Background22q13 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 of providing a comprehensive picture of the medical and behavioral profile of the syndrome.MethodsA 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.ResultsThirty 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.ConclusionsThis study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence 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.

BackgroundAutism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.MethodsNine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.ResultsCompared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.ConclusionsThis study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.

Attentional dysfunction is among the most consistent observations of autism spectrum disorders (ASD). However, the neural nature of this deficit in ASD is still unclear. In this study, we aimed to identify the neurobehavioral correlates of attentional dysfunction in ASD. We used the Attention Network Test-Revised and functional magnetic resonance imaging to examine alerting, orienting, and executive control functions, as well as the neural substrates underlying these attentional functions in unmedicated, high-functioning adults with ASD (n = 12) and matched healthy controls (HC, n = 12). Compared with HC, individuals with ASD showed increased error rates in alerting and executive control, accompanied by lower activity in the mid-frontal gyrus and the caudate nucleus for alerting, and by the absence of significant functional activation in the anterior cingulate cortex (ACC) for executive control. In addition, greater behavioral deficiency in executive control in ASD was correlated with less functional activation of the ACC. These findings of behavioral and neural abnormalities in alerting and executive control of attention in ASD may suggest core attentional deficits, which require further investigation.

Sensory reactivity is a new DSM-5 criterion for autism spectrum disorder (ASD). The current study aims to validate a clinician-administered sensory observation in ASD, the Sensory Processing Scale Assessment (SPS). The SPS and the Short Sensory Profile (SSP) parent-report were used to measure sensory reactivity in children with ASD (n = 35) and typically developing children (n = 27). Sixty-five percent of children with ASD displayed sensory reactivity symptoms on the SPS and 81.1 % on the SSP. SPS scores significantly predicted SSP scores. We next identified the five SPS tasks that best differentiated groups. Our results indicate that a combination of parent-report and at least the five most differentiating observational tasks may be most sensitive in identifying the presence of sensory reactivity issues.

BackgroundSCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products.Case presentationWe describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant’s adaptive and cognitive skills fell in the low range of functioning.ConclusionThis report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD.

The Autism Mental Status Examination (AMSE) described here is an eight-item observational assessment that prompts the observation and recording of signs and symptoms of autism spectrum disorders (ASD). The AMSE is intended to take place seamlessly in the context of a clinical exam and produces a total score. Subjects were independently administered the AMSE and the Autism Diagnostic Observation Schedule (ADOS). The ADOS was used to estimate the most effective criterion cut-off on the AMSE. A score of five or greater produced excellent sensitivity and good specificity in a high-risk sample. Internal consistency was acceptable and inter-rater reliability was good to excellent. Preliminary findings indicate excellent classification accuracy and suggest that the AMSE provides a rapid and reliable observational assessment in a high-risk population.

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Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype.