Non-specific Intellectual Disability Research Articles

Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis.

High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.

Attachment quality of children with ID and its link to maternal sensitivity and structuring

BackgroundAttachment theory produced a fertile field of research and clinical application. Although the topic of attachment of children with intellectual disability (ID) has received increasing research attention over the past 15 years, the empirical evidence is still limited. AimsWe applied theoretical and empirical knowledge of parenting typically developing children to examine the mother-child relationship in the ID population. The aim was to examine maternal sensitivity and structuring and its association with children’s attachment classification and their disability. MethodsForty preschool children (mean age 47.25, range 26–75 months) with non-specific ID and their mothers participated in the study. The mean developmental age was 25.92 months (SD = 10.89), The DQ mean score was 55.45 (SD = 17.28). We assessed children’s quality of attachment using the SSP and maternal interactive behavior using the Emotional Availability Scales. OutcomesForty percent of children showed secure attachment, and 32.5% showed disorganized attachment. Attachment classifications correlated significantly with maternal sensitivity and maternal structuring but not with the child’s cognitive disability. ConclusionsThe results point to the importance of maternal interactive behavior for children with ID. Clinical implication may consider interventions aiming to enhance maternal sensitivity and structuring to improve children’s quality of attachment.

Enhancing the comprehension of visual metaphors in individuals with intellectual disability with or without down syndrome

This study is the first to investigate the effectiveness of deep and shallow intervention programs in the acquisition of visual metaphor comprehension in individuals with non-specific intellectual disability (NSID; aged 15–59, N = 53) or Down syndrome (DS; aged 15–52, N = 50). The deep intervention program was based on dynamic assessment model for enhancing analogical thinking. The shallow intervention program involves memorizing a metaphorical relationship between pairs of pictures. Visual metaphor comprehension was measured by the construction of a metaphorical connection between pairs of pictures. The results indicated that both etiology groups exhibited poor understanding of visual metaphors before the intervention. A significant improvement was observed in both interventions and both etiology groups, with greater improvement among individuals who underwent the deep processing. Moreover, the latter procedure led to greater generalization ability. The results also indicated that vocabulary contributed significantly to understanding unstudied metaphors and that participants with poorer linguistic abilities exhibited greater improvement in their metaphorical thinking. Thus, individuals with ID with or without DS are able to recruit the higher-order cognitive abilities required for visual metaphor comprehension.

Drowning fatalities in childhood: the role of pre-existing medical conditions

ObjectivesThis study is an analysis of the contribution of pre-existing medical conditions to unintentional fatal child (0–14 years) drowning and a of critique prevention stratagems, with an exploration of issues...

Emotion Recognition in Children With Down Syndrome: Influence of Emotion Label and Expression Intensity.

Some children with Down syndrome may experience difficulties in recognizing facial emotions, particularly fear, but it is not clear why, nor how such skills can best be facilitated. Using a photo-matching task, emotion recognition was tested in children with Down syndrome, children with nonspecific intellectual disability and cognitively matched, typically developing children (all groups N = 21) under four conditions: veridical vs. exaggerated emotions and emotion-labelling vs. generic task instructions. In all groups, exaggerating emotions facilitated recognition accuracy and speed, with emotion labelling facilitating recognition accuracy. Overall accuracy and speed did not differ in the children with Down syndrome, although recognition of fear was poorer than in the typically developing children and unrelated to emotion label use. Implications for interventions are considered.

Visual attention and academic performance in children with developmental disabilities and behavioural attention deficits.

Despite well-documented attention deficits in children with intellectual and developmental disabilities (IDD), distinctions across types of attention problems and their association with academic attainment has not been fully explored. This study examines visual attention capacities and inattentive/hyperactive behaviours in 77 children aged 4 to 11years with IDD and elevated behavioural attention difficulties. Children with autism spectrum disorder (ASD; n=23), Down syndrome (DS; n=22), and non-specific intellectual disability (NSID; n=32) completed computerized visual search and vigilance paradigms. In addition, parents and teachers completed rating scales of inattention and hyperactivity. Concurrent associations between attention abilities and early literacy and numeracy skills were also examined. Children completed measures of receptive vocabulary, phonological abilities and cardinality skills. As expected, the results indicated that all groups had relatively comparable levels of inattentive/hyperactive behaviours as rated by parents and teachers. However, the extent of visual attention deficits varied as a result of group; namely children with DS had poorer visual search and vigilance abilities than children with ASD and NSID. Further, significant associations between visual attention difficulties and poorer literacy and numeracy skills were observed, regardless of group. Collectively the findings demonstrate that in children with IDD who present with homogenous behavioural attention difficulties, at the cognitive level, subtle profiles of attentional problems can be delineated.

Working memory studies among individuals with intellectual disability: An integrative research review

BackgroundIntegrative research review infers generalizations about a substantive subject, summarizes the accumulated knowledge that research has left unresolved and generates a new framework on these issues. Due to methodological issues emerging from working memory (WM) studies in the population with non-specific intellectual disability (NSID) (N=64) between 1990–2014, it is difficult to conclude on WM performance in this population. AimThis integrative research review aimed to resolve literature conflicts on WM performance among individuals with NSID and to identify the conditions/moderators that govern their WM performance compared to controls with Typical development. Method/procedureWe used the six stages of integrative research review: problem formulation, data collection, evaluation, data analysis, results, interpretation and discussion. Outcomes and resultsThe findings indicate two types of moderators that determine WM performance in the population with NSID: Participants’ moderators (criteria for matching the ID and TD groups, CA and MA), and task moderators [the three WM components of Baddeley and Hitch’s (1974) model and task load]. Only an interaction between the two moderators determines WM performance in this population. The findings indicate a hierarchy (from more to less preserved) in WM performance of individuals with NSID: The visuospatial tasks, then some of the executive functions tasks, and the phonological loop tasks being less preserved. Furthermore, at a low level of control, the performance of participants with NSID was preserved beyond the modality and vice versa. Conclusions and implicationsModality and MA/intelligence determine WM performance of individuals with ID. Educators should prepare intervention programs take the impact of the two moderators into account.

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability.

Intellectual disability is a heterogeneous disease with many genes and mutations influencing the phenotype. Consanguineous families constitute a rich resource for the identification of rare variants causing autosomal recessive disease, due to the effects of inbreeding. Here, we examine three consanguineous Arab families, recruited in a quest to identify novel genes/mutations. All the families had multiple offspring with non-specific intellectual disability. We identified homozygosity (autozygosity) intervals in those families through SNP genotyping and whole exome sequencing, with variants filtered using Ingenuity Variant Analysis (IVA) software. The families showed heterogeneity and novel mutations in three different genes known to be associated with intellectual disability. These mutations were not found in 514 ethnically matched control chromosomes. p.G410C in WWOX, p.H530Y in RARS2, and p.I69F in C10orf2 are novel changes that affect protein function and could give new insights into the development and function of the central nervous system.

Severe behavioral disturbances in bipolar disorder: A case report

IntroductionBehavioral disturbances are common in psychiatric patients. This symptom may be caused by several disorders and clinical status.Case reportWe report the case of a 40 year-old male who was diagnosed of nonspecific psychotic disorder, alcohol dependence, cannabis abuse and intellectual disability. The patient was admitted into a long-stay psychiatric unit because of behavioral disturbances consisted in aggressive in the context of a chronic psychosis consisted in delusions of reference and auditory pseudohallucinations. During his admission the patient received the diagnosis of bipolar disorder type 1, presenting more severe behavioral disturbances during these mood episodes. It was necessary to make diverse pharmacological changes to stabilize the mood of the patient. Finally, the treatment was modified and it was prescribed clozapine (25 mg/24 h), clotiapine (40 mg/8 h), levomepromazine (200 mg/24 h), topiramate (125 mg/12 h), clomipramine (150 mg/24 h) and clorazepate dipotassium (50 mg/24 h). With this treatment, the patient showed a considerable improvement of symptoms, presenting euthymic and without behavioral disturbances.DiscussionIn this case report, we present a patient with severe behavioral disturbances. The inclusion of bipolar disorder in the diagnosis of the patient was very important for the correct treatment and management, because of depressive and manic mood episodes the behavioral disturbances were exacerbated.ConclusionsPatients with behavioral disturbances could present psychotic and affective symptoms as cause of them. It is necessary to explore these symptoms and try different treatments to improve them.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Impaired functional differentiation for categories of objects in the ventral visual stream: A case of developmental visual impairment

We report the case of a 14-year-old girl suffering from severe developmental visual impairment along with delayed language and cognitive development, and featuring a clear-cut dissociation between spared dorsal and impaired ventral visual pathways. Visual recognition of objects, including faces and printed words, was affected. In contrast, movement perception and visually guided motor control were preserved. Structural MRI was normal on inspection, but Voxel Based Morphometry (VBM) revealed reduced grey matter density in the mesial occipital and ventral occipito-temporal cortex. Functional MRI during the perception of line drawings uncovered impaired differentiation which is normally observed at even younger ages: no local category preferences could be identified within the occipito-temporal cortex for faces, houses, words or tools. In contrast, movement-related activations appeared to be normal. Finally, those abnormalities evolved on the background of chronic bilateral occipital epileptic activity, including continuous spike-wave discharges during sleep, which may be considered as the primary cause of non-specific intellectual disability and visual impairment.

Participation in recreation and cognitive activities as a predictor of cognitive performance of adults with/without Down syndrome

Objective: The Cognitive Activity Theory suggests an association between participation in cognitive activities during midlife and cognitive functioning in the short term. We examined the impact of participation in cognitively stimulating activities conveyed during leisure activities on crystallized and fluid tests' performance among adults with intellectual disabilities (ID).Method: Adults (n = 32; chronological age = 25–55) with non-specific ID and with Down syndrome rated the frequency of their participation in leisure activities. Pursuits included more cognitively involving (reading, participating in academic courses) and less cognitively involving (cooking, dancing) activities. Three judges ranked activities according to their cognitive load on a 1 (few cognitive components) to 5 (many cognitive components) points scale. The findings indicate two new scales: cognitively stimulating activities and recreational stimulating activities. The crystallized battery included phonemic fluency, synonyms, idioms, and verbal metaphors. The fluid battery included the Homophone Meaning Generation Test, Metaphoric Triad Test, Novel Metaphors Test, and Trail Making Test.Results: Hierarchal regression with chronological and mental age, recreational, and cognitively stimulating activities indicated that participation in recreational activities contributed significantly to the explained variance of word fluency. Participation in cognitive activities contributed significantly to the explained variance of most of the crystallized and fluid tests.Conclusions: The findings support the Cognitive Activity Theory in populations with ID. The findings also support the Compensation Age Theory: not only endogenous factors (age, etiology, IQ level), but also exogenous factors such as life style determining the cognitive functioning of adults with ID. However, frequency and the cognitive load of the activities influenced their cognitive functioning.

Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis.

Genetic testing for non-specific intellectual disability (ID) presents challenges in daily clinical practice. Historically, the focus of the genetic elucidation of non-specific ID has been on genes on the X chromosome, and recent research has brought attention to the growing contribution of autosomal genes. In addition, next-generation sequencing (NGS) has greatly improved the ability to simultaneously analyze multiple genetic loci, making large panel testing a practical approach to testing for non-specific ID. We performed NGS analysis of a total of 90 genes implicated in non-specific ID. The 90 genes included 56 X-linked genes and 34 autosomal genes. Pathogenic variants were identified in 11 of 52 (21%) patient samples. Nine of the eleven cases harbored mutations in autosomal genes including AP4B1, STXB1, SYNGAP1, TCF4 and UBE3A. Our mutation-positive cases provide further evidence supporting the prevalence of autosomal mutations in patients referred for non-specific ID testing and the utility of their inclusion in multi-gene panel analysis.

Learning by observation and learning by doing in Prader-Willi syndrome.

BackgroundNew competencies may be learned through active experience (learning by doing) or observation of others’ experience (learning by observation). Observing another person performing a complex action accelerates the observer’s acquisition of the same action, limiting the time-consuming process of learning by doing. Here, we compared learning by observation and learning by doing in individuals with Prader-Willi syndrome (PWS). It is hypothesized that PWS individuals could show more difficulties with learning by observation than learning by doing because of their specific difficulty in interpreting and using social information.MethodsThe performance of 24 PWS individuals was compared with that of 28 mental age (MA)- and gender-matched typically developing (TD) children in tasks of learning a visuo-motor sequence by observation or by doing. To determine whether the performance pattern exhibited by PWS participants was specific to this population or whether it was a nonspecific intellectual disability effect, we compared the PWS performances with those of a third MA- and gender-matched group of individuals with Williams syndrome (WS).ResultsPWS individuals were severely impaired in detecting a sequence by observation, were able to detect a sequence by doing, and became as efficient as TD children in reproducing an observed sequence after a task of learning by doing. The learning pattern of PWS children was reversed compared with that of WS individuals.ConclusionsThe observational learning deficit in PWS individuals may be rooted, at least partially, in their incapacity to understand and/or use social information.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-015-9102-0) contains supplementary material, which is available to authorized users.

Genomic structural variants are linked with intellectual disability.

Mutations in more than 500 genes have been associated with intellectual disability (ID) and related disorders of cognitive function, such as autism and schizophrenia. Here we aimed to unravel the molecular epidemiology of non-specific ID in a genetic isolate using a combination of population and molecular genetic approaches. A large multigenerational pedigree was ascertained within a Dagestan Genetic Heritage research program in a genetic isolate of indigenous ethnics. Clinical characteristics of the affected members were based on combining diagnoses from regional psychiatric hospitals with our own clinical assessment, using a Russian translation of the structured psychiatric interviews, the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies, based on DSM-IV criteria. Weber/CHLC 9.0 STRs set was used for multipoint parametric linkage analyses (Simwalk2.91). Next, we checked CNVs and LOH (based on Affymetrix SNP 5.0 data) in the linked with ID genomic regions with the aim to identify candidate genes associated with mutations in linked regions. The number of statistically significant (p ≤ 0.05) suggestive linkage peaks with 1.3 < LOD < 3.0 we detected in a total of 10 genomic regions: 1q41, 2p25.3-p24.2, 3p13-p12.1, 4q13.3, 10p11, 11q23, 12q24.22-q24.31, 17q24.2-q25.1, 21q22.13 and 22q12.3-q13.1. Three significant linkage signals with LOD >3 were obtained at 2p25.3-p24.2 under the dominant model, with a peak at 21 cM flanked by loci D2S2976 and D2S2952; at 12q24.22-q24.31 under the recessive model, with a peak at -120 cM flanked by marker D12S2070 and D12S395 and at 22q12.3 under the dominant model, with a peak at 32 cM flanked by marker D22S683 and D22S445. After a set of genes had been designated as possible candidates in these specific chromosomal regions,we conducted an exploratory search for LOH and CNV based on microarray data to detect structural genomic variants within five ID-linked regions with LOD scores between 2.0 and 3.9. In these selected regions we obtained 173 ROH segments and 98 CN segments. Further analysis of region 2p25.3-p24.2 revealed deletions within genes encoding MYTL, SNTG2 and TPO among five of 21 affected cases at 2p25.3-p24.2. In the ID-linked region at 12q24.22-12q24.31 19 out of 21 ID cases carried segmental CNV and 20 of 21 them displayed ROH segments with mean size lengths for ID cases 2512 kb (500-6,472 kb) and for healthy control 682 kb (531-986 kb), including the genes MED13L, HRK, FBXW8, TESC, CDK2AP1 and SBNO1. Seven of 21 affected pedigree members displayed segmental deletions at 22q12.3 that includes the gene LARGE. Eight affected pedigree members carried ROH segments and 6 CN segments at 10p11.23-p11.21 containing the genes ZEB1, c10orf68 and EPC1. Our linkage and structural genomic variation analyses in a remote highland genetic isolate with aggregation of ID demonstrated that even highly isolated single kindred ID has oligo/polygenic pathogenesis. The results obtained implicate 10 genomic regions linked with ID that contain some of previously reported candidate genes, including HRK, FBXW8, TESC, CDK2AP1 and SBNO1 at 12q24 that were shown in recent studies as associated with brain measures derived from MRI scans.

Emotional Lexicon Understanding and Emotion Recognition: A Longitudinal Study in Children with Down Syndrome

Several studies have shown deficits in emotion recognition in children with Down syndrome (DS). However, most of these studies required the understanding of verbal labels of emotion in their instructions, which may have been a disadvantage for these children, given their common language difficulties. This study addressed this issue by investigating the abilities of children with DS to recognize emotion from emotional terms, using the same visual material as in a previous nonverbal study with which they had no difficulty. Their performance was compared to that of typically developing children (TD) and children with nonspecific intellectual disability (NSID) of the same developmental age, during a 3-year longitudinal follow-up. Results showed that the abilities of children with DS were significantly poorer and developed slower than those of TD children, but not children with NSID. These cross-sectional and longitudinal data tend to show that children with DS have a lack of understanding of emotional verbal labels. The implications of these findings for future emotion recognition studies in these children, notably the need to design nonverbal experiments using dynamic stimuli, are discussed. The consequences of a potential deficit affecting the emotional lexicon are also raised with a view to orienting therapeutic and educational support.

Working memory in adolescent males with Down syndrome and males with autism and intellectual disability: Implications for the classroom

Background To develop effective education strategies, a detailed knowledge of the working memory profile in Down syndrome (DS) and autism with intellectual disability (ID) is required.Materials and Methods Fifteen adolescents with DS, 11 boys with autism and ID, and 12 boys with nonspecific ID (NSID) were compared on 2 versions of a novel working memory task that varied only in modality of presentation (visual or auditory).Results The groups with DS and with autism and ID demonstrated significantly poorer working memory performances than the group with NSID. No predictors of working memory performance were found.Conclusions Recommendations to support the working memory difficulties of the groups with DS and autism and ID in the classroom include reducing the amount of information to be processed at a time, as well as providing visual or verbal (as appropriate) prompts and cues to reduce the need to hold information in working memory.

The c.429_452 duplication of the ARX gene: a unique developmental-model of limb kinetic apraxia

BackgroundThe c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as “non-specific Intellectual Disability”. The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation.MethodsWe clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control.ResultsNeuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular “reach and grip” impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia.ConclusionThese findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.

Mental Illness, Behavior Problems, and Social Behavior in Adults With Down Syndrome

Little is known about the behavioral characteristics of adults with Down syndrome (DS) without dementia. The main purpose of this study was to investigate the psychopathology and social behavior among adults with DS compared to adults with nonspecific intellectual disability (NSID). Thirty-four adults with DS were individually matched with 34 adults with NSID for raw scores on a task that measured nonverbal reasoning ability. Participants' caregivers completed 3 questionnaires assessing mental illness, behavior problems, and social behavior. The group with DS presented fewer difficulties associated with mental illness and behavior problems, as well as better adapted social behavior, than the group with NSID despite a similar level of nonverbal reasoning ability. Aging in the group with DS was found to be positively correlated with behavioral signs of depression and autistic symptoms. These findings highlight the specificity of the behavioral profile of adults with DS without dementia.

Adolescent onset cognitive regression and neuropsychiatric symptoms associated with the A140V MECP2 mutation

The phenotype attributed to MECP2 mutations continues to expand. In addition to classic and variant Rett syndrome, phenotypes include non-specific intellectual disability and autism spectrum disorder in females, and fatal neonatal encephalopathy in males. One particular phenotype of parkinsonism, pyramidal signs, and neuropsychiatric symptoms (PPM-X) has been described only in males. We report on the first female with the A140V MECP2 mutation presenting with late onset cognitive regression, pyramidal symptoms, parkinsonism, and bipolar symptoms. This finding emphasizes the need to consider MECP2 sequencing in females with non-classic Rett phenotypes, particularly those with intellectual disability and neuropsychiatric features.

ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing

In this report, we describe two adult brothers affected by moderate non-specific intellectual disability (ID). They showed minor facial anomalies, not clearly ascribable to any specific syndromic patterns, microcephaly, brachydactyly and broad toes. Both brothers presented seizures. Karyotype, subtelomeric and FMR1 analysis were normal in both cases.We performed array-CGH analysis that revealed no copy-number variations potentially associated with ID. Subsequent exome sequence analysis allowed the identification of the ATRX c.109C>T (p.R37X) mutation in both the affected brothers. Sanger sequencing confirmed the presence of the mutation in the brothers and showed that the mother is a healthy carrier.Mutations in the ATRX gene cause the X-linked alpha thalassemia/mental retardation (ATR-X) syndrome (MIM #301040), a severe clinical condition usually associated with profound ID, facial dysmorphism and alpha thalassemia. However, the syndrome is clinically heterogeneous and some mutations, including the c.109C>T, are associated with a broad phenotypic spectrum, with patients displaying a less severe phenotype with only mild-moderate ID. In the case presented here, exome sequencing provided an effective strategy to achieve the molecular diagnosis of ATR-X syndrome, which otherwise would have been difficult to consider due to the mild non-specific phenotype and the absence of a family history with typical severe cases.