Specific genetic disorders and autism: Clinical contribution towards their identification

Service de Psychiatrie de l'Enfant et de l'Adolescent, Groupe Hospitalier Pitié-Salpétrière, Paris.
Journal of Autism and Developmental Disorders (Impact Factor: 3.34). 03/2005; 35(1):103-16. DOI: 10.1007/s10803-004-1038-2
Source: PubMed

ABSTRACT Autism is a heterogeneous disorder that can reveal a specific genetic disease. This paper describes several genetic diseases consistently associated with autism (fragile X, tuberous sclerosis, Angelman syndrome, duplication of 15q11-q13, Down syndrome, San Filippo syndrome, MECP2 related disorders, phenylketonuria, Smith-Magenis syndrome, 22q13 deletion, adenylosuccinate lyase deficiency, Cohen syndrome, and Smith-Lemli-Opitz syndrome) and proposes a consensual and economic diagnostic strategy to help practitioners to identify them. A rigorous initial clinical screening is presented to avoid unnecessary laboratory and imaging studies. Regarding psychiatric nosography, the concept of "syndromal autism"--autism associated with other clinical signs should be promoted because it may help to distinguish patients who warrant a multidisciplinary approach and further investigation.

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Available from: Alain Verloes, Jul 25, 2015
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    • "Il semblerait que les différences entre le QI verbal et le QI performance diminuent lorsque le langage est préservé. D'autre part, il est important de noter que la présence de comorbidité est la règle dans le groupe TSA avec déficience intellectuelle (par exemple l'épilepsie [33]) confinant parfois à un tableau d'autisme syndromique [34]. Plusieurs déficits cognitifs spécifiques ont été associés aux TSA. "
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    ABSTRACT: Myotonic dystrophy type 1 (DM1) is an autosomal multisystemic dominant disease caused by the expansion of a CTG triplet repeat within the 3′ untranslated region of dystrophy myotonic protein kinase (DMPK) gene on chromosome 19q13.3. The occurrence of a brain involvement is now widely accepted and well-recognized as a common feature in a substantial proportion of DM1 population. Depending of the phenotypic expression, the degree of cognitive impairment remains heterogeneous, ranging from moderate to severe mental retardation, which is characteristic of the congenital form, to executive, visuospatial and personality dysfunction in the adult-onset form. In contrast, studies exploring the cognitive or psychiatric impairments in the childhood DM1 are scarce and show conflicting results in regards to a comorbid diagnosis of Autism Spectrum Disorders (ASD). The objective of this article is to examine, on the basis of previous clinical studies, the plausible co-occurrence of childhood DM1 and ASD by (1) highlighting the specific cognitive and psychiatric profiles reported in both populations and (2) comparing the neuroanatomical and neuro-functional features of these two pathologies. For cognitive ability, the mean full-scale IQ of individuals with the childhood form of DM1 was globally assessed in the borderline range but a significant discrepancy was found with performance IQ being lower than verbal IQ. In ASD subjects with no mental retardation, a reverse dissociation was predominantly reported with lower VIQ than PIQ. Concerning psychiatric disorders in childhood DM1, most of the studies found that internalizing disorders were the most frequent whereas one study reported high prevalence of ASD. However, the DM1 patients with ASD were described as correlating with severity of DM1 and intellectual disability. Executive functions (predominantly working memory deficit in childhood DM1) and alexithymia or social cognition impairments were observed in both pathologies. Brain imaging studies in the childhood phenotype of DM1 revealed white matter abnormalities with no evidence of regional variation while a disrupted cortical connectivity pattern was suggested in ASD population. In conclusion, it could be hypothesized that different forms of DM1 illustrate a continuum of dysfunctions in the area of socialization (isolation, lack of initiative in social interactions, social anxiety and autism) as suggested by Douniol et al. (2012). Recognition of specific cognitive and psychiatric features in the childhood-onset form of DM1 should be fundamental for detecting early symptoms and implementing optimal individual support.
    Neuropsychiatrie de l Enfance et de l Adolescence 12/2014; 63(2). DOI:10.1016/j.neurenf.2014.11.005
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    • "Additionally, 10–20% of FXS patients experience seizures (Incorpora et al., 2002; Hagerman and Stafstrom, 2009). Approximately 15–33% of individuals with FXS meet the three diagnostic criteria for autism, with approximately 5% of autism cases attributed to FXS (Bailey et al., 1998; Cohen et al., 2005). Consistent with autism spectrum disorder, many individuals with FXS display deficits in social behavior, repetitive behavior, and abnormalities in communication. "
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    ABSTRACT: Fragile X syndrome (FXS) is an inherited form of intellectual disability and autism. Among other symptoms, FXS patients demonstrate abnormalities in sensory processing and communication. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity in humans with FXS. Consistent with observations in humans, the Fmr1 KO mouse model of FXS also shows evidence of altered auditory processing and communication deficiencies. A well-known and commonly used phenotype in pre-clinical studies of FXS is audiogenic seizures. In addition, increased acoustic startle response is seen in the Fmr1 KO mice. In vivo electrophysiological recordings indicate hyper-excitable responses, broader frequency tuning, and abnormal spectrotemporal processing in primary auditory cortex of Fmr1 KO mice. Thus, auditory hyper-excitability is a robust, reliable, and translatable biomarker in Fmr1 KO mice. Abnormal auditory evoked responses have been used as outcome measures to test therapeutics in FXS patients. Given that similarly abnormal responses are present in Fmr1 KO mice suggests that cellular mechanisms can be addressed. Sensory cortical deficits are relatively more tractable from a mechanistic perspective than more complex social behaviors that are typically studied in autism and FXS. The focus of this review is to bring together clinical, functional, and structural studies in humans with electrophysiological and behavioral studies in mice to make the case that auditory hypersensitivity provides a unique opportunity to integrate molecular, cellular, circuit level studies with behavioral outcomes in the search for therapeutics for FXS and other autism spectrum disorders.
    Frontiers in Cellular Neuroscience 02/2014; 8:19. DOI:10.3389/fncel.2014.00019
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    • "Their behaviour was considered to be autistic-type in terms of deficits in social relatedness, impaired communication and repetitive behaviours. In case a specific genetic syndrome was diagnosed, we used 'syndromic autism' (Cohen et al. 2005 "
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    ABSTRACT: Background  In some of our patients with intellectual disabilities (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment. In these patients melatonin levels at noon were extremely high (>50 pg/ml). We hypothesise that the disappearing effectiveness is associated with slow metabolisation of melatonin because of a single nucleotide polymorphism (SNP) of CYP1A2. Method  In this pilot study we analysed DNA extracted from saliva samples of 15 consecutive patients with disappearing effectiveness of melatonin. Saliva was collected at noon and 4 pm for measuring melatonin levels. Results  In all patients' salivary melatonin levels at noon were >50 or melatonin half time was >5 h. A SNP was found in eight of 15 patients. The allele *1C was found in two patients and in six patients the *1F allele was found. Conclusions  Of 15 patients with disappearing effectiveness of melatonin, seven were diagnosed with autism spectrum disorder, and in four of them a SNP was found. The other eight patients were known with a genetic syndrome. In six of them behaviour was considered to be autistic-type and in three of them a SNP was found. This finding may give a new direction for research into the genetic background of autism.
    Journal of Intellectual Disability Research 07/2012; 57(11). DOI:10.1111/j.1365-2788.2012.01595.x
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