Chiara Gagliardi

Disruption of the ProSAP2 Gene in a t(12;22)(q24.1;q13.3) Is Associated with the 22q13.3 Deletion Syndrome

The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patients karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.

Is everybody always my friend? Perception of approachability in Williams syndrome

Individuals with Williams syndrome (WS) are well known for their friendly behaviour and tendency to approach strangers indiscriminately as if everybody were their friend. This tendency to approach strangers is mirrored in their ratings of unfamiliar face stimuli. Here we examined their perception of unfamiliar expressive faces and found that individuals with WS do not always see faces as being highly approachable. Happy faces were rated as more approachable by individuals with WS than by controls. In contrast, the other less approachable face stimuli were rated lower on approachability by individuals with WS than by controls. Thus, it appears that although individuals with WS will discriminate people in terms of approachability, they have difficulty inhibiting their strong compulsion towards social interaction. The form of this strong pro-social compulsion is discussed both in terms of friendliness and in terms of the heightened salience of social stimuli (social stimulus attraction).

Facial expression recognition in Williams syndrome

Individuals with Williams syndrome (WS) excel in face recognition and show both a remarkable concern for social stimuli and a linguistic capacity for, in particular, emotionally referenced language. The animated full facial expression comprehension test (AFFECT), a new test of emotional expression perception, was used to compare participants with WS with both chronological and mental age-matched controls. It was found that expression recognition in WS was worse than that of chronologically age-matched controls but indistinguishable from that of mental age controls. Different processing strategies are thought to underlie the similar performance of individuals with WS and mental age controls. The expression recognition performance of individuals with WS did not correlate with age, but was instead found to correlate with IQ. This is compared to earlier findings, replicated here, that face recognition performance on the Benton test correlates with age and not IQ. The results of the Benton test have been explained in terms of individuals with WS being good at face recognition; since a piecemeal strategy can be used, this strategy is improved with practice which would explain the correlation with age. We propose that poor expression recognition of the individuals with WS is due to a lack of configural ability since changes in the configuration of the face are an important part of expressions. Furthermore, these reduced configural abilities may be due to abnormal neuronal development and are thus fixed from an early age.

Relationship between clinical and genetic features in “inverted duplicated chromosome 15” patients

Inverted duplicated chromosome 15 (Inv dup [15]) syndrome is a genetic disorder characterized by psychologic or intellectual language delay; neurologic signs, such as hypotonia, ataxia, and epilepsy; mental retardation ranging from mild to severe; and facial dysmorphisms. All patients present with a psychopathologic impairment that is highly variable in severity but always classifiable as pervasive developmental disorder (PDD). Many genetic mechanisms have been hypothesized to explain the clinical variability. This article describes the neurologic and psychopathologic features of six Inv dup(15) patients, one male and five females, between 8 and 14 years of age, all with a maternal marker chromosome. Four patients were diagnosed with PDD not otherwise specified, whereas two patients received a diagnosis of autism. Epilepsy was present in three patients (two generalized symptomatic and one focal symptomatic), and a correlation between the severity of the disease and its outcome was not always observed. Nevertheless, the influence of gene content of the marker chromosome, particularly the three gamma-aminobutyric acid-A receptor subunit genes, may represent the link between epilepsy, mental retardation, and PDD.

Focal cognitive impairment in mitochondrial encephalomyopathies: a neuropsychological and neuroimaging study

Mitochondrial encephalomyopathies (ME) are a multisystemic group of diseases characterized by a wide range of biochemical and genetic mitochondrial defects with a variable mode of inheritance. We studied the neuropsychological profile, magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) data in a group of ME patients in order to look for common or specific cognitive defects and a possible correlation with related brain areas. Three main cognitive areas were assessed: general intelligence, memory functions and visuo-perceptual skills. Our sample included 16 ME patients (nine males, seven females) aged 25-68 years (mean age 45.2, SD 13.0). No sign of mental deterioration was found in the group of elderly subjects. Despite subjects showing no global cognitive impairment they scored lower in nonverbal versus verbal tasks. Visuo-spatial skills and short-term memory were selectively impaired. There was no correlation between neuropsychological results and age, illness duration, age of onset, clinical phenotypes, genetic mitochondrial alterations and pharmacological therapy. The most frequent SPECT pattern observed was the hypoperfusion of temporal lobes, with a direct localization in the temporal cortex and with prevalent mesial involvement. The neuropsychological profile and SPECT imaging revealed similarities with focal defects.

Cognitive ability assessment by Brain–Computer Interface: Validation of a new assessment method for cognitive abilities

Brain-Computer Interfaces (BCIs) are systems which can provide communication and environmental control to people with severe neuromuscular diseases. The current study proposes a new BCI-based method for psychometric assessment when traditional or computerized testing cannot be used owing to the subjects output impairment. This administration protocol was based on, and validated against, a widely used clinical test (Raven Colored Progressive Matrix) in order to verify whether BCI affects the brain in terms of cognitive resource with a misstatement result. The operating protocol was structured into two phases: phase 1 was aimed at configuring the BCI system on the subjects features and train him/her to use it; during phase 2 the BCI system was reconfigured and the test performed. A step-by-step checking procedure was adopted to verify progressive inclusion/exclusion criteria and the underpinning variables. The protocol was validated on 19 healthy subjects and the BCI-based administration was compared with a paper-based administration. The results obtained by both methods were correlated as known for traditional assessment of a similarly culture free and reasoning based test. Although our findings need to be validated on pathological participants, in our healthy population the BCI-based administration did not affect performance and added a further control of the response due to the several variables included and analyzed by the computerized task.

