Mild-moderate Intellectual Disability Research Articles

CDK13-related disorder: a deep characterization of speech and language abilities and addition of 33 novel cases.

Speech and language impairments are central features of CDK13-related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and development in 41 individuals with CDK13-related disorder from 10 countries (male = 22, median-age 7 years 1 month, range 1-25 years; 33 novel). Most participants used augmentative and alternative communication (AAC) in early childhood (24/41). CAS was common (14/22). Performance varied widely across intellectual ability, social behaviour and expressive language skills, with participants ranging from within average through to the severely impaired range. Receptive language was significantly stronger than expressive language ability. Social motivation was a relative strength. In terms of abroader healthphenotype, a quarter had one or more of: renal, urogenital, musculoskeletal, and cardiac malformations, vision impairment, ear infections and/or sleep disturbance. All had gross and fine motor impairments (41/41). Other conditions included mild-moderate intellectual disability (16/22) and autism (7/41). No genotype-phenotype correlations were found. Recognition of CAS, a rare speech disorder, is required to ensure appropriately targeted therapy. The high prevalence of speech and language impairment underscores the importance of tailored speech therapy, particularly early access to AAC supports.

Life Story Narratives of Adults with Intellectual Disability and Mental Health Problems: Personal Identity, Quality of Life and Future Orientation

The narrative is a functional skill and a means for sharing stories which consist of a single event or events causally related to the individual’s past, present, and future. In this study we aimed to explore the narratives of a voiceless population in society and in research: adults with a dual diagnosis of intellectual disability (ID) and a mental health problem (MHP). Our operative goals were to explore the meaning of their lives as people with a dual diagnosis, their quality of life, and their aspirations for the future. The core questions of the study were: which type of disability is assimilated in their identity: ID, MHP, or both? What is their perception regarding their quality of life in the present and their horizon for the future? Our study was based on the three functions (the directive personal identity, a social function, and a directive/problem-solving function) of the Autobiographical Memory Model. We analyzed semi-structured interviews of twelve adults (aged 31-60) with mild-moderate ID and an MHP using mixed qualitative and quantitative methods. The findings yielded four themes: personal identity, directive problem-solving function, current quality of life, and future orientation. Wilcoxon analysis indicated that the MHP is more prominent in the participants’ personal identities. Thus, people with a dual diagnosis cannot bear the burden of two disabilities. The medical staff still exhibits a medical approach. Social theories such as the Multidimensional Insight Model, Stigma Theory, the Social Inclusion Model, and the Future Time Perspective Theory can serve as explanations.

Biallelic PAN2 variants in individuals with a syndromic neurodevelopmental disorder and multiple congenital anomalies.

PAN2 encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2 was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2. The affected individuals presented with significant overlap in their clinical features, including mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. Our data confirm that biallelic predicted loss-of-function variants in PAN2 cause a syndrome with multiple congenital anomalies, and suggest an important role of mRNA polyA tail length for proper organ formation.

EP296: Familial MECP2 variants: a report of 4 affected families highlighting the variable phenotypic spectrum and implications for genetic counseling

Pathogenic variants in MECP2 cause a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT; 312750). Although historically this was considered an X-linked dominant diagnosis with male lethality, it is now known that males can also be affected, with a disease spectrum ranging from severe neonatal encephalopathy to intellectual disability (ID). Other features commonly seen in RTT are inconsistently present in males. A qualified genotype-phenotype correlation exists, with variants that are known to cause RTT in females most often leading to more severe phenotypes in males. Additionally, whereas pathogenic MECP2 variants identified in affected females with classic and atypical RTT are most often de novo variants, pathogenic variants in males may be either de novo or maternally inherited. Here we report 4 novel families with pathogenic MECP2 variants. In all 4 families, the affected probands were male and maternal inheritance was identified. Family 1: The proband is a now 8-year-old male with mild global developmental delay, epilepsy, ataxia, and hypotonia. He also has significant anxiety. Epilepsy gene panel identified a hemizygous pathogenic variant in MECP2 (c.491C>T; p.Ala140Val); targeted testing confirmed maternal inheritance. His mother has no significant medical issues or learning issues, but endorses a history of anxiety. He has four clinically unaffected siblings; one brother has been tested and is negative. His other brother and sisters have not been tested. Family 2: The proband is a now 47-year-old male with mild-moderate intellectual disability. Genetic testing was initiated after MRI performed in the context an episode of confusion and shaking concerning for a panic attack revealed signal abnormalities in the bilateral cerebral peduncles possibly concerning for Fragile X Associated Tremor Ataxia Syndrome (FXTAS). He also experienced a motor regression and onset of dystonia after an episode of rhabdomyolysis in his mid 40’s and has not returned to baseline. Trio exome sequencing identified a maternally inherited hemizygous pathogenic variant (c.499C>T; p.Arg167Trp) in MECP2. Cascade testing identified that his sister and niece also both carry the familial MECP2 variant. His sister has a history of learning difficulties, significant anxiety, obsessive compulsive disorder, and has developed progressive spasticity with hyperreflexia and sustained clonus over time. His niece also has anxiety, obsessive compulsive disorder, and bipolar disorder. Family 3: The proband is a now 37-year-old male with mild intellectual disability and autism spectrum disorder. He also has a history of anxiety and depression. Trio exome sequencing identified a maternally inherited hemizygous pathogenic variant (c. 1136_1151del16; p.Pro379HfsX25) in MECP2. Testing was initiated after the onset of abnormal movements in his thirties suggestive of dystonia. Exam was notable for kyphosis and shuffling gait. His mother reports a history of anxiety, but no learning or cognitive concerns and no other neurologic symptoms. He has one clinically unaffected sister who has not yet been tested. Exome sequencing also identified a de novo, heterozygous c.1672C>T (p.Arg558Cys) variant of uncertain significance in ALDH18A1, though it is unclear whether or not this is contributing to his phenotype. Family 4: The proband is a now 8-year-old male who initially presented for evaluation due to concern for global developmental delay, hypotonia, and macrocephaly. Family history was unremarkable. MRI identified prominent perivascular spaces. Trio exome sequencing identified a maternally inherited likely pathogenic hemizygous variant (c.1244delC; p.Pro415LeufsX6) in MECP2. The proband’s younger brother subsequently presented with expressive language delay and was also macrocephalic. Targeted testing confirmed the presence of the familial MECP2 variant. These 4 familial reports of pathogenic MECP2 variants add to the data provided by previous publications describing the phenotypic spectrum in affected males and supporting that many of the variants may be maternally inherited. Affected male probands in all cases presented with developmental delay and/or intellectual disability. Only 1/4 probands had epilepsy. Anxiety was present in 3/4. Cascade testing identified carrier female relatives with a prominent neuropsychiatric phenotype in one family. Anxiety was also reported in the mothers of two other families, without any other cognitive or neurologic features. Although two families harbored pathogenic missense variants previously known to be associated with an X-linked intellectual disability phenotype, two families with mildly affected male probands and unaffected female carrier mothers had novel, predicted loss of function variants that would have been expected to result in a RTT phenotype. These families highlight the clinical variability that can be seen with pathogenic MECP2 variants and challenge reported genotype-phenotype correlations, providing important information for genetic counseling.

Mitochondrial bioenergetics of astrocytes in Fragile X syndrome: new perspectives on culture conditions and sex effects.

