Dataset Information

Phelan-McDermid Syndrome and SHANK3: Implications for Treatment.

ABSTRACT: Phelan-McDermid syndrome (PMS), also called 22q13.3 deletion syndrome, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, severe speech delays, poor motor tone and function, and autism spectrum disorder (ASD). Although the overall prevalence of PMS is unknown, there have been at least 1200 cases reported worldwide, according to the Phelan-McDermid Syndrome Foundation. PMS is now considered to be a relatively common cause of ASD and intellectual disability, accounting for between 0.5% and 2.0% of cases. The cause of PMS has been isolated to loss of function of one copy of SHANK3, which codes for a master scaffolding protein found in the postsynaptic density of excitatory synapses. Reduced expression of SH3 and multiple ankyrin repeat domains 3 (SHANK3) leads to reduced numbers of dendrites, and impaired synaptic transmission and plasticity. Recent mouse and human neuronal models of PMS have led to important opportunities to develop novel therapeutics, and at least 2 clinical trials are underway, one in the USA, and one in the Netherlands. The SHANK3 pathway may also be relevant to other forms of ASD, and many of the single-gene causes of ASD identified to date appear to converge on several common molecular pathways that underlie synaptic neurotransmission. As a result, treatments developed for PMS may also affect other forms of ASD.

SUBMITTER: Costales JL

PROVIDER: S-EPMC4489957 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phelan-McDermid Syndrome and SHANK3: Implications for Treatment.

Costales Jesse L JL Kolevzon Alexander A

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20150701 3

Phelan-McDermid syndrome (PMS), also called 22q13.3 deletion syndrome, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, severe speech delays, poor motor tone and function, and autism spectrum disorder (ASD). Although the overall prevalence of PMS is unknown, there have been at least 1200 cases reported worldwide, according to the Phelan-McDermid Syndrome Foundation. PMS is now considered to be a relatively common cause of ASD and intellectual ...[more]

PMID: 25894671

Similar Datasets

Project description:Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions. We report, for the first time, a call and response acoustic playback assay of bidirectional social communication in juvenile Shank3 rats. Interestingly, we found that Shank3-deficient null males did not demonstrate the enhanced social approach behavior typically exhibited following playback of pro-social USV. Concomitantly, we discovered that emission of USV in response to playback was not genotype-dependent and emitted response calls were divergent in meaning. This is the first report of these socially relevant responses using a genetic model of ASD. A comprehensive and empirical analysis of vigorous play during juvenile reciprocal social interactions further revealed fewer bouts and reduced durations of time spent playing by multiple key parameters, including reduced anogenital sniffing and allogrooming. We further discovered that male null Shank3-deficient pups emitted fewer isolation-induced USV than Shank3 wildtype controls. Postnatal whole brain anatomical phenotyping was applied to visualize anatomical substrates that underlie developmental phenotypes. The data presented here lend support for the important role of Shank3 in social communication, the core symptom domain of ASD. By increasing the number of in vivo functional outcome measures, we improved the likelihood for identifying and moving forward with medical interventions. Autism Res 2018, 11: 587-601. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY:Clinically relevant outcomes are required to demonstrate the utility of therapeutics. We introduce findings in a rat model, and assess the impact of mutations in Shank3, an autism risk gene. We found that males with deficient expression of Shank3 did not demonstrate typical responses in a bi-directional social communication test and that social interaction was lower on key parameters. Outcome measures reported herein extend earlier results in mice and capture responses to acoustic calls, which is analogous to measuring receptive and expressive communication.

Project description:BackgroundPhelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking.MethodsWe provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information.ResultsSHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems.ConclusionsHaploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3.

Project description:Phelan-McDermid syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability (ID), and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Domains and tasks examined in adults included measures of general health, neurological reflexes, motor abilities, sensory reactivity, social behavior, repetitive behaviors, cognition and behavioral inflexibility, and anxiety. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, sensory alterations were detected in both neonatal and adult mice, and motor behavior was strongly altered, especially in the open field and rotarod locomotor tests. While social behaviors measured with the three-chambered social approach and male-female interaction tests were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects in novel object recognition, repetitive novel object contact, marble burying, and nest building tasks, indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear testing, which are memory tasks involving hippocampal-prefrontal circuits. In contrast, working memory in the Y-maze spontaneous alternation test was not altered. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models.

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.

Dataset Information

Phelan-McDermid Syndrome and SHANK3: Implications for Treatment.

Publications

Phelan-McDermid Syndrome and SHANK3: Implications for Treatment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets