Search Results (28)

Phelan–McDermid syndrome (PMS; #MIM: 606232) is a rare neurodevelopmental disorder primarily caused by the haploinsufficiency of the SHANK3 gene, most often due to deletions encompassing the gene or single nucleotide variants within it. Individuals with PMS display a wide range of clinical abnormalities and considerable genetic heterogeneity. This study aims to investigate genotype–phenotype correlations in a cohort of 213 individuals with PMS and to identify novel candidate genes, beyond SHANK3, that may contribute to the syndrome’s diverse clinical manifestations. Unsupervised clustering based on deletion size and Global Functional Assessment of the Patient (GFAP, previously described and developed by our group), along with additional analytical approaches, were employed to explore genotype–phenotype relationships. Deletion size within the 22q13.3 region emerged as a major determinant of phenotype, with larger deletions associated with more severe global functional impairment. Furthermore, CERK, TBC1D22A, CELSR1, and GRAMD4 were identified as candidate genes within 22q13.3, potentially contributing to core PMS phenotypes, and their putative interactions were explored. Our findings support the central role of SHANK3 in PMS, while also indicating that it does not account for the full phenotypic spectrum. This study underscores the variable impact of distinct genetic alterations in PMS and proposes additional loci implicated in its pathogenesis. These insights may inform future therapeutic strategies, emphasizing the importance of patient stratification and precision medicine. Full article

Phelan–McDermid syndrome (PMS) is a rare genetic disorder primarily caused by deletions or structural alterations of chromosome 22q13, often involving the SHANK3 gene. However, mutations in other genes, such as CELSR1, or deletions in the interstitial regions of 22q13 contribute to the phenotypic variability of PMS. The syndrome is characterized by developmental delay, cognitive impairment, absent or significant impairment speech, autism spectrum disorder (ASD), and distinctive craniofacial features. Lymphedema, present in 10–25% of cases, typically affects peripheral regions, while facial involvement has not been documented to date. Orofacial manifestations frequently include dolichocephaly, widely spaced eyes, prominent ears, and dysmorphic features, such as a bulbous nose and arched palate. This scoping review analyzed seven studies on orofacial features associated with PMS, highlighting a higher phenotypic variability, with frequent findings of intellectual disability, hypotonia, and craniofacial dysmorphisms. Genomic analyses identified consistent deletions in 22q13.31–q13.33 and complex genomic rearrangements. This review, through the report of the first documented case of hemifacial lymphedema in the literature, analyzes the facial features of patients with PMS and their genetic origins. It also highlights the importance of interdisciplinary collaboration and inclusive genetic testing to better define the phenotypic spectrum of this syndrome. A deeper understanding of the genetic and clinical characteristics of PMS can facilitate early diagnosis and personalized management for these patients. Full article

Phelan–McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by a developmental delay and autism spectrum disorder (ASD)-like behaviors. Emerging research suggests a link between gut microbiota and neuropsychiatric conditions, including PMS. This study aimed to investigate the fecal microbiota and immune profiles of children with PMS compared to healthy controls. Fecal samples were collected from children diagnosed with PMS and age-matched healthy controls. The bacterial composition was analyzed using 16S rRNA gene sequencing, while short-chain fatty acids (SCFAs) were quantified through gas chromatography. Immunological profiling was conducted using a multiplex cytokine assay. Significant differences were observed in the gut microbiota composition between PMS patients and controls, including a lower abundance of key bacterial genera such as Faecalibacterium and Agathobacter in PMS patients. SCFA levels were also reduced in PMS patients. Immunological analysis revealed higher levels of several pro-inflammatory cytokines in the PMS group, although these differences were not statistically significant. The findings indicate that children with PMS have distinct gut microbiota and SCFA profiles, which may contribute to the gastrointestinal and neurodevelopmental symptoms observed in this syndrome. These results suggest potential avenues for microbiota-targeted therapies in PMS. Full article

Cytosolic sulfotransferases (SULTs) are Phase 2 drug-metabolizing enzymes that catalyze the conjugation of sulfonate to endogenous and xenobiotic compounds, increasing their hydrophilicity and excretion from cells. To date, 13 human SULTs have been identified and classified into five families. SULT4A1 mRNA encodes two variants: (1) the wild type, encoding a 284 amino acid, ~33 kDa protein, and (2) an alternative spliced variant resulting from a 126 bp insert between exon 6 and 7, which introduces a premature stop codon that enhances nonsense-mediated decay. SULT4A1 is classified as an SULT based on sequence and structural similarities, including PAPS-domains, active-site His, and the dimerization domain; however, the catalytic pocket lid ‘Loop 3’ size is not conserved. SULT4A1 is uniquely expressed in the brain and localized in the cytosol and mitochondria. SULT4A1 is highly conserved, with rare intronic polymorphisms that have no outward manifestations. However, the SULT4A1 haplotype is correlated with Phelan–McDermid syndrome and schizophrenia. SULT4A1 knockdown revealed potential SULT4A1 functions in photoreceptor signaling and knockout mice display hampered neuronal development and behavior. Mouse and yeast models revealed that SULT4A1 protects the mitochondria from endogenously and exogenously induced oxidative stress and stimulates cell division, promoting dendritic spines’ formation and synaptic transmission. To date, no physiological enzymatic activity has been associated with SULT4A1. Full article

