Central nervous system (CNS) development is a finely tuned process that relies on multiple factors and intricate pathways to ensure proper neuronal differentiation, maturation, and connectivity. ...Disruption of this process can cause significant impairments in CNS functioning and lead to debilitating disorders that impact motor and language skills, behavior, and cognitive functioning. Recent studies focused on understanding the underlying cellular mechanisms of neurodevelopmental disorders have identified a crucial role for insulin-like growth factor-1 (IGF-1) in normal CNS development. Work in model systems has demonstrated rescue of pathophysiological and behavioral abnormalities when IGF-1 is administered, and several clinical studies have shown promise of efficacy in disorders of the CNS, including autism spectrum disorder (ASD). In this review, we explore the molecular pathways and downstream effects of IGF-1 and summarize the results of completed and ongoing pre-clinical and clinical trials using IGF-1 as a pharmacologic intervention in various CNS disorders. This aim of this review is to provide evidence for the potential of IGF-1 as a treatment for neurodevelopmental disorders and ASD.
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by SHANK3 haploinsufficiency with clinical manifestations that can be devastating and profoundly affect quality of life.
The ...Externally Led Patient-Focused Drug Development (EL-PFDD) meeting was an opportunity for families affected by PMS to share with the Food and Drug Administration (FDA) how symptoms impact their lives and how treatments could be most meaningful. The Voice of the Patient report serves as a summary of this meeting to influence upcoming drug development and clinical trials. The purpose of this report is to provide a clinical perspective on the results of the EL-PFDD meeting to amplify the voice of these caregivers to the scientific community.
Caregivers prioritize an improved quality of life for their loved ones characterized by improved cognitive function, improved communication, increased independence, and reduced risk of regression. With these caregiver priorities in mind, this report provides the FDA and the scientific community with a clear understanding of which aspects of PMS should influence the development of future therapeutics.
We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished ...trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10
), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10
). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.
We conducted a meta-analysis of epidemiological studies investigating the association between maternal age and autism.
Using recommended guidelines for performing meta-analyses, we systematically ...selected, and extracted results from, epidemiological scientific studies reported before January 2012. We calculated pooled risk estimates comparing categories of advancing maternal age with and without adjusting for possible confounding factors. We investigated the influence of gender ratio among cases, ratio of infantile autism to autism spectrum disorder (ASD), and median year of diagnosis as effect moderators in mixed-effect meta-regression.
We found 16 epidemiological papers fulfilling the a priori search criteria. The meta-analysis included 25,687 ASD cases and 8,655,576 control subjects. Comparing mothers ≥ 35 years with mothers 25 to 29 years old, the crude relative risk (RR) for autism in the offspring was 1.52 (95% confidence interval CI = 1.12-1.92). Comparing mothers ≥ 35 with mothers 25-29, corrected the adjusted relative risk (RR) for autism in the offspring was 1.31 (95% CI = 1.19-1.45). corrected For mothers <20 compared with mothers 25 to 29 years old, there was a statistically significant decrease in risk (RR = 0.76; 95% confidence interval = 0.60-0.97). Almost all studies showed a dose-response effect of maternal age on risk of autism. The meta-regression suggested a stronger maternal age effect in the studies with more male offspring and for children diagnosed in later years.
The results of this meta-analysis support an association between advancing maternal age and risk of autism. The RR increased monotonically with increasing maternal age. The association persisted after the effects of paternal age and other potential confounders had been considered, supporting an independent relation between higher maternal age and autism.
Individuals with autism spectrum disorder (ASD), in addition to the core features of the disease, experience a higher burden of co-occurring medical conditions. This study sought to describe the ...frequency and distribution of comorbidit conditions in individuals with ASD, and systematically evaluate the possibility that pre- and postnatal exposures (e.g., preterm birth, hypoxia at birth, traumatic brain injury, and fetal alcohol syndrome) associated with ASD may also be linked with distinct comorbidities. We used the SPARK study database, launched by the Simons Foundation Autism Research Initiative (SFARI). Comorbidities considered in the study included neurological, cognitive, psychiatric, and physical conditions. The study sample consisted of 42,569 individuals with ASD and their 11,389 non-ASD siblings (full and half siblings). Majority (74%) of individuals with ASD had at least one comorbidity, and had a greater average number of comorbidities than their non-ASD siblings. Preterm birth and hypoxia at birth were the most common peri-natal exposures in the sample. In logistic regression models adjusted for covariates, these exposures were associated with several distinct comorbidities in ASD cases, including attention and behavior problems, psychiatric and neurological disorders, and growth conditions. A similar pattern of association was also observed in non-ASD siblings. Our findings underscore that individuals with ASD experience a greater burden of comorbidities, which could be partly attributable to the higher rates of perinatal exposures compared to their non-ASD siblings. Study findings, if replicated in other samples, can inform the etiology of comorbidity in ASD.
Data science advances in behavioral signal processing and machine learning hold the promise to automatically quantify clinically meaningful behaviors that can be applied to a large amount of data. ...The objective of this study was to identify an automated behavioral marker of treatment response in social communication in children with autism spectrum disorder (ASD). First, using an automated computational method, we successfully derived the amount of time it took for a child with ASD and an adult social partner (N pairs = 210) to respond to each other while they were engaged in conversation bits ("latency") using recordings of brief, natural social interactions. Then, we measured changes in latency at pre- and post-interventions. Children with ASD who were receiving interventions showed significantly larger reduction in latency compared to those who were not receiving interventions. There was also a significant group difference in the changes in latency for adult social partners. Results suggest that the automated measure of latency derived from natural social interactions is a scalable and objective method to quantify treatment response in children with ASD.
ADNP syndrome is a neurodevelopmental disorder characterized by autism spectrum disorder (ASD), intellectual disability, sensory reactivity symptoms, facial dysmorphisms, and a wide variety of other ...physical and behavioral health manifestations. Research on ADNP syndrome has been limited, and there are currently no validated tools for assessing clinical outcomes in ADNP syndrome specifically. The goal of this qualitative study was to ascertain the symptoms of ADNP syndrome based on caregiver interviews, with the primary aim of identifying areas for clinical improvement that may inform the development of outcome measures specific to ADNP syndrome. Data collection consisted of loosely structured interviews with 10 caregivers of children with ADNP syndrome, representing 6 males and 4 females of ages 4 to 17 (M = 10.1; SD = 4.2). Interviews were conducted via phone between November 2020 and April 2021. The analysis of coded interview data identified three overarching themes: symptoms, therapies, and challenges. Each theme encompasses several distinct codes, which were individually addressed. Our results could ultimately be useful in educating clinicians about ADNP syndrome, selecting or designing refined outcome measures for clinical trials, and informing efforts to increase support for caregivers.
Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the
gene on chromosome 22q13.33 and is characterized by intellectual disability, hypotonia, severe speech impairments, and autism ...spectrum disorder. Emerging evidence indicates that there are changes over time in the phenotype observed in individuals with PMS, including severe neuropsychiatric symptoms and loss of skills occurring in adolescence and adulthood. To gain further insight into these phenomena and to better understand the long-term course of the disorder, we conducted a systematic literature review and identified 56 PMS cases showing signs of behavioral and neurologic decompensation in adolescence or adulthood (30 females, 25 males, 1 gender unknown). Clinical presentations included features of bipolar disorder, catatonia, psychosis, and loss of skills, occurring at a mean age of 20 years. There were no apparent sex differences in the rates of these disorders except for catatonia, which appeared to be more frequent in females (13 females, 3 males). Reports of individuals with point mutations in
exhibiting neuropsychiatric decompensation and loss of skills demonstrate that loss of one copy of
is sufficient to cause these manifestations. In the majority of cases, no apparent cause could be identified; in others, symptoms appeared after acute events, such as infections, prolonged or particularly intense seizures, or changes in the individual's environment. Several individuals had a progressive neurological deterioration, including one with juvenile onset metachromatic leukodystrophy, a severe demyelinating disorder caused by recessive mutations in the
gene in 22q13.33. These reports provide insights into treatment options that have proven helpful in some cases, and are reviewed herein. Our survey highlights how little is currently known about neuropsychiatric presentations and loss of skills in PMS and underscores the importance of studying the natural history in individuals with PMS, including both cross-sectional and long-term longitudinal analyses. Clearer delineation of these neuropsychiatric symptoms will contribute to their recognition and prompt management and will also help uncover the underlying biological mechanisms, potentially leading to improved interventions.
A knowledge gap exists about the risk of cancer in individuals with intellectual disability (ID). The primary aim of this study was to estimate the cancer risk among individuals with ID compared to ...individuals without ID.
We conducted a population-based cohort study of all children live-born in Sweden between 1974 and 2013 and whose mothers were born in a Nordic country. All individuals were followed from birth until cancer diagnosis, emigration, death, or 31 December 2016 (up to age 43 years), whichever came first. Incident cancers were identified from the Swedish Cancer Register. We fitted Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of cancer risk in relation to ID after adjusting for several potential confounders. We analyzed ID by severity, as well as idiopathic ID and syndromic ID separately. We performed a sibling comparison to investigate familial confounding. The study cohort included a total of 3,531,305 individuals, including 27,956 (0.8%) individuals diagnosed with ID. Compared with the reference group (individuals without ID and without a full sibling with ID), individuals with ID were in general more likely to be male. The median follow-up time was 8.9 and 23.0 years for individuals with ID and individuals without ID, respectively. A total of 188 cancer cases were identified among individuals with ID (incidence rate IR, 62 per 1,000 person-years), and 24,960 among individuals in the reference group (IR, 31 per 1,000 person-years). A statistically significantly increased risk was observed for any cancer (HR 1.57, 95% CI 1.35-1.82; P < 0.001), as well as for several cancer types, including cancers of the esophagus (HR 28.4, 95% CI 6.2-130.6; P < 0.001), stomach (HR 6.1, 95% CI 1.5-24.9; P = 0.013), small intestine (HR 12.0, 95% CI 2.9-50.1; P < 0.001), colon (HR 2.0, 95% CI 1.0-4.1; P = 0.045), pancreas (HR 6.0, 95% CI 1.5-24.8; P = 0.013), uterus (HR 11.7, 95% CI 1.5-90.7; P = 0.019), kidney (HR 4.4, 95% CI 2.0-9.8; P < 0.001), central nervous system (HR 2.7, 95% CI 2.0-3.7; P < 0.001), and other or unspecified sites (HR 4.8, 95% CI 1.8-12.9; P = 0.002), as well as acute lymphoid leukemia (HR 2.4, 95% CI 1.3-4.4; P = 0.003) and acute myeloid leukemia (HR 3.0, 95% CI 1.4-6.4; P = 0.004). Cancer risk was not modified by ID severity or sex but was higher for syndromic ID. The sibling comparison showed little support for familial confounding. The main study limitations were the limited statistical power for the analyses of specific cancer types, and the potential for underestimation of the studied associations (e.g., due to potential underdetection or delayed diagnosis of cancer among individuals with ID).
In this study, we found that individuals with ID showed an increased risk of any cancer, as well as of several specific cancer types. These findings suggest that extended surveillance and early intervention for cancer among individuals with ID are warranted.
PDF
