Mutations in the MECP2 gene are not a major cause of Rett syndrome-like or related neurodevelopmental phenotype in male patients

Rett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.Moónica Santos was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) with the PhD fellowship SFRH/BD/9111/2002 and the postdoc fellowship SFRH/BPD/28555/2006. Research in Rett syndrome is supported by FSE/FEDER and FCT, Grant POCTI 41416/2001

Portuguese National Surveillance of Cerebral Palsy: TORCH infection in children with cerebral palsy born in 2001-2010

As infeções TORCH são causa de perturbação neurossensorial grave no feto e recém-nascido, podendo ser causa ou associar-se à paralisia cerebral (PC). Os registos do Programa de Vigilância Nacional da Paralisia Cerebral (PVNPC) foram usados para identificar e caracterizar, aos 5 anos de idade, as crianças com PC e infeção TORCH, nascidas em 2001-2010, e estimar a frequência desta associação em Portugal. Foi estimada a prevalência da associação da PC à infeção TORCH em 5,8% (IC95% 4,64-7,29). Os agentes infeciosos mais frequentemente registados foram: citomegalovirus (45 casos), vírus da imunodeficiência humana (15 casos) e Treponema pallidum (6 casos), a grande maioria em crianças nascidas em Portugal. Nas crianças com PC e infeção TORCH predomina o tipo clínico de PC espástica bilateral com 4 membros afectados, sendo frequentes morbilidades e défices associados. Na ressonância magnética encefálica é mais frequente o predomínio das lesões do 1º e 2º trimestres da gestação. A prevenção primária, parece ter maior potencial de sucesso quando pré-natal, no início da gestação ou na transmissão perinatal. A elevada suspeição clínica e epidemiológica poderá aumentar o sucesso da prevenção terciária. Os dados da vigilância epidemiológica nacional ajudam a entender e aplicar estratégias de prevenção na PC associada à infeção TORCH.TORCH infection causes severe foetal and neonatal disease and neurological disorders, such as cerebral palsy (CP) may occur. Data from the Por tuguese National Sur veillance of Cerebral Palsy (PVNPC) are used to characterize, at 5 years of age, children with CP born 2001-2010 with TORCH infection and to estimate the prevalence of the the association in Por tugal. The prevalence of the association of CP with TORCH infection was estimated in 5.8% (95%CI 4.64-7.29). The infeccious agents most frequently registered were cy tomegalovirus (45), HIV (15) and Treponema pallidum (6), the large majority are children born in Por tugal. The predominant clinical type in children with CP and TORCH infection is bilateral spastic CP with 4 af fected limbs, frequently with associated morbidity and functional impairments. Cranial magnetic ressonance shows mostly predominant lesions originated in the 1st and 2nd trimester of pregnancy. These results highlight the potential for primar y prevention, with higher potential for success in cases of either prenatal or early gestational infection or perinatal transmission; high clinical and epidemiological suspition can increase the success of terciar y prevention. Data from national epidemiologic sur veillance contribute to better understand and implement strategies to prevent CP associated to TORCH infection.info:eu-repo/semantics/publishedVersio

Rett syndrome with and without detected MECP2 mutations: an attempt to redefine phenotypes

Background: The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. Patients and methods: We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. Results: Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. Conclusion: A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II

Rett syndrome with and without detected MECP2 mutations: An attempt to redefine phenotypes

Abstract Background: The diagnosis of Rett syndrome (RTT) is based on a set of clinical criteria, irrespective of mutation status. The aims of this study were (1) to define the clinical differences existing between patients with Rett syndrome with (Group I) and without a MECP2 mutation (Group II), and (2) to characterize the phenotypes associated with the more common MECP2 mutations. Patients and methods: We analyzed 87 patients fulfilling the clinical criteria for RTT. All were observed and videotaped by the same paediatric neurologist. Seven common mutations were considered separately, and associated clinical features analysed. Results: Comparing Group I and II, we found differences concerning psychomotor development prior to onset, acquisition of propositive manipulation and language, and evolving autistic traits. Based on age at observation, we found differences in eye pointing, microcephaly, growth, number of stereotypies, rigidity, ataxia and ataxic-rigid gait, and severity score. Patients with truncating differed from those with missense mutations regarding acquisition of propositive words and independent gait, before the beginning of the disease, and microcephaly, growth, foot length, dystonia, rigidity and severity score, at the time of observation. Patients with the R168X mutation had a more severe phenotype, whereas those with R133C showed a less severe one. Patients with R294X had a hyperactive behaviour, and those with T158M seemed to be particularly ataxic and rigid. Conclusion: A clear regressive period (with loss of prehension and language, deceleration of growth) and the presence of more than three different stereotypies, rigidity and ataxic-rigid gait seemed to be very helpful in differentiating Group I from Group II

Identification of novel genetic causes of Rett syndrome-like phenotypes

Background The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. Methods and results We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Conclusions Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.This work was supported by the Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 262055. This work was also supported by the FEDER through the Programa Operacional Factores de Competitividade-COMPETE and by Portuguese national funds through the FCT-Fundacao para a Ciencia e Tecnologia, grants number PIC/IC/83026/2007 and PIC/IC/83013/2007, PhD scholarship grant to MB number SFRH/BDINT/ 51549/2011 and PhD scholarship grant to FL number SFRH/BD/84650/2010.info:eu-repo/semantics/publishedVersio