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.

Cognitive, adaptive, and behavioral effects of adjunctive rufinamide in Lennox-Gastaut syndrome: A prospective observational clinical study.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy. METHODS: This was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ±â€¯16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300-2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered. RESULTS: After 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL. CONCLUSION: Adjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up.

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.

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.

Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder.

In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. ADGRB3, also known as BAI3, belongs to the subfamily of adhesion G protein-coupled receptors (adhesion GPCRs) that regulate many aspects of the central nervous system, including axon guidance, myelination, and synapse formation. Single nucleotide polymorphisms and copy number variants involving ADGRB3 have recently been associated with psychiatric disorders. These findings further support this association and also suggest that biallelic variants affecting the function of the ADGRB3 gene may also cause cognitive impairments and ataxia.

Reading Deficits in Intellectual Disability Are still an Open Question: A Narrative Review.

BACKGROUND: In children with intellectual disability (ID), the acquisition of reading skills constitutes a basic step towards the possibility of independent living, social inclusion and participation. METHODS: We carried out a narrative review of the literature on reading fluency and accuracy of individuals with ID resulting from different genetic syndromes (Fragile X, Williams, Velocardiofacial, Prader-Willi, and Down syndrome). Our aim was to define their reading profiles in light of the dual-route reading model. For this purpose, studies that examined both word and non-word reading in children with ID were included in the analysis. RESULTS: Seventeen studies emerged based on the selection criteria. The results were different depending on the control group used. A deficit in reading non-words emerged in studies that used the reading-level match design but not when standardized scores were used, when controls were age-matched or when a mental age matching was used. Thus, a deficit in reading non-words emerged only in studies that used the reading-level match design. However, severe methodological criticisms were recently raised about the use of this matching design. CONCLUSIONS: In view of the methodological problems in using grade equivalents, it is premature to draw definite conclusions about the reading profile of children with ID resulting from different genetic syndromes. In any case, the reviewed evidence provides little support for the idea that children with ID have selective difficulty in phonological reading. Thus, the reading profile of children with ID remains an open question that needs to be investigated by means of methodologically sound research.

Tele-assistance in intellectual disability.

We conducted a trial of multidisciplinary tele-assistance to support 20 families of patients with intellectual disability. Psychological, educational, social and medical support was provided by videoconferencing, email and on-line sharing of diagnostic and rehabilitation tools. The main topics dealt with were self-care, learning processes, adaptation skills, management of problem behaviours and health problems. A computer network was developed which connected workstations at the patients' houses and two main sites at the Oasi Institute. It was based on ISDN transmission. During the study, 840 videoconference sessions and 805 programme planning and case discussions took place. After one year of tele-assistance, most families (84%) stated that they were satisfied with the experience, underlining, among various advantages, the availability of professional and continuous support, the reduction of inconvenient travelling to specialized centres and the increase in adaptation skills of their children. Although the present study was empirical, our experience suggests that tele-assistance can satisfy some of the main needs of persons with intellectual disability and their families.

[Neuropsychological profiles, personality features and familial relational patterns in parents of children with Autism Spectrum Disorders]. / Profilo neuropsicologico, caratteristiche di personalità e dinamiche familiari nei genitori di bambini con disturbo dello spettro dell'autismo.

INTRODUCTION: The study of neuropsychological profiles and personality features of parents of persons with Autism Spectrum Disorder (ASD) has highlighted specific traits that turned out to be useful for diagnostic purposes. AIM AND METHODS: In our study, psychodiagnostic measures have been used to investigate cognitive profiles, personality features and familial relational patters in a group of parents of children with ASD associated to Intellectual Disability (ID). This group was then compared with a another group of parents of children with Prader-Willi syndrome. RESULTS: Results show no differences between the two groups with regard to Intellectual Quotient, while significant differences were found at the intelligence test Wechsler, which partially confirmed data from the literature relating to the performances of parents of persons with ASD. No differences were found in the executive functioning and memory abilities. As for familial relational patters, families of children with ASD showed decreased cohesion and higher disengagement. DISCUSSION AND CONCLUSIONS: Results obtained in the domains of familial relational patterns and emotional personality components seem to confirm how children's disability can significantly impact on the entire household, in particular in the case of children with ASD. This data suggest the need for intervention programs aimed at supporting the entire household, with the objective of improving coping strategies and resilience resources of the family.

The in cis T251I and P587L POLG1 base changes: description of a new family and literature review.

Mutations in the polymerase gamma-1 (POLG1) gene, encoding the catalytic subunit of the mtDNA-specific polymerase-γ, compromise the stability of mitochondrial DNA (mtDNA) and are responsible for numerous clinical presentations as autosomal dominant or recessive progressive external ophthalmoplegia (PEO), sensory ataxia, neuropathy, dysarthria and ophthalmoparesis (SANDO), spinocerebellar ataxia with epilepsy (SCAE) and Alpers syndrome. POLG1 mutations result in extremely heterogeneous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes, and genotype-phenotype correlations are still unclear. We describe a new family with a particular spectrum of clinical signs, that carried the c.752C>T mutation in exon 3 (T251I) and the c.1760C>T in exon 10 (P587L) in cis. These mutations were associated in the proband and in her brother with the new probably pathogenic mutation c.347C>A in exon 2 (P116Q). The proband presented a progressive cognitive impairment, mild myopathy, dilated cardiac right atrium and posterior white matter mild signal alteration, while her brother had migraine, mild myopathy, palpebral ptosis and posterior white matter mild signal alteration. Their mother and their sister carried the in cis T251I and the P587L mutations. The first presented neurosensorial hypoacusia, fatigue, heart block and a cerebral arteriovenous malformation nidus, while the latter had borderline intellectual functioning and signs of muscular involvement. Their father, with the P116Q mutation, had diabetes and myopathy. The complexity of the genotype-phenotype correlations associated with POLG1 mutations is reinforced in this work as evidenced by the presence of different clinic features in patients carrying the same mutations.