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PubMed2025

Genomic and Developmental Models to Predict Cognitive and Adaptive Outcomes in Autistic Children.

IMPORTANCE: Although early signs of autism are often observed between 18 and 36 months of age, there is considerable uncertainty regarding future development. Clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). OBJECTIVE: To predict ID in children diagnosed with autism. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study involved the development and validation of models integrating genetic variants and developmental milestones to predict ID. Models were trained, cross-validated, and tested for generalizability across 3 autism cohorts: Simons Foundation Powering Autism Research (SPARK), Simons Simplex Collection, and MSSNG. Autistic participants were assessed older than 6 years of age for ID. Study data were analyzed from January 2023 to July 2024. EXPOSURES: Ages at attaining early developmental milestones, occurrence of language regression, polygenic scores for cognitive ability and autism, rare copy number variants, de novo loss-of-function and missense variants impacting constrained genes. MAIN OUTCOMES AND MEASURES: The out-of-sample performance of predictive models was assessed using the area under the receiver operating characteristic curve (AUROC), positive predictive values (PPVs), and negative predictive values (NPVs). RESULTS: A total of 5633 autistic participants (4574 male [81.2%]) were included in this analysis. On average, participants were diagnosed with autism at 4 (IQR, 3-7) years of age and assessed for ID at 11 (8-14) years of age, with 1159 participants (20.6%) being diagnosed with ID. The model integrating all predictors yielded an AUROC of 0.653 (95% CI, 0.625-0.681), and this predictive performance was cross-validated and generalized across cohorts. This modest performance reflected that only a subset of individuals carried large-effect variants, high polygenic scores, or presented delayed milestones. However, combinations of genetic variants that are typically not considered clinically relevant by diagnostic laboratories achieved PPVs of 55% and correctly identified 10% of individuals developing ID. The addition of polygenic scores to developmental milestones specifically improved NPVs rather than PPVs. Notably, the ability to stratify ID probabilities using genetic variants was up to 2-fold higher in individuals with delayed milestones compared with those with typical development. CONCLUSIONS AND RELEVANCE: Results of this prognostic study suggest that the growing number of neurodevelopmental condition-associated variants cannot, in most cases, be used alone for predicting ID. However, models combining different classes of variants with developmental milestones provide clinically relevant individual-level predictions that could be useful for targeting early interventions.

Humans↗

PubMed1990

Postoperative complications in patients with disabling psychiatric illnesses or intellectual handicaps. A case-controlled, retrospective analysis.

The purpose of this study was to quantitate the operative risk and costs encountered in the surgical treatment of institutionalized patients. Operative complications and duration of hospitalization for 200 institutionalized patients were compared with those in a control group of patients matched for age, sex, and type of operation drawn from the general hospital population. Postoperative complications occurred in 53 (26.5%) of the patients in the study group compared with 15 (7.5%) of the patients in the control group. Elective laparotomy was followed by a complication in 48% of institutionalized patients compared with 11.6% of matched controls. Emergency celiotomy carried a 75% complication rate in the study group. Atelectasis and pneumonia accounted for 50% of the postoperative complications and occurred with greatest frequency following intra-abdominal procedures. The median hospital stay for all institutionalized patients was 3 days more than for matched controls. A strategy for postoperative treatment is presented, with particular emphasis on prevention of pulmonary complications.

Anesthesia↗

PubMed2026

Functional Reading Activities to Motivate and Empower: Maintenance of Reading Outcomes for Young Adults With Intellectual and Developmental Disabilities Following a Randomized Controlled Trial.

PURPOSE: This study examined whether the effects of Functional Reading Activities to Motivate and Empower (FRAME), a functional, strategy-based reading comprehension intervention for young adults with intellectual and developmental disabilities (IDDs), were maintained 6 months following the completion of the intervention and explored participants' perceptions of the intervention's feasibility, relevance, and perceived impact. METHOD: Participants were 44 young adults with IDDs (ages 18-26 years) who participated in a previously reported randomized controlled trial (FRAME participants: n = 23; controls: n = 21). Trial outcomes were assessed via telepractice at pretest, posttest, and 6-month follow-up. Six-month maintenance analyses focused on outcomes that demonstrated significant posttest group differences: use of (a) reading comprehension strategies (proximal) and (b) reading comprehension questions (distal). Participant perceptions (social validity) were collected post-intervention from FRAME participants using a structured interview protocol with closed- and open-ended items. RESULTS: At the 6-month follow-up, FRAME participants demonstrated sustained but reduced improvements in strategy use relative to controls (p = .040). Between-groups differences were not maintained for reading comprehension questions (p = .091). Participants reported high acceptability and perceived relevance of FRAME, with qualitative themes reflecting perceived improvements in comprehension, self-improvement, and increased independence. CONCLUSION: Findings suggest that FRAME supports sustainable gains in reading comprehension strategy use and is perceived as meaningful and feasible for young adults with IDDs, although additional supports may be needed to promote sustained improvements in distal comprehension outcomes. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.33307218.

Humans↗

PubMed1991

The post-school experiences of young people with a disability.

The transition of young people with disabilities from school to work and adult living has been the focus of attention for the Centre for Educational Research and Innovation (CERI) of OECD for some years. Various member countries of OECD have implemented transition education programmes as a result of community-based educational policies for students with disabilities. To establish a baseline of the post-school experiences of disabled students a follow-up study of a sample of ex-students in New South Wales, Australia, was conducted. While the responses to the survey came essentially from students who had been in special schools and hence may be unrepresentative of the total population of disabled ex-students, the data indicate some interesting trends. Only 42% were in open employment. Those with a moderate or severe intellectual disability were generally in sheltered workshops, activity centres or at home. The majority of respondents indicated that work was an important part of their lives, not so much from an economic perspective, but especially as it afforded them a social outlet. The implications of the findings are discussed in the context of the current emphasis upon community-based rather than sheltered employment for people with disabilities.

Adaptation, Psychological↗

PubMed1979

Alcohol-induced brain damage and liver damage in young males.

37 alcoholic males under the age of 35 were examined clinically, by psychometric tests, by computerised tomography (CT scans), and by liver biopsy. Factors other than alcoholism that might have caused brain damage were excluded. The prevalence of brain damage in this group was far greater than that of severe liver damage: 59% were intellectually impaired and 49% had cerebral atrophy on CT scan, whereas only 19% had cirrhosis. There was no significant correlations between the degree of liver damage and the degree of intellectual impairment (p greater than 0-05), nor between the degree of intellectual impairment and the presence of cerebral atrophy. The CT scan is an inadequate measure of functional brain damage, psychometric testing is preferable. Other neurological complications of alcoholism were not impressive. Disabling intellectual impairment may be the earliest complication of chronic alcoholism and may arise early in the alcoholic career.

Adult↗

PubMed1991

Neuropsychologic (cognitive) disabilities in long-term survivors of childhood cancer.

Intelligence and academic achievement testing of long-term survivors of childhood cancer reveal a high incidence of memory deficits, visual-spatial skill impairment, and attention deficit disorders. While the results of various studies must be interpreted carefully, the data available identify CNS irradiation and the toxic synergism of CNS irradiation and intrathecal chemotherapy as primary etiologic factors in the neuropsychologic sequelae of curative therapy. Early education intervention is mandatory to identify survivors of childhood cancer who require assistance in overcoming intellectual disabilities.

Attention Deficit Disorder with Hyperactivity↗

PubMed1991

Tuberous sclerosis complex in Olmsted County, Minnesota, 1950-1989.

The incidence of tuberous sclerosis complex in Olmsted County, Minnesota, was 0.28 per 100,000 person-years from 1950 through 1989, the point prevalence on December 31, 1989, was 6.9 per 100,000 persons, and the incidence at birth was 6.0 per 100,000 live births. The incidence was 0.13 per 100,000 person-years from 1950 through 1974 and 0.46 per 100,000 person-years from 1975 through 1989. The higher rate of diagnosis during the later period is believed to be due to the use of computed tomography. Of the 12 patients considered in this study, one patient presented with seizures and severe intellectual disability, six patients presented with seizures, three patients presented with multiple facial angiofibroma, and two patients were asymptomatic.

Female↗

PubMed1987

Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test.

