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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↗

PubMed2005

Behavioral aspects of Angelman syndrome: a case control study.

Angelman syndrome (AS) is a rare congenital disorder characterized by impairments in intellectual, neurological and motor functioning and a postulated behavioral profile. This study compared behavioral characteristics of 62 individuals with genetically confirmed AS and 29 individuals with presumed AS from clinical features, with a control group of young persons with intellectual disability (ID) derived from an Australian epidemiological register. Twelve behavioral items from the developmental behavior checklist (DBC) were used for this comparison. The groups were matched for chronological age, gender, and level of ID. In the AS group, significant differences were found for 10 behaviors, with poor attention span and impulsivity being less common, and overactivity/restlessness, chewing or mouthing objects, eating non-food items, gorging food, food fads, fascination for water, hand flapping and sleep disturbance being more common. Interestingly, there was no difference in prevalence of unprovoked laughter. Comparison of the results of the genetically confirmed with the genetically unconfirmed AS cases showed no significant differences between individual behavior prevalence. These findings show that a "behavioral phenotype" of AS can be distinguished from others of similar level of ID, but it is different from that hitherto published. Abnormal food related behaviors, hyperactivity, fascination for water, hand flapping, and sleep disturbance should be included in a "behavioral phenotype" for AS. Apart from hyperactivity, "ADHD-type" behaviors are not more characteristic of AS than in ID generally. Therefore, the Consensus Criteria for the diagnosis of AS need to be reviewed.

Adolescent↗

PubMed2005

Mosaic monosomy of a neocentric ring chromosome maps brachyphalangy and growth hormone deficiency to 13q31.1-13q32.3.

We describe a boy with moderate intellectual disability associated with distinctive hand malformations (hypoplastic and angel-shaped middle phalanges) and partial growth hormone (GH) deficiency associated with mosaic deletion of 13q31.1-13q32.3. The deleted segment was mapped to a 20-Mb region bounded by BACs RP11-1143C2 and RP11-139C1, narrowing the previously described locus for hand malformations at this region and suggesting that a locus for GH deficiency is also present at this location. The deleted segment contains at least three candidate genes, glypican-5, FARP1 and SOX21, that may be contributing to the phenotype in this boy. In a significant proportion (approximately 50%) of cells, the deleted region is present as a supernumerary ring chromosome stabilized by the formation of a neocentromere at 13q31-q32, within a region with a known propensity for neocentromere formation. The ring chromosome appears to be prone to low-level misdivision and loss in vitro which, in vivo, must be countered by selection for the balanced karyotype because the level of mosaicism has remained stable over 13 years.

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↗

PubMed2003

Self-injurious behavior in rhesus monkeys: new insights into its etiology, physiology, and treatment.

Self-injurious behavior (SIB) is a significant human health problem frequently associated with profound intellectual disabilities, genetic diseases, and psychiatric conditions. However, it also occurs in subclinical populations and appears to be on the rise in adolescents and young adults. SIB is also seen in a small percentage of nonhuman primates that injure themselves through biting. We have begun to characterize SIB in rhesus monkeys to identify some of the risk factors associated with this disorder, and to determine the parallels with the human condition. In our study population, 14% of individually housed monkeys (the vast majority of which are males) have a veterinary record for self-inflicted wounding. Wounding is rare, but self-directed biting is common. SIB can be elicited during aggressive altercations and may be associated with husbandry events. Some monkeys appear to be more vulnerable to acquiring SIB. This increased vulnerability is associated with certain social experiences in the first 2 years of life and with exposure to a larger number of moderately stressful events as compared to controls. Monkeys with SIB also have a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, indicated by a blunted cortisol response to mild stressors. Our findings suggest that SIB may be a coping strategy to reduce arousal. Biting appears to rapidly lower an escalating heart rate. The potentially reinforcing effects of SIB may account for the failure of some treatment regimens. These findings are compared to studies of SIB in humans, and concordances are identified.

Aggression↗

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↗

PubMed2006

Cancer incidence of persons with Down syndrome in Finland: a population-based study.

Individuals with Down syndrome (DS) have a predisposition to leukaemia and testicular cancer, but data on the incidence of cancers are yet sparse. A cohort of 3,581 persons with DS was identified from a National Registry of Finnish persons with intellectual disability collected between 1978 and 1986 and followed-up for cancer incidence until 2002. Standardised incidence ratios (SIRs) were defined as ratios of observed number of cancer cases to those expected from the national cancer incidence rates, by age and sex. The overall cancer risk was equal to that of the general population, but a significantly high risk of leukaemia (SIR 10.5, CI 95% 6.6-15.8) and testicular cancer (SIR4.8, CI 95% 1.8-10.4) was found.

Adolescent↗

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↗

PubMed1996

Movement disorder in Down's syndrome: a possible marker of the severity of mental handicap.

This study examined the nature and prevalence of abnormal movements in adults with Down's syndrome and also the clinical correlates of orofacial dyskinesia and the relationship between dyskinesia and the level of functional and intellectual disability. Movement disorder, language age, and disability were assessed in an epidemiologically based sample of 145 individuals with Down's syndrome. Abnormal involuntary movements were common, with > 90% exhibiting dyskinesia, predominantly orofacial. Stereotypes were present in one-third of the sample. There was an association between the severity of dyskinesia and both current language age and functioning in terms of self-care and practical and academic skills, which suggested that dyskinesia may be a marker of the severity of mental handicap. The presence of dyskinesia was unrelated to neuroleptic exposure. Dyskinesia and stereotypies are very common in individuals with Down's syndrome and may represent an inherent manifestation of the disorder. The relationship between mental age and dyskinesia in Down's syndrome warrants further research.

Activities of Daily Living↗

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↗

PubMed2003

Spectrum of cognitive, behavioural and emotional problems in children and young adults with Down syndrome.

In comparison to most other groups with intellectual disability individuals with Down syndrome are at lower risk for significant psychopathology, although relative to their typically developing peers they have higher rates of behavioural and emotional problems. A total of 43 Down syndrome patients (21 females and 22 males), who ranged in age from 5.33 to 30.58 years, were examined for the presence of age-related changes in the spectrum of externalizing and internalizing problems. Intelligence tests included Hamburg-Wechsler-Intelligenz Test für Kinder III (HAWIK-III), Hamburg-Wechsler-Intelligenz Test für Erwachsene (HAWIE-R) and Kaufman-Assessment-Battery for Children, German Version (K-ABC). Behavioural and emotional problems were assessed by the the Strengths and Difficulties Questionnaire for Parents, German Version (SDQ) and the Clinical Assessment Scale for Child and Adolescent Psychopathology (CASCAP). IQ was significantly inversly related to the age of patients. Externalizing behaviours (dominant, opposing/refusing, impulsiveness, inattention and increased motor activity) were significantly higher in the 5-10 years old group, whereas internalizing behaviours (shy/insecure, low self confidence, decreased motor activity) where more prevalent in adolescents and adults (10-30 years). Possible relationships between this age-related changes and increased risks of later-onset psychopathology (depression and dementia) are discussed.

Adolescent↗

PubMed1994

Atelosteogenesis type III: a case report.

We present a case of rhizomelic dwarfism with clinical, radiographic and histologic features in keeping with atelosteogenesis type III (spondylohumerofemoral hypoplasia). Unlike most other skeletal chondrodysplasias presenting with neonatal dwarfism, a proportion of patients with atelosteogenesis type III may survive well beyond the neonatal period, and hence early identification of the condition is important. Our surviving patient further defines the radiographic features of the condition and the natural history and prognosis for physical and intellectual disability.

Bone Diseases, Developmental↗

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↗

PubMed2001

Developmental outcomes of newborn encephalopathy in the term infant.

Newborn encephalopathy is a clinically defined condition of abnormal neurological behaviours in the newborn period. Though most cases have their origin in the preconceptional and antepartum period, newborn encephalopathy represents a crucial link between intrapartum events and permanent neurological problems in the child. The birth prevalence of newborn encephalopathy ranges from 1.8 to 7.7 per 1000 term live births according to the definition used and the population to which it is applied. Few studies have investigated the outcomes of newborn encephalopathy other than for cases solely attributed to intrapartum hypoxia. These adverse outcomes range from death to cerebral palsy, intellectual disability, and less severe neurological disabilities such as learning and behavioural problems. Outcomes following newborn encephalopathy may vary from country to country with 9.1% of affected babies dying in the newborn period in Western Australia and 10.1% manifesting cerebral palsy by the age of two. These compare to a case fatality of 30.5% in Kathmandu and a cerebral palsy rate of 14.5% by one year of age. The study by Robertson et al which followed children with hypoxic ischaemic encephalopathy found an incidence of impairment of 16% among survivors assessed at 8 years with 42% requiring school resource room help or special classes. This review emphasises the great need for comprehensive clinical and educational assessment as these infants approach school entry to enable appropriate educational provisions to be made.

Brain Damage, Chronic↗

PubMed2004

Iodine deficiency and development of brain.

Iodine is a trace element essential for the synthesis of triodothyronine (T3) and thyroxine (T4). Inadequate intake of iodine leads to insufficient production of these hormones, which play a vital role in the process of early growth and development of most organs, especially the brain. The neurological sequele of iodine deficiency are mediated by thyroid hormone deficiency, varying from minimal brain function to a syndrome of severe intellectual disability. All the basic processes of neurogenesis: cellular proliferation, differentiation, migration, and selective cell death are impaired during period of brain growth spurt. Evidence suggests alterations in synaptology, neurons, myelin sheaths, glial cells, and morphology of cerebrum and cerebellum in severe iodine deficiency. Foetal thyroid ontogenesis occurs after the first trimester. Until then foetus is dependent on maternal T4. A thyroid dependent event important for subsequent brain development occurs in the beginning of the third trimester of pregnancy.

Animals↗