Luís Pires

Oculo-auriculo-vertebral spectrum: Clinical and molecular analysis of 51 patients.

INTRODUCTION Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. METHODS We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. RESULTS Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. DISCUSSION In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).

Pronoun Resolution to Commanders and Recessors: A View from Event-Related Brain Potentials

We present results from an online experiment designed to probe the cognitive underpinnings of intra-sentential pronoun resolution. Event-related brain potentials were used to test the hypothesis that the processing of anaphoric links established between pronouns and non commanding antecedents demands more cognitive resources than the processing of anaphoric links to commanding antecedents. The experimental results obtained show, among others, a major N400-like effect elicited by the pronouns resolved to the non-commanding antecedent. This enhanced negativity suggests that, as hypothesized, resolving a pronoun to a non commanding antecedent is a more resource demanding process than resolving it to an antecedent in a commanding position. Our results can be interpreted within a theoretical framework for anaphor resolution that distinguishes two processing routes: a more resource-demanding discourse-based route and a less taxing syntax-only route.

Confirmatory Factor Analysis of Neurocognitive Measures in Healthy Young Adults: The Relation of Executive Functions with Other Neurocognitive Functions

OBJECTIVE The present study aimed to investigate the factor structure of a set of neurocognitive tests theoretically assessing executive functions (EF), verbal abilities (VA), and processing speed (PS). This study extended previous research by analyzing if each test is better explained by the specific factor to which it theoretically belongs or by a more general neurocognitive factor; and also by analyzing the relations between the neurocognitive factors. METHODS Using confirmatory factor analysis (CFA) we examined the factor structure of nine neurocognitive tests (EF: Working Memory, Tower, Divided Attention, Stroop, and Verbal Fluency tests; VA: Word List and Confrontation Naming tests; PS: Coding and Telephone Search tests) in a nonclinical sample (N = 90; 18-33 years old, 76 women). We tested five factor models of neurocognitive functioning: a one-factor model; two models with two-correlated factors; and two models with three-correlated factors. RESULTS A three-correlated-factor model, with EF, VA, and PS factors, was the most suitable for our neuropsychological data. The Verbal Fluency test was better explained by the VA factor rather than by the EF factor. The EF factor was correlated with the PS factor, but not with the VA factor. CONCLUSIONS Most of the neurocognitive measures used in the present study loaded in the expected factors (with the exception of the Verbal Fluency that was apparently more related to VA). EF and PS represent related but separable functions. Our results highlight the need for a careful interpretation of test scores since performance on one test usually requires multiple functions.

MLPA analysis in a cohort of patients with autism

BackgroundAutism is a global neurodevelopmental disorder which generally manifests during the first 2 years and continues throughout life, with a range of symptomatic variations. Epidemiological studies show an important role of genetic factors in autism and several susceptible regions and genes have been identified. The aim of our study was to validate a cost-effective set of commercial Multiplex Ligation dependent Probe Amplification (MLPA) and methylation specific multiplex ligation dependent probe amplification (MS-MLPA) test in autistic children refered by the neurodevelopmental center and autism unit of a Paediatric Hospital.ResultsIn this study 150 unrelated children with autism spectrum disorders were analysed for copy number variation in specific regions of chromosomes 15, 16 and 22, using MLPA. All the patients had been previously studied by conventional karyotype and fluorescence in situ hybridization (FISH) analysis for 15(q11.2q13) and, with these techniques, four alterations were identified. The MLPA technique confirmed these four and identified further six alterations by the combined application of the two different panels.ConclusionsOur data show that MLPA is a cost effective straightforward and rapid method for detection of imbalances in a clinically characterized population with autism. It contributes to strengthen the relationship between genotype and phenotype of children with autism, showing the clinical difference between deletions and duplications.