Pubmed du 11/06/13

Pubmed du jour

2013-06-11 12:03:50

1. Betancur C, Buxbaum JD. {{SHANK3 haploinsufficiency: a « common » but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders}}. {Molecular autism}. 2013 Jun 11;4(1):17.

Autism spectrum disorders (ASD) are etiologically heterogeneous, with hundreds of rare, highly penetrant mutations and genomic imbalances involved, each contributing to a very small fraction of cases. As reviewed here, Phelan-McDermid syndrome, caused by deletion of 22q13.33 or SHANK3 mutations, is one of the more prevalent monogenic causes of ASD, explaining at least 0.5% of cases. In this issue of Molecular Autism, Soorya and colleagues evaluated 32 patients with SHANK3 haploinsufficiency using gold-standard diagnostic assessments and showed that 84% met criteria for ASD, including 75% meeting criteria for autism. This study and prior studies demonstrate that this syndrome is also one of the more penetrant causes of ASD. We note that SHANK3 haploinsufficiency remains underdiagnosed, although with the increasingly widespread use of chromosomal microarray analysis and targeted sequencing of SHANK3, the number of cases is bound to rise.

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2. Kirkham YA, Allen L, Kives S, Caccia N, Spitzer RF, Ornstein MP. {{Trends in Menstrual Concerns and Suppression in Adolescents With Developmental Disabilities}}. {The Journal of adolescent health : official publication of the Society for Adolescent Medicine}. 2013 Jun 11.

PURPOSE: Demonstrate changes in methods of menstrual suppression in adolescents with developmental disabilities in a recent 5-year cohort compared with an historical cohort at the same hospital. METHODS: Retrospective cohort study of patients with physical and cognitive challenges presenting for menstrual concerns at an Adolescent Gynecology Clinic between 2006 and 2011 compared with a previous published cohort (1998 to 2003). RESULTS: Three hundred patients with developmental disabilities aged 7.3 to 18.5 years (mean 12.1 +/- 1.6) were analyzed. Caregiver concerns included menstrual suppression, hygiene, caregiver burden, and menstrual symptoms. Ninety-five percent of patients had cognitive disabilities, 4.4% had only physical impairments. Thirty-two (31.7) percent of patients presented premenarchally. The most commonly selected initial method of suppression was extended or continuous oral contraceptive pill (OCP) (42.3%) followed by patch (20%), expectant management (14.9%), depot medroxyprogesterone acetate (DMPA) (11.6%), and levonorgestrel intrauterine system (LNG-IUS) (2.8%). Published data from 1998 to 2003 indicated a preference for DMPA in 59% and OCP in 17% of patients. The average number of methods to reach caregiver satisfaction was 1.5. Sixty-five percent of initial methods were continued. The most common reasons for discontinuation were breakthrough bleeding, decreased bone mineral density, or difficulties with patch adherence. Second-choice selections included OCP (42.5%), LNG-IUS inserted under general anesthesia (19.2%), DMPA (17.8%), and patch (13.7%). CONCLUSIONS: Since identification of decreased bone mineral density with DMPA and emergence of new contraceptive options, use of extended OCP or patch has surpassed DMPA for menstrual suppression in our patient population. LNG-IUS is an accepted, successful second-line option in adolescents with developmental disabilities.

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3. Malow BA, Adkins KW, Reynolds A, Weiss SK, Loh A, Fawkes D, Katz T, Goldman SE, Madduri N, Hundley R, Clemons T. {{Parent-Based Sleep Education for Children with Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2013 Jun 11.

This study provided sleep education to parents of children with autism spectrum disorder (ASD) to determine whether an individual or group format was more effective in improving sleep and aspects of daytime behavior and family functioning. Eighty children, ages 2-10 years, with ASD and sleep onset delay completed the study. Actigraphy and parent questionnaires were collected at baseline and 1 month after treatment. Mode of education did not affect outcomes. Sleep latency, insomnia subscales on the Children’s Sleep Habits Questionnaire, and other outcomes related to child and family functioning improved with treatment. Parent-based sleep education, delivered in relatively few sessions, was associated with improved sleep onset delay in children with ASD. Group versus individualized education did not affect outcome.

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4. Massand E, Bowler DM. {{Atypical Neurophysiology Underlying Episodic and Semantic Memory in Adults with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2013 Jun 11.

Individuals with autism spectrum disorder (ASD) show atypicalities in episodic memory (Boucher et al. in Psychological Bulletin, 138 (3), 458-496, 2012). We asked participants to recall the colours of a set of studied line drawings (episodic judgement), or to recognize line drawings alone (semantic judgement). Cycowicz et al. (Journal of Experimental Child Psychology, 65, 171-237, 2001) found early (300 ms onset) posterior old-new event-related potential effects for semantic judgements in typically developing (TD) individuals, and occipitally focused negativity (800 ms onset) for episodic judgements. Our results replicated findings in TD individuals and demonstrate attenuated early old-new effects in ASD. Late posterior negativity was present in the ASD group, but was not specific to this time window. This non-specificity may contribute to the atypical episodic memory judgements characteristic of individuals with ASD.

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5. Poelmans G, Franke B, Pauls DL, Glennon JC, Buitelaar JK. {{AKAPs integrate genetic findings for autism spectrum disorders}}. {Translational psychiatry}. 2013;3:e270.

Autism spectrum disorders (ASDs) are highly heritable, and six genome-wide association studies (GWASs) of ASDs have been published to date. In this study, we have integrated the findings from these GWASs with other genetic data to identify enriched genetic networks that are associated with ASDs. We conducted bioinformatics and systematic literature analyses of 200 top-ranked ASD candidate genes from five published GWASs. The sixth GWAS was used for replication and validation of our findings. Further corroborating evidence was obtained through rare genetic variant studies, that is, exome sequencing and copy number variation (CNV) studies, and/or other genetic evidence, including candidate gene association, microRNA and gene expression, gene function and genetic animal studies. We found three signaling networks regulating steroidogenesis, neurite outgrowth and (glutamatergic) synaptic function to be enriched in the data. Most genes from the five GWASs were also implicated-independent of gene size-in ASDs by at least one other line of genomic evidence. Importantly, A-kinase anchor proteins (AKAPs) functionally integrate signaling cascades within and between these networks. The three identified protein networks provide an important contribution to increasing our understanding of the molecular basis of ASDs. In addition, our results point towards the AKAPs as promising targets for developing novel ASD treatments.

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6. Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, Frank Y, Wang AT, Cai G, Parkhomenko E, Halpern D, Grodberg D, Angarita B, Willner JP, Yang A, Canitano R, Chaplin W, Betancur C, Buxbaum JD. {{Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency}}. {Molecular autism}. 2013 Jun 11;4(1):18.

BACKGROUND: 22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal to provide a comprehensive picture of the medical and behavioral profile of the syndrome. METHODS: A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G. RESULTS: Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features. CONCLUSIONS: This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the predominance of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

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