Can family affectedness inform infant sibling outcomes of autism spectrum disorders?

BACKGROUND: Difficulties in communication and reciprocal social behavior are core features of autism spectrum disorders (ASD) and are often present, to varying degrees, in other family members. This prospective longitudinal infant sibling study examines whether social-communicative features of family members may inform which infants are at increased risk for ASD and other developmental concerns. METHOD: Two hundred and seventeen families participated in this study. Infant siblings were recruited from families with at least one older child diagnosed with an ASD (n = 135) or at least one typically developing older child (n = 82). Families completed the Social Responsiveness Scale to assess social and communication features of the broader autism phenotype (BAP), sometimes called quantitative autistic traits (QAT). Family affectedness was assessed in two ways: categorically, based on number of affected older siblings (i.e., typical, simplex, multiplex risk groups) and dimensionally, by assessing varying degrees of QAT in all family members. Infant siblings were assessed at 36 months of age and completed the Autism Diagnostic Observation Schedule and the Mullen Scales of Early Learning. RESULTS: In structural equation models, comparisons between multiplex, simplex and typical groups revealed the highest rates of QAT in the multiplex group followed by the simplex and typical groups. Infant sibling outcomes were predicted by gender, family risk group, proband QAT, and additional sibling QAT. CONCLUSIONS: Replicating previous cross-sectional and family history findings, the present study found elevated social and communication features of the BAP in siblings and fathers of ASD families, but not in mothers. While social and communication features of the BAP in mothers, fathers, and undiagnosed siblings did not predict infant sibling outcomes, having more than one affected older sibling did. Infant siblings from multiplex families were at significantly higher risk for ASD than infant siblings from simplex families in this sample.

[Assessment of comorbidity in autism spectrum disorders]. / De diagnostiek van comorbiditeit bij patiënten met een autismespectrumstoornis.

BACKGROUND: It is often difficult to determine whether there is psychiatric comorbidity in addition to an autism spectrum disorder (ASD) or whether the observed behavior is described adequately by the ASD diagnosis. AIM: To show when the possibility of comorbidity needs to be seriously considered in children and adults with ASD. We will focus on the most common comorbid disorders in children and adults with ASD, namely anxiety, depression and ADHD. METHOD: Discussion of the literature and clinical experiences. RESULTS: In order to diagnose ASD and comorbidities it is important to record a detailed developmental history. This can also serve as a baseline for the client's behaviour. Changes in the pattern of behaviour with respect to the baseline can often be indicative of the presence of a comorbid disorder. CONCLUSION: Since ASD is a life long disorder and comorbidity needing treatment or interventions can be present during various phases of life, the diagnostic procedure needs to continue even after ASD has been diagnosed.

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society.

Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Cognitive impairment in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is associated with a broad range of relatively nonspecific cognitive impairments, including low IQ, learning disabilities, and behavioral difficulties. While early studies indicated that the cognitive phenotype of NF1 resembles that of nonverbal learning disabilities (NLD), later research has found that the impairments are broader and do not fit the NLD profile well. Language-based deficits and executive dysfunction have also been found in empirical studies. There is some evidence that neuropsychological impairment may be correlated with the underlying central nervous system involvement of NF1, but this theory has not been consistently supported across studies. Further work clarifying the cognitive phenotype of NF1 is needed, especially investigations that employ appropriate comparison groups matched for intellectual level. Am. J. Med. Genet. (Semin. Med. Genet.) 89:45-52, 1999.

Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys.

In this study we examined several behavioral, personality, and cognitive characteristics of boys with FG syndrome. We confirmed high rates of attention and activity level problems, which were described previously. Nine of the 11 patients met criteria for attention deficit/hyperactivity disorder. The boys did not manifest autistic behavior, and none met criteria for an autism spectrum disorder, though their parents reported substantial repetitive behavior. The personalities of the participants often were described as friendly, good-natured, and cheerful, but they did not differ empirically on a standardized measure of personality structure from typically developing comparison children, even after controlling for the effects of IQ. Specifically, higher rates of agreeableness and extraversion were not confirmed, though these constructs do not correspond perfectly with the traits of affability and gregariousness described in earlier published case studies of FG syndrome. In terms of neuropsychological assessment, the boys had relatively less developed language, fine motor, and executive function skills, and visual-spatial abilities were a relative strength. Limitations and suggestions for future research are discussed.

Developmental aspects of attachment behavior in young children with pervasive developmental disorders.

OBJECTIVE: The present study applied a continuous, clinically based rating system to compare predictions about attachment behavior in autism resulting from three different theoretical views and to characterize differences in attachment behavior of young autistic children. METHOD: The attachment behaviors of 32 young children with autism or pervasive developmental disorder were examined in a modified "strange situation." Attachment behaviors were rated on a continuous scale and on the Ainsworth subscales. Attachment ratings were compared with several developmental variables, including chronological age, mental age, language level, and social level. RESULTS: The continuous rating scale distinguished signs of security from signs of insecurity, allowing for behavioral idiosyncracies in the expression of attachment behavior seen in autistic children. The study found that 50% of the children demonstrated some behaviors indicative of secure attachment, that no children were unattached, and that developmental level rather than severity of autism was the strongest predictor of attachment security. CONCLUSIONS: Autism does not preclude the development of secure attachment relationships in young children, but rather it delays the development of secure attachment and may alter the behavioral patterns that express attachment security.

A comparative study of attachment behavior in young children with autism or other psychiatric disorders.

The present study examined attachment behavior in children with autism and children with other developmental or psychiatric disorders. The groups were matched on chronological and mental age, IQ, and socioeconomic status. When a modified Strange Situation paradigm was used, no group differences were found in proximity seeking, contact maintenance, proximity avoidance, or contact resistance; the groups also did not differ in their overall security ratings. Attachment security was related to several developmental variables in the autistic group but not in the nonautistic comparison group. This suggests that attachment formation may involve different processes in autistic children than in nonautistic children of equivalent intellectual level.

Multisite, double-blind, placebo-controlled trial of porcine secretin in autism.

OBJECTIVE: To examine the efficacy of intravenous porcine secretin for the treatment of autistic disorder. METHOD: Randomized, double-blind, placebo-controlled, crossover design. Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Observation Schedule (ADOS) and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects. RESULTS: For the primary efficacy analysis, change of ADOS social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-0.8 +/- 2.9) and secretin groups (-0.6 +/- 1.4; t54 = 0.346, p < .73). The other measures showed no treatment effect for secretin compared with placebo. CONCLUSION: There was no evidence for efficacy of secretin in this randomized, placebo-controlled, double-blind trial.

Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder.

OBJECTIVE: To test the hypothesis that amantadine hydrochloride is a safe and effective treatment for behavioral disturbances--for example, hyperactivity and irritability--in children with autism. METHOD: Thirty-nine subjects (intent to treat; 5-19 years old; IQ > 35) had autism diagnosed according to DSM-IV and ICD-10 criteria using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. The Aberrant Behavior Checklist-Community Version (ABC-CV) and Clinical Global Impressions (CGI) scale were used as outcome variables. After a 1-week, single-blind placebo run-in, patients received a single daily dose of amantadine (2.5 mg/kg per day) or placebo for the next week, and then bid dosing (5.0 mg/kg per day) for the subsequent 3 weeks. RESULTS: When assessed on the basis of parent-rated ABC-CV ratings of irritability and hyperactivity, the mean placebo response rate was 37% versus amantadine at 47% (not significant). However, in the amantadine-treated group there were statistically significant improvements in absolute changes in clinician-rated ABC-CVs for hyperactivity (amantadine -6.4 versus placebo -2.1; p = .046) and inappropriate speech (-1.9 versus 0.4; p = .008). CGI scale ratings were higher in the amantadine group: 53% improved versus 25% (p = .076). Amantadine was well tolerated. CONCLUSIONS: Parents did not report statistically significant behavioral change with amantadine. However, clinician-rated improvements in behavioral ratings following treatment with amantadine suggest that further studies with this or other drugs acting on the glutamatergic system are warranted. The design of these and similar drug trials in children with autistic disorder must take into account the possibility of a large placebo response.

