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: email@example.com Published online 9 September 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ajmg.a.34229 2459 2460 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. 2461 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. 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