Intellectual Disability Patient Research Articles

Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability

Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary proteins that regulate crucial aspects of receptor function. Here, we investigate a mutant form of the TARP family member stargazin, described in an ID patient. Molecular dynamics analyses predicted that the ID-associated stargazin variant, V143L, weakens the overall interface of the AMPAR:stargazin complex and impairs the stability of the complex. Knock-in mice harboring the V143L stargazin mutation manifest cognitive and social deficits and hippocampal synaptic transmission defects, resembling phenotypes displayed by ID patients. In the hippocampus of stargazin V143L mice, CA1 neurons show impaired spine maturation, abnormal synaptic transmission and long-term potentiation specifically in basal dendrites, and synaptic ultrastructural alterations. These data suggest a causal role for mutated stargazin in the pathogenesis of ID and unveil a new role for stargazin in the development and function of hippocampal synapses.

Healthcare workers' experiences of caring for patients diagnosed with intellectual disability co-occurrent with psychiatric disorders.

WHAT IS KNOWN ON THE SUBJECT?: Intellectual disability (ID) involves problems with general mental abilities and affects intellectual functioning and adaptive functioning. People diagnosed with ID present higher levels of functional disability, which means they usually have difficulty or the inability to independently perform basic activities of daily living. Little to no attention has been paid to the issues of the mental health of people diagnosed with ID. Specifically, healthcare workers' experiences of caring for patients with IDPD have been neglected. WHAT DOES THE PAPER ADD TO EXISTING KNOWLEDGE?: The findings increase our understanding and partially address the knowledge gap regarding the situations and circumstances faced by healthcare workers in caring for patients diagnosed with intellectual disability co-occurrent with psychiatric disorders (IDPD). In cases of insufficient staffing, healthcare workers may be forced to ignore the individualized needs of patients so as to facilitate management. Healthcare workers may also feel frustrated by not being able to anticipate or deal with patients' unexpected problem behaviours or accidents. They adapt by adjusting their expectations of their patients. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Healthcare administrators need to understand the difficulties faced by staff in caring for patients diagnosed with IDPD, arrange appropriate in-service education to increase the healthcare workers' knowledge and skills in caring for patients diagnosed with IDPD, and create warm and supportive environments for them. The government department responsible for the management of ID patient care institutions should be able to regularly monitor the overall staffing and quality of care in these institutions. ABSTRACT: Introduction When intellectual disability co-occurs diagnosed with psychiatric disorders (IDPD), the impact of the burden of illness on the affected individuals, their caregivers, their family and friends, and the services that provide for them is particularly high. The issues of the mental health of people diagnosed with ID have received little, if any, attention. One specific area of neglect is healthcare workers' experiences of caring for patients diagnosed with IDPD. Aim The aim of this study was to understand healthcare workers' experiences of caring for patients diagnosed with IDPD. Methods A qualitative descriptive research approach and semi-structured interviews were used in this study. We interviewed 15 participants who had experience in caring for patients diagnosed with a dual diagnosis of IDPD. Findings Four themes were found, as follows: (1) Negative impacts of insufficient staffing on the quality of care, (2) Constantly worrying about harmful incidents, (3) Discovering effective ways to provide individual patient care and (4) Adjusting expectations and attitudes towards patients. Participants' experiences revealed that they perceived the importance and effectiveness of providing individualized care for IDPD patients. However, when staffing is insufficient, they may be forced to ignore the individualized needs of patients so as to facilitate management. They may also feel frustrated by not being able to anticipate or deal with patients' unexpected problem behaviours or accidents. In addition, they adapt by adjusting their expectations of the patients. Discussion The findings from this research help to fill the knowledge gap in our understanding of healthcare workers' experiences of and their perspectives on caring for patients diagnosed with IDPD. Implications for Practice Healthcare administrators need to understand the difficulties faced by staff in caring for patients diagnosed with IDPD, arrange appropriate in-service education to increase the healthcare workers' knowledge and skills in caring for patients diagnosed with IDPD, and create warm and supportive environments for them. The government department overseeing the management of institutions providing ID patient care should be empowered to conduct regular monitoring of the overall staffing and quality of care in such institutions.

