Sindrome dello spettro autistico e macrocefalia: la sindrome di Cowden

Autism spectrum disorder (ASD) is among the most common neurodevelopmental conditions in humans. While public awareness of the challenges faced by individuals with autism is steadily increasing, the underlying causes of abnormalities observed in ASD remains incompletely understood. The autism spectrum is notably broad, with symptoms that can manifest in various forms and degrees of severity. Core features of ASD, such as communication difficulties, impaired social interactions, and restricted patterns of behavior, interests, and activities, are often accompanied by other co‑occurring conditions, such as anxiety. ASD affects individuals regardless of gender, race, or ethnicity. Although we are currently unable to pinpoint a single definitive cause of autism, it is clear that genetics play a crucial role in its development. The first genes associated with an increased risk for ASD were discovered in rare monogenic disorders, such as fragile X syndrome (FXS), caused by mutations in the fragile X messenger ribonucleoprotein 1 (FMR1) gene, and macrocephaly, linked to mutations in the phosphatase and tensin homolog (PTEN) gene. This review aims to summarize the current knowledge of ASD in patients with mutations in the FMR1 and PTEN genes.

Elaboration of a Framework for Assessment of IT-based Interventions in the Field of Autism Disorder

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as >or=2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte-Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.

M11 - DE NOVO GENIC MUTATIONS AMONG A CHINESE AUTISM SPECTRUM DISORDER COHORT

To assess to what extent child neurologists (CNs) and developmental-behavioral pediatricians (DBPs) order diagnostic tests that are not recommended/indicated and/or fail to order tests that are recommended/indicated when evaluating children with an autism spectrum disorder (ASD). CNs and DBPs in the United States were asked which laboratory tests they would "routinely order" for a preschool child with ASD and IQ = 58 (ASD + Intellectual Disability (ID)), and a preschool child with ASD and IQ = 85 (ASD-ID). Chi-square tests were performed to identify differences (CNs vs DBPs) in laboratory testing. The sample consisted of 267 respondents (127 CN's; 140 DBPs). When evaluating ASD + ID or ASD - ID, inappropriate tests (≥1) were ordered by 76.8% and 76.4% of MDs, respectively. There was no significant difference between specialties in compliance with evaluation guidelines for ASD + ID (CN = 20.5% vs DBP = 16.4%; χ = 0.73). No significant differences were noted (DBP vs CN) regarding the percent ordering inappropriate tests for either clinical case or within each specialty when comparing testing for ASD + ID versus ASD - ID. Relative to DBPs, CNs were more likely to order EEGs and MRIs when evaluating children with ASD + ID or ASD - ID. 10% and 40% of respondents did not order any recommended genetic tests when evaluating ASD + ID and ASD - ID, respectively. When evaluating children with ASD, many CNs and DBPs fail to order tests that should be routinely performed and often order tests that are not routinely indicated yet are neither benign nor inexpensive. Recommended molecular genetic tests are often not ordered. Clinical guidelines must be updated and better promulgated.

The genetic aetiology of autism remains elusive. Occasionally, individuals with Cowden syndrome (a cancer syndrome) and other related hamartoma disorders such as Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like conditions, are...

The promise of precision medicine in autism

The present study aims to assess the incidence of microsatellite instability (MSI) and mutations in the PTEN and beta-catenin (CTNNB1) genes in endometrial carcinomas and to analyze the detected defects in these factors in relation to each other and to the clinico-pathological features of tumors. In a series of 56 endometrioid endometrial carcinomas, the status of MSI was determined using nine polymorphic markers, and mutations in all exons of the PTEN gene and in exon 3 of the CTNNB1 gene were evaluated by SSCP and sequencing methods. Microsatellite instability was found in 18 carcinomas (32.1%, MSI+); the remaining 38 tumors were microsatellite stable (MSI-). In 15 cases (26.8%), a loss of heterozygosity (LOH) at the studied microsatellite markers also occurred. In 29 carcinomas (51.8%), mutations were found in the PTEN gene and in nine tumors (16.1%) in the CTNNB1 gene. PTEN mutations occurred significantly more frequently in MSI+ than in MSI- tumors (77.8 vs. 39.5%, p = 0.007), but, except for one, none of them was attributable to MSI. In contrast, incidence of CTNNB1 mutations in MSI+ and MSI- tumors no significantly differed between themselves (16.7 vs. 15.8%, p = 0.760). Interestingly, mutations in the CTNNB1 gene most frequently coexisted with mutations in the PTEN gene (7/9, 77.8%). However, this finding requires future verification on a larger group of cases. The incidence of MSI and PTEN, but not CTNNB1 mutations, was significantly more common in poorly, than in well-to-moderately, differentiated tumors (G3 vs. G1 + G2; p = 0.042, 0.039 and 0.958, respectively). We conclude that most frequently occurring mutations in the PTEN gene may be a key event for the tumorigenesis of endometrioid endometrial carcinomas, while coexistence or absence of microsatellite instability or mutations in the CTNNB1 gene may reflect the heterogeneity of molecular mechanisms contributing to the development of these tumors.

Background/Objectives: Twin and family studies suggest that 90% of the risk for autism spectrum disorder (ASD) is due to genetic factors, with 800 genes recognized as playing a role. An important gene is phosphatase and tensin homolog (PTEN), which plays a significant role in cancer as a tumor suppressor best known for causing overgrowth and PTEN hamartoma tumor syndromes (PHTS). Less well known are PTEN germline mutations with adverse neurodevelopmental impacts of macrocephaly, intellectual disability, and ASD, as well as other behavioral and psychiatric disturbances. There remains a limited understanding of whether these gene variants are associated with differing manifestations of PTEN-associated neurodevelopmental disorders. Methods: This review utilized comprehensive literature searches such as PubMed, OMIM, and Gene Reviews with keywords of PTEN, genetic factors, autism, and human studies and by searching genomic-protein functional networks with STRING computer-based programs for functional and genetic mechanisms. Results: This review explored the genetic underpinnings of PTEN gene variants causing altered interactive proteins and their mechanisms, biological processes, molecular functions, pathways, and disease–gene associations. We characterized specific gene–gene or protein–protein interactions and their functions relating to neurodevelopment, psychiatric disorders, and ASD that were found to be increased with PTEN gene variants. Conclusions: PTEN gene defects are among the most recognized genetic causes of ASD. PTEN gene variants and altered protein interactions and mechanisms described in our study are associated with an increased risk for tissue and organ overgrowth, macrocephaly, and distinct brain anomalies, specifically newly identified abnormal CSF dynamics. These genetic underpinnings and impacts on neurodevelopment are discussed. The genetic and protein findings identified may offer clues to effective treatment interventions, particularly when instituted at a young age, to improve long-term outcomes.

Neurodevelopmental disorders in children with macrocephaly: A prevalence study and PTEN gene analysis

ObjectivesPTEN Hamartoma Tumour Syndrome (PHTS) is a heterogeneous autosomal dominant condition associated with pathogenic variants in the PTEN (Phosphatase and tensin homolog deleted on chromosome 10) gene.1 2 PHTS encompasses...

M15 - SPECTRUM OF COMMON AND RARE MUTATIONS CONTRIBUTING TO AUTISM RISK IN FAMILIES

Recent research increasingly suggests that autism spectrum disorders (ASDs) can be caused by genetic factors. ASDs are one of the fastest growing neurodevelopmental disorders, encompassing a spectrum of disorders marked by difficulties with social interaction, communication (verbal and non-verbal), and unusual, repetitive behaviors. The etiology, or specific factors that cause a disorder, are is relatively uncertain for ASDs. Consequently, viable treatment options for ASDs have received greater attention among autism researchers – in particular, the neurological consequences of genetic mutations found in people with ASDs. In the past year, the literature has presented many novel treatments to address this promising neurobiological etiology of ASDs. The current trajectory of autism research, supported by a wealth of studies connecting genetic mutations in neural substrates to the core symptoms of ASDs, suggests a greater appreciation for and understanding of the genetic complexity that underlies ASDs. Additionally, results of ASD twin studies have encouraged consideration of environmental factors that may act as triggers for gene mutations associated with ASDs. Genetic and environmental factors are increasingly accepted as joint contributors to the etiology of ASDs, rather than isolated factors strictly regulated by nature or nurture, respectively. While there has been substantial progress on the geneticneurobiological front of ASD research in the past decade, there is a burgeoning avenue of geneticenvironmental ASD research. With impending changes to the definition of ASDs in the newest edition of the Diagnostic and Statistical Manual (5th edition) in May 2013, it is likely that these multifactorial etiologies of ASDs will receive even greater attention in the field.

Using bumetanide to treat autism appears promising but further clinical trials are needed to confirm this approach.

INTRODUCTION A population-based study has found that approximately one quarter of individuals diagnosed with congenital hydrocephalus (CH) are also diagnosed with autism spectrum disorder (ASD); however, a common mechanism underlying these seemingly disparate disorders is unknown. We hypothesize that rare, damaging mutations in genes cause a pleiotropic effect responsible for the development of both CH and ASD. METHODS Using WES studies >250 CH patients, we selected 42 DNMs in genes with the greatest probability of loss-of-function (LoF) (pLI > .9), to determine whether there was an enrichment of ASD genes (pLI > .9) found in denovo-db, a national database of ASD DNMs A 2 × 2 contingency table revealed a 2.18-fold enrichment of ASD genes in sporadic CH genes (P-value = . 011). Gene Ontology analysis found >100-fold enrichment of TORC1 signaling (GO: 0031931) as a significantly enriched module (P-value = .000152). We recapitulated the CH phenotype in a genetic mouse model; wherein, Pten, a direct negative regulator of torc1 signaling, is conditionally knocked-out (Pten cKO) in a select subset of NSCs previously associated with an ASD phenotype in mice. Kaplan-Meier survival curves were constructed for Pten cKO and their WT, control littermates. Rapamycin was injected intraperitoneally in Pten cKO and WT mice daily from postnatal (P) days 10 to 22. RESULTS Pten cKO resulted in fully penetrant, fatal hydrocephalus with a median survival of P17.5. WT mice (n = 41) survived significantly longer than Pten cKO mice (n = 10) (P < .0001). Rapamycin rescued the fatal hydrocephalus phenotype (n = 8) by inhibition of mTOR (P < .0001). CONCLUSION PTEN mutations have previously been identified in ASD patients. Here, we present statistical analyses and a mouse model to support our hypothesis that ASD diagnoses in some CH patients may be a neurodevelopmental sequelae of PTEN LoF. These findings suggest that early ASD service interventions may benefit a subset of CH patients who would otherwise be managed solely with surgery.