scans
were available for 5 patients, and general cerebellar at-
rophy with sparing of the brainstem was detected on the
scans of all 5 patients. The SARA scores for all patients,
except for patient IV:7 (because he died before the SARA
scores were made available), are shown in Figure 3.
To calculate the mean age at onset and the mean du-
ration of disease, additional information from 2 de-
ceased ataxic patients (III:3 and III:5) was included. Thus,
the mean age at onset of our patients is 48 years (range,
38-64 years), and the mean disease duration for both de-
ceased patients was 49.5 years. Patient IV:7 was ex-
cluded from this average because he died earlier of an
unrelated disease. There is no evidence of anticipation
in the age at onset in the 3 generations for which data
are available.
JAMA NEUROL
2013 American Medical Association. All rights reserved.
Nineteen asymptomatic relatives were identified and
examined (mean age, 42 years [range, 9-75 years]). Of
these, 2 patients (V:7 and V:10), 32 and 40 years of age,
respectively, showed dysmetric vertical saccades and ir-
regular vertical pursuit; their horizontal eye move-
ments and the results of their remaining standardized neu-
rological examinations were normal. Patient V:7
participated in the enhanced serial clinical investiga-
tion, and the electro-oculographic studies (Tables 1, 2,
raphy, echocardiography, transcranial magnetic stimu-
18 23 26 36 38
lation tests, magnetic resonance imaging, and nerve con-
duction studies yielded normal results. Both individuals
(ie, patients V:7 and V:10) were later found to carry the
risk haplotype. The results of the neurological and eye
movement examinations were normal for the other 17
asymptomatic relatives. Among them, patients V:8 and
VI:7 were also later found to carry the risk haplotype. Pa-
tient V:8 was excluded from the clinical study because
of a history of drug abuse, and, as expected, patient VI:7
had normal eye movements, given that he is currently
22 years of age, which is well before the average age at
onset. As for the second asymptomatic patient who par-
ticipated in the enhanced serial clinical protocol (pa-
tient IV:3, who was last assessed at 74 year of age), all
the ancillary tests, including electro-oculographic stud-
ies, yielded normal results, and he was later found not
to carry the risk haplotype.
ELECTRO-OCULOGRAPHIC STUDIES
OF PATIENTS IV:5 AND IV:6
From the results of the first electro-oculographic study
(2 years after disease onset), it was found that patient IV:5
was more severely affected than patient IV:6. Patient IV:5
showed both downward and upward hypermetric sac-
cades, and patient IV:6 revealed hypometric upward sac-
cades and hypermetric downward saccades. For both pa-
tients, the latency and velocity of the vertical saccades
were normal. For both patients, vertical smooth pursuit
was diminished, and vertical ON showed slow pursuit
velocity. Patient IV:5 showed an altered horizontal ON
as the unique abnormal finding in the horizontal plane
because the horizontal ON was normal in her sister (pa-
tient IV:6) and because the horizontal saccades and
smooth pursuit were normal for both patients.
Electro-oculographic data are included in Tables 1-3 from
the second electro-oculographic study (5 years after dis-
ease onset). The accuracies of the vertical saccades were
abnormal (Table 1), the vertical smooth pursuits were de-
ficient (Table 2), and vertical ON showed slow pursuit ve-
locities (Table 3) for both siblings (ie, patients IV:5 and IV:
6). The latencies and velocities of the vertical saccades
remained normal (data not shown). The vertical eye move-
ments of patient IV:5 remain unchanged. For patient IV:6,
the altered vertical eye movements worsened, particularly
in the downward direction. Figure 2C shows downward
hypermetria and saccadic intrusions, particularly in down-
ward saccades. Figure 2D shows cogwheel pursuit in both
upward and downward pursuit. For patient IV:5, horizon-
tal saccades were normal, whereas for patient IV:6, hori-
zontal saccades were hypermetric in both directions
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 Table 1. Data on the Accuracy of Vertical and Horizontal Fixed and Random Saccades in 3 Patients and 6 Healthy Controls a