Differences in native and foreign language repetition tasks between subjects with William's and Down's syndromes

Abstract The capacity to repeat verbal stimuli in the mother tongue (Italian) and in unfamiliar (or scarcely familiar) foreign languages (English and German) was compared across Williams Syndrome (WS) subjects, Downs Syndrome (DS) subjects and mental-age-matched control subjects. In all repetition tasks (words, nonwords and sentences) in the mother tongue WS subjects performed significantly better than DS subjects. In the sentence repetition task in Italian WS subjects scored significantly lower than controls. In the sentence repetition task in unfamiliar (or scarcely familiar) foreign languages WS subjects performed significantly better than DS subjects but scored significantly lower than controls. The lower performances of WS subjects may be related to a dysfunction of the basal ganglia involved in syntactic processing, while the lower performances of DS subjects may be explained in terms of an impairment of the fronto-cerebellar structures involved in articulation and working memory.

Sequence memory skills in Spastic Bilateral Cerebral Palsy are age independent as in normally developing children

Purpose: To study the development of sequence memory skills in a group of participants with Spastic Bilateral Cerebral Palsy (CP) and their matched controls (TD). Sequence memory skills are defined as a blend of implicit and explicit competences that are crucial for the acquisition and consolidation of most adaptive skills along the lifespan. Method: A computerized sequence learning task was administered to 51 participants with CP (age range: 4.1–14.7) and their controls. General performance, accuracy and learning strategy were analyzed, as well as cognitive competencies (IQ and explicit visual spatial memory). Results: Explicit learning developed along with age in all participants. Sequence learning skills were age independent and unevenly distributed among CP participants: most TD (96.1%) and only about half (58.8%) of CP participants succeeded in sequence learning, in dynamic relation with cognitive and manipulation abilities. Conclusion: Sequence memory skills should be verified to plan therapeutic strategies. Therapeutic plans based on implicit learning (more resistant to disruption and stress) could be effective and highly advantageous for most but not for all CP children. Independently from age, many CP children could fix sequences more efficiently by explicit strategies, a more effortful but probably more effective way. Implications for Rehabilitation “Sequence memory skills in Spastic Bilateral Cerebral Palsy (CP) are age-independent as in normally developing children” Sequence memory skills (a blend of explicit and implicit components) represent a basic competence whose impairment could in a dynamic perspective affect multiple motor and non-motor developmental features. The prevalence and importance of implicit learning as a point of strength in therapeutic choice has been formerly emphasized: implicit learning is far more resistant to disruption and stress during rehabilitation and therefore potentially far reaching. Sequence memory skills are unevenly distributed in our clinical group. A majority of CP participants (58.8%) can rely on efficient sequence learning and therefore may specifically benefit from therapeutic programs privileging implicit learning (that is, relying on progressive and not necessarily explicit consolidation of sequences). In those children failing to fix sequences, sequence learning skills need to be specifically supported and explicit strategies (such as for example verbal and visual guides along the task) could be helpful to support consolidation.

Audiological findings in Williams syndrome: A study of 69 patients

The aim of this study was to investigate, in a clinical setting, the auditory function of a group of individuals affected by Williams syndrome (WS). Sixty‐nine patients with WS, aged 2–30, underwent comprehensive audiological testing including air/bone conduction behavioral audiometry, speech audiometry, tympanometry and measurement of the acoustic reflex, transient evoked otoacoustic emissions and brainstem auditory evoked responses. Hearing loss, defined by a pure‐tone average above 15 dB HL, affected 22.6% of the patients studied with traditional audiometry and was mostly slight in severity. Hearing loss was conductive in 9.4% of patients, mainly children with otitis media with effusion, and sensorineural in 13.2% of patients. However, 30% of the ears studied had a hearing impairment in the high frequency range (high‐frequency pure‐tone audiometry above 15 dB HL), higher in participants above 15 years (46.15%) than in the younger ones (23.45%). Contralateral stapedial reflexes were present in all patients with A‐type tympanograms. Transient otoacoustic emissions were absent in 44% of the ears of patients with normal hearing. Brainstem auditory evoked responses fell within normal ranges thus confirming the absence of retrocochlear dysfunction. Although hearing loss does not seem to be frequent, a cochlear fragility, especially in the high frequency range, related to outer hair cells is characteristic of WS. Therefore we strongly recommend monitoring patients affected by WS using annual audiometric tests and performing otoacoustic emissions in order to identify a subclinical cochlear dysfunction which might benefit from an audiological follow up before the possible onset of hearing loss.

Facial emotion recognition in Williams syndrome and Down syndrome: A matching and developmental study

In this study both the matching and developmental trajectories approaches were used to clarify questions that remain open in the literature on facial emotion recognition in Williams syndrome (WS) and Down syndrome (DS). The matching approach showed that individuals with WS or DS exhibit neither proficiency for the expression of happiness nor specific impairments for negative emotions. Instead, they present the same pattern of emotion recognition as typically developing (TD) individuals. Thus, the better performance on the recognition of positive compared to negative emotions usually reported in WS and DS is not specific of these populations but seems to represent a typical pattern. Prior studies based on the matching approach suggested that the development of facial emotion recognition is delayed in WS and atypical in DS. Nevertheless, and even though performance levels were lower in DS than in WS, the developmental trajectories approach used in this study evidenced that not only individuals with DS but also those with WS present atypical development in facial emotion recognition. Unlike in the TD participants, where developmental changes were observed along with age, in the WS and DS groups, the development of facial emotion recognition was static. Both individuals with WS and those with DS reached an early maximum developmental level due to cognitive constraints.