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Biomedical subjects

Peter Szatmari

Publications and source records attributed to Peter Szatmari.

At least 19 recordsLinked to original sources
PubMed2007

Informative phenotypes for genetic studies of psychiatric disorders.

Despite its initial promise, there has been both progress and some set backs in genetic studies of the major psychiatric disorders of childhood and adulthood. Finding true susceptibility genes may be delayed because the most genetically informative phenotypes are not being used on a regular basis in linkage analysis and association studies. It is highly likely that using alternative phenotypes instead of DSM diagnostic categories will lead more rapid success in the search for these susceptibility genes. The objective of this paper is to describe the different types of informative phenotypes that can be employed in psychiatric genetic studies, to clarify their uses, to identify several methodologic issues the design and conduct of linkage and association studies that use alternative phenotypes and finally to suggest possible solutions to those difficulties. This is a conceptual review with a focus on methodological issues that may arise in psychiatric genetics and examples are taken from the literature on autism, schizophrenia, bipolar disorder, and alcoholism.

Diagnostic and Statistical Manual of Mental Disord↗
PubMed2007

Stereotyped motor behaviors associated with autism in high-risk infants: a pilot videotape analysis of a sibling sample.

This study examined motor behaviors in a longitudinal cohort of infant siblings of children with autism. Stereotypic movements and postures occurring during standardized observational assessments at 12 and 18 months were coded from videotapes. Participants included eight infant siblings later diagnosed with autism spectrum disorder (ASD), a random sample of nine non-diagnosed siblings, and 15 controls. Videos were coded blind to diagnostic group. At 12 and 18 months the ASD group "arm waved" more frequently and at 18 months, one posture ("hands to ears") was more frequently observed in the ASD and non-diagnosed group compared to the controls. Overall, the siblings subsequently diagnosed with ASD and the comparison groups had considerable overlap in their repertoires of stereotyped behaviors.

Autistic Disorder↗
PubMed2007

A prospective case series of high-risk infants who developed autism.

The present paper documents the development of autism/autistic spectrum disorder in a consecutive series of nine high-risk infants followed prospectively from 6 months of age. Evidence is provided for two broadly defined subgroups: the first subgroup (n = 6) showed a decrease in IQ between 12 and 24 or 36 months (from average/near average to severe cognitive impairment), whereas the second subgroup (n = 3) continued to obtain average or near average IQs. Signs of autism emerged and/or were more striking earlier in the first subgroup. In all nine children, early impairment in social-communicative development coexisted with atypical sensory and/or motor behaviors, as did a temperamental profile marked by irritability/distress and dysregulated state. Discussion focuses on issues raised by the pattern of findings.

Autistic Disorder↗
PubMed2007

Brief report: a scale for rating conversational impairment in autism spectrum disorder.

There are few well-standardized measures of conversational breakdown in Autism Spectrum Disorders (ASD). The study's objective was to develop a scale for measuring pragmatic impairments in conversations of individuals with ASD. We analyzed 46 semi-structured conversations of children and adolescents with high-functioning ASD using a functional linguistic paradigm. Five constructs were developed that assessed difficulties related to the pragmatics of conversation: atypical intonation; semantic drift; terseness; pedantic speech; perseveration. The scale shows good inter-rater reliability and variation in the scales is not simply a reflection of IQ or language competence. This tool represents a way of characterizing language use in ASD and is an initial step towards developing a tool to evaluate change in degree of social impairments in conversation.

Adolescent↗
PubMed2006

Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia.

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

Apraxias↗
PubMed2006

Early language and communication development of infants later diagnosed with autism spectrum disorder.

It is well recognized that delayed "first words" is among the most common presenting symptoms of autistic spectrum disorders (ASD). However, data on earlier language and communication development in children with ASD are limited to retrospective reports from parents and from home videos. In this study, we prospectively collected parent report data on early communication and language development in 97 infant siblings of children with ASD and 49 low-risk controls. Parents completed the MacArthur Communicative Development Inventory--Infant Form at 12 and 18 months. Analysis compared 3 groups defined on the basis of diagnostic assessment at 24 months: (1) siblings with ASD (n = 15), (2) siblings not meeting diagnostic criteria for ASD (n = 82), and (3) low-risk controls, none of whom had ASD (n = 49). Children with ASD showed delays in early language and communication compared with non-ASD siblings and controls. At 12 months, the ASD group was reported to understand significantly fewer phrases and to produce fewer gestures. At 18 months, they showed delays in their understanding of phrases, comprehension and production of single words, and use of gestures. Siblings not diagnosed with ASD also used fewer play-related gestures at 18 months than low-risk controls, even when children with identified language delays were excluded. Overall, this prospective study confirms that delays in communication and language development are apparent early in life in children with ASD, and emphasizes that developmental surveillance should include monitoring for delays in gesture, which may be among the earliest signs of ASD.

