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Visual processing in Noonan syndrome Dorsal and ventral stream sensitivity.

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RESEARCH ARTICLE
Visual Processing in Noonan Syndrome:
Dorsal and Ventral Stream Sensitivity
Paolo Alfieri,1 Laura Cesarini,2 Paola De Rose,1 Daniela Ricci,2 Angelo Selicorni,3 Deny Menghini,1
Andrea Guzzetta,4 Giovanni Baranello,2,6 Francesca Tinelli,4 Maria Mallardi,2 Giuseppe Zampino,5
Stefano Vicari,1 Janette Atkinson,7 and Eugenio Mercuri2*
1
Child Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù, Children’s Hospital, Rome, Italy
2
Pediatric Neurology Unit, Catholic University, Rome, Italy
3
Ambulatorio di Genetica Clinica Pediatrica, Fondazione MBBM, A.O. San Gerardo, Monza, Italy
Department of Developmental Neuroscience, Scientific Institute Stella Maris, Calambrone, Pisa, Italy
4
5
Servizio di Epidemiologia e Clinica dei Difetti Congeniti Istituto di Clinica Pediatrica, Catholic University, Rome, Italy
6
Developmental Neurology Unit, Carlo Besta National Neurological Institute, Milano, Italy
Visual Development Unit, Department of Psychology, University College London, London, UK
7
Received 10 November 2009; Accepted 30 June 2011
Global spatial and motion processing abilities were assessed in 18
patients with Noonan syndrome (NS) and in 43 matched controls
using form and motion coherence testing, respectively. We
observed a discrepancy between the two groups since the study
group had significantly lower performances than the control
group for form coherence while there was no impairment on
motion coherence. All the patients were also assessed on the
Movement Assessment Battery for Children (M-ABC) to evaluate
visuomotor skills. Thirteen of the 18 (72%) also had global poor
performances on the M-ABC. The results show that children with
NS have a specific impairment in the global processing of
visuospatial information and are likely to have a specific ventral
stream deficit as also suggested by the frequent visuomotor
perceptual difficulties. Testing form and motion coherence
thresholds may be a useful diagnostic tool for this group of
patients, despite their normal cognitive abilities, since aspects of
global form processing and visuomotor perceptual difficulties
can be identified and potentially targeted for a specific rehabilitation program. 2011 Wiley-Liss, Inc.
Key words: Noonan syndrome; visual processing; ventral stream;
dorsal stream; visuomotor skills
INTRODUCTION
Noonan syndrome (NS) occurs in 1/1,000–2,500 live births and is a
clinically heterogeneous disorder characterized by dysmorphic
facial features, proportionate short stature, cardiac defects, frequent
multiple skeletal defects, webbed and/or short neck, variable cognitive deficits, cryptorchidism, hematologic abnormalities, as well
as ophthalmologic anomalies [Noonan, 1994; Allanson, 2007]. In
the past NS was considered a single clinical entity, but it has become
2011 Wiley-Liss, Inc.
How to Cite this Article:
Alfieri P, Cesarini L, De Rose P, Ricci D,
Selicorni A, Guzzetta A, Baranello G, Tinelli F,
Mallardi M, Zampino G, Vicari S, Atkinson J,
Mercuri E. 2011. Visual processing in Noonan
syndrome: Dorsal and ventral stream
sensitivity.
Am J Med Genet Part A 155:2459–2464.
increasingly obvious that it can be due to mutations in different
genes. Mutations in one of nine genes (PTPN11, SOS1, KRAS,
NRAS, RAF1, BRAF, MEK1, SHOC2, and CBL) can be detected in
approximately 75% of affected individuals [Tartaglia et al., 2002,
2007, 2010; Carta et al., 2006; Pandit et al., 2007; Cirstea et al., 2010;
Martinelli et al., 2010]. A few studies have investigated neurological
function and cognitive development in NS [Verhoeven et al., 2008;
Cesarini et al., 2009; Pierpont et al., 2009]. Cognitive abilities,
assessed using the Wechsler scales, were often within normal range
with intellectual disability only occurring in approximately 15%.
