Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health.

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

Toward an integrative socio-cognitive approach in autism spectrum disorder: NEAR method adaptation-study protocol.

Background: The cognitive impairments exhibited by people with ASD, threaten the development of social skills that are essential for establishing and maintaining harmonious social relationships. Cognitive remediation and social skills training are now considered as crucial therapeutic approaches in the management of these disorders. Several programs have already been validated and have shown improvements in social skills or cognitive performance. However, the effects of these training methods seem to be difficult to generalize to other everyday life. The aim of our study is to alleviate cognitive and social deficiencies by using a socio-cognitive framework to adapt the Neuropsychological Educational Approach to Remediation (NEAR) method for adolescents with ASD. Methods/design: Adolescents meeting the DSM-5 criteria for ASD, older than 13 years, and following a regular school curriculum will be recruited from clinical population at the Child and Adolescent Psychiatry in Razi University Hospital-Manouba- Tunisia. Our study is an open and non-randomized controlled trial including 30 patients: NEAR group / control group. The NEAR method combines computerized cognitive exercises and bridging groups inspired from cognitive behavioral therapy. NEAR group will be divided into three groups of five patients each. The duration of the sessions will vary according to the capacities of the participants and the exchanges between them (about 60­120 min). In our study, bridging groups will be amended by adding other tasks including planning role plays and scenarios of problematic social situations in autism, taking into account cultural particularities in order to promote social skills. Computerized exercises will be enriched by adding other tasks aiming to improve the recognition and expression of facial emotions by using digital videos and photographs expressing the six basic emotions. The duration of the program will be about 6 months. All selected patients will have an assessment of cognitive function: social cognition, neurocognition and pragmatic skills, social skills, self-esteem and global functioning at baseline, 1 week after the end of the NEAR program and 6 months later. Conclusion: This adaptive program is a promising socio-cognitive intervention that create new perspectives for adolescents with autism spectrum disorder.

Assessment of theory of mind in Tunisian verbal children with autism spectrum disorder.

The present study examined performance in Theory of Mind (ToM) in a group of 31 Arabic-speaking verbal children (7-12 years-old) with autism spectrum disorder (ASD), in comparison with neurotypical controls (NT) matched for age and for cognitive abilities. An innovative task in a digital format named "The Tunisian Social Situations Instrument" (TSSI) was used and allowed us to study four different subdomains of ToM: attribution of intention and epistemic ToM (cognitive ToM), affective ToM, and detection of faux pas (advanced ToM). Our study showed impairments in ToM in children with ASD, similar to those reported in the literature. Our findings additionally suggested that affective and advanced ToM, specifically the detection of faux pas, might be more challenging for ASD children than other components of ToM. Future studies with larger number of children may lead us to specify which subdomains are the most impaired in order to develop specific tools targeting these specific impairments.

Cognitive deficits in children with autism spectrum disorders: Toward an integrative approach combining social and non-social cognition.

Autism spectrum disorder (ASD) is associated with neurocognitive impairment, including executive dysfunctioning and social cognition (SC) deficits. Cognitive remediation (CR) is a behavioral training-based intervention aiming to improve cognitive processes. Its first use in psychiatry interested patients with schizophrenia, in whom promising results have been shown. Integrated CR programs targeting both social and non-social cognition have demonstrated to be effective in improving both cognitive domains and functional outcomes. CR studies in children and adolescents with ASD are still new, those regarding CR approaches combining social and executive functioning remediation are scares. One study examining the efficacy of cognitive enhancement therapy (CET) for improving cognitive abilities in ADS adults, showed significant differential increases in neurocognitive function and large social-cognitive improvements. Therefore, taking into account the overlap between ASD and schizophrenia, and considering the close link between executive functions (EF) and SC, we suggest that integrative approach in ASD could result in better outcomes. The present perspective aimed to highlight cognitive remediation (CR) programs contributions in ASD (especially in children and adolescents), and to discuss the value of combining social and non-social programs.

Validation of the Tunisian Empathy Scale for Children (TESC) in General Population and Children With Autism Spectrum Disorder.

Background: Several empathy assessment tests have been proposed worldwide but none of them took into account cultural variations that seem to affect empathic manifestations. The aim of this study was to create and validate an empathy assessment questionnaire for school-aged Tunisian children entitled "Tunisian Empathy Scale for Children" (TESC). Methods: An evaluative cross-sectional study was conducted. The questionnaire was administered to parents of 197 neuro-typical children and 31 children with autism without associated intellectual deficits, aged between 7 and 12 years. Validation steps included: face validity, content validity, construct validity, and reliability study. A ROC curve analysis was used to investigate the diagnostic performance of the TESC. Results: Face validity was verified with an expert panel. Content validity was examined, and 11 items were removed as irrelevant or not assessable by parents. Exploratory factor analysis extracted four domains that explained 43% of the total variance. All these domains were significantly correlated with the total score (p < 10-3) and are, respectively: empathic behaviors, affective empathy, cognitive empathy, and a combined affective and cognitive domain. The reliability study showed a satisfactory level of internal consistency of the TESC, with a Cronbach's alpha of 0.615.The diagnostic performance of the TESC in relation to autism was evaluated by the ROC curve with a sensitivity and specificity of 84.3 and 62.1%, respectively, for a total score of 16. Conclusion: A 15-item questionnaire assessing empathy in a multidimensional and culturally adapted way was obtained. The psychometric qualities of the TESC were satisfactory.

Validation of the Tunisian Test for Facial Emotions Recognition: Study in Children From 7 to 12 Years Old.

Background: Facial expressions transmit information about emotional state, facilitating communication and regulation in interpersonal relationships. Their acute recognition is essential in social adaptation and lacks among children suffering from autism spectrum disorders. The aim of our study was to validate the "Recognition of Facial Emotions: Tunisian Test for Children" among Tunisian children in order to assess facial emotion recognition in children with autism spectrum disorders (ASD). Methods: We conducted a cross-sectional study among neurotypical children from the general population. The final version of or test consisted of a static subtest of 114 photographs and a dynamic subtest of 36 videos expressing the six basic emotions (happiness, anger, sadness, disgust, fear and surprise), presented by actors of different ages and genders. The test items were coded according to Ekman's "Facial Action Coding System" method. The validation study focused on the validity of the content, the validity of the construct and the reliability. Results: We included 116 neurotypical children, from 7 to 12 years old. Our population was made up of 54 boys and 62 girls. The reliability's study showed good internal consistency for each subtest: the Cronbach coefficient was 0.88 for the static subtest and 0.85 for the dynamic subtest. The study of the internal structure through the exploratory factor analysis of the items of emotions and those of intensity showed that the distribution of the items in sub-domains was similar to their theoretical distribution. Age was significantly correlated to the mean of the overall score for both subtests (p < 10-3). Gender was no significantly correlated to the overall score (p = 0.15). High intensity photographs were better recognized. The emotion of happiness was the most recognized in both subtests. A significant difference between the overall score of the static and dynamic subtest, in favor of the dynamic one, was identified (p < 10-3). Conclusion: This work provides clinicians with a reliable tool to assess recognition of facial emotions in typically developing children.

Impaired Recognition of Static and Dynamic Facial Emotions in Children With Autism Spectrum Disorder Using Stimuli of Varying Intensities, Different Genders, and Age Ranges Faces.

A multitude of research on facial emotion recognition (FER) in Autism Spectrum Disorders (ASD) have been published since several years. However, these studies have mainly used static high intensity stimuli, including adult and/or children facial emotions. This current study investigated FER in children with ASD using an innovative task, composed of a combination of static (114 pictures) and dynamic (36 videos) subtests, including children, adolescent, and adult male and female faces, with high, medium, and low intensity of basic facial emotions, and neutral expression. The ASD group consisted of 45 Tunisian verbal children, and the control group consisted of 117 tunisian typically developing children. Both groups were aged 7-12 years. After adjusting for sex, age, mental age, and school grade, the ASD group scored lower than controls on all tests except for the recognition of happiness and fear in the static subtest, and the recognition of happiness, fear, and sadness in the dynamic subtest (p ≥ 0.05). In the ASD group, the total score of both the static and the dynamic subtest were positively correlated with the school grade (p < 0.001), but not with age, or mental age. Children with ASD performed better in recognizing facial emotions in children than in adults and adolescents on videos and photos (p < 0.001). Impairments in FER would have negative impact on the child's social development. Thus, the creation of new intervention instruments aiming to improve emotion recognition strategies at an early stage to individuals with ASD seems fundamental.

Similarities and differences between tutoring and mentoring in medical education.

Supporting medical students involves two broad concepts that are often confused, namely tutoring and mentoring. These approaches, implemented in a heterogeneous way in medical schools, have been the topic of numerous publications. The objective of this update was therefore to define, then clarify, based on a literature review, the common characteristics and the differences between tutoring and mentoring in medical studies.

Validation of the Tunisian Social Situation Instrument in the General Pediatric Population.

BACKGROUND: In order to better understand the deployment of the theory of mind (ToM) in Tunisian neurotypical children, we have developed a new tool of assessment of the ToM called the "Tunisian Social Situations Instrument" (TSSI). We opted for the creation of this test in view of the intercultural differences in the development of social skills. Our purpose was to validate this tool in general pediatric population. METHODS: It was a cross-sectional evaluative study that aimed to validate the TSSI in the general pediatric population. We initially conducted a beta test and a pre-validation study before taking the initial version of the TSSI on 123 neurotypical children. Then, we followed the typical validation procedure: appearance validity, content validity, construct validity, and reliability study. RESULTS: Regarding the validity of appearance, the TSSI was comprehensible and adapted to the Tunisian pediatric population. About content validity, the exploratory factor analysis extracted 6 factors that explain 69.3% of the total variance. These factors were respectively social clumsiness types 1 and 2, intention attribution, emotional ToM, epistemic ToM, and simple comprehension questions. The subdomains of social clumsiness (types 1 and 2) and emotional ToM had a Cronbach alpha higher than 0.8. This factor structure as well as the significant inter-correlation between subdomains and the global score were in favor of a good construct validity. The internal consistency study showed good reliability of the final version of the TSSI (alpha of Cronbach at 0,809). Regarding the performance of children at the TSSI, we have noticed a significant association between the global score, age, and verbal intelligence. CONCLUSION: This work offers valuable insights about ToM and provides clinicians with a reliable tool to assess social clumsiness and emotional ToM in typically developing children.

Contributions of autism evaluation unit in the clinical diagnosis of autism spectrum disorders.

BACKGROUND: Based on the recognized principles of assessment of autistic disorders, the child and adolescent psychiatry department in Razi Hospital developed, in coordination with the department of neurology of Razi Hospital and the department of genetics of Charles Nicolle's Hospital an assessment unit for autism spectrum disorders. OBJECTIVE: To describe the clinical characteristics in terms of severity and comorbidities of children assessed for autism spectrum disorders. METHODS: We compiled data about clinical examination of autistic symptoms using the Autism Diagnostic Interview Revised (ADI-R) and the Childhood autism Rating Scale (CARS). Each child developmental age was determined using the Psycho Educative Profile (PEP-R). Neurological examination completed with electroencephalography and genetics testing (caryoptype and X fragile) were performed. RESULTS: Fifty-two children were included in our study. The mean age was 6.6 years with a sex ratio of 6.5. The severity of the clinical presentations was assessed through the following score means: CARS 35, ADI-B: 20, ADI-C: 13, ADI-D: 7, functional developmental age: 2.4 years. Comorbidity with epilepsy was present in 7% of cases and an intellectual disability was found in 80% of them. Genetic tests were normal. CONCLUSION: Our results will be discussed in the light of international recommendations.

Epigenetics and ADHD: Toward an Integrative Approach of the Disorder Pathogenesis.

OBJECTIVE: Epigenetic hypothesis is one of the research pathways used to explain the complex etiology of neurodevelopmental disorders. This review highlights the findings of recent studies in the field of epigenetics in ADHD. METHODS: An electronic literature search using Medline. RESULTS: In the Gene × Environment interaction model, several clinical, genetic and molecular arguments support the epigenetic hypothesis in ADHD etiology. Environmental ADHD risk factors including toxic, nutritional factors and stressful life events lead to changes in DNA methylation and in histone modification levels. One critical CpG site located in the promoter of the DRD4 gene exhibited a specific pattern in ADHD children. A methylome wide exploration of DNA showed decreased methylation in vasoactive intestinal peptide receptor 2 gene, which was not replicated by further research. CONCLUSION: Current data require consolidation and could lead to the identification of biomarkers and the introduction of new modalities of treatment.

Sensitivity to pain in autistic spectrum disorders: Its links with self-gressivity.

OBJECTIVES: To investigate the link between pain sensitivity in autism spectrum disorders (ASD) and self-aggressive behavior. METHODS: we performed a cross-sectional study which involved 50 children fulfilling DSM-V criteria for ASD; confirmed by the Autism Diagnostic Interview Revised. The severity of autism was determined using the Childhood Autism Rating Scale (CARS).The psycho-educational profile (PEP-R) was used to assess the age of development and perception.  Sensitivity to pain was assessed with item IX of the CARS. Self-aggressive behavior was assessed by the Behavior Problems Inventory. RESULTS: Pain sensitivity was lowered in 40% and elevated in 4% of children. In the univariate analysis, no statistically significant association was found between normal sensitivity or hyper sensitivity to pain and the presence of auto-aggressiveness. A significant association was found between the presence of hypo-sensitivity to pain and the following variables: auto-aggression (p = 0.007, OR = 5.8, 95% CI = 1.5-21) , frequency of self-aggression (p = 0.001), intensity of self-aggression (p = 0.05), location of auto-aggressiveness at head and (P = 0.007, OR = 7.6, 95% CI = 1.8-14), higher score at CARS, and lower perception score at PEP-R (p = 0.012). Multiple-varied analysis identified risk factors for hypo-sensitivity to pain: lower perceptual score (p = 0.003, adjusted OR = 4.3, 95% CI = 1.9-54) and location of self-aggression at head and hands (p = 0.001, adjusted OR = 1.09, 95% CI = 1.02-1.09). CONCLUSION: It would be interesting to develop tools allowing a fine and precise evaluation of the painful sensation.

Quality of live among parents of children with autism spectrum disorders in Tunisia.

BACKGROUND: Studies on parents of children with autistic spectrum disorders' (ASD) quality of life (QOL) agree on its alteration and seek to identify risk factors in order to target interventions. AIMS: To study the QOL of a Tunisian population of parents of children with ASD and to look for risk factors specific to the Tunisian population. METHODS: We conducted a cross-sectional descriptive study of 50 parents of 50 children who met the DSM V criteria for autism spectrum disorder. A pre-established record was used to collect the biographical and clinical data. The severity of autism was determined using CARS. The SF-36, validated in Tunisia, made it possible to assess the QOL of the parents. RESULTS: The proportion of parents with impaired QOL was 64%. The average mental score was lower than the average physical summary score. Aggressiveness was the predominant factor that significantly altered parents' QOL at the total SF-36 score (p=0,03) and 5-dimensional levels (0.006

Theory of mind in adolescents with early-onset schizophrenia: correlations with clinical assessment and executive functions.

OBJECTIVE: We examined Theory of Mind (ToM) abilities in adolescents with early-onset schizophrenia (EOS) and their correlation with clinical findings and Executive Functions (EF). METHODS: The ToM abilities of 12 adolescents with EOS were compared with those of healthy participants matched in age and educational level. The Moving Shapes Paradigm was used to explore ToM abilities in three modalities: random movement, goal-directed movement and ToM - scored on the dimensions of intentionality, appropriateness and length of each answer. EF was tested using Davidson's Battery and the clinical psychopathology with the Positive and Negative Syndrome Scale (PANSS). RESULTS: Adolescents with EOS were significantly more impaired than controls in the three dimensions evaluated for the goal-directed and ToM modalities. Regarding the random movement modality, the only difference was in appropriateness (p<0.01). No correlation with age or level of education was evident for ToM skills. Total PANSS score was negatively correlated with appropriateness score for the goal-directed (p=0.02) and ToM modalities (p=0.01). No correlation existed between performance in the ToM Animated Tasks and positive, negative or disorganisation PANSS subscores. No correlations were found among the three scores in the Moving Shapes Paradigm and any measures of the accuracy of the three tasks assessing EF. CONCLUSION: Our results confirm previous findings of ToM deficits in adult individuals with schizophrenia and attest the severity of these deficits in patients with EOS.

Autism in Phenylketonuria Patients: From Clinical Presentation to Molecular Defects.

Autism has been reported in untreated patients with phenylketonuria. The authors aimed to explore autism in 15 Tunisian and 4 Algerian phenylketonuria patients, and report their clinical, biochemical and molecular peculiarities. The Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised were used for the diagnosis of autism. Five exons of phenylalanine hydroxylase gene (7, 6, 10, 11, and 5) were amplified by polymerase chain reaction and directly sequenced. Among these patients, 15 were suffering from autism at the time of evaluation. Six mutations were identified: p.E280K, p.G352Vfs, IVS10nt11, p.I224T, p.R261Q, and p.R252W. There was no correlation between autism and mutations affecting the phenylalanine hydroxylase gene, but the age of diet onset was the determining factor in autistic symptoms' evolution.

Distinctive findings in a boy with Simpson-Golabi-Behmel syndrome.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition characterized by pre and post natal overgrowth, facial malformations, and visceral, skeletal, and neurological anomalies. The physical characteristics of SGBS have been well documented; however there is a lack of description regarding the behavioral phenotype. We report the case of a 6-year-old boy, with confirmed deletion of 6-8 exons of the glypican-3 gene (GPC3) who presents three distinctive findings: the persistence of the craniopharyngeal canal, an immune-allergic specificity, and a scarcely behavioral phenotype consisting in the association of Austim Spectrum Disorder with accompanying mild intellectual disability and language impairments. He also fulfilled the criteria of Attention Deficit Hyperactivity Disorder and Oppositional Defiant Disorder according to DSM 5 criteria. The specificities of the case are discussed in the light of recent pathophysiological data.

Parental satisfaction of an assessment unit for autistic spectrum disorders.

Background - Based on the recognized principles of assessment of autistic disorders, the child and adolescent psychiatry department in Razi Hospital developed an assessment unit with diagnostic as well as therapeutic roles. The aim of this work was to examine its functioning and to analyze the parents' perceptions about the unit services. Methods - We gathered the parental satisfaction about the unit by the means of a hetero-questionnaire. Results - Fifty-two parents of children evaluated within the unit were included.  Patients had received the diagnosis of Autistic Disorder, Pervasive Developmental Disorders Not Otherwise Specified and Asperger Syndrome in accordance with DSM IV criteria, and than that of Autism Spectrum Disorder after DSM 5 publication. The overall satisfaction rate was 63%. Most parents (84.6%) rated the Psycho Educative Profile examination positively, 75% appreciated the neurological examination and the final report steps, 55.8% appreciated step of the Autism Diagnostic Interview revised and 42.3% the genetic exploration. 67% of the parents reported an improvement of their child following the evaluation. This improvement was attributed to the unit in 57.7% of cases. Parents whose children did not have associated disorders such as intellectual disability (p = 0.02), aggressive behavior (p = 0.04), affective disorder (p = 0.01) and sleep-related disorders (p = 0.03) were the most satisfied. Parents of children with epilepsy comorbidity were the least satisfied (p <10-3). 96% of parents suggested repeating the assessment once a year. Conclusion - Assessment units are based on international recommendations. However, it would be interesting to adapt assessments and orientation to the parents' expectations.