Biomedical subjects

P Szatmari

Publications and source records attributed to P Szatmari.

At least 19 recordsLinked to original sources

PubMed2006

An inversion inv(4)(p12-p15.3) in autistic siblings implicates the 4p GABA receptor gene cluster.

INTRODUCTION: We describe the case of two brothers diagnosed with autism who both carry a paracentic inversion of the short arm of chromosome 4 (46,XY, inv(4)(p12-p15.3)). We have determined that this inversion is inherited from an apparently unaffected mother and unaffected maternal grandfather. Methods/ RESULTS: Using fluorescence in situ hybridisation analysis and Southern blot hybridisation we identified the breakpoints. The proximal breakpoint (4p12) maps to a region containing a cluster of gamma-aminobutyric acid A (GABA(A)) receptor genes, and directly interrupts the GABRG1 gene, the distal-most gene of the cluster. We also identified an insertion/deletion polymorphism for a approximately 2 kb LINE1 (L1) element that occurs within intron 7 of GABRG1. Our genotype analysis amongst autism families indicated that the L1 deletion allele did not show increased transmission to affected individuals. No linkage disequilibrium was evident between the L1 and single nucleotide polymorphisms in adjacent GABA(A) receptor genes on 4p, where a recent study has identified significant association with autism. DISCUSSION: Despite this, the identification of an inversion breakpoint disrupting GABRG1 provides solid support for the genetic involvement of the short arm of chromosome 4 in the genetic aetiology of autism, and for the hypothesis of disrupted GABA neurotransmission in autism.

Adult↗

PubMed2003

Predictors of outcome among high functioning children with autism and Asperger syndrome.

BACKGROUND: The objective of this paper is to assess the extent to which measures of cognitive abilities taken in an inception cohort of young high functioning children with autism and Asperger syndrome predict outcome roughly two and six years later. METHOD: Children who received a diagnosis of autism or Asperger syndrome (AS) and who had a nonverbal IQ score in the 'non-retarded' range were included in the inception cohort. Measures of language and nonverbal skills were taken when the children were 4-6 years of age and outcome assessments were completed when the children were 6-8 and 10-13 years of age. The three outcome measures consisted of scales of adaptive behaviours in socialisation and communication and a composite measure of autistic symptoms (abnormal language, abnormal body and object use, difficulties relating to others, sensory issues and social and self-help difficulties). RESULTS: The explanatory power of the predictor variables was greater for communication and social skills than for autistic symptoms. The power of prediction was stable over time but did differ by PDD subtype. In general, the association between language skills and outcome was stronger in the autism group than in the AS group. CONCLUSIONS: These results support the emphasis of early intervention programmes on language but more work needs to be done on understanding variables that influence outcome in social skills and autistic behaviours, particularly in those with AS.

Adaptation, Psychological↗

PubMed2001

Birth order effects on nonverbal IQ scores in autism multiplex families.

Lord (1992) published a brief report showing a trend for decreasing nonverbal IQ scores with increasing birth order in a sample of 16 autism multiplex families, and urged replication in a larger sample. In this report, analyses of nonverbal IQ scores for a sample of 144 autism multiplex families indicated that nonverbal IQ scores were significantly lower in secondborn compared with firstborn siblings with autism. This birth order effect was independent of gender as well as the age differences within sib pairs. No such birth order effects were found for social or communicative deficits as measured by the Autism Diagnostic Interview-Revised (ADI-R), but there was a modest tendency for increased scores for ritualistic behaviors for the firstborn sibs. Further, there were no gender differences on nonverbal IQ scores in this sample. Results are discussed in terms of implications for genetic studies of autism.

Autistic Disorder↗

PubMed2000

Ring chromosome 22 and autism: report and review.