Fragile X syndrome (FXS) is a genetic disorder that is characterized by a range of cognitive and behavioral deficits, including mild-moderate intellectual disability. The disease is characterized by an X-linked mutation of the Fmr1 gene, which causes silencing of the gene coding for fragile X mental retardation protein (FMRP), a translational regulator integral for neurodevelopment. Mitochondrial dysfunction has been recently associated with FXS, with reports of increases in oxidative stress markers, reactive oxygen species, and lipid peroxidation being present in the brain tissue. Astrocytes, a prominent glial cell within the central nervous system (CNS), play a large role in regulating oxidative homeostasis within the developing brain and dysregulation of astrocyte redox balance in FXS, which may contribute to oxidative stress. Astrocyte function and mitochondrial bioenergetics are significantly influenced by oxygen availability and circulating sex hormones; yet, these parameters are rarely considered during in vitro experimentation. Given that the brain normally develops in a range of hypoxic conditions and FXS is a sex-linked genetic disorder, we investigated how different oxygen levels (normoxic vs. hypoxic) and biological sex affected mitochondrial bioenergetics of astrocytes in FXS. Our results demonstrate that both mitochondrial respiration capacity and reactive oxygen species emission are altered with Fmr1 deletion in astrocytes and these changes were dependent upon both sexual dimorphism and oxygen availability.

DDB1 binds histone reader BRWD3 to activate the transcriptional cascade in adipogenesis and promote onset of obesity.

Obesity has become a global pandemic. Identification of key factors in adipogenesis helps to tackle obesity and related metabolic diseases. Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity. Although typically recognized as a component of the CUL4-RING E3 ubiquitin ligase complex, DDB1 stimulates adipogenesis independently of CUL4. A DDB1 mutant that does not bind CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient cells. Ddb1+/- mice show delayed postnatal development of white adipose tissues and are protected from diet-induced obesity. Mechanistically, by interacting with BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of ELK1 downstream immediate early response genes and facilitates the release of paused RNA polymerase II, thereby activating the transcriptional cascade in adipogenesis. Our findings have uncovered a CUL4-independent function of DDB1 in promoting the transcriptional cascade of adipogenesis, development of adipose tissues, and onset of obesity.

A cross-sectional cariogram-based comparison of caries risk profile in children with various levels of intellectual disability.

To compare the caries risk profile in children with mild, moderate, and severe intellectual disability (ID) using cariogram. A cross-sectional study was conducted to compare caries risk profile using cariogram among 150 children aged 6-18 years, with various levels of ID (50 each in Mild ID, Moderate ID, and Severe ID groups), attending special schools in Bengaluru city. The risk assessment consisted of: a questionnaire, an interview, estimation of oral hygiene, saliva sampling, microbial evaluation and clinical examination. Statistical analysis of the results obtained was performed using Chi-square/Fischer's exact test, Kruskal-Wallis test and Mann-Whitney test. The overall comparison showed significant differences between the groups across all parameters except diet (P = 0.131), fluoride exposure (P = 1), salivary flow rate (P = 0.3), and buffer capacity (P = 1). Caries risk was high among children with severe intellectually disability while the actual chance to avoid caries was found to be high in the Mild ID group. Bacteria was one of the dominant caries risk sectors followed by susceptibility, circumstances, and diet. Cariogram can be used as an effective tool in assessing caries prediction, thus aiding in identifying different risk groups in a community so that appropriate preventive measures can be implemented to overcome the caries risk.

Exploring the vividness of mental imagery and eidetic imagery in people with intellectual disability (ID) in comparison with typically developing (TD) individuals

BackgroundMental imagery (MI) has been described as the “ability to simulate in the mind information that is not currently being perceived by the sense organs” (Moran, 2012, p. 166). The vividness of mental imagery has been defined as the clarity, brightness, or intensity of an image as reported by the individual (Marks, 1973). There are many studies conducted on vividness in typically developing (TD) individuals, however, no attempt has been made either to assess the vividness of mental imagery in people with intellectual disability (ID) or compare it with that of typically developing (TD) adults. MetodsA vividness of imagery test (comprising a modified version of the Vividness of Visual Imagery Questionnaire 2, (VVIQ-2; Marks, 1995), and two items of the Age Projection Test, (APT; Ahsen, 1988) were administered to participants with mild, moderate, and severe ID. Their performance on the vividness scale was compared with typically developing individuals. Measures for cognitive and adaptive functioning were administered to ascertain the ID level of participants. ResultsThe results of this study reveal a non-significant group difference between people with mild ID, moderate ID, and TD on the vividness of mental imagery and eidetic imagery. People with severe ID performed significantly lower than the other three groups. ConclusionDespite their cognitive impairment, a non-significant difference between the performance of people with mild and moderate ID and typically developing individuals on imagery vividness scale is noteworthy.