Autistic Disorder↗
PubMed2006

Combining information from multiple sources in the diagnosis of autism spectrum disorders.

BACKGROUND: Standard case criteria are proposed for combined use of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule to diagnose autism and to define the broader category of autism spectrum disorders. METHOD: Single and combined Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule algorithms were compared to best estimate diagnoses in four samples: U.S. (n = 960) and Canadian (n = 232) participants 3 years and older, U.S. participants younger than 36 months (n = 270), and U.S. participants older than 36 months with profound mental retardation (n = 67). RESULTS: Sensitivities and specificities of 80% and higher were obtained when strict criteria for an autism diagnosis using both instruments were applied in the U.S. samples, and 75% or greater in the Canadian sample. Single-instrument criteria resulted in significant loss of specificity. Specificity was poor in the sample with profound mental retardation. Lower sensitivity and specificity were also obtained when proposed criteria for broader spectrum disorders were applied. CONCLUSIONS: The Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule make independent, additive contributions to the judgment of clinicians that result in a more consistent and rigorous application of diagnostic criteria.

Asperger Syndrome↗
PubMed2006

Investigating the structure of the restricted, repetitive behaviours and interests domain of autism.

BACKGROUND: The Restricted, Repetitive Behaviours and Interests (RRBIs) are represented in the DSM-IV and measured by the Autism Diagnostic Interview-Revised (ADI-R) as one of the three homogeneous symptom categories of Pervasive Developmental Disorders. Although this conceptualisation is well accepted in the field, the grouping of symptoms is based primarily on clinical judgment rather than on empirical evidence. METHODS: The objective of this study was to examine the factor structure of the RRBI domain of autism. Eleven items from this domain of the ADI-R were used in a Principal Components Analysis (PCA). Our sample consisted of 339 individuals with a Best Estimate diagnosis of Pervasive Developmental Disorder (PDD). RESULTS: Findings indicate that the RRBI domain is composed of two distinct factors or dimensions: Insistence on Sameness (IS) and Repetitive Sensory and Motor Behaviours (RSMB). RSMB is negatively correlated with adaptive skills; that is, lower functioning individuals tend to have higher levels of repetitive sensory and motor behaviours. On the other hand, IS is positively correlated with autistic symptoms in the communication and language domain. Further analyses suggest moderate familial aggregation among affected sibling pairs within the IS but not the RSMB factor. CONCLUSIONS: These results provide evidence for the heterogeneity of the RRBI domain of the ADI-R in terms of both clinical presentation and other correlates. In addition, the IS factor seems to be under familial (presumably genetic) control, while RSMB appears to simply reflect variation in developmental level.

Adaptation, Psychological↗
PubMed2005

Challenges in evaluating psychosocial interventions for Autistic Spectrum Disorders.

In 2002, the National Institutes of Health sponsored a meeting concerning methodological challenges of research in psychosocial interventions in Autism Spectrum Disorders. This paper provides a summary of the presentations and the discussions that occurred during this meeting. Recommendations to federal and private agencies included the need for randomized clinical trials of comprehensive interventions for autism as the highest, but not the sole priority. Ongoing working groups were proposed to address psychosocial interventions with a focus on relevant statistics, standardized documentation and methods of diagnosis, development of outcome measures, establishment of standards in research; and the need for innovative treatment designs, including application of designs from other research areas to the study of interventions in ASD.

Autistic Disorder↗
PubMed2005

A pilot feasibility study of an extension of the acquaintanceship recruitment procedure in recent-onset psychosis.

The acquaintanceship recruitment procedure is an appealing yet infrequently used method to recruit controls, allowing a very close match between patients and controls. We used an extension of the acquaintanceship procedure to investigate the feasibility of this method to recruit controls in a neuropsychological study of recent-onset psychotic patients. Twenty-five recent-onset psychotic patients attending a multidisciplinary program devoted to recent-onset psychoses were contacted, among whom 13 agreed to participate to the study. At the end of the process, only four control participants were assessed. This pilot study suggests that several obstacles prevent the use of this procedure to recruit controls in this research focusing on recent-onset psychotic disorders.

Adult↗
PubMed2004

Modifier effects in autism at the MAO-A and DBH loci.

