Laura Cesarini

Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade

Mutations in genes coding for transducers participating in the RAS/MAPK pathway have been identified as the molecular cause underlying a group of clinically related developmental disorders with cognitive deficits of variable severity. To determine the spectrum of cognitive defects associated with dysregulation of this signal cascade, we studied the profile of cognitive abilities in patients with mutations affecting the PTPN11, SOS1, HRAS, KRAS, BRAF, RAF1, and MEK1 genes and phenotype–genotype correlations. Our findings support the observation that heterogeneity in cognitive abilities can be at least partially ascribed to the individual affected genes and type of mutation involved. While mutations affecting transducers upstream of RAS were less frequently associated with mental retardation, mutations in downstream components of the pathway were generally associated with a more severe cognitive impairment. Among patients with a heterozygous PTPN11 mutation, the T468M substitution was associated with a mean IQ significantly higher compared to that of individuals carrying the N308D change. Our study provides insights on the range of cognitive abilities in patients with gene mutations causing dysregulation of RAS signaling suggesting that the presence and severity of cognitive involvement can be predicted in part by the gene involved.

Neurological examination of preterm infants at term equivalent age

BACKGROUND We previously reported the neurological findings of the Dubowitz neonatal examination in a cohort of 157 low-risk preterms born between 25 and 33 weeks gestational age (GA) and examined at term equivalent age (TEA). Median and range of scores were wider than those found in term-born infants and preterms showed a different neurological behaviour in specific items. However, the cohort number was too small to draw any definitive conclusion about the distribution of findings. AIMS We provide normative data from a low-risk cohort of 380 preterm infants; we also assess the findings and their relationship to motor outcome in preterms with major cranial ultrasound (US) abnormality. STUDY DESIGN We assessed, at TEA, 380 low-risk preterms born <35 weeks gestation (range 25-34.9, median 29) with normal 2 year motor outcome and 85 preterm infants with major US abnormality. RESULTS At TEA low-risk preterms had less flexor limb tone, poorer head control but better visual following than term-born infants. For 28/34 of the neurological items the range and median scores were similar across gestational ages. In infants with major US lesions the range and median scores differed from low-risk preterms in 20/34 items; 40% of infants developing a diplegia and 80% developing a tetraplegia had >7 items outside the 90th centile; all infants with >12 items outside the 90th centile developed a tetraplegia. CONCLUSIONS We provide reference values for the neurological examination of low-risk preterms at TEA. In infants with major US abnormality the number of items outside the 90th centile was an indicator of outcome severity.

Behavioral profile in RASopathies.

Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS‐MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ‐L), and Modified Checklist for Autism in toddlers (M‐CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut‐off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ‐L/M‐CHAT. Our findings indicate that mutations promoting dysregulation of the RAS‐MAPK cascade mark an increased psychopathological risk and highlight that autistic‐like behavior could be underdiagnosed in patients with RASopathies.

Enhanced human brain associative plasticity in Costello syndrome

Costello syndrome (CS) is a rare multiple congenital anomaly disorder which is caused by germline mutations in the v‐Ha‐ras Harvey rat sarcoma viral oncogene homologue (HRAS) proto‐oncogene. Experimental data suggest perturbing effects of the mutated protein on the functional and structural organization of networks of cerebral cortex and on the activity‐dependent strengthening of synaptic transmission known as long term potentiation (LTP). In five patients with molecularly proven diagnosis of CS and in a group of 13 age‐matched control subjects we investigated activity‐dependent synaptic plasticity. To this end, we used a paired associative stimulation (PAS) protocol, in which left ulnar nerve stimuli were followed by transcranial magnetic stimulation (TMS) pulses to right cortical hand area, and recorded motor evoked potentials (MEPs) by single pulse TMS from left first dorsal interosseus (FDI) muscle before and after PAS. In 4 out of 5 CS patients and in a subgroup of nine control subjects we also evaluated the time course and the topographical specificity of PAS after‐effects. In these two subgroups, MEPs were measured before, immediately after and 30 min after PAS in the left FDI and left abductor pollicis brevis (APB). While the PAS protocol led to a 65% increase of the FDI MEP amplitude in controls, the LTP‐like phenomenon was significantly more pronounced in CS patients, with motor responses increased by 230%. In addition, CS patients showed a similar MEP increase in both muscles while control subjects showed a slight increase in APB and only immediately after PAS. We hypothesize that the extremely enhanced PAS after‐effects could be due to the influence of HRAS activity on the susceptibility of synapses to undergo LTP.

Cortical visual function in preterm infants in the first year.