The external validity of Asperger disorder: lack of evidence from the domain of neuropsychology.

The present study compared individuals with high-functioning autism (HFA) and Asperger disorder (AD) in intellectual, motor, visuospatial, and executive function domains. Participants with AD demonstrated significantly higher Verbal and Full Scale IQ scores, significantly larger Verbal-Performance IQ discrepancies, and significantly better visual-perceptual skills than those with HFA. Once the superior intellectual abilities of the AD group were controlled (both statistically through analysis of covariance and by examining IQ-matched subgroups of HFA and AD participants), no significant group differences in motor, visuospatial, or executive functions were evident, save a marginally significant trend toward poorer fine motor performance in the AD group. This suggests that AD may simply be "high-IQ autism" and that separate names for the disorders may not be warranted. The relation of these findings to theories of autism and AD are discussed.

Effectiveness of a home program intervention for young children with autism.

This project evaluated the effectiveness of a TEACCH-based home program intervention for young children with autism. Parents were taught how to work with their preschool autistic child in the home setting, focusing on cognitive, academic, and prevocational skills essential to later school success. To evaluate the efficacy of the program, two matched groups of children were compared, a treatment group and a no-treatment control group, each consisting of 11 subjects. The treatment group was provided with approximately 4 months of home programming and was tested before and after the intervention with the Psychoeducational Profile-Revised (PEP-R). The control group did not receive the treatment but was tested at the same 4-month interval. The groups were matched on age, pretest PEP-R scores, severity of autism, and time to follow-up. Results demonstrated that children in the treatment group improved significantly more than those in the control group on the PEP-R subtests of imitation, fine motor, gross motor, and nonverbal conceptual skills, as well as in overall PEP-R scores. Progress in the treatment group was three to four times greater than that in the control group on all outcome tests. This suggests that the home program intervention was effective in enhancing development in young children with autism.

Teaching theory of mind: a new approach to social skills training for individuals with autism.

This study examined the effectiveness of a social skills training program for normal-IQ adolescents with autism. Five boys participated in the 4 1/2-month treatment condition; four boys matched on age, IQ, and severity of autism constituted the no-treatment control group. In addition to teaching specific interactional and conversational skills, the training program provided explicit and systematic instruction in the underlying social-cognitive principles necessary to infer the mental states of others (i.e., theory of mind). Pre- and post-intervention assessment demonstrated meaningful change in the treatment group's performance on several false belief tasks, but no improvement in the control sample. No changes, however, were demonstrated on general parent and teacher ratings of social competence for either group.

Further evidence of intact working memory in autism.

Earlier investigations have found mixed evidence of working memory impairment in autism. The present study examined working memory in a high-functioning autistic sample, relative to both a clinical control group diagnosed with Tourette Syndrome and a typically developing control group. No group differences were found across three tasks and five dependent measures of working memory. Performance was significantly correlated with both age and IQ. It is concluded that working memory is not one of the executive functions that is seriously impaired in autism. We also suggest that the format of administration of working memory tasks may be important in determining whether or not performance falls in the impaired range.

Inhibitory function in nonretarded children with autism.

This study examined inhibitory function in nonretarded children with autism (n = 13) and normally developing controls (n = 13) matched on age and IQ. Tasks measuring motor and cognitive components of inhibition were administered to both groups. On the Stop-Signal paradigm, children with autism were able to inhibit motor responses to neutral and prepotent stimuli as well as control subjects. On the Negative Priming task, the groups were equally capable of inhibiting processing of irrelevant distractor stimuli in a visual display. Results suggest that at least two components of inhibition are spared in individuals with autism, standing in contrast to flexibility and other executive deficits that have been found in previous studies. These findings may help distinguish children with autism from those with other neurodevelopmental conditions that involve executive dysfunction.

Can standard measures identify subclinical markers of autism?

This study compared the executive function and theory-of-mind abilities of siblings of autistic individuals to those of siblings of learning-disabled controls. Three different analyses of the dependent measures provided convergent support for a potential subclinical marker in the executive function domain. No group differences in theory-of-mind abilities were found. However, power analyses revealed that the measures employed in this study, which are typically used with autistic individuals, were not sufficiently sensitive to detect any group differences that might exist in "unaffected" family members. Suggestions for future research are provided, including the need to develop more sensitive tasks that produce larger effects and measure more elementary cognitive operations.

The screening and diagnosis of autistic spectrum disorders.

The Child Neurology Society and American Academy of Neurology recently proposed to formulate Practice Parameters for the Diagnosis and Evaluation of Autism for their memberships. This endeavor was expanded to include representatives from nine professional organizations and four parent organizations, with liaisons from the National Institutes of Health. This document was written by this multidisciplinary Consensus Panel after systematic analysis of over 2,500 relevant scientific articles in the literature. The Panel concluded that appropriate diagnosis of autism requires a dual-level approach: (a) routine developmental surveillance, and (b) diagnosis and evaluation of autism. Specific detailed recommendations for each level have been established in this document, which are intended to improve the rate of early suspicion and diagnosis of, and therefore early intervention for, autism.

Autism and autistic behavior in Joubert syndrome.

To determine whether individuals with Joubert syndrome exhibit features of autism as defined by the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV), we examined 11 children with Joubert syndrome using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-Generic. Three children met DSM-IV criteria for autistic disorder and one for pervasive developmental disorder not otherwise specified. The other seven all demonstrated at least one DSM-IV symptom of autism, but did not meet criteria for a pervasive developmental disorder. Both total number of DSM-IV symptoms and number of social symptoms distinguished the autism and nonautism subgroups. In contrast, the two subgroups displayed similar levels of communication impairments and repetitive or stereotyped behavior. The key to diagnosing autism in Joubert syndrome is to focus on social behaviors, particularly milestones typically achieved very early in life (eg, attending to human voices, showing objects of interest, enjoyment of social interactions). Implications for the role of the cerebellum in nonmotor behavior and for clinical management of Joubert syndrome also are discussed.

An exploration of right-hemisphere contributions to the pragmatic impairments of autism.

This study examined the potential contribution of the right hemisphere to the communicative impairments of autism. Pragmatic language measures sensitive to right-hemisphere damage were administered to nonretarded adults with autism and to controls matched on age and intellectual ability. The experimental battery included measures of humor, inference, and indirect request comprehension. Autistic subjects performed significantly less well than controls on all measures, replicating results of an earlier investigation by Rumsey and Hanahan (Journal of Clinical and Experimental Neuropsychology, 12, 81, 1990). The performance of the autistic group on the three tasks was also similar to that of right-hemisphere stroke patients reported previously (Molloy, Brownell, & Gardner, in Y. Joanette and H. M. Brownell (Eds.), Discourse ability and brain damage: Theoretical and empirical perspectives, New York: Springer-Verlag, 1990,pp. 113-130). Generalizability of these results and implications for the neuropathology of autism are discussed.

Autism treatment in the first year of life: a pilot study of infant start, a parent-implemented intervention for symptomatic infants.

The goal of early autism screening is earlier treatment. We pilot-tested a 12-week, low-intensity treatment with seven symptomatic infants ages 7-15 months. Parents mastered the intervention and maintained skills after treatment ended. Four comparison groups were matched from a study of infant siblings. The treated group of infants was significantly more symptomatic than most of the comparison groups at 9 months of age but was significantly less symptomatic than the two most affected groups between 18 and 36 months. At 36 months, the treated group had much lower rates of both ASD and DQs under 70 than a similarly symptomatic group who did not enroll in the treatment study. It appears feasible to identify and enroll symptomatic infants in parent-implemented intervention before 12 months, and the pilot study outcomes are promising, but testing the treatment's efficacy awaits a randomized trial.