Autism is one of a group of pervasive developmental disorders (PDD) characterized by qualitative impairments in reciprocal social communication and by a preference for repetitive, stereotyped activities, interests, and behaviors. The disorder is caused in large part by genetic mechanisms, though no disease genes have yet been identified. The objective of this study was to investigate three markers, two in the DBH gene and one in the MAO-A gene, for maternal or fetal modifier effects on level of functioning (IQ). At the same time, the possibility of maternal or fetal susceptibility effects was also examined. We assembled 67 affected sibpairs and 45 singletons and determined allele frequencies at the three markers among the affected children and first degree relatives. Sizeable and significant modifier effects were found at the MAO locus and, to a lesser extent, at the DBH locus. Susceptibility effects were also found but not without qualification. We conclude that maternal genotypes at the MAO-A locus, and possibly at the DBH one, may modify IQ in children with autism through the intrauterine environment.

Autistic Disorder↗
PubMed2004

The search for autism disease genes.

Autism is a heritable disorder characterized by phenotypic and genetic complexity. This review begins by surveying current linkage, gene association, and cytogenetic studies performed with the goal of identifying autism disease susceptibility variants. Though numerous linkages and associations have been identified, they tend to diminish upon closer examination or attempted replication. The review therefore explores challenges to current methodologies presented by the complexities of autism that might underlie some of the current difficulties, and finishes by describing emerging phenotypic, statistical, and molecular investigational approaches that offer hope of overcoming those challenges.

Autistic Disorder↗
PubMed2004

Conducting genetic epidemiology studies of autism spectrum disorders: issues in matching.

The objective of this review is to clarify the role of matching in family genetic studies of autism as a way of defining endophenotypes for linkage analysis. The concept of a confounding variable is reviewed and the importance of considering these in family studies of three endophenotypes in autism are considered: cognitive/language impairments, psychiatric disorders, and autistic-like traits. The importance of matching in infant sibling studies of autism is also addressed. Matching as a way of dealing with confounding variables has an important impact on understanding the extent to which these phenotypes are associated with the genes that confer susceptibility to autism and to the early detection of the disorder. Matching continues to be an important issue in the planning and conduct of family-genetic studies of the autism spectrum disorders, particularly as the search for autism susceptibility genes enters the next generation of studies.

Autistic Disorder↗
PubMed2004

Specifying PDD-NOS: a comparison of PDD-NOS, Asperger syndrome, and autism.

OBJECTIVE: To describe the clinical characteristics of children given a diagnosis of pervasive developmental disorder-not otherwise specified (PDD-NOS) by expert clinicians and to compare these to the clinical characteristics of children given a diagnosis of autism and Asperger syndrome (AS). METHOD: Two hundred sixteen children with autism, 33 with AS, and 21 with PDD-NOS were compared on measures of level of functioning (communication, daily living and social skills, IQ, and age of acquisition of language) and on various symptoms of autism (impaired communication and reciprocal social interaction and a preference for repetitive and stereotyped activities). RESULTS: In terms of level of functioning measures, the PDD-NOS children had scores that were between those of the children with autism and those of the children with AS. In contrast, the PDD-NOS group had fewer autistic symptoms, especially repetitive stereotyped behaviors, than both the autism and AS groups (chi2 = 11.06, p =.004). Children with PDD-NOS could be placed into one of three subgroups: a high-functioning group (24%) who resembled AS but had transient language delay or mild cognitive impairment; a subgroup resembling autism (24%) but who had late age of onset or too severe cognitive delays or were too young to potentially meet the full diagnostic criteria for autism; and a group (52%) not fulfilling the criteria for autism because of fewer stereotyped and repetitive behaviors. CONCLUSIONS: With some revision to current diagnostic criteria, a more homogenous atypical group with significant impairments in social-communication but fewer repetitive behaviors can be differentiated from the more nonspecific PDD-NOS group. This differentiation may lead to better reliability in diagnosis and to further progress in studies of etiology.

Asperger Syndrome↗
PubMed2003

Human chromosome 7: DNA sequence and biology.

DNA sequence and annotation of the entire human chromosome 7, encompassing nearly 158 million nucleotides of DNA and 1917 gene structures, are presented. To generate a higher order description, additional structural features such as imprinted genes, fragile sites, and segmental duplications were integrated at the level of the DNA sequence with medical genetic data, including 440 chromosome rearrangement breakpoints associated with disease. This approach enabled the discovery of candidate genes for developmental diseases including autism.

Animals↗