Ring chromosome 22 has been described in over 50 cases. A characteristic phenotype has not been fully delineated; however, long face, thick eyebrows, 2-3 toe syndactyly, mental retardation, adequate somatic growth and the absence of major malformations are noted in many cases. An 11-year-old boy with ring chromosome 22 and 46,XY,r(22)(p11.31-q13.31 approximately q13.33) karyotype presented with global developmental delay, autistic disorder, and dolichocephaly, apparently low-set and large ears, midface hypoplasia, and 2-3 toe syndactyly. This is the second report of a ring chromosome 22 with autistic disorder. There appears to be an association between abnormalities of chromosome 22, including r(22), and autistic disorder; however, this occurrence may be a result of the association of autistic disorder with mental retardation rather than specifically due to r(22). The physical findings in this case also suggest that ring chromosome 22 causes a subtle but distinct phenotype which has previously been proposed.

Abnormalities, Multiple↗

PubMed2000

Prolongation of brainstem auditory-evoked responses in autistic probands and their unaffected relatives.

BACKGROUND: Brain function, as indexed by brain electrical activity, is heritable in humans, and it may be impaired in autism. Autism also has strong genetic determinants, and like all major psychiatric disorders, its complex clinical phenotype renders genetic studies difficult. Innovative strategies focused on alternative biological phenotypes are needed. METHODS: The early brain auditory-evoked response was assessed in 73 autistic probands and 251 relatives who were compared with 521 normal controls. RESULTS: We first confirmed in the autistic probands the presence of a slowing in nerve conduction in the auditory system as expressed by the prolongation of early brain auditory-evoked response under the form of I-III interpeak latencies (IPLs). Furthermore, we observed the same I-III IPL prolongation in the unaffected first degree relatives of the autistic probands compared with controls. Despite clear evidence of a coaggregation of autism and I-III IPL prolongation in families, the IPLs did not seem to be the sole liability factor for autism as suggested by the observation of 52% of families in which the autistic proband and relatives showed normal IPLs. CONCLUSION: A prolongation of the early brain auditory-evoked response IPLs may be a marker for one of several deficits underlying autism and deserves further analysis as a potential alternative phenotype for the disorder.

Adult↗

PubMed2000

High functioning autism and Childhood Disintegrative Disorder in half brothers.

Childhood Disintegrative Disorder (CDD) is grouped with autism as a subtype of Pervasive Developmental Disorder (PDD) in ICD-10 and DSM-IV. This is the first report of autism and CDD cosegregating within a sibship. J. P. and M. P. are half-brothers with the same mother. J. P. is an 18-year-old with impairments in communication, social reciprocity, and stereotypies and was diagnosed with autism. M. P. is a 7-year-old who developed normally to 2 years 4 months. He then underwent a profound regression, becoming nonverbal and socially withdrawn, and lost adaptive skills. Investigations did not reveal any neurodegenerative process. M. P. was diagnosed with CDD. The rarity of the two conditions suggests a shared transmissible mechanism. The implications for autism/PDD genetic studies are discussed.

Adolescent↗

PubMed2000

The familial aggregation of the lesser variant in biological and nonbiological relatives of PDD probands: a family history study.

OBJECTIVE: To determine the risk of the lesser variant (or PDD-like traits) in the biological and nonbiological second- and third-degree relatives of PDD probands using a screening questionnaire and to investigate the extent to which the risk of the lesser variant differs according to various characteristics of the proband. METHOD: The sample consists of a series of 34 nuclear families with 2 affected PDD children (multiplex, MPX), 44 families with a single PDD child (simplex, SPX), and 14 families who adopted a PDD child. Data on characteristics of the lesser variant in 1362 biological and 337 nonbiological second- and third-degree relatives were collected from parents by telephone interview and from several maternal and paternal relatives by questionnaire. RESULTS: All components of the lesser variant were more common in biological relatives (BR) than nonbiological relatives (NBR), confirming the familial aggregation of the traits. Proband characteristics associated with an increased risk of the lesser variant in relatives were a higher level of functioning and coming from a MPX family. CONCLUSIONS: These findings on the familial aggregation of the lesser variant suggest that the genes for PDD also confer susceptibility to the lesser variant and that PDD may be a genetically heterogeneous disorder.

Adolescent↗

PubMed2000

Two-year outcome of preschool children with autism or Asperger's syndrome.

OBJECTIVE: DSM-IV specifies that Asperger's disorder is a type of pervasive developmental disorder without clinically significant cognitive or language delay. There are no data, however, on the outcome of children with Asperger's disorder or on whether their outcome differs from that of children with autism. The objectives of this study were to compare the outcome of groups of children with these disorders over a period of 2 years on variables independent of the defining criteria and to identify variables that might account for these differences. METHOD: All children 4-6 years of age who came for assessment or were currently in treatment at a pervasive developmental disorder service of one of several centers in a large geographic region were identified. Children who received a diagnosis of autism (N=46) or Asperger's syndrome (N=20) on the basis of a diagnostic interview and had an IQ in the nonretarded range were given a battery of cognitive, language, and behavioral tests. Families were contacted roughly 2 years after the date of their enrollment in the study, and many of the tests were readministered. RESULTS: Children with Asperger's syndrome had better social skills and fewer autistic symptoms 2 years after study enrollment than the children with autism. The differences in outcome could not be explained by initial differences in IQ and language abilities. Children with autism who had developed verbal fluency at follow-up were very similar to the children with Asperger's syndrome at study enrollment. CONCLUSIONS: Although the exact mechanism for the differences in outcome remain to be determined, it appears that Asperger's disorder and autism represent parallel but potentially overlapping developmental trajectories.

Asperger Syndrome↗

PubMed2000

The classification of autism, Asperger's syndrome, and pervasive developmental disorder.

OBJECTIVE: The current classification of the pervasive developmental disorders (PDDs) as conceptualized in both the DSM-IV and ICD-10 is deeply unsatisfying to many parents, front-line clinicians, and academic researchers. Is the diagnostic validity of the various disorders simply lacking empirical data for full substantiation, or does the overall conceptualization of the category have more fundamental problems, not reflecting the "true" nature of the phenomena? This paper argues the latter hypothesis. I review the historical development of the classification of PDD, summarize recent empirical data on issues of reliability and validity, and suggest a new approach to classification and understanding.

Adolescent↗

PubMed1999

Effects of misclassification on estimates of relative risk in family history studies.

Two types of misclassification that commonly occur in family-genetic studies are distinguished: 1) nondifferential misclassification, in which the probability of error as to phenotype (presence or absence of psychiatric disorder) does not depend on exposure status (being kin to a case or control proband) and 2) differential misclassification, in which it does. Nondifferential misclassification of phenotype reduces the observed relative risk towards the null value, sometimes quite dramatically. Differential misclassification can bias the observed relative risk in either direction, depending on the different values of sensitivity and specificity among relatives of cases and controls. The impact of these biases on genetic-epidemiologic studies is reviewed and discussed. In particular, the ability to detect major gene effects from the pattern of relative risks in first-, second-, and third-degree relatives can be severely compromised. Although there are some methods available to correct the effects of nondifferential misclassification, a major priority for family history studies is to minimize differential misclassification.

Bias↗

PubMed1999

Evidence of linkage in subtypes of alcoholism.

We believed that subtyping alcoholism might be an efficient strategy for mapping susceptibility genes. Cluster analysis is one of the possible statistical techniques for such a purpose. We required that, ideally, the variables to be used in cluster analysis should be: 1) related to alcoholism, 2) related to the severity of alcoholism, and 3) familial, i.e., correlated within families. Only three variables met all three conditions. Those included age of onset of ALDX1, smoking, and TPQ-HA. A global score of symptoms of alcoholism was systematically introduced as one of the variables composing a subset for cluster analysis, although this score did not show any familial aggregation. Our strategy led to a strong evidence of linkage at D15S230 in only 20 families whose members are mainly characterized by heavy smoking.

Age of Onset↗

PubMed1999

Influence of parental concordance for psychiatric disorders on psychopathology in offspring.

