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.SHANK3has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype ofSHANK3deficiency 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 withSHANK3deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome.Methods: A serially ascertained sample of patients withSHANK3deficiency (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 withde novo SHANK3mutations 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 toSHANK3haploinsufficiency, 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 inSHANK3deficiency, 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 inSHANK3deficiency.

Autism Spectrum Disorders (ASD) and Schizophrenia Spectrum Disorders (SSD) share clinical and genetic components that have long been recognized. The two disorders co-occur more frequently than would be predicted by their respective prevalence, suggesting that a complex, multifactor association is involved. However, DSM-5 maintains the distinction between ASD, with core social and communication impairments, and SSD, including schizophrenia (SCZ), with hallucinations, delusions and thought disorder as essential features. ASD and SSD have common biological underpinnings that may emerge early in development and unfold over time. One of the hypotheses supporting the similarities in the social and cognitive disturbances of ASD and SSD relates to abnormalities in the ratio of excitatory to inhibitory cortical activity (E/I imbalance). E/I imbalance in neurodevelopmental disorders could be the consequence of abnormalities in genes coding for glutamatergic and GABAergic receptors or synaptic proteins followed by system derangements. Altered genes coding for synaptic proteins have been reported in both ASD and SSD and preclinical models have confirmed their role in synaptic transmission and relevant behaviors. SSD and ASD have been characterized as polygenic disorders in which to the onset and progression of disease is triggered by interactions among multiple genes. Mammalian Target of Rapamycin (mTOR) signaling is under intense investigation as a convergent altered pathway in the two spectrum disorders. Current understanding of shared and divergent patterns between ASD and SSD from molecular to clinical aspects is still incomplete and may be implemented by the Research Domain Criteria (RDoC) approach.

Autism spectrum disorders (ASDs) are more frequently associated with tic disorders than expected by chance. Variable rates of comorbidity have been reported and common genetic and neurobiological factors are probably involved. The aim of this study was to determine the rate of tic disorders in a clinical sample (n = 105) of children and adolescents with ASDs and to describe the clinical characteristics of a group with comorbid ASDs and tics (n = 24). The overlap between tics and other repetitive movements and behaviors in ASDs was carefully assessed. Among individuals with ASDs, 22 percent presented tic disorders: 11 percent with Tourette disorder (TD), and 11 percent with chronic motor tics. All had various degrees of cognitive impairment. An association between the level of mental retardation and tic severity was found. It is concluded that the occurrence of tics in ASDs should not be overlooked and should be carefully evaluated.

The association of epilepsy and autism is recognized, and it has been reported at a percentage that varies between 8 and 42%, depending on age and diagnostic criteria. One third of autistic children undergo a regression of language and behavior between 2 and 3 years, and epileptiform abnormalities and epilepsy can be concomitant in an undetermined percentage of them. The aim of this study was to investigate the prevalence of epilepsy and paroxysmal abnormalities in a group of children with autism and to determine the percentage of regression course in this group. Forty-six patients with autism (mean age 7.8 ± 2.7 years; 34 boys and 12 girls) were consecutively examined, and clinical evaluation, assessment, and electroencephalographic (EEG) recordings were performed in all of them. Thirty-five percent showed paroxysmal abnormalities and epilepsy, 22% had only paroxysmal abnormalities without seizures, and 13% of the children suffered from epilepsy. Sixty-five percent had a normal EEG. No difference in regression rate was observed between patients with paroxysmal abnormalities and epilepsy and those with a normal EEG and without seizures. In the study group, the prevalence of epilepsy was in the low range of individuals with autism, and different types of epilepsy were observed. Autism with regression was not influenced by paroxysmal abnormalities and epilepsy. (J Child Neurol 2005;20:27—31).

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication abnormalities. Heterogeneity in the expression and severity of the core and associated symptoms poses difficulties in classification and the overall clinical approach. Synaptic abnormalities have been observed in preclinical ASD models. They are thought to play a major role in clinical functional abnormalities and might be modified by targeted interventions. An imbalance in excitatory to inhibitory neurotransmission (E/I imbalance), through altered glutamatergic and GABAergic neurotransmission, respectively, is thought to be implicated in the pathogenesis of ASD. Glutamatergic and GABAergic agents have been tested in clinical trials with encouraging results as to efficacy and tolerability. Further studies are needed to confirm the role of E/I modulators in the treatment of ASD and on the safety and efficacy of the current agents.