OBJECTIVE To assess visual function in low-risk preterm infants at 3, 5, and 12 months corrected age to determine whether the maturation of visual function in the first year is similar to that reported in term-born infants. STUDY DESIGN Seventy-five low-risk infants (25.0-30.9 weeks gestation) underwent ophthalmological examinations and a battery of tests (fix and follow, visual fields, acuity, attention at distance, and fixation shift) designed to assess various aspects of visual function at 3, 5, and 12 months corrected age. RESULTS The results were comparable with normative data from term-born infants in all tests but fixation shift, suggesting that maturation of most aspects of visual function is not significantly affected by preterm birth. In contrast, >25% of preterm infants failed the fixation shift test at 3 months, with a higher percentage of failing at 5 and 12 months. CONCLUSIONS There is a specific profile of early visual behavior in low-risk preterm infants, with a high percentage of infants failing a test that specifically assesses visual attention and provides a measure of cortical processing.

Visual Function in Noonan and LEOPARD Syndrome

The aim of the study was to assess various aspects of visual and visuoperceptual function in patients with Noonan syndrome (NS) or LEOPARD syndrome (LS) with mutations affecting the PTPN11, SOS1 and RAF1 genes. Twenty-four patients were assessed with a battery of tests assessing visual function including ophthalmological and orthoptic evaluation and age appropriate behavioural visual tests, including measures of crowding acuity (Cambridge crowding cards), and stereopsis (TNO test). Twenty-one subjects were also assessed with the visuo-motor integration (VMI) test. Twenty of the 24 patients (83%) had abnormalities of visual function on at least one of the tests used to assess visual function or on ophthalmological examination, and 7 of 21 (33%) also had abnormalities on VMI. Ocular movements and stereopsis were most frequently abnormal (50% and 79%, respectively). Our results suggest that visual and visuoperceptual abilities are commonly impaired in patients with Noonan and LEOPARD syndrome and they are probably related to a multifactorial etiology.

Epilepsy in Shunted Posthemorrhagic Infantile Hydrocephalus Owing to Pre- or Perinatal Intra- or Periventricular Hemorrhage

Epilepsy is relatively common in infants with hydrocephalus. Its mechanism is controversial; in fact, studies on etiologically heterogeneous series are not able to clarify the mechanism generating epilepsy or to suggest effective prevention and treatment strategies. Our study is aimed at assessing the onset and evolution of epilepsy, as well as concurrent cognitive development of a homogeneous series of shunted posthemorrhagic hydrocephalus owing to pre- or perinatal intra- or periventricular hemorrhage. Forty patients were enrolled in the study. Twenty-six were patients with grade II—III intraventricular hemorrhage, 16 of whom had associated ischemic lesions. In the remaining 14 patients, a grade IV intraventricular hemorrhage was found. Epilepsy was observed in 27 patients. Aside from 10 cases with nonsyndromic forms of epilepsy, it was possible to define at least three different age-dependent epileptic syndromes: symptomatic neonatal location-related epilepsy with transient Wests syndrome in infancy in 5 patients; Wests syndrome in 8 patients; and continuous spike-waves during sleep in 4 patients. Epilepsy was significantly correlated with ischemic lesions only. Early thalamic injuries frequently evolved toward continuous spike-waves during sleep, indicating that patients with thalamic injury must be monitored to detect continuous spike-waves during sleep early. Cerebellar atrophy, in addition to epilepsy and other brain injuries, accounted for disorders of cognitive development. (J Child Neurol 2005;20:219—225).

Long term memory profile of disorders associated with dysregulation of the RAS-MAPK signaling cascade.

In the present study we evaluated long term memory in twenty individuals with molecularly confirmed diagnosis of Noonan syndrome and LEOPARD syndrome, two disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. The profile of explicit long term memory abilities was investigated using PROMEA, which includes a battery of tests specifically developed to assess memory and learning in verbal, visual and spatial domains. Ten individuals (50%) had impaired (≤5th percentile) or below average (≤15th percentile) performance on a delayed verbal free recall memory task, four (20%) on a delayed visual recognition memory task, and only one (5%) on a delayed spatial recognition memory task. Our data suggest that dysregulation of the RAS-MAPK cascade may be associated with a pattern of reduced verbal recall memory performance but relative sparing of visual and spatial recognition memory.

Visual development in infants with prenatal post-haemorrhagic ventricular dilatation

Objective: The aim of this study was to assess visual function in 13 infants with evidence of prenatal post haemorrhagic ventricular dilatation. Design: Infants were assessed at 5, 12 and 24 months using a battery of tests specifically designed to assess various aspects of visual function in infancy. Visual findings were correlated with several variables, including extent of the lesion and presence of epilepsy. Results and conclusions: Abnormalities of visual function were frequent (over 60%) in our cohort at age 2 years, ranging from isolated abnormal ocular movements to severe abnormalities of all the aspects of visual function assessed. The most severe and persistent abnormalities of visual function were found in infants with grade IV intraventricular haemorrhage and shunted hydrocephalus who also had epilepsy in the first year.

Visual processing in Noonan syndrome: dorsal and ventral stream sensitivity

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.