Phelan–McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS. Full article

Background: Phelan–McDermid syndrome (PMS) is caused by the loss (deletion) of a small portion of chromosome 22 in a region designated q13.3 (22q13.3 deletion). PMS is one of the most common genetic forms of autism spectrum disorder (ASD) in which sensory reactivity difficulties have been described on limited occasions. Methods: The objective of this study is to identify whether changes in sensory reactivity skills occur after one year of follow-up in a group of 44 participants diagnosed with PMS. All participants completed the Short Sensory Profile (SSP). Two-factor ANOVA tests were performed with repeated measures for the study of the evolution of the scores. Results: Participants with PMS showed significant changes after one year of follow-up in sensory reactivity skills associated with tactile hyperreactivity (p = 0.003). The rest of the study variables did not show significant differences compared to the baseline assessment, showing definite differences associated with patterns of hypo-responsiveness and sensory seeking, low/weak energy, and difficulties in auditory filtering. Conclusions: Understanding the evolution of sensory reactivity skills can facilitate the adjustment to behavioral changes in people with PMS and design-targeted interventions to address sensory reactivity challenges. Full article

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed. Full article

Phelan-McDermid syndrome is an inherited global developmental disorder commonly associated with autism spectrum disorder. Due to a significantly increased radiosensitivity, measured before the start of radiotherapy of a rhabdoid tumor in a child with Phelan-McDermid syndrome, the question arose whether other patients with this syndrome also have increased radiosensitivity. For this purpose, the radiation sensitivity of blood lymphocytes after irradiation with 2Gray was examined using the G0 three-color fluorescence in situ hybridization assay in a cohort of 20 patients with Phelan-McDermid syndrome from blood samples. The results were compared to healthy volunteers, breast cancer patients and rectal cancer patients. Independent of age and gender, all but two patients with Phelan-McDermid syndrome showed significantly increased radiosensitivity, with an average of 0.653 breaks per metaphase. These results correlated neither with the individual genetic findings nor with the individual clinical course, nor with the respective clinical severity of the disease. In our pilot study, we saw a significantly increased radiosensitivity in lymphocytes from patients with Phelan-McDermid syndrome, so pronounced that a dose reduction would be recommended if radiotherapy had to be performed. Ultimately, the question arises as to the interpretation of these data. There does not appear to be an increased risk of tumors in these patients, since tumors are rare overall. The question, therefore, arose as to whether our results could possibly be the basis for processes, such as aging/preaging, or, in this context, neurodegeneration. There are no data on this so far, but this issue should be pursued in further fundamentally based studies in order to better understand the pathophysiology of the syndrome. Full article

Phelan–McDermid syndrome (PMS) is a multisystem disorder that is associated with deletions of the 22q13 genomic region or pathogenic variants in the SHANK3 gene. Notable features include developmental issues, absent or delayed speech, neonatal hypotonia, seizures, autism or autistic traits, gastrointestinal problems, renal abnormalities, dolichocephaly, and both macro- and microcephaly. Assessment of the genetic factors that are responsible for abnormal head size in PMS has been hampered by small sample sizes as well as a lack of attention to these features. Therefore, this study was conducted to investigate the relationship between head size and genes on chromosome 22q13. A review of the literature was conducted to identify published cases of 22q13 deletions with information on head size to conduct a pooled association analysis. Across 56 studies, we identified 198 cases of PMS with defined deletion sizes and head size information. A total of 33 subjects (17%) had macrocephaly, 26 (13%) had microcephaly, and 139 (70%) were normocephalic. Individuals with macrocephaly had significantly larger genomic deletions than those with microcephaly or normocephaly (p < 0.0001). A genomic region on 22q13.31 was found to be significantly associated with macrocephaly with CELSR1, GRAMD4, and TBCD122 suggested as candidate genes. Investigation of these genes will aid the understanding of head and brain development. Full article

Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials. Full article

(1) Background: Parents of children with rare diseases experience great uncertainty and employ different strategies to care for their children and cope with the disease. The purpose of the present study was to describe the perspective of parents with children with Phelan McDermid Syndrome (PMS). (2) Methods: A non-probabilistic purposeful sampling was used to perform this qualitative descriptive study. Thirty-two parents with children with PMS were interviewed. In-depth interviews and research field notes were analyzed using an inductive thematic analysis. (3) Results: Four themes emerged from the data. “Understanding and accepting the disease” described how parents experienced their child’s diagnosis and the lack of information. The second theme, called “Living day by day”, highlighted the daily difficulties faced when caring for a child with PMS. The third theme, “Expectations versus reality”, was based on the parents’ expectations of parenthood and the reality they face. Expectations for the future are also included. Finally, “Pain and happiness” describes how parents alternate feelings of distress and suffering but also joy with what they learn from these experiences. (4) Conclusions: Health professionals can use these results to support parents. Full article

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder (NDD) characterized by impaired social communication and repetitive behavior, among other symptoms. ASD is highly heritable, with SHANK3 being one of the high-risk genes for ASD. In recent years, knowledge has been growing regarding the neuroplasticity effect induced by hyperbaric oxygen therapy (HBOT) and its potential use for ASD. Here, we characterized the effect of HBOT on a mouse model for ASD with the human genetic condition of InsG3680 mutation in the Shank3 gene. As compared to placebo, HBOT improved social behavior and reduced neuroinflammation in the cortex of the InsG3680^(+/+) mice. Specifically, HBOT induced upregulation of Insulin-like growth factor 1 (Igf1) expression levels and reduced the number of Iba1-positive cells in the mouse model for ASD compared to placebo control. Together, our research suggests that HBOT has the potential to improve the clinical outcome of ASD by ameliorating some of the core pathophysiological processes responsible for the development of the disorder. Full article

(1) Background: Phelan-McDermid Syndrome (PMS) in children causes significant challenges affecting social and family relationships. The purpose of this study was to explore the experience of parents with children diagnosed with PMS regarding interactions with their social environment; (2) Methods: A qualitative descriptive study was conducted. Participants were recruited using non-probabilistic purposeful sampling. In total, 32 parents of children with PMS were included. In-depth interviews and researchers’ field notes were used to collect the data. An inductive thematic analysis was performed; (3) Results: Five themes were identified: (a) challenges in the relationship as a couple; (b) challenges within the family and close social relationships; (c) challenges in the educational-school environment; (d) challenges in the health environment and with health professionals, and (e) reconnection through the PMS association. It would be beneficial for parents to create training programs on PMS in the educational and healthcare settings, to promote the participation of professionals in the PMS association and to develop care programs focusing in their physical, psychological and social health. Full article

Although autism spectrum disorder (ASD) is mainly characterized by developmental delay in social and communication skills, it has been shown that neuromotor deficits are an early component of ASD. The neuromotor development of B6.129-Shank3^tm2Gfng/J (Shank3B^−/−) mice as an animal model of autism has not been analyzed yet. The aim of this study was to compare the early neuromotor development of Shank3B^−/− to wild-type mice. The mice underwent a multitude of neurodevelopmental tests and observations from postnatal day 1 (PND = 1) to weaning. Shank3B^−/− mice opened their eyes later than their wild-type litter mates (p < 0.01). Shank3B^−/− mice were also slower in the negative geotaxis test from PND = 13 to PND = 16 (p < 0.001) in both sexes. The results of this study indicate neurodevelopmental deficits in Shank3B^−/− mice. The test is partially dependent on truncal motor control, and these lines of evidence suggest a phenotype of developmental hypotonia, which corresponds with the phenotypes seen in patients with Phelan-McDermid Syndrome. There was no observable effect of sex in any of the tests. There were no observed differences in upper and lower incisor eruption, ear unfolding, air righting, surface righting and ear twitch reflexes. Further studies should prove whether the delay in neuromotor development is linked to social or communication deficits, and thus, whether it may serve as an early indicator of autistic-like phenotype in mice. Full article

Intellectual disability (ID) and autism spectrum disorder (ASD) are complex neurodevelopmental disorders with high heritability. To search for the genetic deficits in two siblings affected with ID and ASD in a family, we first performed a genome-wide copy number variation (CNV) analysis using chromosomal microarray analysis (CMA). We found a 3.7 Mb microdeletion at 22q13.3 in the younger sister. This de novo microdeletion resulted in the haploinsufficiency of SHANK3 and several nearby genes involved in neurodevelopment disorders. Hence, she was diagnosed with Phelan–McDermid syndrome (PMS, OMIM#606232). We further performed whole-genome sequencing (WGS) analysis in this family. We did not detect pathogenic mutations with significant impacts on the phenotypes of the elder brother. Instead, we identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders: KLHL17, TDO2, TRRAP, EIF3F, ATP10A, DICER1, and CDH15. These variants were transmitted from his unaffected parents, indicating these variants have only moderate clinical effects. We propose that these variants worked together and led to the clinical phenotypes in the elder brother. We also suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders. Full article