Vertical Horizontal
Vertical Fixed Saccades Horizontal Fixed Saccades
Random Saccades Random Saccades
At 20 At 30 at 6-32 At 20 At 30 at 6-32
Up, Down, Up, Down, Up, Down, Right, Left, Right, Left, Right, Left,
Participant(s)/Age, y % % % % % % % % % % % %
IV:5/69 89 123 91 124 93 125 93 92 85 89 89 90
IV:6/64 118 155 94 109 102 113 112 114 114 111 115 113
V:7/32 77 81 92 92 89 98 85 92 83 88 85 86
3 Controls/65-74 97.7 88.0 93.0 96.3 98.7 92.5 83.3 82.7 81.7 80.7 83.7 85.3
(3.5) (6.9) (8.6) (10.1) (6.4) (3.5) (8.1) (7.0) (6.1) (6.0) (11.9) (5.0)
3 Controls/40-44 101.0 93.5 102.5 106 102.5 106.5 85.3 82.7 83.3 79.7 89.7 89.7
(0.1) (4.9) (4.9) (2.8) (0.7) (5.7) (5.1) (5.5) (6.0) (6.0) (6.7) (2.0)

a Oculographic studies from affected patients IV:5 and IV:6 (5 years from onset), asymptomatic at-risk patient V:7 (at 32 years of age), and 6 healthy controls.
Mean (SD) values are presented for the 6 healthy controls, by age group. Abnormal results are shown in bold.

Table 2. Data on Vertical and Horizontal Smooth Pursuit Velocities and Gains in 3 Patients and 6 Healthy Controls a

Vertical Smooth Pursuit

At 20/s At 40/s Horizontal Smooth Pursuit at 40/s
Participant(s)/Age, y Velocity, /s Gain b Velocity, /s Gain b Velocity, /s Gain b
IV:5/69 4.2 0.20 8.1 0.20 20 0.5
IV:6/64 9.5 0.47 8.3 0.20 26 0.65
V:7/32 13.7 0.68 19 0.47 33.2 0.83
3 Controls/65-74 17.9 (3.7) 0.9 (0.2) 28.7 (2.2) 0.7 (0.1) 26.8 (6.0) 0.7 (0.1)
3 Controls/40-44 21.7 (3.2) 1.08 (0.2) 36.8 (4.4) 0.9 (0.1) 29.5 (4.9) 0.7 (0.1)

Abbreviation: /s, Degrees per second.

a Oculographicstudies from affected patients IV:5 and IV:6 (5 years from onset), asymptomatic at-risk patient V:7 (at 32 years of age), and 6 healthy controls.
Mean (SD) values are presented for the 6 healthy controls, by age group. Abnormal results are shown in bold.
b Gain is shown as the ratio between eye velocity and stimulus velocity. The gain value ranges from 0 to 1, with 1 being the expected maximum normal value.

Table 3. Data on Vertical and Horizontal Velocities of Optokinetic Nystagmus in 3 Patients and 6 Healthy Controls a

Optokinetic Nystagmus
Vertical Velocity at 20/s Vertical Velocity at 40/s Horizontal Velocity at 20/s Horizontal Velocity at 40/s
Participant(s)/Age, y U/R, /s D/L, /s U/R, /s D/L, /s U/R, /s D/L, /s U/R, /s D/L, /s
IV:5/69 11 12 0 9 13 15 19 19
IV:6/64 13 14 14 14 16 16 20 15
V:7/32 19 20 21 41 17 17 33 29
3 Controls/65-74 20.7 20.6 28.0 27.5 19.3 19.6 34.0 35.3
(1.1) (1.5) (0.0) (3.5) (1.1) (0.6) (3.0) (1.2)
3 Controls/40-44 19.0 21.5 34.5 40.0 19.5 19.0 34.0 31.0
(0.0) (2.1) (6.4) (0.0) (0.7) (1.4) (4.2) (8.5)

Abbreviations: D/L: down/left; U/R: up/right; /s, degrees per second.

a Oculographic studies from affected patients IV:5 and IV:6 (5 years from onset), asymptomatic at-risk patient V:7 (at 32 years of age), and 6 healthy controls.
Mean (SD) values are presented for the 6 healthy controls, by age group. Abnormal results are shown in bold.

(Table 1), with normal velocity (data not shown). Hori-
zontal smooth pursuit was impaired for both siblings
(Table 2). Horizontal ON showed a slow automatic pur-
suit velocity for both siblings, with velocity down to 19/s
at 40/s for patient IV:5 (Table 3).
In addition to the alterations already described, from
the results of the third electro-oculographic study (7 years
after disease onset), it was found that patient IV:5 showed
horizontal nystagmus, but her horizontal saccades re-
mained normal. For patient IV:6, vertical saccadic intru-
sions began to appear. The results of a study of patient
V:7 (32 years of age) were that this asymptomatic pa-
tients horizontal movements were strictly normal, that
abnormal accuracy was detected for vertical saccades
(Table 1), and that abnormal velocity was noted for ver-
tical pursuit (Table 2) and vertical ON (Table 3).
GENETICS STUDIES
The initial genome-wide linkage analysis of 6 healthy and
6 affected relatives using the Illumina LINKAGE_12 ar-
ray, including 6609 SNPs, revealed suggestive genetic link-
age to 1p32 (zmax = 2.03; = 0.00). Further linkage analy-
sis with 21 additional family members revealed a significant

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2013 American Medical Association. All rights reserved.

 Table 4. Two-Point Logarithm of Odds Scores Between the Locus Trait and the 10 Markers Analyzed on Chromosome 1p32

Logarithm of Odds Score

Marker Distance,
Order cM = 0.0 = 0.05 = 0.1 = 0.15 = 0.2 = 0.25 = 0.3 = 0.35 = 0.4 = 0.45 zmax max
D1S319 75.66 4.038 0.357 0.106 0.001 0.043 0.053 0.047 0.033 0.018 0.007 0.053 0.25
D1S2661 78.25 1.684 1.532 1.355 1.162 0.959 0.752 0.548 0.354 0.186 0.061 1.684 0.0
D1S417 79.80 2.977 2.575 2.17 1.766 1.37 0.993 0.652 0.368 0.161 0.04 2.977 0.0
D1S2652 80.77 0.649 0.53 0.426 0.336 0.257 0.19 0.135 0.09 0.054 0.024 0.649 0.0
D1S475 82.41 3.03 2.641 2.249 1.858 1.473 1.102 0.756 0.449 0.201 0.043 3.03 0.0
D1S200 82.41 2.545 2.231 1.924 1.619 1.319 1.026 0.75 0.501 0.288 0.119 2.545 0.0
D1S2742 a 83.07 3.831 3.424 3.004 2.574 2.138 1.701 1.275 0.872 0.511 0.211 3.831 0.0
D1S2690 83.07 0.312 0.331 0.321 0.292 0.25 0.201 0.151 0.103 0.06 0.025 0.331 0.05
D1S2867 85.68 0.62 0.602 0.537 0.452 0.358 0.264 0.179 0.108 0.055 0.019 0.62 0.0
rs151062149 96.04 b 0.057 3.648 3.513 3.226 2.861 2.442 1.983 1.498 0.999 0.5 3.648 0.05

a The maximum logarithm of odds score obtained with maker D1S2742 is shown in bold, along with its z
max and max values (ie, zmax = 3.831, = 0.0).
b The relative distance in centimorgans of marker rs151062149 is estimated with the closest marker obtained in the Marshfield Medical Research Foundation
map.16

