Dataset Information

Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome.

ABSTRACT: OBJECTIVE:Phelan-McDermid syndrome is caused by haploinsufficiency of SHANK3 on terminal chromosome 22. Knowledge about altered neuroanatomic circuitry in Phelan-McDermid syndrome comes from mouse models showing striatal hypertrophy in the basal ganglia, and from humans with evidence of cerebellar atrophy. To date, no studies have performed volumetric analysis on Phelan-McDermid syndrome patients. METHODS:We performed volumetric analysis of baseline brain MRIs of Phelan-McDermid syndrome patients (ages three to 21 years) enrolled in a prospective natural history study (ClinicalTrials.gov NCT02461420). Using MRI segmentations carried out with PSTAPLE algorithm, we measured relative volumes (volume of the structure divided by the volume of the brain parenchyma) of basal ganglia and cerebellar structures. We compared these measurements to those of age- and sex-matched healthy controls part of another study. Among the patients, we performed linear regression of each relative volume using Repetitive Behavior Scale-Revised total score and Aberrant Behavior Checklist stereotypy score. Eleven patients with Phelan-McDermid syndrome (six females, five males) and 11 healthy controls were in this analysis. RESULTS:At time of MRI, the mean age of the patients and controls was 9.24 (5.29) years and 9.00 (4.49) years, respectively (P = 0.66). Compared to controls, patients had decreased caudate (P ? 0.013), putamen (P ? 0.026), and left pallidum (P?=?0.033) relative volumes. Relative volume of cerebellar vermal lobules I to V (beta coefficient = -17119, P?=?0.017) decreased with increasing Repetitive Behavior Scale-Revised total score. CONCLUSIONS:The volumes of the striatum and left pallidum are decreased in individuals with Phelan-McDermid syndrome. Cerebellar vermis volume may predict repetitive behavior severity in Phelan-McDermid syndrome. These findings warrant further investigation in larger samples.

SUBMITTER: Srivastava S

PROVIDER: S-EPMC6309632 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome.

Srivastava Siddharth S Scherrer Benoit B Prohl Anna K AK Filip-Dhima Rajna R Kapur Kush K Kolevzon Alexander A Buxbaum Joseph D JD Berry-Kravis Elizabeth E Soorya Latha L Thurm Audrey A Powell Craig M CM Bernstein Jonathan A JA Warfield Simon K SK Sahin Mustafa M

Pediatric neurology 20180921

<h4>Objective</h4>Phelan-McDermid syndrome is caused by haploinsufficiency of SHANK3 on terminal chromosome 22. Knowledge about altered neuroanatomic circuitry in Phelan-McDermid syndrome comes from mouse models showing striatal hypertrophy in the basal ganglia, and from humans with evidence of cerebellar atrophy. To date, no studies have performed volumetric analysis on Phelan-McDermid syndrome patients.<h4>Methods</h4>We performed volumetric analysis of baseline brain MRIs of Phelan-McDermid s ...[more]

PMID: 30396833

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Project description:Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS. However, it is still unclear to what extent SHANK3 deletions contribute to the PMS phenotype, and what other genes nearby are causal to the neurologic disease. In an effort to better understand the functional landscape of the PMS region during normal neurodevelopment, we assessed RNA-sequencing (RNA-seq) expression data collected from post-mortem brain tissue from developmentally normal subjects over the course of prenatal to adolescent age and analyzed expression changes of 65 genes on 22q13. We found that the majority of genes within this region were expressed in the brain, with ATNX10, MLC1, MAPK8IP2, and SULT4A1 having the highest overall expression. Analysis of the temporal profiles of the highest expressed genes revealed a trend towards peak expression during the early post-natal period, followed by a drop in expression later in development. Spatial analysis revealed significant region specific differences in the expression of SHANK3, MAPK8IP2, and SULT4A1. Region specific expression over time revealed a consistently unique gene expression profile within the cerebellum, providing evidence for a distinct developmental program within this region. Exon-specific expression of SHANK3 showed higher expression within exons contributing to known brain specific functional isoforms. Overall, we provide an updated roadmap of the PMS region, implicating several genes and time periods as important during neurodevelopment, with the hope that this information can help us better understand the phenotypic heterogeneity of PMS.

Project description:BackgroundPhelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability.MethodsWe used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison.ResultsWe found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size.ConclusionsThis study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.

Project description:BackgroundPhelan-McDermid syndrome (PMS) is a genetic condition characterized by intellectual disability, speech and language deficits, hypotonia, autism spectrum disorder, and epilepsy. PMS is caused by 22q13.33 deletions or mutations affecting SHANK3, which codes for a critical scaffolding protein in excitatory synapses. SHANK3 variants are also known to be associated with an increased risk for regression, as well as for psychiatric disorders, including bipolar disorder and catatonia. This study aimed to further describe these phenomena in PMS and to explore any relationship between psychiatric illness and regression after early childhood.MethodsThirty-eight people with PMS were recruited to this study through the Phelan-McDermid Syndrome Foundation based on caregiver report of distinct development of psychiatric symptoms. Caregivers completed a clinician-administered semi-structured interview focused on eliciting psychiatric symptomatology. Data from the PMS International Registry were used to confirm genetic diagnoses of participants and to provide a larger sample for comparison.ResultsThe mean age of the 38 participants was 24.7 years (range = 13 to 50; SD = 10.06). Females (31 of 38 cases; 82%) and sequence variants (15 of 38 cases; 39%) were over-represented in this sample, compared to base rates in the PMS International Registry. Onset of psychiatric symptoms occurred at a mean age of 15.4 years (range = 7 to 32), with presentations marked by prominent disturbances of mood. Enduring substantial loss of functional skills after onset of psychiatric changes was seen in 25 cases (66%). Symptomst indicative of catatonia occurred in 20 cases (53%). Triggers included infections, changes in hormonal status, and stressful life events.ConclusionsThis study confirms that individuals with PMS are at risk of developing severe neuropsychiatric illness in adolescence or early adulthood, including bipolar disorder, catatonia, and lasting regression of skills. These findings should increase the awareness of these phenotypes and lead to earlier diagnosis and the implementation of appropriate interventions. Our findings also highlight the importance of genetic testing in the work-up of individuals with intellectual disability and acute psychiatric illness or regression. Future research is needed to clarify the prevalence and nature of psychiatric disorders and regression among larger unbiased samples of individuals with PMS.

Project description:BackgroundPhelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS.MethodsEighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period.ResultsThere was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events.LimitationsThe small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results.ConclusionOur results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.

Dataset Information

Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome.

Publications

Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome.

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