There were no signs of cerebral palsy or other major neurological
abnormalities even though clumsiness or difficulties in everyday life
activities were often reported by the patients or their families. We
assessed ophthalmologic and visual findings in NS reporting that
visual and visuoperceptual abilities were commonly impaired in
*Correspondence to:
Eugenio Mercuri, Neuropsichiatria Infantile, Policlinico Gemelli, Largo
Gemelli, Rome 00168, Italy. E-mail: mercuri@rm.unicatt.it
Published online 9 September 2011 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/ajmg.a.34229
2459
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these patients [Alfieri et al., 2008], but no systematic assessment has
reported visual processing.
It is unknown whether the difficulties in everyday life activities
may be ascribed to impairment of selective mechanisms of visual
processing such as those related to dorsal or ventral ‘‘streams’’ that
are both essential in visual processing mechanisms. The ventral
stream (which asks ‘‘what’’), connecting primary visual cortex to
inferotemporal cortex, plays a role in processing information about
the physical characteristics of objects while the dorsal stream
(asking ‘‘how’’), connecting visual cortex to posterior parietal
cortex, is involved in visual processing of spatial localization
(visuomotor control) [Milner and Goodale, 1993, 2008]. A few
studies had previously reported that the dorsal and ventral streams
can be independently affected in some genetic conditions such as
Williams syndrome or Down syndrome [Atkinson et al., 1997;
Elliott et al., 2006; Vicari et al., 2006], or in children with dyspraxia
[O’Brien et al., 2002] or dyslexia [Tsermentseli et al., 2008] while no
studies had been performed in NS. In all previous studies, two
different psychological measures had been used to specifically assess
and compare dorsal and ventral stream functions in children.
Motion coherence tasks had been used to test dorsal stream
function, and form coherence tasks tested ventral stream function
[O’Brien et al., 2002]. In this study, we assessed a group of patients
with NS using form and motion coherence tasks. Specifically, we
wished to evaluate possible selective impairments of the two
streams and the correlation between dorsal and ventral stream
performances and mutations in the different genes involved in NS.
SUBJECTS AND METHODS
The subjects included in the study were followed regularly in the
Department of Pediatrics of the Catholic University (Rome, Italy)
and at the Pediatric Clinic of the Regina Elena Hospital (Milan,
Italy), and are part of a prospective study of the clinical and
molecular characterization of these disorders. Subjects were examined by experienced clinicians, and diagnoses were based on clinical
features reported previously [Voron et al., 1976; Van der Burgt et al.,
1994; Allanson, 2007; Sarkozy et al., 2009]. All the patients included
in the study were part of cohort for which molecular diagnosis was
attained until 2008 (genes known at the time of our study: PTPN11,
SOS1, KRAS, BRAF, RAF1, MEK1) [Tartaglia et al., 2002, 2007;
Carta et al., 2006; Pandit et al., 2007]. Primer sequences and
protocols utilized for molecular characterization of patients are
available on request. In the present study, only patients in whom
mutations in one of the NS disease-causing genes had been identified were included. As part of this study, patients underwent a
detailed assessment of cognitive, visual, and perceptual abilities.
The spectrum of cognitive abilities has already been reported
[Cesarini et al., 2009]. The study was approved by the Research
Ethical Committee of The Catholic University.
All children underwent a detailed assessment of visual processing
consisting of a form coherence and a motion coherence test. None
of the study patients had major neurological deficits. To determine
whether these patients had minor neurological signs such as
abnormalities of visuomotor abilities, we also performed the
Movement Assessment Battery for Children (M-ABC) [Henderson
nd Sugden, 1992]. To study form and motion abilities, we selected a
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
control group of 43 children of Italian origin matched to NS
participants for chronological age, sex, and cultural background.