2-point logarithm of odds score between the locus trait and
the marker D1S2742 (zmax = 3.83; = 0.00) (Table 4). A
multipoint linkage analysis using the LINKMAP function
of FASTLINK further located the SCA37 locus to a 0.66-cM
interval flanked by markers D1S200 and D1S2742
(zmax = 6.539; P .0001). Significant linkage (zmax = 3.27)
was also obtained in an affected-only analysis that avoided
any influence of considerations of penetrance of the unaf-
fected members of the pedigree. Whole-exome sequenc-
ing identified 26 974 single-nucleotide variants and 472
insertions or deletions in patient IV:16, and 25 754 single-
nucleotide variants and 894 insertions or deletions in pa-
tient V:15. After database filtering, we identified 6 pre-
dicted damaging heterozygous coding variants shared by
both patients. Although none of these variants segregated
with the disease in all affected members, a rare single-
nucleotide variant undetected in whites, rs151062149
(c.1438AG) within the USP1 gene, was identified with
significant linkage proximally located on 1p32 (zmax = 3.65;
= 0.05; Table 4).
In summary, of the 13 examined patients who inher-
ited the risk haplotype (ie, patients IV:5, IV:6, IV:7, IV:
10, IV:11, IV:16, IV:19, IV:21, V:7, V:8, V:10, V:15, and
VI:7), 11 had altered vertical eye movements. The only
individual with a risk haplotype who did not have al-
tered vertical movements was patient VI:7, and he was
20 years of age. Patient V:8 was excluded from the study
because of drug use. Of the 11 patients presenting with
abnormal vertical eye movements, patients IV:5, IV:6, and
V:7 had registered oculographic data confirming the clini-
cal examination. Vertical eye movement abnormalities
were noted in 2 young asymptomatic individuals (ie, pa-
tients V:7 and V:10) who were later found to have the
risk haplotype, and these abnormalities constituted the
isolated ocular involvement at onset of 3 ataxic patients
(IV:5, IV:6, and IV:7), 2 of whom later developed hori-
zontal eye abnormalities (ie, patients IV:5 and IV:6). Fur-
thermore, vertical eye movement abnormalities, to-
gether with horizontal eye movement abnormalities, were
detected in 6 ataxic patients with long-standing disease
(ie, patients IV:10, IV:11, IV:16, IV:19, IV:21, and V:15).
The results of neurological and eye examinations were
normal for 14 asymptomatic relatives who were found
not to carry the risk haplotype.
DISCUSSION
Herein, we report a new SCA subtype of late onset asso-
ciated with chromosome 1p32, which the Human Ge-
nome Nomenclature Committee has assigned as SCA37.
The phenotype is characterized by a relatively pure cer-
ebellar ataxia. As a distinct clinical feature, an accurate ex-
amination of the eye movements detected vertical abnor-
malities in early stages of the disease, which correlated with
the results of the electro-oculographic studies. This ini-
tial subtle sign later became very evident during the fol-
low-up visits and was identified in all affected patients. Dif-
fuse horizontal eye movement abnormalities were also
detected in this family. They were milder and appeared
later in patients IV:5 and IV:6 and were common in all pa-
tients with a long-standing disease. Remarkably, patient
IV:5 exhibited normal horizontal saccades 7 years after dis-
ease onset. Impaired horizontal eye movements are re-
garded as a well-known clinical sign in several SCA sub-
types: SCA1,20 SCA2,21 SCA3,20 SCA4,22 SCA5,23 SCA6,24,25
SCA7,26 SCA8,27 and SCA17.28 In SCA1,29 SCA6,25 SCA7,26
and SCA17,28 those abnormalities may appear even in pre-
symptomatic stages. However, vertical eye movement ab-
normalities have been rarely reported. Abnormal vertical
saccades were detected in SCA625 and SCA30,30 whereas
impaired vertical smooth pursuit has been described in
SCA6 and SCA26.31 Interestingly, the vertical abnormali-
ties reported in these SCA subtypes are usually part of dif-
fuse ocular abnormalities or well-developed cerebellar syn-
dromes. However, we suggest that the vertical ocular
alterations identified in our patients may constitute a pre-
dominant or a presymptomatic clinical sign. We found that
one of our patients (patient IV:5) supported this hypoth-
esis by having initial severe vertical eye movement abnor-
malities that were extensively confirmed by the electro-
oculographic studies and that appeared much earlier than
his only mild ataxic signs or than the horizontal eye move-
ment alterations. Furthermore, vertical eye movement ab-
normalities were clinically identified in 2 at-risk asymp-
tomatic young patients (V:7 and V:10) and were confirmed
by electro-oculography for patient V:7. Genetics studies
revealed thereafter that all 3 patients had inherited the risk
haplotype.

JAMA NEUROL PUBLISHED ONLINE APRIL 29, 2013 WWW.JAMANEURO.COM

E6

2013 American Medical Association. All rights reserved.

 The pathological process underlying the ocular move-
ment abnormalities in this Spanish family is unclear be-
cause postmortem studies are not yet available. From pre-
viously described observations in a few SCAs,32 we assume
that most of the abnormal horizontal eye movements ob-
served in our patients may be related to cerebellar struc-
tures, such as the posterior vermis (lobules VI and VII),
the fastigial nucleus, the flocculus, and the ventral para-
flocculus. Similar to the saccadic velocities associated with
SCA17,33 those associated with SCA37 were poorly af-
fected in our patients, which suggests relative sparing of
the pons. However, the pathological mechanism under-
lying the specific vertical abnormalities in our patients
is difficult to assess because it is widely accepted that both
horizontal and vertical eye movements are controlled by
the same cerebellar structures.34,35 Because P cells from
the deep cerebellar nuclei have a distinct discharge be-
havior due to horizontal and vertical eye stimuli in the
flocculus of primates,36 we suggest that they may be in-
volved in this specific disease pattern in our patients.
The progression of the disease is slow, although vari-
able, and the SARA scores in this family followed a lin-
ear pattern, as expected. For the initial stages of the dis-
order, this scale was not useful for measuring disease
progression because the cerebellar syndrome was not fully
developed and because SARA is not considered to be a
diagnostic tool; it was originally designed to measure wors-
ening ataxia. However, for this specific phenotype, we
found the electro-oculographic studies to be very useful
for detecting the progress of the ongoing pathologic pro-
cess before ataxia completely developed.
The genetics studies in this family revealed a distinct
genetic linkage to a 0.66-cM genomic region flanked by
D1S200 and D1S2742 markers on 1p32. Remarkably, 2
other autosomal dominant SCA subtypes have also been
associated with chromosome 1 deficits, SCA19 and
SCA22.37,38 Both SCA19 and SCA22 have recently been
associated with mutations in the potassium channel
KCND3 in Chinese, Dutch, and French kindreds, where
the clinical variability among SCA19/22 families was cor-
related with specific mutations.39,40 In contrast, none of
our patients revealed mutations in the KCND3 gene.
In conclusion, we report the clinical and genetic find-
ings of a new SCA subtype, SCA37, in a Spanish kin-
dred. Affected patients present with a relatively pure cer-
ebellar phenotype consisting of ataxia and altered vertical
eye movements. With the genetics studies, we found an
association between this clinical phenotype and a new
locus on chromosome 1p32. According to the Univer-
sity of California Santa Cruz genome browser assembly
(GRCh37/hg19), the genomic region identified spans
11 108 563 bases containing 71 known genes, 35 pseu-
dogenes, and 10 predicted open-reading frames (eTable
3). Whole-exome sequencing identified no causative
SCA37 mutation, which indicates that it may lie in a non-
coding genomic region or that it may consist of large re-
peat expansions or structural variants within the newly
identified delimited region.
Accepted for Publication: December 20, 2012.
Published Online: April 29, 2013. doi:10.1001/jamaneurol
.2013.2311
JAMA NEUROL PUBLISHED ONLINE APRIL 29, 2013
E7
2013 American Medical Association. All rights reserved.
Author Affiliations: Neurology Unit, Department of In-
ternal Medicine, Hospital St Joan de Deu, Martorell (Dr
Serrano-Munuera), Basic, Translational, and Molecular
Neurogenetics Research Unit in Neurodegenerative Dis-
eases, Department of Neurosciences, Health Sciences Re-
search Institute Germans Trias i Pujol, Badalona (Mr Cor-
ral-Juan and Drs Sanchez and Matilla-Duenas), Centre
de Diagnostic Genetic-MolecularInstitut dInvestigacio
Biomdica de Bellvitge, lHospitalet (Messrs San Nico-
las and Corral, Drs Campos and Volpini, and Ms de Jorge),
Department of Neurology, Hospital de la Sta, Creu i St
Pau (Dr Roig), and Institut de Biologia Evolutiva (UPF-
CSIC), Parc de Recerca Biomdica de Barcelona (Drs
Morcillo-Suarez and Navarro), National Institute for Bio-
informatics, Universitat Pompeu Fabra (Drs Morcillo-
Suarez and Navarro), Movement Disorders Unit, Neu-
rology Department, Sant Pau Hospital (IIB Sant Pau),
Universitat Autonoma de Barcelona and Centro de In-
vestigacion Biomedica en Red sobre Enfermedades
Neurodegenerativas (Dr Kulisevsky), and Department of
Medicine, Universitat Autonoma de Barcelona (Drs Ser-
rano-Munuera, Roig, Sanchez, and Matilla-Duenas and
Mr Corral-Juan), Barcelona, and Catalan Institution for
Research and Advanced Studies, Catalonia (Dr Na-
varro), Spain; and Institut National de la Sante et de la
Recherche Medicale, U975, Universite Pierre-et-Marie-
Curie, Universite Paris VI, Centre de Recherche de
lInstitut du Cerveau et de la Moelle epiniere, EPHE, and
Centre national de la recherche scientifique, Unite mixte
de recherche 7225, Groupe Hospitalier Pitie-
Salpetriere, Paris, France (Drs Stevanin, Forlani, Durr,
and Brice).
Correspondence: Antoni Matilla-Duenas, PhD, Health
Sciences Research Institute Germans Trias I Pujol, Ctra
de Can Ruti, Cami de les Escoles s/n, Badalona, 08916
Barcelona, Spain (amatilla@igtp.cat).
Author Contributions: Study concept and design: Serrano-
Munuera, Durr, Brice, Volpini, and Matilla-Duenas. Ac-
quisition of data: Serrano-Munuera, Corral-Juan, Ste-
vanin, San Nicolas, Roig, Corral, Campos, de Jorge,
Forlani, Durr, Volpini, and Matilla-Duenas. Analysis and
interpretation of data: Serrano-Munuera, Corral-Juan, Ste-
vanin, Roig, Morcillo-Suarez, Navarro, Kulisevsky, San-
chez, Volpini, and Matilla-Duenas. Drafting of the manu-
script: Serrano-Munuera, San Nicolas, Roig, Corral,
Campos, de Jorge, Navarro, Durr, Brice, Volpini, and Ma-
tilla-Duenas. Critical revision of the manuscript for impor-
tant intellectual content: Serrano-Munuera, Stevanin, Cor-
ral-Juan, Morcillo-Suarez, Navarro, Forlani, Kulisevsky,
Sanchez, Volpini, and Matilla-Duenas. Statistical analy-
sis: Stevanin, Morcillo-Suarez, Navarro, Volpini, and Ma-
tilla-Duenas. Obtained funding: Serrano-Munuera, Roig,
Sanchez, Volpini, and Matilla-Duenas. Administrative, tech-
nical, and material support: Serrano-Munuera, Corral-
Juan, San Nicolas, Roig, Corral, Campos, de Jorge, For-
lani, Kulisevsky, Volpini, and Matilla-Duenas. Study
supervision: Serrano-Munuera, Durr, Brice, Volpini, and
Matilla-Duenas.
Conflict of Interest Disclosures: Dr Matilla-Duenas is a
Miguel Servet Investigator in Neurosciences of the Span-
ish National Health System. In the last 3 years, he acted
as a consultant for Ataxia UK and the European Com-
WWW.JAMANEURO.COM
mission, and he received an award from the Spanish Fed-
eration of Ataxia Associations. Dr Kulisevsky received
honoraria for scientific lectures from Abbot, UCB, and
Boehringer. Dr Serrano-Munuera performed this work
as a part of a PhD project in the Department of Medicine
at the Universitat Autonoma de Barcelona.
Funding/Support: This work was funded by the Spanish
Ministry of Science and Innovation (grant BFU2008-00527/
BMC to Dr Matilla-Duenas), the Carlos III Health Insti-
tute (grant CP08/00027 to Dr Matilla-Duenas and grant
PS09/02342 to Dr Volpini), the Latin American Science and
Technology Development Programme (Ciencia y Tecno-
logia para el Desarrollo) (RIBERMOV grant 210RT0390 to
Drs Matilla-Duenas, Sanchez, and Volpini), the European
Commission (EUROSCA project LHSM-CT-2004-
503304 of Drs Matilla-Duenas and Brice), the Fundacio de
la Marato de TV3 Televisio de Catalunya (grant 10073 to
Drs Matilla-Duenas, Sanchez, Serrano-Munuera, and Vol-
pini), the Verum Foundation (Dr Brice), and the Associa-
tion Connaitre les Syndromes Cerebelleux (Dr Stevanin).
Dr Kulisevsky has received public research funding from
Centro de Investigacion Biomedica en Red sobre Enfer-
medades Neurodegenerativas and research grants from
Fondo de Investigaciones Sanitarias (Instituto de Salud Car-
los III, Spain) and restricted research grants from Merck
Serono. He acted as a consultant for the Michael J. Fox Foun-
dation for Parkinsons Research.
Online-Only Material: The eAppendix and eTables are
available at jamaneuro.com.
Additional Contributions: We are indebted to all the pa-
tients and family members for their generous participa-
tion in this work. We are grateful to Eveli Peral, MD, Merce
Martinez, MD, Purificacion Cacabelos, MD, Luisa Juan, MD,
PhD, Joel Puig, BSc, MSc, Ariadna Navarro Aragall, BSc,
Emeline Mundwiller, BSc, and Wassila Carpentier, PhD,
for technical assistance and to Sistemas Genomicos (Spain)
for whole-exome sequencing studies and bioinformatics
analysis. We are indebted to the Spanish Ataxia Associa-
tion, the Spanish Federation for Rare Diseases, and the pa-
tients for their continuous support and motivation. The SNP
genotyping services were provided by the Spanish Cen-
tro Nacional de Genotipado (CEGEN-ISCIII).
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