Is it feasible to assess self-reported quality of life in individuals who are deaf and have intellectual disabilities?

PurposeThere is consensus that Quality of Life (QOL) should be obtained through self-reports from people with intellectual Disability (ID). Thus far, there have been no attempts to collect self-reported QOL from people who are deaf and have ID.MethodsBased on an established short measure for QOL (EUROHIS-QOL), an adapted easy-to-understand sign language interview was developed and applied in a population (n = 61) with severe-to-profound hearing loss and mild-to-profound ID. Self-reports were conducted at two time points (t1 and t2), 6 months apart. The Stark QOL, an established picture-based questionnaire, was also obtained at t2 and three Proxy ratings of QOL (from caregivers) were conducted for each participant at t1.ResultsSelf-reported QOL was successfully administered at both time points for 44 individuals with mild and moderate ID (IQ reference age between 3.3 and 11.8 years).The self-reports showed sufficient test–retest reliability and significant correlations with the Stark QOL. As anticipated, self-reported QOL was higher than proxy-reported QOL. Test–retest reliability and internal consistency were good for self-reported QOL.ConclusionReliable and valid self-reports of QOL can be obtained from deaf adults with mild-moderate ID using standard inventories adapted to the linguistic and cognitive level of these individuals.

ZMYND11-related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum.

Pathogenic variants in ZMYND11, which acts as a transcriptional repressor, have been associated with intellectual disability, behavioral abnormalities, and seizures. Only 11 affected individuals have been reported to date, and the phenotype associated with pathogenic variants in this gene have not been fully defined. Here, we present 16 additional patients with predicted pathogenic heterozygous variants in including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11-related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild-moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense-mediated decay. Two ZMYND11 variants located in the final exon-p.(Gln586*) (likely escaping nonsense-mediated decay) and p.(Cys574Arg)-are predicted to disrupt the MYND-type zinc-finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss-of-function.

Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth-intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.

Establishing the concurrent validity of the Clinical Outcome in Routine Evaluation-Learning Disabilities scale

PurposeIndividuals with an intellectual disability (ID) develop mental health difficulties at similar rates to individuals in the general population. Using Patient Reported Outcome Measures can help track deterioration and improve the outcomes of individuals seeking help for their difficulties. The Clinical Outcome in Routine Evaluation-Learning Disabilities (CORE-LD) is a multi-trait measure of psychological distress which has shown moderate test-rest reliability. However, the CORE-LD is yet to be validated for the population it was designed for. Therefore the purpose of this paper is to establish the concurrent validity of the CORE-LD in a population of individuals with a diagnosis of mild–moderate ID.Design/methodology/approachParticipants with a diagnosis of mild–moderate ID, as well as other co-morbidities, were recruited from two UK inpatient hospitals and asked to complete the CORE-LD and its general population counterpart the Clinical Outcome in Routine Evaluation-Outcome Measure (CORE-OM).FindingsStatistically significant differences were found regarding the CORE-LD across gender, with females scoring higher on the CORE-LD than males. There was no significant difference between security levels. The overall mean scores on each measure were moderately correlated. The data from this analysis suggest a significant positive correlation (rs=0.68).Originality/valueThis initial study’s findings have demonstrated the CORE-LD may have concurrent validity, and further replication studies in larger and more diverse samples are needed.

Clinical features and genetic characteristics of myoclonic-atonic epilepsy caused by SLC6A1 gene mutation

Objective To explore the clinical features and genetic characteristics of myoclonic-atonic (MAE) caused by gene mutation. Methods The clinical data of a patient with gene mutation from Xiangya Hospital of Central South University was collected. The related literatures were reviewed from Wanfang Data, China National Knowledge Infrastructure, PubMed (until July 2019) by using keywords SLC6A1 and myoclonic-atonic epilepsy . The characteristics of gene mutation and the clinical phenotype of children with myoclonic-atonic were summarized. Results A 8 year and 8 months old girl was enrolled in the study. Her first attack happened at the age of 19 months, and multiple seizure types including myoclonic-atonic, atonic and absence were observed. The seizures were well controlled by valproate (VPA), but she has mild-moderate intellectual disability. Whole exome-sequencing study identified a de novo nonsense variant of c. 46G>T(p.Glu16*)in gene. A total of 27 cases including the present case with gene mutation were analyzed. 22 mutations were identified, including 11 missense mutations, 5 nonsense mutations, 3 frameshift mutations, 2 splicing mutation and 1 with chromosome microdeletion. Among them 26 patients had more one type of seizures, 20 cases had absence seizures, 17 cases had atonic seizures, 14 cases had myoclonic seizures, 11 cases had myoclonic-atonic seizures, 4 cases had generalized tonic-clonic seizures, 3 cases had eyelid myoclonias, 2 cases had nonconvulsive status epilepticus and 2 cases had tonic seizure. 24 patients had described intelligence assessment. Among them, 18 had developmental delay before onset, 11 had developmental regression after onset. There were 9 cases with autistic features, 4 cases with attention deficit hyperactivity disorder and 3 cases with ataxia. The seizures of 17 cases were controlled, 4 cases had partial seizure control, 3 cases had no significant improvement, and other 3 cases were unclear. Conclusions The main clinical feature of MAE patients with gene mutations is absence and atonic seizures, cognition before onset can be impaired, and some patients had behavioral problems, such as autistic features or attention deficit hyperactivity disorders. VPA is recommend as first-line treatment. Key words: Epilepsies, myoclonic; Epilepsy, absence; Glucose transporter type 1; Mutation; Child

Effect of arts based therapy on functionality of children with intellectual disability

Background: To explore the effect of arts based therapy on basic skill level and behavior parameters as measured by Behavior Assessment Scale for Indian Children with Mental Retardation (BASIC-MR) and performance on Arts-Based Therapy (ABT) rating scale in children with intellectual disability (ID). Method: Six children (4 males) aged 5 to 13 years with mild-moderate intellectual disability underwent individualized ABT modules with music, rhythm, drama and visual arts in a child friendly academic environment for 9 months. BASIC-MR and ABT rating scale were administered quarterly till the end of study. Results: Median (range) BASIC-MR scores for basic skill level, BASIC-MR behavior score and ABT rating scale score at 3, 6 and 9 months were 725(349-1208), 855(389-1262) and 936(432-1291); 14(0-22), 6(0-14) and 3(0-16) and 16(12-23), 20(13-26) and 23(15-29) respectively (p< 0.05 by Friedman test for all) indicating steady improvement in the skill scores as measured by BASIC-MR & ABT rating scale at 3,6 and 9 months. Posthoc analysis showed that these improvements were steady across the quarters. Conclusion: ABT results in a medium-term improvement in skill, behavior and ABT parameters in children with ID. This study suggests the need for restructuring remedial education to include performing and visual arts.

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

Exercise interventions to improve balance for young people with intellectual disabilities: a systematic review and meta-analysis.

To conduct a systematic review and meta-analysis of the effects of exercise interventions designed to improve balance in young people with intellectual disabilities. A systematic literature search was performed on 10 databases. Studies in press or published in English in a peer-reviewed journal were included if: (1) participants were young people with intellectual disabilities; (2) exercise interventions were designed to improve balance; and (3) they used quasi-experimental or experimental designs. Studies focusing only on a specific subpopulation of young people with intellectual disabilities or having a specific physical characteristic were excluded. Risk of bias was assessed for randomization, allocation sequence concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases. The search strategy identified 937 articles and 15 studies, published between 1991 and 2017, that met the inclusion criteria. Exercise intervention groups showed a significant and larger improvement in static (pooled effect size, Hedges' g=0.98) and dynamic (g=1.34) balance compared with the control groups. However, although the pooled improvement of static-dynamic balance was large (g=2.80), the result was non-significant. None of the subgroup analyses were significant, except for the improvement in: (1) static balance (higher in quasi-experimental than in experimental studies); and (2) dynamic balance (higher in young people with a mild vs a mild-moderate intellectual disability). The reviewed exercise interventions seem to represent an effective means for improving the static and dynamic balance of young people with intellectual disabilities. However, the present findings should be considered as preliminary given the small number of studies and their limitations. Exercise intervention results in large and significant improvements in static and dynamic balance in young people with intellectual disabilities. Exercise intervention results in a large but non-significant improvement in static-dynamic balance. Static balance improvement was significantly higher in quasi-experimental versus experimental studies. Dynamic balance improvement was significantly higher in young people with mild versus mild-moderate intellectual disability. No significant differences related to age group, balance measures, and components of exercise intervention were found.

High Incidence of Copy Number Variants in Adults with Intellectual Disability and Co-morbid Psychiatric Disorders

A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs—including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1—providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services.

Rate and characteristics of urgent hospitalisation in persons with profound intellectual disabilities compared with general population

Little is known about the hospitalisation rate of adults with severe/profound intellectual disability (PID) presenting at emergency services or about the appropriateness of hospital admissions in this population. Examining the possible differences in the patterns of hospitalisation between people with PID and those without intellectual disability (ID) may shed light on aspects of health and illness in these patients and may in turn make it possible to differentiate more clearly between mild-moderate ID and PID. After an evaluation of the emergency visits made by adults with PID and by people without ID, patients in both groups requiring one or more hospitalisations were subsequently followed up for 18months. The appropriateness of the decision to hospitalise was assessed using the ambulatory care-sensitive conditions index. There were no differences in the proportion of people with PID and controls admitted to hospital after their emergency visit. The median hospital stay was higher for PIDs: 7.5 vs. 4days for controls. People with PID were admitted more than controls for respiratory reasons and somewhat less for other somatic causes unrelated to the nervous system. There were no admissions for psychiatric causes in the group with PID other than unspecified conduct disorders. There were no differences in other diagnostic groups. The rate of inappropriate admissions was similar in the two study groups. In contrast to previous results reported for the group with ID as a whole, patients with PID consulting the emergency service were not admitted to hospital more frequently than the general population nor did they present a higher rate of inappropriate admissions. These results support the utility of maintaining two distinct groups of people with ID: mild-moderate and severe-profound.

Increased Evoked Potentials and Behavioral Indices in Response to Pain Among Individuals with Intellectual Disability

Previous studies on the sensitivity and reactivity to pain of individuals with intellectual disability (ID) are inconsistent. The inconsistency may result from the reliance on self-reports and facial expressions of pain that are subject to internal and external biases. The aim was therefore to evaluate the reactivity to pain of individuals with ID by recording pain-evoked potentials (EPs), here for the first time, and testing their association with behavioral pain indices. Forty-one healthy adults, 16 with mild-moderate ID and 25 controls. Subjects received series of phasic heat stimuli and rated their pain on self-report scales. Changes in facial expressions and in pain EPs were recorded and analyzed offline. Pain self-reports, facial expressions, and the N2P2 amplitudes of the EPs exhibited stimulus-response relationship with stimulation intensity in both groups. The facial expressions and N2P2 amplitudes of individuals with ID were increased and N2P2 latency prolonged compared with controls. N2P2 amplitudes correlated with self-reports only in controls. Individuals with ID are hypersensitive/reactive to pain, a finding bearing clinical implications. Although pain EPs may reflect a somewhat different aspect of pain than the behavioral indices do, there is evidence to support their use to record pain in noncommunicative individuals, pending further validation.

Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation.

BackgroundWe report striking and unanticipated improvements in maladaptive behaviours in Prader–Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild–moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia.MethodsThree individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post‐implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly.ResultsVagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food‐seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours.ConclusionsWe propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally.