Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Specific Learning Disorders: Variation Analysis of 15 Candidate Genes in 9 Multiplex Families.

Background and Objectives: Specific Learning Disorder (SLD) is a complex neurobiological disorder characterized by a persistent difficult in reading (dyslexia), written expression (dysgraphia), and mathematics (dyscalculia). The hereditary and genetic component is one of the underlying causes of SLD, but the relationship between genes and the environment should be considered. Several genetic studies were performed in different populations to identify causative genes. Materials and Methods: Here, we show the analysis of 9 multiplex families with at least 2 individuals diagnosed with SLD per family, with a total of 37 persons, 21 of whom are young subjects with SLD, by means of Next-Generation Sequencing (NGS) to identify possible causative mutations in a panel of 15 candidate genes: CCPG1, CYP19A1, DCDC2, DGKI, DIP2A, DYM, GCFC2, KIAA0319, MC5R, MRPL19, NEDD4L, PCNT, PRMT2, ROBO1, and S100B. Results: We detected, in eight families out nine, SNP variants in the DGKI, DIP2A, KIAA0319, and PCNT genes, even if in silico analysis did not show any causative effect on this behavioral condition. In all cases, the mutation was transmitted by one of the two parents, thus excluding the case of de novo mutation. Moreover, the parent carrying the allelic variant transmitted to the children, in six out of seven families, reports language difficulties. Conclusions: Although the present results cannot be considered conclusive due to the limited sample size, the identification of genetic variants in the above genes can provide input for further research on the same, as well as on other genes/mutations, to better understand the genetic basis of this disorder, and from this perspective, to better understand also the neuropsychological and social aspects connected to this disorder, which affects an increasing number of young people.

Reading and spelling disorders in a school-based population screening in Sicily (Italy).

This research was carried out according to the Italian Consensus Conference on Specific Learning Disability guidelines for screening initiatives. It describes a three-year screening project involving 2.469 students, aged 8-15 years, from various classes of primary, lower and upper secondary schools of Sicily. Students were assessed for reading and spelling skills. Overall, 4.9% met the risk criteria for suspected reading disorder, 6.1% for spelling disorder, while 8.5% for both conditions. Results showed that out of 932 pupils in the primary school, 4.6% met the risk criteria for reading disorder and 6.5% for spelling disorder; out of 855 pupils of the lower secondary school, 5.3% for reading disorder and 5.5% for spelling disorder; out of 652 pupils of the upper secondary school, 4.9% for reading disorder and 6.1% for spelling disorder. No significant difference in the prevalence of students at risk of reading disorder or spelling disorder, within the three grade-levels over 3 years, was found. At project conclusion further clinical investigation to verify the screening results on student sub-sample (57%) was carried out. The percentage of students with SLD was equal to 3.15%, in the primary school, 3.76% in the lower secondary school and 2.51%, in the upper secondary school.

Prader-Willi Syndrome with Angelman Syndrome in the Offspring.

We report the second case, to the best of our knowledge, of a mother with Prader-Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The menarche occurred when she was 16, and the following menstrual cycles were irregular, but she never took sexual hormone replacement therapy. At the age of 26, our patient with PWS became pregnant. The diagnosis was confirmed by molecular genetic testing that revealed a ~5.7 Mb deletion in the 15q11.1-15q13 region on the paternal allele in the mother with PWS and the maternal one in the daughter with AS, respectively. Both the mother with PWS and the daughter with AS showed peculiar clinical and genetic features of the two syndromes. Our case report reaffirms the possible fertility in PWS; therefore, it is very important to develop appropriate socio-sexual education programs and fertility assessments in order to guarantee the expression of a healthy sexuality.

An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation.

INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aß, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aß40 and Aß42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aß correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aß42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aß and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.

Definition of minimal duplicated region encompassing the XIAP and STAG2 genes in the Xq25 microduplication syndrome.

Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder.

Low TGF-ß1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-ß1 (TGF-ß1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-ß1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-ß1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-ß1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-ß1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-ß1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-ß1 concentrations in DS subjects at higher risk to develop cognitive decline.

3q29 microdeletion syndrome: Cognitive and behavioral phenotype in four patients.

The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations. A thorough neuropsychiatric evaluation has never been reported in patients with such syndrome. We analyzed the clinical phenotype of four individuals with 3q29 microdeletion syndrome, with special emphasis on the cognitive and behavioral assessment, in order to delineate the neuropsychiatric phenotype related to this condition. We assessed these patients with standardized scales or checklists measuring the cognitive (WISC III or LIPS-R), behavioral (CBCL) and adaptive (VABS) performances. An accurate evaluation in our sample highlights different degrees of ID, variable behavioral disorders, and a preservation of communicative skills among remaining adaptive areas, as the neuropsychiatric hallmark of 3q29 microdeletion syndrome.

The Intellectual Profile of Adults with Specific Learning Disabilities.

Despite growing research on adults with specific learning disabilities (SLDs), evidence concerning their intellectual profile remains scarce. The present study examined the results of the administration of the Wechsler Adult Intelligence Scale-Fourth Edition to 301 adults diagnosed with SLDs and compared them to the results obtained from previous studies with a large sample of children with SLDs. The results showed that: (1) as observed among children, adults with SLDs also presented higher scores in the subtests implying reasoning (associated with the General Ability Index, GAI) and lower scores in the subtests involving working memory and processing speed; (2) the discrepancy between full-scale IQ and the GAI had a good predictive value in discriminating adults with and without SLDs; (3) the four-factor hierarchical structure of intelligence proposed for the general adult population held for adults with SLDs as well, even though there were substantial differences in the loadings and a five-factor structure could be more appropriate; (4) similarities as well as strong differences were present between adults and children with SLDs. In adults, scores on subtests were generally lower, particularly in working memory and processing speed. However, in some cases, scores were equal or even higher (as in the "Similarity" subtest) among adults, meaning that the discrepancy between the full scale and the GAI was accentuated.

Low-Cost Technology-Aided Programs for Supporting People With Motor, Visual, and Intellectual Disabilities in Functional Forms of Occupation and Communication: Proof-of-Concept Study.

BACKGROUND: People with motor, visual, and intellectual disabilities may have serious problems in independently accessing various forms of functional daily occupation and communication. OBJECTIVE: The study was aimed at developing and assessing new, low-cost technology-aided programs to help people with motor or visual-motor and intellectual disabilities independently engage in functional forms of occupation and communication with distant partners. METHODS: Two programs were set up using a smartphone interfaced with a 2-switch device and a tablet interfaced with 2 pressure sensors, respectively. Single-subject research designs were used to assess (1) the first program with 2 participants who were blind, had moderate hand control, and were interested in communicating with distant partners through voice messages; and (2) the second program with 2 participants who possessed functional vision, had no or poor hand control, and were interested in communicating with their partners through video calls. Both programs also supported 2 forms of occupational engagement, that is, choosing and accessing preferred leisure events consisting of songs and music videos, and listening to brief stories about relevant daily topics and answering questions related to those stories. RESULTS: During the baseline phase (when only a conventional smartphone or tablet was available), 2 participants managed sporadic access to leisure or leisure and communication events. The other 2 participants did not show any independent leisure or communication engagement. During the intervention (when the technology-aided programs were used), all participants managed to independently engage in multiple leisure and communication events throughout the sessions and to listen to stories and answer story-related questions. CONCLUSIONS: The findings, which need to be interpreted with caution given the nature of the study and the small number of participants, seem to suggest that the new programs may be viable tools for helping people with motor or visual-motor and intellectual disabilities independently access leisure, communication, and other forms of functional engagement.

The structure, profile, and diagnostic significance of intelligence in children with ADHD are impressively similar to those of children with a specific learning disorder.

This study examines the structure, profile, and diagnostic significance of intelligence in a group of 948 children diagnosed with attention deficit/hyperactivity disorder (ADHD) assessed with the WISC-IV and compared with children with specific learning disorders (SLDs) and with typically developing children. Based on four indexes, the WISC-IV configuration found in TD resulted applicable to ADHD, but with generally lower loadings on g. The Perceptual Reasoning and Verbal Comprehension indexes not only had higher loadings compared to the other two indexes but also represented the relative strengths of children with ADHD, as previously observed for children with SLD. In fact, the WISC pattern could be successfully used for discriminating between ADHD and TD, but not between ADHD and SLD. The latter result was not due to a co-occurrence of a learning disorder because the presence or absence of an associated diagnosis of SLD negligibly affected the pattern observed in ADHD. We concluded that the characteristics of intelligence in children with ADHD can be relevant for assessing this disorder, and that ADHD and SLDs share largely similar underlying cognitive features.

Italian Diagnostic Adaptive Behavior Scale: Reliability and diagnostic accuracy compared with the Vineland-II.

BACKGROUND: The Diagnostic Adaptive Behavior Scale (DABS) is a short scale with excellent properties to assess the conceptual, social, and practical adaptive behavior domains for the diagnosis of intellectual disability (ID) in individuals aged 4-21 years. AIMS: Investigate the test-retest and inter-respondent reliability of the Italian adaptation of the DABS, verify its diagnostic accuracy in identifying individuals with ID and excluding individuals with typical development (TD), and compare its psychometric properties to those of the Vineland-II. METHODS: Test-retest reliability: The same respondent completed the Italian DABS for the same assessed person at two separate times (n = 71). Inter-respondent reliability: Two respondents for the same assessed person completed the Italian DABS independently (n = 57). Diagnostic accuracy: The same respondent completed the Italian DABS and Vineland-II for the same assessed person (n = 378; 50 % ID, 50 % TD). RESULTS: Italian DABS test-retest and inter-respondent correlation coefficients were excellent. Italian DABS sensitivity was 86 % and specificity was 99 %, Italian DABS Areas Under the ROC Curves were excellent (or good, practical skill domain), and comparable to the results reported for the Vineland-II. CONCLUSIONS: The Italian DABS is an excellent measure to evaluate the adaptive behavior for ID diagnosis; it is comparable to the Vineland-II but being shorter, the Italian DABS requires less time to administer.

Everyday Technology to Help People with Intellectual and Other Disabilities Access Stimulation via Functional Motor Responses and Improved Body Posture.

PURPOSE: This study assessed everyday technology to help eight participants with intellectual and sensory-motor disabilities access stimulation via functional arm/hand responses and improved body posture. METHODS: An ABABB1BB1 design was used for each participant, with A representing baseline phases, B intervention phases in which arm/hand responses led to a 12-s stimulation, and B1 intervention phases in which the stimulation for arm/hand responses was conditional on an improved/correct torso and head posture. The technology involved a Samsung Galaxy A10 smartphone fitted with Google Assistant and MacroDroid, a mini voice-recording device, and a portable mini voice amplifier. RESULTS: All participants had a large increase in arm/hand responses from the baseline periods to the B and B1 phases. They also had a large increase in correct posture from the B phases to the B1 phases. CONCLUSION: This technology-aided approach may be a helpful resource for people similar to the participants of this study.

Spelling deficits in children with intellectual disabilities: Evidence from a regular orthography.

Introduction: In individuals with intellectual disabilities (ID), efficient reading and writing skills promote social integration, self-autonomy, and independence. However, research has mainly focused on reading skills, while evidence on spelling skills is scarce and mostly on English-speaking subjects. In the present research project, we compared the spelling skills of children with intellectual disabilities (ID) learning in Italian, a regular orthography, to those of typically developing children matched for school level. Methods: In the first study, the performance on a Passage Dictation Test of forty-four children with ID attending regular classrooms from 4th to 8th grades (mean age = 12.16 years; SD = 1.57) were compared with controls matched for sex and grade. In the second study, a Words and Nonwords Dictation Test was administered (with stimuli varying for lexicality, orthographic complexity, regularity of transcription, and the presence of different types of phonetic-phonological difficulties) to twenty-two children with ID attending regular classrooms from 4th to 8th grades (mean age = 12.2 years; SD = 1.37) and 22 controls matched for sex and grade. In both studies, an error analysis was performed to characterize types of misspellings. Separate ANOVAs were performed on z scores. Results: Children with ID generally had a lower performance than controls. In the Passage Dictation Test, they showed a higher number of phonological (and phonetic-phonological) errors than phonologically plausible ones, indicating, as a group, predominant phonological difficulties as compared to lexical-orthographic ones. In the Words and Nonwords Dictation Test, they performed poorly on regular stimuli presenting specific types of phonetic-to-phonological difficulties (geminates, non-continuant consonants) and committed more minimal distance, context-sensitive and simple conversion misspellings. However, deficits in the orthographic-lexical procedure, as indicated by a low performance in words with unpredictable spelling, were present in a high percentage of children. Discussion: It is concluded that children with ID have significant spelling difficulties not confined to the orthographic process but also in phoneme-to-grapheme mapping that, in a regular orthography like Italian, should be acquired early and easily.

Dyslexia and Attention Deficit Hyperactivity Disorder Associated to a De Novo 1p34.3 Microdeletion.

The authors report on a boy with dyslexia and attention deficit hyperactivity disorder. A protocol of standardized tests assessed the neuroadaptive profile, allowing deep neuropsychiatric phenotyping. In addition to the diagnosis of dyslexia and attention deficit hyperactivity disorder, such methodology led to endeavor cognitive, adaptive, and academic skills. Chromosomal microarray analysis detected a 452.4 Kb de novo heterozygous microdeletion in chromosomal region 1p34.3, including seven OMIM genes. The authors took a thorough evaluation of the association to the phenotype of the deleted genes. Further reports could strengthen such association.

Behavioral phenotypes of genetic syndromes with intellectual disability: comparison of adaptive profiles.

The study of distinctive and consistent behaviors in the most common genetic syndromes with intellectual disability is useful to explain abnormalities or associated psychiatric disorders. The behavioral phenotypes revealed outcomes totally or partially specific for each syndrome. The aim of our study was to compare similarities and differences in the adaptive profiles of the five most frequent genetic syndromes, i.e. Down syndrome, Williams syndrome, Angelman syndrome, Prader-Willi syndrome, and Fragile-X syndrome (fully mutated), taking into account the relation with chronological age and the overall IQ level. The research was carried out using the Vineland Adaptive Behavior Scale (beside the Wechsler Intelligence scales to obtain IQ) with a sample of 181 persons (107 males and 74 females) showing genetic syndromes and mental retardation. Syndrome-based groups were matched for chronological age and mental age (excluding the Angelman group, presenting with severe mental retardation). Similarities and differences in the adaptive profiles are described, relating them to IQs and maladaptive behaviors. The results might be useful in obtaining a global index of adjustment for the assessment of intellectual disability level as well as for educational guidance and rehabilitative plans.

Definition of the neurological phenotype associated with dup (X)(p11.22-p11.23).

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.

Ageing and health status in adults with intellectual disabilities: results of the European POMONA II study.

BACKGROUND: POMONA II was a European Commission public health-funded project. The research questions in this article focus on age-specific differences relating to environmental and lifestyle factors, and the 17 medical conditions measured by the POMONA Checklist of Health Indicators (P15). METHOD: The P15 was completed in a cross-sectional design for a stratified sample of 1,253 adults with ID across 14 European member states. RESULTS: Older people (55+) were more likely to live in larger residential homes. Rates of smoking and use of alcohol were lower than in the general population but were higher with older age. More than 60% of older adults had a sedentary lifestyle. Cataract, hearing disorder, diabetes, hypertension, osteoarthritis/arthrosis, and osteoporosis were positively associated with advancing age; allergies and epilepsy, negatively associated. CONCLUSIONS: Some evidence of health disparities was found for older people with ID, particularly in terms of underdiagnosed or inadequately managed preventable health conditions.

Executive Functions and Attention Processes in Adolescents and Young Adults with Intellectual Disability.

(1) Background: We made a comprehensive evaluation of executive functions (EFs) and attention processes in a group of adolescents and young adults with mild intellectual disability (ID). (2) Methods: 27 adolescents and young adults (14 females and 13 males) with ID, aged between 15.1 and 23 years (M = 17.4; SD = 2.04), were compared to a control group free of cognitive problems and individually matched for gender and age. (3) Results: As for EFs, individuals with ID were severely impaired on all subtests of the Behavioral Assessment of Dysexecutive Syndrome (BADS) battery. However, we also found appreciable individual differences, with eight individuals (approximately 30%) scoring within normal limits. On the attention tests, individuals with ID were not generally slower but presented specific deficits only on some attention tests (i.e., Choice Reaction Times, Color Naming and Color-Word Interference, and Shifting of Attention for Verbal and for Visual Targets).The role of a global factor (i.e., cognitive speed) was modest in contributing to the group differences; i.e., when present, group differences were selectively associated with specific task manipulations, not global differences in cognitive speed. (4) Conclusions: The study confirmed large group differences in EFs; deficits in attentional processing were more specific and occurred primarily in tasks taxing the selective dimension of attention, with performance on intensive tasks almost entirely spared.

Clinical management of individuals with Intellectual Disability: The outbreak of Covid-19 pandemic as experienced in a clinical and research center Research in Developmental Disabilities.

During the COVID-19 pandemic, the Oasi Research Institute of Troina (Italy) became an important hotbed for infection; in fact, 109 patients with different levels of Intellectual Disability (ID) tested positive for COVID-19. The procedures and interventions put in place at the Oasi Research Institute due to the COVID-19 pandemic are exhaustively reported in this paper. The description of the clinical procedures as well as remote/in person psychological support services provided to people with ID and their families are here divided into three different sections: Phase I (or Acute phase), Phase II (or Activity planning), and Phase III (or Activity consolidation). In each section, the main psycho-pathological characteristics of patients, the reactions of family members and the multidisciplinary interventions put in place are also described.