Autistic spectrum disorders in preschool children.
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OBJECTIVE: To review existing data on early signs of autistic spectrum disorders (ASD) and on how these disorders can be distinguished from other atypical patterns of development, and to describe a developmental surveillance approach that family physicians can use to ensure that children with these diagnoses are detected as early as possible. QUALITY OF EVIDENCE: MEDLINE was searched from January 1966 to July 2000 using the MeSH terms autistic disorder/diagnosis AND diagnosis, differential AND (infant OR child, preschool). Articles were selected based on relevance to developmental surveillance in primary care and on experimental design, with emphasis on prospective studies with systematic measurement procedures using up-to-date diagnostic criteria. MAIN MESSAGE: Autistic spectrum disorders are characterized by impairments in social interaction and verbal and nonverbal communication, and by preferences for repetitive interests and behaviours. Early signs that distinguish ASD from other atypical patterns of development include poor use of eye gaze, lack of gestures to direct other people's attention (particularly to show things of interest), diminished social responsiveness, and lack of age-appropriate play with toys (especially imaginative use of toys). Careful attention to parents' concerns and specific inquiry into and observation of how children interact, communicate, and play will help ensure that early signs are detected during regular health maintenance visits. CONCLUSION: Family physicians have an important role in early identification of children with ASD. Early diagnosis of these disorders is essential to ensure timely access to interventions known to improve outcomes for these children. (+info)
Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.
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Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi(2)=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder. (+info)
Distinct phenotypes distinguish the molecular classes of Angelman syndrome.
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BACKGROUND: Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. METHODS: We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. RESULTS: In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. CONCLUSIONS: Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15. (+info)
A genomewide scan identifies two novel loci involved in specific language impairment.
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Approximately 4% of English-speaking children are affected by specific language impairment (SLI), a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and concordance in monozygotic twins consistently exceeds that in dizygotic twins. However, like many behavioral traits, SLI is assumed to be genetically complex, with several loci contributing to the overall risk. We have compiled 98 families drawn from epidemiological and clinical populations, all with probands whose standard language scores fall > or =1.5 SD below the mean for their age. Systematic genomewide quantitative-trait-locus analysis of three language-related measures (i.e., the Clinical Evaluation of Language Fundamentals-Revised [CELF-R] receptive and expressive scales and the nonword repetition [NWR] test) yielded two regions, one on chromosome 16 and one on 19, that both had maximum LOD scores of 3.55. Simulations suggest that, of these two multipoint results, the NWR linkage to chromosome 16q is the most significant, with empirical P values reaching 10(-5), under both Haseman-Elston (HE) analysis (LOD score 3.55; P=.00003) and variance-components (VC) analysis (LOD score 2.57; P=.00008). Single-point analyses provided further support for involvement of this locus, with three markers, under the peak of linkage, yielding LOD scores >1.9. The 19q locus was linked to the CELF-R expressive-language score and exceeds the threshold for suggestive linkage under all types of analysis performed-multipoint HE analysis (LOD score 3.55; empirical P=.00004) and VC (LOD score 2.84; empirical P=.00027) and single-point HE analysis (LOD score 2.49) and VC (LOD score 2.22). Furthermore, both the clinical and epidemiological samples showed independent evidence of linkage on both chromosome 16q and chromosome 19q, indicating that these may represent universally important loci in SLI and, thus, general risk factors for language impairment. (+info)
Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia.
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Genetic speech and language disorders provide the opportunity to investigate the biological bases of language and its development. Critical to these investigations are the definition of behavioural phenotypes and an understanding of their interaction with epigenetic factors. Here, we report our investigations of the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The cognitive manifestations of this disorder were investigated using a number of linguistic and non-linguistic tests. The aims of these investigations were to establish the existence of a 'core' deficit, or behavioural phenotype, and to explain how such a deficit during development might give rise to the range of other impairments demonstrated by affected family members. The affected family members were compared both with the unaffected members and with a group of adult patients with aphasia resulting from a stroke. The score on a test of repetition of non-words with complex articulation patterns successfully discriminated the affected and unaffected family members. The affected family members and the patients with aphasia had remarkably similar profiles of impairment on the tests administered. Pre-morbidly, however, the patients with aphasia had enjoyed a normal course of cognitive development and language experience. This benefit was reflected on a number of tests in which the patients with aphasia performed significantly better than the affected family members and, in the case of some tests, at normal levels. We suggest that, in the affected family members, the verbal and non-verbal deficits arise from a common impairment in the ability to sequence movement or in procedural learning. Alternatively, the articulation deficit, which itself might give rise to a host of other language deficits, is separate from a more general verbal and non-verbal developmental delay. (+info)
MRI analysis of an inherited speech and language disorder: structural brain abnormalities.
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Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family. (+info)
Language and reading acquisition in children with and without cochlear implants.
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These data provide a coherent view of the spoken language and reading skills of children receiving cochlear implants. The data reveal both spoken language gains and clear benefit to these children with regard to reading. Improvement in reading is consistent with predictions based on prior research demonstrating a strong association between spoken language and reading. An intervention such as a cochlear implant has a direct effect on spoken language, and this can subsequently affect reading performance. This provides some of the first experimental evidence supporting the causal relationship between spoken language and reading. (+info)
Language in ageing persons with Down syndrome.
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Several cross-sectional studies and one longitudinal study were conducted on the language abilities of various cohorts of persons with Down syndrome aged between 14 and 50 years. No significant difference was observed on any of the receptive and productive morphosyntactic and lexical measures used, suggesting no marked change in the language of these persons from adolescence onto late adulthood. Repeated measures of cerebral metabolic rate (CMR) for fluorodeoxyglucose using a Positron Emission Tomography were made over a 4-year interval with 7 participants with Down syndrome aged between 37 and 49 years. A gradual decrease in global CMR for both cerebral hemispheres and for each participant was documented. It was particularly marked for 3 participants. However, no language deterioration could be associated with their marked lowering in CMR. (+info)