Form and Motion Coherence Tests
Coherence stimuli were displayed on an Acorn A5000 computer
monitor viewed at a distance of 40 cm (visual angle 38 28 ). The
form stimulus was a static array of randomly orientated short line
segments (white lines on a black background, density 1.3 segments/
degree2) containing a ‘‘target’’ area on one side of the display where
segments were orientated tangentially to form concentric circles
(Fig. 1). The proportion of tangentially oriented (‘‘coherent’’) line
segments amongst the randomly oriented ‘‘noise’’ segments in the
target area defined the coherence value for each trial.
The motion stimulus comprised two random dot kinematograms (white dots on a black background, density 4 dots/degree2),
one of which was segregated into three horizontal strips, such that
the direction of the coherent motion of the middle ‘‘target’’ strip
was opposite to that of the two outer strips (Fig. 2). The dot array on
the opposite side of the screen displayed a uniform direction of
coherent motion consistent with the direction of the two outer
strips. During trials a variable proportion of the dots oscillated
horizontally across each array forming coherent motion (velocity
6 /sec), while the remaining dots moved in random directions
(incoherent motion) (updates occurred every 20 msec). The direction of coherent motion reversed every 240 msec. To limit the
subjects’ use of tracking strategies, the trajectory of each ‘‘signal’’
dot had a limited lifetime of 6 video frames (120 msec). The
additional ‘‘noise’’ created by the disappearance of signal dots at
the end of their lifetime was taken into account when calculating
coherence levels on this task. Perceptual thresholds were obtained
FIG. 1. Schematic illustration of the form coherence stimuli. The form
stimulus was a static array of randomly orientated short line
segments (white lines on a black background, density
1.3 segments/degree2) containing a ‘‘target’’ area on one side of
the display where segments were orientated tangentially to form
concentric circles. On the left there is a circular region where 100%
of the line segments are disposed in a pattern of concentric circles.
ALFIERI ET AL.
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Movement Assessment Battery for Children
The M-ABC was used to assess the children’s visuomotor abilities
on a range of functional tasks. The total score and the three
manual dexterity items, two ball skill items and three balance
items were scored according to the manual and expressed as centiles
based on age specific-normative data. Centiles of the total and
partial scores (manual dexterity, ball skill, and balance) were then
grouped into three classes of scores: a score >15th has been
considered indicative of normal performance, a score between
5th and 15th mild impaired, a score 5th impaired. The number
and percentage of patients within each class were then calculated.
Statistical Analysis
FIG. 2. Schematic illustration of motion coherence stimulus. The
motion stimulus comprises two random dot kinematograms, one of
which (presented here right of center) was segregated into three
horizontal strips, such that the direction of the coherent motion of
the middle ‘‘target’’ strip was opposite to that of the two outer
strips. The dot array on the opposite side of the screen displayed a
uniform direction of coherent motion consistent with the direction
of the two outer strips.
using two-alternative forced-choice paradigms whereby participants were required to locate the target regions, which were
presented either in the left or the right half of the display. To ensure
that the children understood the tasks, descriptive questions were
used such as ‘‘the snow is falling and you have to find the road’’ and
‘‘can you see the ball hidden in the grass?’’. Stimuli were presented
on the screen for a maximum of 10 sec and between trials subjects’
attention was drawn to the midline with a flashing or oscillating
spot. In either task, the initial coherence level on each task was set to
100% and two to six practice trials were conducted. In the test phase
the coherence level of the target regions was varied according to a
modified version of the two-up/one-down staircase procedure
[Wetherill and Levitt, 1965; Swanson and Birch, 1990]. Starting
at 100%, coherence was decreased stepwise between
pffiffiffi each trial (by a
factor of H2 in the form coherence task and 4 2 for the motion
coherence), and the level at which the first incorrect response
occurred formed the starting point for four reversals. Threshold
was defined as the mean coherence level during the last four
reversals. Each subject performed the staircase procedure once
for each task. The motion and form coherence tasks were run
successively for each subject, with the order of presentation of the
two tasks counterbalanced across subjects.
A lower threshold is associated with better performances and vice
versa and expressed in centiles. Normative data using the same
apparatus were available, allowing converting thresholds in centiles.
Centiles were then grouped into three classes of scores: a score
>15th has been considered indicative of normal performance, a
score between 5th and 15th mild impaired, a score 5th impaired.
The number of patients (frequency) within each class of score was
then calculated.
The form and motion coherence measures were analyzed by means
of a c2 test.
RESULTS
The cohort included 18 patients (8 males and 10 females) with a
clinical diagnosis of NS, and heterozygous for a missense mutation
in PTPN11 (13), SOS1 (2), or RAF1 (3). Their age ranged between 4
and 17 years (mean age 10.0 years). Cognitive abilities of all the
subjects included in the study had been previously studied [Cesarini
et al., 2009]. In three patients with intellectual disability, the M-ABC
and form and motion tests were scored according to their mental
age (Table I). The control group included 43 typically developing
children (TD) matched for age and sex (age range 4–17 years, mean
11.1 years).
Form Coherence Test
Of 18 NS patients, 8 (44%) had normal, 3 (17%) mild impaired,
and 7 (39%) impaired results (Table I). Of 43 TD controls, 36
(84%) had normal, 3 (7%) mild impaired, and 4 (9%) impaired
results. Figure 3 shows the mean of centiles.
Motion Coherence Test
Of 18 NS patients, 14 (78%) had normal, 2 (11%) mild impaired,
and 2 (11%) impaired results (Table I). One control did not
perform the motion task. Of 43 TD controls, 37 (86%) had
normal, 3 (7%) mild impaired, and 2 (5%) impaired results.
Figure 3 shows the mean of centiles.
Statistical Analysis
We compared the form and motion coherence abilities of the three
performance groups (normal, mild impaired, and impaired). To
determine which groups were the major contributors to the
significant c2 value, standardized residuals were computed
[Haberman, 1978].
Results on the form coherence task indicated significant differences among the three performance groups and between groups
[c2 (5) ¼ 10.08; P < 0.006, Yates’ c2: 7.25; P < 0.026]. Computation
of the standardized residuals revealed that NS children and TD
controls were not similarly distributed in the ‘‘impaired’’ class. The
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2462
TABLE I. Summary of 18 patients with Noonan Syndrome: Genetic and psychologic test data
ABC
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Age
8.1
15.9
6.7
7.9
14.0
9.2
4.8
9.1
12.5
12.3
8.6
7.7
7.7
8.7
15.7
7.4
6.3
17.4
Sex
f
m
f
m
m
f
m
m
f
m
m
f
f
m
f
f
f
f
Gene
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
PTPN11
RAF1
RAF1
RAF1
SOS1
SOS1
Mutation
M504V
M504V
Y279C
N308D
N308D
T468M
T468M
T468M
T468M
T468M
Q79Y
P491L
Y62D
S257L
S612T
S257L
R502K
C441Y
IQ
95
84
102
78
89
108
99
99
115
96
88
99
86
70
70
104
118
44
Form
<5
<15
40
20
<5
60
<5
<15
<5
80
65
<5
<15
25
60
<5
<5
55
scores of the NS children were significantly lower than TD (R ¼ 2.1)
and in the ‘‘normal’’ class, since TD children number was significantly higher than NS (R ¼ 6.4). In contrast, analysis of NS children
on the motion coherence task did not detect significant differences
among the three classes and between groups [c2 (5) ¼ 1.16;
P ¼ 0.56, Yates’ c2: 0.17; P ¼ 0.9].
Movement ABC
Of 18 NS patients, 13 (72%) had impaired and 5 (28%) had normal
total scores on the M-ABC test. No subjects had mild impaired
FIG. 3. The mean of form and motion coherence centiles are plotted
with standard error bars for Noonan syndrome and controls.
Motion
<15
>95
>95
>95
85
>95
<15
40
80
80
90
>95
85
>95
<5
85
>95
<5
Global
score
3
3
32
1
1
3
56
40
2
26
3
1
1
3
1
20
3
1
Manual
dexterity
<15
<5
>15
<5
<5
<15
>15
>15
15
<5
>15
5
<5
<5
<5
>15
<5
>15
Skill
ball
<5
>15
<15
15
>15
<5
>15
>15
<5
<5
>15
<5
<5
<5
<5
<15
<5
<15
Balance
>15
<15
>15
<5
<5
>15
>15
>15
<15
>15
15
<5
<5
>15
<5
<5
<5
>15
results. Table I lists details of the subtests for manual dexterity,
skill ball and balance.
Genotype–Phenotype Analysis
The number of patients with mutations other than PTPN11 was too
small to allow formal genotype–phenotype comparison (PTPN11
13, SOS1 2, RAF1 3).
DISCUSSION
Patients with NS perform worse on tests of form coherence (39%
impaired, 17% mildly impaired) compared to testing for motion
coherence (11% impaired, 11% mildly impaired). Formal
genotype–phenotype analysis is not possible at this time, but there
did not appear striking differences associated with mutations in
individual genes. The patients with ‘‘impaired’’ performance do
not appear to have a more general cognitive impairment since only
3 of the 18 patients had intellectual disability and their results
on form and coherence threshold assessment was similar to the
others with normal Intelligence Quotient (IQ). The discrepancy
between form and motion performances in our cohort may indicate
that children with NS are more prone to develop a deficit in the
ventral pathway. These results are contrast with those reported in
patients with Williams syndrome or Down syndrome [Atkinson
et al., 1997; Elliott et al., 2006] or in those affected by autism who
have an inverted pattern [Spencer et al., 2000; Spencer and O’Brien,
2006]. In these patients, form coherence performances were similar
to controls, while motion performances were significantly lower
suggesting a specific deficit of processing of the dorsal stream
pathway. Conversely NS patients had a low rate of impaired results
ALFIERI ET AL.
on motion performance and better overall scores than in the control
group. Their deficit on the form coherence test is in consistent with
an abnormality of the ventral pathway which has been reported also
in patients with dyspraxia [O’Brien et al., 2002].
Most of our patients had normal developmental milestones and
normal IQ, with poor visuomotor perceptual performances on the
M-ABC, a battery of tests used to diagnose dyspraxia according to
the criteria suggested by the DSM-IV (2000). This association may
be only partly explained by the influence that ventral and dorsal
stream have on the different tasks of the M-ABC, as there was not a
consistent association between individual tasks on the M-ABC and
results on form and motion assessment. Ball skills, for example, that
can be considered related to dorsal stream functioning, showed
often impaired or mild impaired results (13/18) even though 10 of
these 13 had normal results on motion coherence assessment that
also reflects dorsal stream.
A possible limitation of the study is that the IQ scores for the TD
group are not available, and that the results may be conflated with
IQ measures. Future studies should include the evaluation of the
intelligence level also for TD participants and include a larger
cohort of syndromic patients.
The ventral pathway is typically related to occipitotemporal
cortical areas. We did not perform a brain MRI in all subjects,
and do not know if the abnormalities of visual processing found in
our cohort would be related to overt occipitotemporal lesions on
structural imaging although brain changes in NS have been
reported in isolated cases consistent with Chiari I malformation
[Holder-Espinasse and Winter, 2003; Beier et al., 2009]. Future
studies with concurrent neuroimaging and/or physiologic scans
would be needed to determine if there is an anatomic basis.
CONCLUSIONS
Patients with NS are likely to have specific aspects of impairment of
global processing with lower performances in form coherence test
compared to controls, and to have dissociation between dorsal and
ventral streams. The poor performances on the M-ABC in our
cohort confirm ventral stream involvement in patients with visuomotor perceptual difficulties and normal cognitive development,
suggesting a specific occipitotemporal deficit. This pattern of
discrepancy differs from that observed in other genetic syndromes
such as Williams syndrome or Down syndrome. The identification
of these difficulties in patients who often have overall normal
cognitive abilities may help to provide advice on how to improve
these aspects with specific training.
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