OBJECTIVE: To examine the influence of parental mating types for substance abuse and anxiety/affective disorders on the risk of psychopathology among child and adolescent offspring. METHOD: Emotional and behavioral disorders were assessed in offspring, aged 7 to 17 years, of male and female parents who served as probands from a family study of comorbidity of substance abuse and anxiety disorders. RESULTS: The findings indicated that (1) patterns of psychopathology among offspring were similar for mothers and fathers; (2) spouse concordance for psychopathology was greater among parents with substance abuse than among those with anxiety, particularly among female substance abusers; (3) there was a direct relationship between the number of affected parents and the magnitude of psychopathology in children, particularly with respect to the anxiety disorders; and (4) by contrast, rates of conduct disorder were elevated only among offspring of dually affected parents, irrespective of the specific parental disorders. CONCLUSIONS: These findings underscore the importance of the contribution of both mothers and fathers, particularly those with concordance for psychiatric disorders, to the development of psychopathology in offspring.

Adolescent↗

PubMed1999

Familial factors influence level of functioning in pervasive developmental disorder.

OBJECTIVE: To determine whether siblings with pervasive developmental disorders (PDD) tend to have the same type and number of PDD symptoms or a similar level of functioning. METHOD: The familial correlations for PDD subtype, symptom totals, adaptive behaviors, and nonverbal IQ were calculated for 94 children with PDD from 46 families. RESULTS: On variables measuring PDD symptoms, only impairments in nonverbal communication and verbal/nonverbal status tended to run true within families. There was no familial aggregation of PDD subtype. In contrast, measures of nonverbal IQ and adaptive behaviors in socialization and communication showed a moderate degree of familial resemblance. The degree of familial resemblance did not change if the analysis was restricted only to those families in which both affected children met criteria for autism. CONCLUSION: Insofar as the familial resemblance seen in PDD is due to genetic factors, these data provide some evidence that higher- and lower-functioning PDD children may arise from separate genetic mechanisms. Current gene-mapping studies of PDD may need to take this evidence of genetic heterogeneity into account.

Activities of Daily Living↗

PubMed1999

Age-of-onset classification of conduct disorder: reliability and validity in a prospective cohort study.

OBJECTIVE: To test in a prospective clinical cohort study the reliability and validity of the age-of-onset subtyping of conduct disorder. METHOD: Participants were adolescents referred to psychiatric clinics who met DSM-III-R criteria for conduct disorder by structured diagnostic interview. Age of onset was the reported age of the first conduct disorder symptom. The reliability of age-of-onset report was tested by assessing agreement within informant on interviews 2 to 4 weeks apart. Age-of-onset groups were compared within informant on rates of correlates and symptom and social functioning outcomes over a period of 3 years. RESULTS: The reliability of age-of-onset report was low (kappa of 0.1 and 0.4 by adolescent and parent informant, respectively). Although the early-onset group had elevated rates of attention-deficit/hyperactivity disorder, family disadvantage, and aggressive and nonaggressive antisocial behaviors at inclusion, growth curve analysis showed that age-of-onset subtyping had no predictive validity. CONCLUSIONS: The reliability of ascertainment of age of onset of antisocial behavior requires further study. While age-of-onset subtyping has heuristic value with respect to the study of the causal pathways to conduct disorder, it is premature to use this system in clinic settings.

Adolescent↗

PubMed1999

Imaging of autism: lessons from the past to guide studies in the future.

OBJECTIVE: To review the scientific literature on the imaging of autism with a view to understanding how imaging can contribute to future studies. METHODS: Medline was searched, and bibliographies from retrieved articles were reviewed. Inclusion criteria were a diagnosis of autism according to Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, third edition or later, and a control group without autism. RESULTS: The field suffers from a lack of replication studies and poor methodology in terms of not controlling for confounding variables. Enlarged brain size, particularly in the temporoparietal brain region, and decreased size of the posterior corpus callosum are the only findings that have been independently replicated. CONCLUSION: Future imaging studies should attempt to investigate more homogeneous subgroups of patients such as those with "the lesser variant of PDD" and high-functioning patients with PDD who do not have comorbid medical conditions. A different approach, examining the individual behaviours that constitute the PDD spectrum and exploring these separately along with other associated variables such as neuropsychological deficits, structural and functional brain abnormalities, and genetic information could help identify biological mechanisms that do not follow diagnostic boundaries.

Autistic Disorder↗

PubMed1999

Highly somatizing young adolescents and the risk of depression.

OBJECTIVE: To determine if high levels of somatization symptoms in 13- to 16-year-olds from the general population predict risk of major depression and other psychiatric disorders 4 years later. METHOD: Cohort study, using interview and self-report survey data from the 1983 Ontario Child Health Study (OCHS) and 1987 OCHS Follow-up. The study population included 1015 13- to 16-year-olds from the general community within Ontario. Baseline levels of somatization and emotional disorder were measured by the Survey Diagnostic Instrument, a checklist based on DSM-III criteria. Data were also collected for a range of sociodemographic factors, as well as the presence of chronic health problems. Major depression, anxiety disorders, and substance abuse and dependency at follow-up were measured using a self-administered questionnaire derived from the Diagnostic Interview Schedule. Bivariate and multiple logistic regression techniques were used to assess the relationship between high levels of somatization symptoms (>90th percentile) and later emotional morbidity, with adjustment for potential confounding factors, including gender and baseline disorders. RESULTS: Highly somatizing adolescents are at increased risk of major depression 4 years later, an association that is not explained by detectable emotional disorder at baseline or gender differences between groups. There is an important interaction between somatization and emotional disorder in predicting risk of major depression. It is primarily the group of 13- to 16-year-olds not recognized as being emotionally disordered at the initial OCHS survey in which somatization symptoms increased risk of later depression. The young teen with high levels of somatic complaints had as much risk of later depression as his/her peer with more typical symptoms of emotional disorder. Highly somatizing adolescents were also more likely to describe panic attacks at 4-year follow-up. There was no increased risk of substance abuse/dependency in the highly somatizing group or in generalized anxiety. CONCLUSIONS: High levels of somatic symptoms identified in young adolescents in the community represent a significant risk factor for major depression 4 years later, particularly in those individuals who do not present with more typical symptoms of emotional disorder. To detect the emergence of this serious emotional morbidity, adequate follow-up and continuity of care for these challenging patients are needed.

Adolescent↗

PubMed1999

Heterogeneity and the genetics of autism.

The objective of this review is to summarize recent data on the genetics of autism, highlight the evidence for genetic heterogeneity and extend the implications of these findings for the identification of susceptibility genes in this disorder. Family studies have shown that autism runs in families and twin studies indicate that the basis of that familial aggregation is genetic. As a result the prospects for the identification of susceptibility genes using either linkage or association studies are quite good. However, recent evidence is accumulating suggesting that the disorder is genetically heterogeneous; higher functioning individuals with autism may arise from separate genetic mechanisms that lower functioning ones. If true, this will make the detection of linkage and association much more difficult.

Autistic Disorder↗

PubMed1998

Genetics of autism: overview and new directions.

Genetic epidemiology is the study of inherited factors involved in the etiology of a disease or disorder and uses the methods of both medical genetics and clinical epidemiology. In general, genetic epidemiology tries to answer the following four questions: Is the disorder inherited; What phenotype is inherited; How is it inherited or what is the mode of transmission; and What is the nature of the genetic mutation, if any, that gives rise to the disorder? The hope is that by identifying the gene or genes involved in pathophysiology, a much better understanding of the steps from gene product to phenotype will be possible, leading to improvements in diagnosis, an opportunity for thoughtful family planning, and perhaps, most important, to the development of treatments based on an understanding of the biochemistry of the disorder. We review the current knowledge of the genetic epidemiology of autism and the other pervasive developmental disorders (PDDs) and highlight promising new directions. There seems to be widespread agreement that the PDDs are caused, at least in part, by genetic factors. There is also some agreement on the phenotypic boundaries associated with these same genetic factors. However, many points of uncertainty remain, and several methodologic issues need to be resolved before further progress in mapping susceptibility genes is possible. We do not specifically review molecular studies, medical conditions associated with autism, or the broader autism phenotype, as these topics are covered in other papers in this special issue.

Autistic Disorder↗