Recent physiological and cognitive studies of schizophrenia have implicated dysfunction of prefrontal cortex as a possible explanation for some of the disabling intellectual and social aspects of the disorder. To investigate the potential reversibility of cognitive deficits and the role of state variables, eg, attention and motivation, three groups of patients with schizophrenia were administered the Wisconsin Card Sorting Test on six consecutive occasions. Two of the groups received incremental information on how to do the test, including explicit card-by-card instruction. The third group served as a control. Regardless of the degree of instruction, patients who could not do the test could not learn it. The deficit did not appear generalized, as patients were able to learn word lists on the Selective Reminding memory test and were not globally demented on the Mini-Mental State Examination. These data suggest that prefrontal-type cognitive deficits in schizophrenia may be more profound than is generally appreciated.

Adult↗

PubMed1985

MMPI correlates of verbal-intellectual deficits in patients with left hemisphere lesions.

This study investigated the emotional adjustment of patients (N = 31) with left hemisphere damage (LHD) as a function of the degree of impairment in verbal intelligence as measured by the Wechsler Adult Intelligence Scale. A multivariate comparison was made of the composite MMPI profiles of three groups of LHD patients classified according to Verbal IQ. The three groups produced fairly similar composite profiles, which indicated the presence of mild dysphoria, dissatisfaction, withdrawal, decreased initiative, and mild somatic preoccupations. Significant correlations emerged between the degree of verbal-intellectual disability and MMPI F, PT, SC, and SI. However, when the variance in MMPI scores due to premorbid status (education) was partialled out, these correlations dropped to nonsignificant levels. These findings failed to support previous studies that linked verbal deficits with emotional disturbance, and they underscore the importance of premorbid intelligence in the psychological adjustment to organic impairment.

Adult↗

PubMed1992

Fragile X family with unusual digital and facial abnormalities, cleft lip and palate, and epilepsy.

We present a fragile X family with unusual clinical manifestations. These findings, which often occur in the X-linked FG syndrome, include minor limb anomalies, cleft lip and palate, characteristic facial appearance, gastrointestinal problems and epilepsy, and intellectual disability. In a total sample of 54 fra(X) families, the frequency of minor limb anomalies was estimated to be 32% in the affected males and 19% in the female heterozygotes. These anomalies tend to occur in several members of the same family, where some craniofacial abnormalities reported as characteristic of the FG syndrome have also been encountered. Possible mechanisms for the occurrence of these unusual manifestations in the fra(X) families are discussed.

Abnormalities, Multiple↗

PubMed2026

35 Individuals With HUWE1-Related Neurodevelopmental Disorder and Suggested Clinical Evaluations.

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well as additional multisystemic findings. Intrauterine growth restriction (IUGR) and feeding difficulties were common in the neonatal period. It is notable that nearly all females had de novo variants, and males had de novo or inherited variants from clinically unaffected carrier mothers. Three genetic hotspots were identified in evolutionarily conserved regions of HUWE1 that have clinical impact. This report provides additional characterization of the spectrum of HUWE1-related neurodevelopmental disorder (HNDD).

Humans↗

PubMed2026

Add-on treatment with vinpocetine reduces seizure frequency and improves comorbidities in patients with loss-of-function γ-aminobutyric acid type A receptor variants.

OBJECTIVE: The semisynthetic compound vinpocetine has gained attention as a potential precision medicine for developmental and epileptic encephalopathies caused by loss-of-function (LoF) variants in γ-aminobutyric acid type A (GABAA) receptor genes. As a positive allosteric modulator of GABAA receptors, case reports suggest that vinpocetine can reduce epileptiform activity and seizure frequency, while improving cognitive function in patients with GABAA receptor-related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. METHODS: Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. RESULTS: Nine patients harboring eight GABAA receptor LoF variants were given add-on vinpocetine treatment. Electrophysiological analyses confirmed dose-dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5 years (range = 6-29) continued treatment for a median of 24 months (range = 12-90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure-free, and two experienced a 50%-55% reduction. Electroencephalograms demonstrated improved spike-wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. SIGNIFICANCE: Adjunctive vinpocetine shows promise as a targeted therapy for patients with GABAA receptor LoF variants, decreasing seizure frequency and positively impacting nonseizure factors, with only mild AEs reported. Vinpocetine may be a safe and effective therapy for patients with GABAA receptor-related epilepsies, which should be investigated further in future N-of-1 trials.

Humans↗

PubMed2026

Phenotypic and transcriptomic characterization of biallelic RNU2-2 developmental and epileptic encephalopathy.

OBJECTIVE: A significant proportion of individuals with suspected genetic developmental and epileptic encephalopathies (DEEs) remain unsolved following whole genome sequencing (WGS). Here we describe biallelic RNU2-2 variants causing a recently reported, severe, recessive DEE. METHODS: We screened individuals who have received WGS analyses at the Genomic Medicine Centre Karolinska for Rare Diseases for biallelic RNU2-2 variants. Deep phenotyping was performed through reviewing entire medical histories and phenotypic traits were transcribed to their corresponding Human Phenotype Ontology (HPO) term. HPO terms were used to generate pairwise phenotypic similarity scores and assess for significantly shared phenotype enrichment in the RNU2-2 sub-cohort. RNA sequencing analyses were performed in fibroblast and blood tissues to compare splicing events between RNU2-2 individuals and two independent control groups. RESULTS: We identified 14 individuals from nine families with 12 ultra-rare biallelic RNU2-2 variants clustering in the conserved 5' domains. Genotype data from 13 of 14 individuals has been reported previously as part of a larger cohort. All individuals presented with a highly concordant, severe DEE, characterized by severe to profound intellectual disability, inability to walk or communicate, hyperkinesia, and refractory seizures. Infantile spasms and tonic seizures were the predominant seizure types and a Lennox-Gastaut syndrome-like phenotype was common. These individuals had a significantly similar phenotypic signature when compared with 703 individuals with complex pediatric epilepsies (two-sided Monte Carlo permutation test, p = .005). RNA sequencing analyses showed aberrant splicing, with the most pronounced effects in fibroblast tissues in mutually exclusive exon and alternate 3' splice-site events, which were not detectable in blood. SIGNIFICANCE: We present deep phenotyping data and transcriptomic analyses that provide support for rare, 5' clustering biallelic RNU2-2 variants causing this novel, severe DEE. We propose an RNA sequencing methodology on fibroblast tissue for future validation of RNU2-2 variants.

autosomal recessive disease↗

PubMed2026

Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and KV4.3 Functional Loss.

BACKGROUND: Spinocerebellar ataxia type 19/22 (SCA19/22) is a rare autosomal dominant neurodegenerative disorder caused by KCND3 variants encoding the KV4.3 potassium channel. While most pathogenic variants result in loss-of-function (LOF), no pathogenic variants were previously identified in the channel's selectivity filter, a critical domain for ion selectivity. OBJECTIVES: To elucidate the genetic cause and functional LOF mechanisms underlying severe early-onset cerebellar ataxia and neurodevelopmental impairment in monozygotic twins. METHODS: We evaluated twins presenting with early-onset cerebellar ataxia, developmental delay, and cognitive impairment. Whole-exome sequencing (WES) identified a KCND3 c.1103T>C (p.L368P) variant. Functional impacts were assessed through HEK293T cell protein expression, Xenopus oocyte electrophysiology, and structural homology modeling. RESULTS: WES identified a heterozygous de novo p.L368P variant in the "TLGYG" selectivity filter sequence. Modeling predicted a pore radius reduction, blocking potassium permeation. Biochemical analyses revealed markedly reduced protein expression and impaired trafficking. Electrophysiological recordings confirmed complete potassium current loss and a strong dominant-negative effect on wild-type KV4.3 currents. Clinically, the twins exhibited severe intellectual disability, developmental delay, and cerebellar atrophy with pontine flattening, without epilepsy. CONCLUSIONS: Identifying the first pathogenic variant in the KV4.3 selectivity filter highlights its critical role in channel proteostasis and ion conductance. The p.L368P variant produces a pronounced LOF phenotype and broadens the SCA19/22 clinical spectrum, indicating the filter's structural integrity is a key determinant of disease severity. © 2026 International Parkinson and Movement Disorder Society.

KCND3↗

PubMed2026

Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis.