Generation of an iPSC line (CHWi001-A) from peripheral blood mononuclear cells in a patient with intellectual disability and haploinsufficiency of PLPPR4.

Intellectual disability (ID) is a highly inherited neurodevelopmental disorder. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) in a patient with intellectual disability and carrying a haploinsufficiency for PLPPR4. This iPSC line offers a useful resource to investigate the pathogenesis and molecular mechanisms involved in PLPPR4-related ID.

Intellectual disability; an example of not relying on karyotype or array comparative genomic hybridization alone

Intellectual disability (ID) is a heterogeneous disorder which could have different etiologies. Among these etiologies, genetic causes are important issues. Genetic and pediatric guidelines have suggested using comparative genomic hybridization (CGH) as the first tire test for the diagnosis of such patients. However, in some ID cases such as our patient, we have demonstrated that considering both CGH array and karyotyping without any superiority would be beneficial. In the present report, we demonstrated an ID patient with rare chromosomal abnormalities reported in both conventional karyotype and CGH array.

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Movement Disorders in Adults With Intellectual Disability and Behavioral Problems Associated With Use of Antipsychotics?

__To the Editors:__ We read with great interest the article by Scheifes and colleagues about movement disorders in adults with intellectual disability (ID) and behavioral problems associated with the use of antipsychotics. The authors examined movement disorders in this population. The study shows that 44% of the study populationwith ID and behavioral problems had at least 1 movement disorder (parkinsonism, dyskinesia, akathisia, and dystonia). These results are in line with research in other populations. High prevalence of movement disorders among psychiatric patients using antipsychotics is already known. The conclusion of this study is that the prevalence of movement disorders in people with ID and behavioral problems is high, especially in ID patients using antipsychotics. Current use of antipsychotic drug and a dose in target range seems significantly associated with the risk of having thesemovement disorders. However, in our opinion, there are limitations in the validity of the instruments and the design of the study that compromise the validity of the conclusions. The best available instruments are used despite the limited number of standardized assessments for this population. Unfortunately, the validity of these instruments is unknown for people with ID. In addition, there are avoidable omissions in other measurements that may have biased the results. Information about the medical history of the participants is missing; it is essential to know if the participants had the movement disorder at the moment of their admission in the centers. Other medication use is not included in the analysis, although it was reported. This information is important because it is also known that other medications, such as dopamine receptor blockers, antidepressants, and antiepileptics, can cause these movement disorders. Several cross-sectional studies about movement disorders in ID patients have been performed in the past few years (Table 1). None of these studies are generalizable. In the study population of Scheifes et al, the intelligence quotient (IQ) is much higher compared with the general ID population. It could be that the level of ID influences the prevalence of movement disorders. Because of a lack of valid measurements, several tools are used in different studies. Therefore, the comparison of the study results is difficult. This highlights the need for uniform instruments that are valid, reliable, practical, and feasible in the ID population. There are only 3 instruments developed and validated in people with ID, these are as follows: Akathisia Ratings of Movement Scale for akathisia (ARMS), Dyskinesia Identification System Condensed User Scale (DISCUS) for dyskinesia, and Matson Evaluation of Drug Side Effects (MEDS) for overall adverse effects of psychotropic drugs. In the case of other movement disorders, there are no instruments that are validated for the ID population. More research is needed to acquire valid instruments and subsequently reach consensus on recommended instruments. In the study population of Scheifes et al, most patients have a Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV) classification, and antipsychotics are used on-label, comparable with the studies of Matson et al and Fodstad et al. In the conclusion of Scheifes et al, the results are compared with the study of de Kuijper et al, but these participants use the antipsychotics off-label as shown in Table 1. Therefore, these populations are not comparable. It is still unclear if antipsychotics cause movement disorders in the ID population. It could be a result of the ID itself, an adverse effect of the antipsychotics, or a result of the psychiatric disease. Studies done in this field are all cross-sectional (Table 1), and none of them examined the presence of movement disorders before the start of antipsychotics. Only Fodstad et al compared the use of antipsychotics in patients with or without a psychiatric disorder; the limitation of the study was a small number of participants. A long-term prospective follow-up study with different ID patient groups (eg, adults with ID with on-label use, off-label use, and without antipsychotics use) is needed. That study would be composed of an assessment of movement disorders before the start of antipsychotics, during follow-up, and after the discontinuation of antipsychotic use. In addition, there could be a control group with ID and behavioral problems but without antipsychotic use. In this way, a causal relationship could be demonstrated. In conclusion, further research is needed to develop instruments that diagnose movement disorders that are valid, reliable, practical, and feasible in the ID population.With these instruments, a prospective follow-up study can be done. This subject should no longer be on the sidelines of evidence-based medicine, because it has a great impact on the quality of life of patients with ID.

