Contemplating syndromic autism

Vorstman, Jacob; Scherer, Stephen W.

doi:10.1016/j.gim.2023.100919

Cited by 5 publications

(4 citation statements)

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“…This concept has been deeply criticized, also because it has no single definition, and is probably destined to fall into disuse. 21 We have preferred not to use it in this review.…”

Section: Epidemiology and Etiopathogenesis Of Autism Spectrum Disordermentioning

confidence: 99%

Autism Spectrum Disorder in 2023: A Challenge Still Open

2023

Turk Arch Pediatrics

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In this paper, we provide an update on autism spectrum disorder (ASD), including epidemiology, etiopathogenesis, clinical presentation, instrumental investigations, early signs, onset patterns, neuropsychological hypotheses, treatments, and long-term outcome. The prevalence of this condition has increased enormously over the last few decades. This increase prompted a search for possible environmental factors whose effects would add up to a genetic predisposition leading to the development of autism. But the genetic and environmental variables involved are extremely numerous, and conclusive data regarding the etiopathogenesis are still far away. Assuming that a well-defined etiology is still found today only in a minority of cases, numerous pathogenetic mechanisms have been hypothesized. Among these, we mention oxidative stress, mitochondrial dysfunction, alteration of the intestinal microbiota, immune dysregulation, and neuroinflammation. These pathogenetic mechanisms could alter epigenetic status and gene expression, finally leading to ASD. Inherent in the term spectrum is the great clinical heterogeneity of this condition, mainly due to the frequent comorbidity that characterizes it. The earlier the diagnosis is made and the earlier psychoeducational treatment begins, the better the prognosis. In this sense, the role of pediatricians can be decisive in making children with signs suggestive of autism undergo a specialist diagnostic course. The development of increasingly advanced cognitive-behavioral educational techniques has considerably improved the prognosis of affected individuals, even though only a small minority of them come off the autistic spectrum. Pharmacological therapies are used to treat comorbidities. During childhood, the most important prognostic factor for long-term outcome seems to be intellectual functioning.

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“…This concept has been deeply criticized, also because it has no single definition, and is probably destined to fall into disuse. 21 We have preferred not to use it in this review.…”

Section: Epidemiology and Etiopathogenesis Of Autism Spectrum Disordermentioning

confidence: 99%

Autism Spectrum Disorder in 2023: A Challenge Still Open

2023

Turk Arch Pediatrics

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“…ASD is highly prevalent, affecting approximately 1 in 54 individuals across all racial, ethnic, and socioeconomic groups, and thus presents a significant public health burden (Maenner et al, 2020). Although it is highly heritable, a substantial fraction of genetic susceptibility, perhaps up to 20% (Gaugler et al, 2014), is imparted by de novo mutations with major effects (15-20%)(Geschwind & State, 2015; Vorstman & Scherer, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…ASD is highly prevalent, affecAng approximately 1 in 54 individuals across all racial, ethnic, and socioeconomic groups, and thus presents a significant public health burden (Maenner et al, 2020). Although it is highly heritable, a substanAal fracAon of geneAc suscepAbility, perhaps up to 20% (Gaugler et al, 2014), is imparted by de novo mutaAons with major effects (15-20%) (Geschwind & State, 2015;Vorstman & Scherer, 2023).Studies in large cohorts of paAents and their families -such as the Simons Simplex CollecAon (SSC), and the AuAsm GeneAc Resource Exchange (AGRE) have idenAfied hundreds of genes increasing auAsm risk with various levels of staAsAcal support, most via harboring de novo…”

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confidence: 99%

Enhancer-targeted CRISPR-Activation Rescues Haploinsufficient Autism Susceptibility Genes

Chen,

Nair,

Osorio

et al. 2024

Preprint

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Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD’s genetic susceptibility is imparted byde novomutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes –CHD8andSCN2Aand used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons and cerebral forebrain organoids to correct the effects of haploinsufficiency, taking advantage of the presence of a wildtype allele of each gene and endogenous gene regulation. We found that CRISPR-A induced a sustained increase inCHD8andSCN2Aexpression in treated neurons and organoids, with rescue of gene expression levels and mutation-associated phenotypes, including gene expression and physiology. These data support gene activation via targeting enhancers of haploinsufficient genes, as a therapeutic intervention in ASD and other neurodevelopmental disorders.

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“…mutations of the SHANK3 gene). Yet these cases, pertaining to the so-called syndromic autism, 7 have not been excluded from the diagnosis of ASD according to DSM-5, and in the future, they might be described by combining the diagnosis of ASD with a known genetic etiology (e.g. SHANK3 mutation-induced ASD).…”

mentioning

confidence: 99%