BACKGROUND: Biallelic variants in VPS41, encoding a subunit of the HOPS complex, cause autosomal recessive spinocerebellar ataxia 29 (SCAR29), a rare neurodevelopmental disorder with an incompletely defined phenotypic and molecular spectrum. METHODS: We investigated a 24-year-old man with cerebellar ataxia, hypotonia, and intellectual disability. Exome sequencing identified four candidate VPS41 variants. Because maternal DNA was unavailable, long-read genome sequencing was performed to determine allelic configuration, followed by RNA and protein analyses. RESULTS: In addition to typical SCAR29 features, the patient showed previously unreported findings, including swan-neck deformities and pes cavus. Long-read genome sequencing demonstrated that two VPS41 variants were in trans. RNA analysis revealed distinct splicing consequences: one allele produced an out-of-frame transcript predicted to undergo nonsense-mediated decay, whereas the other generated an in-frame exon-skipped transcript. These complementary defects reduced VPS41 expression at both transcript and protein levels, supporting pathogenicity and variant reclassification. CONCLUSION: Our findings expand the phenotypic spectrum of VPS41-related disease and highlight the value of long-read allelic resolution in clarifying pathogenic mechanisms in rare genetic disorders.

Humans↗

PubMed2026

Clinical Utility of Trio Exome Sequencing in Rwandan Children With Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial genetic and phenotypic heterogeneity. However, populations of African ancestry remain underrepresented in genomic studies, limiting understanding of ASD genetic architecture. This study aimed to characterize rare, clinically relevant genetic variants in a Rwandan pediatric ASD cohort using trio-based whole-exome sequencing (WES). METHODS: Trio-based WES was performed in 31 Rwandan pediatric patients with ASD (aged 2-18 years) and their parents. Variants were analyzed using a trio-based workflow and classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Eleven candidate variants were identified in 9 of 31 patients, including four likely pathogenic variants and seven variants of uncertain significance. This resulted in a diagnostic yield of 12.9% (4/31), expanded to 29.0% when phenotypically concordant variants of uncertain significance were considered. Most likely pathogenic variants were identified in individuals with syndromic ASD who presented with intellectual disability, epilepsy, and global developmental delay. Likely pathogenic findings included two single nucleotide variants in GABRB3, SYNGAP1, and two copy-number variants involving the GNAS locus and chromosome 1p35.3-p35.2. CONCLUSIONS: The diagnostic yield observed in this cohort is consistent with previous trio-based WES studies of ASD. The findings support the clinical utility of WES for the genetic evaluation of ASD and underscore the need for expanded genomic studies in African populations.

Humans↗

PubMed1991

Phenylketonuria does not cause cataracts.

In a study of 46 adults aged 28-71 years with untreated phenylketonuria (PKU) there were 3 (6.5%) with cataracts. This incidence was similar to that in the Australian population and in a control series of intellectually disabled adults. Only two of the PKU patients with cataracts could be examined by slit-lamp biomicroscopy and in both the findings suggested that the prolonged use of phenothiazines may have played a role. Slit-lamp examination of a further ten untreated PKU patients and 13 PKU adults who had been treated in childhood revealed only small lens opacities (in 40%) of a type found in 72.7% of a control group. The study provides no support for claims that PKU can cause cataracts.

Adult↗

PubMed1992

Concentrations of monoamines and their metabolites in the cerebrospinal fluid from patients with senile dementia of the Alzheimer type and vascular dementia of the Binswanger type.

We measured the concentrations of total (conjugated and unconjugated) monoamines (dopamine, DA; norepinephrine, NE) and monoamine metabolites (homovanillic acid, HVA; 3-methoxy-4-hydroxyphenyleneglycol, MHPG; 5-hydroxyindoleacetic acid, 5-HIAA) in the cerebrospinal fluid (CSF), using HPLC-ECD in 11 patients with Alzheimer's disease (AD) or senile dementia of the Alzheimer type (SDAT), 17 patients with vascular dementia of the Binswanger type (VDBT), and 15 controls. In AD/SDAT, there was a significant decrease in the DA concentration and a significant increase in the MHPG concentration. The average NE concentration was not altered, but significantly increased with the progression of intellectual disability. There were no significant changes in HVA and 5-HIAA concentrations. Patients with VDBT showed a significant increase in the DA concentration and a significant decrease in HVA and 5-HIAA concentrations. The DA concentrations increased significantly with the progression of dementia and ventricular enlargement. These results indicate that the noradrenergic and dopaminergic system in particular are altered in AD/SDAT, while the dopaminergic and serotonergic systems are mainly involved in VDBT.

Aged↗