Confirmation: A crucial step in copy number variation analysis after exome sequencing in intellectual disabilities

Intellectual disability (ID) comprises a group of mental disorders which have underlying genetic causes, among which the monogenic causes are one of the causes for ID. One kind of a monogenic cause is the copy number variations (CNVs). These CNVs can be indicated using exome sequencing (ES) and the CoNVex and CoNIFER algorithms. To confirm the possible causative CNVs quantitative PCR (QPCR) was used. In a Pakistani ID patient a homozygous deletion of ENTPD3 was indicated and in an Estonian ID patient CPVL-CHN2 a homozygous duplication was indicated. However the QPCR showed that ENTPD3 did not segregate and CPVL-CHN2 was only duplicated heterozygous. Confirmation, like QPCR, is therefore a crucial step in confirming CNVs analysis of ES in ID patients.

Heart transplantation in children with intellectual disability: An analysis of the UNOS database.

Heart transplantation in children with intellectual disability (ID) is an issue of debate due to the shortage of available donor organs. We sought to perform the first large-scale retrospective cohort study describing the prevalence and outcomes of heart transplantation in this population. The United Network of Organ Sharing database was queried from 2008 to 2015 for pediatric patients (age <19years) receiving first, isolated heart transplant. Recipients were divided into three subgroups: definite ID, probable ID, and no ID. The chi-square test was used to compare patients' baseline characteristics. Kaplan-Meier and Cox proportional hazard regression analyses were used to estimate the association between ID and death-censored graft failure and patient survival. Over the study period, 565 pediatric patients with definite (131) or probable (434) ID received first heart transplant, accounting for 22.4% of all first pediatric heart transplants (n=2524). Recipients with definite ID did not significantly differ from those without ID in terms of gender, ethnicity, ischemia time, severity of pretransplant condition (waitlist status, mechanical ventilation, inotrope dependence, ECMO, VAD, PVRI, infection prior to transplant), or incidents of acute rejection within the first year. ID was associated with prolonged waitlist time (P<.001). Graft and patient survival at 3years was equivalent between children with and without ID (P=.811 and .578, respectively). We conclude that intellectual disability is prevalent in children receiving heart transplants, with 22.4% of recipients over the study period having definite or probable ID. ID does not appear to negatively affect transplantation outcomes. Future studies are needed to assess long-term outcomes of transplantation in this population.

Prevalence and Outcomes of Liver Transplantation in Children With Intellectual Disability.

We sought to describe the prevalence and outcomes of liver transplantation in children with intellectual disability (ID). We hypothesized that recipients with ID have comparable short-term outcomes compared with those without ID. We performed a retrospective cohort analysis of children receiving a first liver-alone transplant in the United Network for Organ Sharing dataset from 2008 to 2013. Recipients with definite or probable ID were compared to children without ID using χ tests. Kaplan-Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between ID and graft failure and patient survival. During the study period, 254 children with definite (115) or probable (139) ID underwent first liver transplant, accounting for 15% of all first pediatric liver transplants (1721). Recipients with definite ID tended to be male have a metabolic indication for transplant, a lower pediatric end-stage liver disease score at listing than recipients with no ID, and were less likely to receive a living donor transplant. Recipients with ID were more likely to have public insurance and had more treatment-related hospitalizations in the first year than those without ID. Functional status tended to improve in all recipients at follow-up. ID was not significantly associated with patient or graft survival. Children with ID form a significant portion of total liver transplant recipients, and their short-term graft and patient survival are comparable with children without ID. Further research is needed to examine long-term outcomes of transplant in this population.

Caring for cancer patients with an intellectual disability: Attitudes and care perceptions of UK oncology nurses

PurposeCaring for people with cancer or an intellectual disability (ID) is stressful: little is known about the combined impact of caring for cancer patients with an ID, though this is expected to be especially challenging. MethodEighty-three nurses, working in oncology or a related field (i.e. palliative care) were recruited. Perceptions of caring for patients with and without an ID were measured, alongside potentially confounding information about participant demographic characteristics and perceived stress. ResultsParticipants felt less comfortable communicating with patients with an ID about their illness (F(1,82) = 59.52, p < 0.001), more reliant on a caregiver for communication (F(1,82) = 26.29, p < 0.001), and less confident that the patient's needs would be identified (F(1,82) = 42.03, p < 0.001) and met (F(1,81) = 62.90, p < 0.001). Participants also believed that caring for this patient group would induce more stress, compared with patients without an ID (F(1,81) = 31.592, p < 0.001). Previous experience working with ID patient groups appears to mitigate some perceptions about providing care to this population. ConclusionsCaring for cancer patients with an ID may intensify this, already difficult, role. Through training and knowledge exchange, oncology nurse's confidence in communication, providing appropriate care, and positivity towards this patient group may be improved.

Diagnosis of Attention Deficit Hyperactivity Disorder in Adults with Intellectual Disability: How Are We Doing with Diagnosis and Treatment?

Introduction Prevalence of ADHD among people with intellectual disability (ID) is higher than people without intellectual disability (Reilly & Holland 2010), however it appears to be underdiagnosed (Rose et al 2009). Objectives Describe the prevalence of ADHD in ID psychiatric clinics and patient characteristics in Surrey, UK. Method Patients' records in ID psychiatric clinics were audited. Results 14 patients attending ID clinics had a diagnosis of ADHD. Age range was 18 to 32. 85% were male. Prescribed ADHD medications were Concerta XL, Medikinet XL, methylphenidate, atomoxetine and clonidine. 21% were on combination of two ADHD medications. 43% of the patients were also on other psychotropic medications. 36% of patients with ADHD also had a diagnosis Autism. 42% had another comorbid mental disorder. Conclusions Given the prevalence rate for ID (1.03%) and ADHD (6.8%), nearly 400 individuals with ID should have a diagnosis of ADHD in this catchment area. Presence of only 14 individual with ADHD shows that ADHD is extremely under diagnosed and under treated within ID population. This raises the issue whether patients are treated with psychotropic medications and psychological methods for behavioural and mental health issues due to under diagnosis of ADHD. Diagnosis of ADHD and complexities of such diagnostic processes among people with ID may be some of the reasons for under diagnosis (White et al 1995, Reiss et al 1982). Screening tools and increasing awareness may be needed to detect ADHD symptoms in this group of people when psychiatric diagnoses are often challenging.

