Nahit Motavalli Mukaddes

Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Deletions of NRXN1 (Neurexin-1) Predispose to a Wide Spectrum of Developmental Disorders

Research has implicated mutations in the gene for neurexin‐1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 × 10−7). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.

Psychiatric disorders in individuals with high-functioning autism and Asperger's disorder: Similarities and differences

Abstract Objectives. To investigate and compare the rate and type of psychiatric co-morbidity in individuals with diagnosis of high functioning autism (HFA) and Aspergers disorder (AS). Methods. This study includes 30 children and adolescents with diagnosis of HFA and 30 with diagnosis of AS. Diagnoses of HFA and AS were made using strict DSM-IV criteria. Psychiatric co-morbidity was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version (K-SADS-PL-T). Results. The rate of comorbid psychiatric disorders was very high in both groups (93.3% in HFA and 100% in AS). The most common disorder in both groups was attention deficit hyperactivity disorder. There was no statistically significant difference between groups in the rate of associated psychiatric disorders, except for major depressive disorder (P = 0.029) and ADHD-combined type (P = 0.030). The AS group displayed greater comorbidity with depressive disorders and ADHD-CT. Conclusion. From a clinical perspective, it could be concluded that both disorders involve a high risk for developing psychiatric disorders, with AS patients at greater risk for depression. From a nosological perspective, the substantial similarities in terms of psychiatric comorbidity may support the idea that both disorders are on the same spectrum and differs in some aspects.

Autistic disorder and 22q11.2 duplication

Although several reports have described the co-occurrence of autism in subjects with chromosome 22 abnormalities including trisomy 22, translocation 20/22, 22q11.2 deletion, ring chromosome 22, and 22q13.3 deletion, there is no report with 22q11.2 duplication. We report a 9-year-old girl, referred to our department for her behavioural problems and language delay. She was diagnosed with autistic disorder according to DSM-IV criteria. Because of her dysmorphic characteristics comprising narrow face, narrow forehead, mandibular prognathism, synophrys, and operated cleft palate and cardiac problems, she had gone under cytogenetic analysis. Although she was ascertained as suspected velocardiofacial syndrome (VCFS), the duplication of 22q11.2 was detected by interphase fluorescence in situ hybridization. Previous reports on the psychiatric aspects of 22q11.2 duplication have shown the existence of hyperactivity, learning disability, speech problems, and aggressive behaviours but not autism. Moreover, the lack of reports of co-occurrence of autism and 22q11.2 duplication may be related to paucity as a result of technical problems.Although several reports have described the co-occurrence of autism in subjects with chromosome 22 abnormalities including trisomy 22, translocation 20/22, 22q11.2 deletion, ring chromosome 22, and 22q13.3 deletion, there is no report with 22q11.2 duplication. We report a 9-year-old girl, referred to our department for her behavioural problems and language delay. She was diagnosed with autistic disorder according to DSM-IV criteria. Because of her dysmorphic characteristics comprising narrow face, narrow forehead, mandibular prognathism, synophrys, and operated cleft palate and cardiac problems, she had gone under cytogenetic analysis. Although she was ascertained as suspected velocardiofacial syndrome (VCFS), the duplication of 22q11.2 was detected by interphase fluorescence in situ hybridization. Previous reports on the psychiatric aspects of 22q11.2 duplication have shown the existence of hyperactivity, learning disability, speech problems, and aggressive behaviours but not autism. Moreover, the lack o...

High rates of psychiatric co-morbidity in individuals with Asperger's disorder

The present study aimed to provide clinical data regarding co-morbidity of psychiatric disorders in individuals diagnosed with Aspergers disorder (AD). This study included 37 individuals (32 male, five female, mean age: 10.9±4.5 years) diagnosed with AD. Psychiatric comorbidity was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children – Present and Lifetime Version (K-SADS – PL). Ninety-four percent of participants had at least one additional psychiatric disorder. The most common were anxiety disorders (54%), disruptive behavioural disorders (48%), and mood disorders (37%). The results of this study highlight the need for detailed assessment of additional psychiatric disorders in this population.

Autism in visually impaired individuals

Abstract  The aim of the present study was to assess the prevalence and associated risk factors of autism in a sample of visually impaired children and adolescents. A total of 257 blind children and adolescents (age range: 7–18 years) were examined for autism using a three‐stage process. The first stage estimated probable cases of autistic disorder based on the Autism Behavior Checklist and the second stage by direct observation of the subjects in different settings. In the third stage, subjects with the probable diagnosis of autistic disorder were asked to undergo psychiatric examination. A final diagnosis of autistic disorder (based on the criteria in DSM‐IV) was given after interviewing the caregivers and clinical observation. Thirty of 257 subjects met the criteria for autistic disorder. Comparison of the characteristics of the two groups (autistic and non‐autistic) with χ2‐squared and independent sample t‐tests revealed a statistically significant difference in terms of severity of blindness (P = 0.015), cerebral palsy (P = 0.02) and intellectual level (P = 0.001). The results of the present study suggest that subjects with blindness plus autism have greater neurological impairment (as suggested by the presence of lower intellectual level and cerebral palsy), and more severe visual impairment than the subjects with blindness only.

Tactile sensitivity of normal and autistic children

Many children with autistic spectrum disorders have unusual reactions to certain sensory stimuli. These reactions vary along a hyper- to hypo-responsivity continuum. For example, some children overreact to weak sensory input, but others do not respond negatively to even strong stimuli. It is typically assumed that this deviant responsivity is linked to sensitivity, although the particular stage of sensory processing affected is not known. Psychophysical vibrotactile thresholds of six male children (age: 8–12) who were diagnosed to have autistic spectrum disorders and six normal male children (age: 7–11) were measured by using a two-alternative forced-choice task. The tactile stimuli were sinusoidal displacements and they were applied on the terminal phalanx of the left middle finger of each subject. By using a forward-masking paradigm, 40- and 250-Hz thresholds of the Pacinian tactile channel and 40-Hz threshold of the Non-Pacinian I tactile channel were determined. There was no significant difference between the thresholds of autistic and normal children, and the autistic children had the same detection and masking mechanisms as the normal children. The sensory responsivity of each subject was tested by clinical questionnaires, which showed again no difference between the two subject groups. Furthermore, no significant correlations could be found between the questionnaire data and the psychophysical thresholds. However, there was a high correlation between the data from the tactile and emotional subsets of the questionnaires. These results support the hypothesis that the hyper- and hypo-responsivity to touch, which is sometimes observed in autistic spectrum disorders, is not a perceptual sensory problem, but may probably be emotional in origin.

Venlafaxine in children and adolescents with attention deficit hyperactivity disorder

Abstract  The primary purpose of this study was to describe tolerability and efficacy of venlafaxine in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). A 6‐week open trial of venlafaxine was conducted in 13 children and adolescents (mean age 9.9 ± 2.5 years) with ADHD, and without comorbid depression. Venlafaxine was initiated at a dose of 18.75 mg/day and flexibly titrated to 56.25 mg/day. The Conners parent scale and Clinical Global Improvement (CGI) severity item were performed at baseline and at the end of the 6‐week trial. All subjects completed the trial. Mean final dose of venlafaxine was 40.3 ± 7.0. Venlafaxine was significantly effective in reducing the total score of the Conners parent scale from baseline to endpoint (P < 0.002, Z =−3.113) and the CGI severity item (P < 0.05). Transient side‐effects such as somnolence (n = 2), stomachache (n = 2), and headache (n = 1) disappeared after second week of treatment. Also three subjects complained of sedation after raising the dose to 56.5 mg/day, therefore the dose was reduced to the previous level. These preliminary data suggest that venlafaxine may be an effective medication in the treatment of some children and adolescents with ADHD. Future double‐blind controlled trials should be undertaken.

Effectiveness of mirtazapine in the treatment of inappropriate sexual behaviors in individuals with autistic disorder.

OBJECTIVE The aim of this study was to investigate the efficacy and safety of mirtazapine in the treatment of excessive masturbation and other inappropriate sexual behaviors (ISB) in individuals with the diagnosis of autistic disorder (AD). METHOD Subjects (n = 10; 2 females, 8 males; age range: 5.2-16.4 years) who suffered from excessive masturbation with or without other ISB were treated with mirtazapine for 8 weeks. Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) scales were used for the evaluation of symptoms severity and effectiveness. Mirtazapine was started at 7.5-15 mg/day and titrated up to 15-30 mg/day (mean 21.6 +/- 7.9 mg/day). The data for this study were collected from reviewing medical records of all subjects that suffered from ISB and treated with mirtazapine. RESULTS CGI scores at baseline and end point ranged from 5 to 7 (mean 6.22 +/- 0.83) and 2 to 4 (mean 3 +/- 0.7), respectively. A nonparametric t-test showed significant difference in CGI-S scores between baseline and end point assessments (Z = -2.725; p = 0.006, p < 0.01). Five subjects showed very much, 3 showed much, and 1 showed moderate improvement in excessive masturbation on the CGI-I scale. One subject dropped out from clinical follow up. Mirtazapine was generally tolerated well. The most frequently reported side effects were increased appetite, weight gain (n = 3; mean 0.78 +/- 1.20 kg), and sedation. CONCLUSIONS Mirtazapine could be an effective treatment to ameliorate ISB in a young population with a diagnosis of AD. Well-designed, placebo-controlled studies are needed regarding this topic.