Expressive semantic deficit in the productive language of males with fragile X syndrome.

Eleven males with fragile x syndrome [fra(X)] between the ages of 6 and 41, with an average communication age of 4 years 4 months and 11 normally developing 4 year old boys were administered a sentence completion task that assessed expressive semantic competence. The fra(X) males produced significantly more semantic errors than the normally developing 4 year children. Additionally, it was shown that sentences which could be correctly completed by a wider choice of words affected fra(X) males more than the nondisabled children. These 2 results suggest that the expressive semantic system is an area of specific deficit in fra(X) males.

Syntactic delay and pragmatic deviance in the language of fragile X males.

The expressive language of 19 fragile X [fra(X)] males with chronological ages between 5 and 36 years and Vineland Adaptive Behavior Scores between 21 and 79 was examined for syntactic as well as pragmatic proficiency. The production of deviant repetitive language was observed with this group, corroborating the results of an earlier study with a smaller sample of fra(X) males. In contrast, when 2 syntax scores, mean length of utterance (MLU), and Index of Productive Syntax (IPSyn) were derived from naturalistic language observations, the relation of complexity to length was observed to be very similar to the known relationship of these 2 facets of syntactic ability in normal preschoolers. These results, and the absence of correlations between syntactic scores and proportions of deviant repetitive language are consistent with the notion that the syntactic development of fra(X) males is typically delayed rather than deviant. For effective assessment and remediation of communicative problems associated with the syndrome to be developed, it is argued, language must be considered as a combination of competencies rather than as a unitary skill.

Effects of age and communication level on eye contact in fragile X males and non-fragile X autistic males.

Dyadic social gaze and eye contact were examined in fragile X [fra(X)] males and in non-fra(X) autistic males as a function of age and level of communicative ability. Lag sequential analysis showed that responsive eye contact was highly correlated with age and communicative ability in non-fra(X) autistic males but not in fra(X) males. Older, more communicative non-fra(X) autistic males exhibited more responsive eye contact than their fra(X) cohorts. Implications of these observations for theory and intervention are discussed.

Tissue differences in fragile X mosaics: mosaicism in blood cells may differ greatly from skin.

The fragile X mutation is diagnosed from the structure of the FMR1 gene in blood cell DNA. An estimated 12 to 41% of affected males are mosaics who carry both a "full mutation" allele from which there is no gene expression and a "premutation" allele which has normal gene expression. We compared the DNA in blood cells and skin fibroblasts from four mosaic fragile X males to see if there was a difference in the relative amounts of premutation and full mutation alleles within the tissues of these individuals. Two of these males showed striking differences in the ratio of premutation to full mutation in different tissues while the other two showed only slight differences. These observations conform with the widely accepted hypothesis that the fragile X CGG repeat is unstable in somatic tissue during early embryogenesis. Accordingly, the mosaicism in brain and skin, which are both ectodermal in origin, may be similar to each other but different from blood which is not ectodermal in origin. Thus, the ratio of full mutation to premutation allele in skin fibroblasts might be a better indicator of psychological impairment than the ratio in blood cells.

Mosaicism for the FMR1 gene influences adaptive skills development in fragile X-affected males.

Fragile X syndrome is one of the most common forms of inherited mental retardation, and the first of a new class of genetic disorders associated with expanded trinucleotide repeats. Previously, we found that about 41% of affected males are mosaic for this mutation in that some of their blood cells have an active fragile X gene and others do not. It has been hypothesized that these mosaic cases should show higher levels of functioning than those who have only the inactive full mutation gene, but previous studies have provided negative or equivocal results. In the present study, the cross-sectional development of communication, self-care, socialization, and motor skills was studied in 46 males with fragile X syndrome under age 20 years as a function of two variables: age and the presence or absence of mosaicism. The rate of adaptive skills development was 2-4 times as great in mosaic cases as in full mutation cases. There was also a trend for cases with autism to be more prevalent in the full-mutation group. These results have implications for prognosis, for the utility of gene or protein replacement therapies for this disorder, and for understanding the association between mental retardation, developmental disorders, and fragile X syndrome.

Identical twins discordant for Sotos syndrome.

The cause of Sotos syndrome is unknown but it usually occurs sporadically. Recent studies have shown no evidence of uniparental disomy. One set of concordant monozygotic twins has been reported. We have identified the Sotos syndrome in one of two 5-year-old male monozygotic twins. Our finding of discordance in these identical twins suggests that a postconceptual mutation, or epigenetic change and/or an environmental factor may be involved in the cause of Sotos syndrome.

A neural network approach to the classification of autism.

A nonlinear pattern recognition system, neural network technology, was explored for its utility in assisting in the classification of autism. It was compared with a more traditional approach, simultaneous and stepwise linear discriminant analyses, in terms of the ability of each methodology to both classify and predict persons as having autism or mental retardation based on information obtained from a new structured parent interview: the Autistic Behavior Interview. The neural network methodology was superior to discriminant function analysis both in its ability to classify groups (92 vs. 85%) and to generalize to new cases that were not part of the training sample (92 vs. 82%). Interrater and test-retest reliabilities and measures of internal consistency were satisfactory for most of the subscales in the Autistic Behavior Interview. The implications of neural network technology for diagnosis, in general, and for understanding of possible core deficits in autism are discussed.

Conversational characteristics of children with fragile X syndrome: tangential language.

The production of tangential language during conversations was studied with people who have fragile X syndrome, autistic disorder, or mental retardation not caused by fragile X. Tangential language was found to be more prevalent among those with fragile X, compared to the control groups, especially within unsolicited comments. These results support our hypothesis that the tangential language seen in fragile X is not the result of either general developmental delay or undiagnosed autistic disorder. We offer a possible interpretation of these results based upon such phenotypic characteristics as social anxiety, hypersensitivity to social and sensory stimuli, and inhibitory control deficits.

Conversational characteristics of children with fragile X syndrome: repetitive speech.

The production of repetitive speech during conversations was studied in people with fragile X syndrome, autistic disorder, or mental retardation not caused by fragile X. Repetitive speech was found to be more prevalent among those with fragile X compared to the control groups, especially within atypical utterances. These results suggest that the repetitive speech seen in individuals with fragile X is not the result of either general developmental delay or undiagnosed autistic disorder, and they support our hypothesis that such speech dysfluency reflects the effects of physiological arousal caused by hypersensitivity to social and sensory stimuli. Our results are interpreted within Perkins' theory of neuropsycholinguistic function.

Conversational analyses of males with fragile X, Down syndrome, and autism: comparison of the emergence of deviant language.

Deviant, repetitive language of 33 males (9 with Down syndrome, 12 with fragile X (fra[X]) syndrome, and 12 with autism) was analyzed within three conversational contexts: direct responses, initiation of new material, and topic maintenance. Results indicated that males with fra(X) manifest deviant, repetitive language that is distinct from males with either Down syndrome or autism. Thus, the deviant repetitive language of males with fra(X) cannot be accounted for by either their level of adaptive functioning or autistic-like behaviors per se. Possible explanations for this etiologically specific language deviance were discussed.

Social gaze, social avoidance, and repetitive behavior in fragile X males: a controlled study.

Preference for social gaze as well as the percentage occurrence of social gaze, nonverbal social avoidance, and nonverbal repetitive behaviors were examined in autistic and nonautistic prepubertal males with the fragile X syndrome (fra[X]) during social interaction with a parent or stranger. Comparison groups were nonhandicapped, Down syndrome, atypical pervasive developmental disorder, and autistic males. The subjects with fra(X) and the nonhandicapped and Down syndrome control subjects discriminated parent from stranger as evidenced by their avoidance behavior. The overall percentage of avoidance was higher, however, for both parent and stranger, among the males with fra(X). Autistic and atypical groups without fra(X) failed to discriminate parent from stranger in their avoidance behavior. Possible explanations for these group differences in terms of language level or degree of language demand were ruled out. Implications for research concerning the relations among fra(X), autism, and mental retardation were discussed.

Parent-child dyadic gaze patterns in fragile X males and in non-fragile X males with autistic disorder.

Parent-child dyadic gaze patterns were examined in fragile X [fra(X)] males and in non-fra(X) autistic males across three age groups--early childhood, middle childhood and adolescence. Absolute probabilities of social gaze did not significantly differ across diagnostic groups. Event lag sequential analyses indicated that fra(X) males were sensitive to social gaze initiation by their parents but found eye contact aversive. Non-fra(X) autistic males, by contrast, were insensitive to parent-initiated social gaze, and did not find eye contact aversive. Implications for research on the social characteristics of fra(X) and autistic children are discussed.

Why are autism and the fragile-X syndrome associated? Conceptual and methodological issues.

Investigations of the association between autism and the fragile-X syndrome have yielded conflicting results with some studies indicating a strong correlation and others indicating no relation between the disorders. In this paper, we review the relevant research on this controversy and discuss the conceptual and methodological problems involved in such an inquiry. We conclude that autism and fragile X are associated and that this relation will prove fruitful in understanding the role of the X chromosome in a variety of behavior disorders and in unraveling various theoretical accounts on the etiology of autism.

Annotation: Deconstructing the attention deficit in fragile X syndrome: a developmental neuropsychological approach.

BACKGROUND: Fragile X syndrome is one of the world's leading hereditary causes of developmental delay in males. The past decade has witnessed an explosion of research that has begun to unravel the condition at its various levels: from the genetic and brain levels to the cognitive level, and then to the environmental and behavioural levels. Our aim in this review is to attempt to integrate some of the extensive body of knowledge to move the research a step closer to understanding how the dynamics of atypical development can influence the specific cognitive and behavioural end-states frequently observed in children and adolescents with fragile X syndrome. METHODS: We conducted a review of the current neuropsychological and neuropsychiatric approaches that have attempted to delineate the pattern of 'spared' and 'impaired' functions associated with the phenotype. RESULTS: The profile of findings suggests that fragile X syndrome should not be viewed merely as a catalogue of spared and impaired cognitive functions or modules. Instead, there appears to be a process of almost gradual modularisation whereby cognitive mechanisms become domain specific as a function of development itself (Karmiloff-Smith, 1992). The results of a decade of intense research point towards an early weakness in one or more components of executive control rather than single, static higher-level deficits (e.g., spatial cognition, speech processing). This weakness affects both the development of more complex functions and current performance. CONCLUSIONS: The prevailing tendency to interpret developmental disorders in terms of fixed damage to distinct modular functions needs to be reconsidered. We offer this review as an example of an alternative approach, attempting to identify an initial deficit and its consequences for the course of development. Through better definition of the cognitive and behavioural phenotype, in combination with current progress in brain imaging techniques and molecular studies, the next decade should continue to hold exciting promise for fragile X syndrome and other neurodevelopmental disorders.