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients

The c-Jun N-terminal kinases (JNKs) are stress-activated serine-threonine kinases that have recently been linked to various neurological disorders. We previously described a patient with intellectual disability (ID) and seizures (Patient 1), carrying a de novo chromosome translocation affecting the CNS-expressed MAPK10/JNK3 gene. Here, we describe a second ID patient (Patient 2) with a similar translocation that likewise truncates MAPK10/JNK3, highlighting a role for JNK3 in human brain development. We have pinpointed the breakpoint in Patient 2, which is just distal to that in Patient 1. In both patients, the rearrangement resulted in a predicted protein interrupted towards the C-terminal end of the kinase domain. We demonstrate that these truncated proteins, although capable of weak interaction with various known JNK scaffolds, are not capable of phosphorylating the classical JNK target c-Jun in vitro, which suggests that the patient phenotype potentially arises from partial loss of JNK3 function. We next investigated JNK3-binding partners to further explore potential disease mechanisms. We identified PSD-95, SAP102 and SHANK3 as novel interaction partners for JNK3, and we demonstrate that JNK3 and PSD-95 exhibit partially overlapping expression at synaptic sites in cultured hippocampal neurons. Moreover, JNK3, like JNK1, is capable of phosphorylating PSD-95 in vitro, whereas disease-associated mutant JNK3 proteins do not. We conclude that reduced JNK3 activity has potentially deleterious effects on neuronal function via altered regulation of a set of post-synaptic proteins.

Balanced translocation t(3;18)(p13;q22.3) and points mutation in the ZNF407 gene detected in patients with both moderate non-syndromic intellectual disability and autism

Intellectual disability (ID) is a common disease. While the etiology remains incompletely understood, genetic defects are a major contributor, which include mutations in genes encoding zinc finger proteins. These proteins modulate gene expression via binding to DNA. Consistent with this knowledge, we report here the identification of mutations in the ZNF407 gene in ID/autistic patients. In our study of an ID patient with autism, a reciprocal translocation 46,XY,t(3;18)(p13;q22.3) was detected. By using FISH and long-range PCR approaches, we have precisely mapped the breakpoints associated with this translocation in a gene-free region in chromosome 3 and in the third intron of the ZNF407 gene in chromosome18. The latter reduces ZNF407 expression. Consistent with this observation, in our subsequent investigation of 105 ID/autism patients with similar clinical presentations, two missense mutations Y460C and P1195A were identified. These mutations cause non-conservative amino acid substitutions in the linker regions between individual finger structures. In line with the linker regions being critical for the integrity of zinc finger motifs, both mutations may result in loss of ZNF407 function. Taken together, we demonstrate that mutations in the ZNF407 gene contribute to the pathogenesis of a group of ID patients with autism.

High Proportion of 22q13 Deletions and SHANK3 Mutations in Chinese Patients with Intellectual Disability

Intellectual disability (ID) is a heterogeneous disorder caused by chromosomal abnormalities, monogenic factors and environmental factors. 22q13 deletion syndrome is a genetic disorder characterized by severe ID. Although the frequency of 22q13 deletions in ID is unclear, it is believed to be largely underestimated. To address this issue, we used Affymetrix Human SNP 6.0 array to detect the 22q13 deletions in 234 Chinese unexplained ID patients and 103 controls. After the Quality Control (QC) test of raw data, 22q13 deletions were found in four out of 230 cases (1.7%), while absent in parents of the cases and 101 controls. A review of genome-wide microarray studies in ID was performed and the frequency of 22q13 deletions from the literatures was 0.24%, much lower than our report. The overlapping region shared by all 4 cases encompasses the gene SHANK3. A heterozygous de novo nonsense mutation Y1015X of SHANK3 was identified in one ID patient. Cortical neurons were prepared from embryonic mice and were transfected with a control plasmid, shank3 wild-type (WT) or mutant plasmids. Overexpression of the Y1015 mutant in neurons significantly affected neurite outgrowth compared with shank3 WT. These findings suggest that 22q13 deletions may be a more frequent cause for Chinese ID patients than previously thought, and the SHANK3 gene is involved in the neurite development.