Marlene Briciet Lauritsen

Validity of Childhood Autism in the Danish Psychiatric Central Register: Findings from a Cohort Sample Born 1990–1999

The purpose of this study was to assess the validity of the diagnosis of childhood autism in the Danish Psychiatric Central Register (DPCR) by reviewing medical records from 499 of 504 total children with childhood autism born 1990–1999. Based on review of abstracted behaviors recorded in case records from child psychiatric hospitals, case status determination was performed using a standardized coding scheme. In 499 children diagnosed with childhood autism in the DPCR, the diagnosis could be confirmed in 469 children (94%). Of the 30 non-confirmed cases, five were classified by the reviewers as non-autistic cases and the remaining 25 cases were either classified with another ASD diagnosis or the specific diagnosis was not possible to determine.

The genetics of autism

Objective: To review systematically the empirical evidence for the involvement of genetic risk factors in infantile autism.

Infantile Autism and Associated Autosomal Chromosome Abnormalities: A Register-based Study and a Literature Survey

Infantile autism is a heterogenous disorder with unknown aetiology. Evidence from the relatively few family and twin studies suggests a genetic component. Co-occurrence or cosegregation between infantile autism and chromosomal abnormalities may identify candidate regions, which could be tested in linkage or association studies. The purpose of this study was to use the Danish Cytogenetic Central Register in order to detect autosomal chromosome abnormalities associated with infantile autism, and to review the literature for cases of autism associated with autosomal chromosome abnormalities to identify candidate chromosomal regions. The register-based study identified possible candidate regions on chromosome 7q21 and 10q21.2, which have not previously been reported. A few interesting candidate regions, 15q11-13, 16q23, and 17p11.2 were found in the literature survey.

Parental age and autism spectrum disorders.

PURPOSE We sought to study the possible association between parental age and autism spectrum disorder (ASD) by using both a cohort design and a sibling design. METHODS Our cohort included all singleton births in Denmark from January 1, 1980, through December 31, 2003, a total of 1,311,736 children. Cases of ASDs were obtained from the Danish National Psychiatric Register using International Classification of Diseases (ICD)-8 and ICD-10. RESULTS A total of 9556 children were diagnosed with an ASD. Both maternal and paternal age were associated with a greater risk of ASD in the offspring (hazard ratios ranging from 1.21 (1.10-1.34) to 1.65 (1.09-2.48) depending on combinations of parental age categories; <35, 35-39, and 40+ years). For mothers younger than 35 years, the risk of ASD increased with increasing fathers age group. For fathers younger than 35 years, the risk of ASD increased with increasing maternal age. CONCLUSIONS We found an association between parental age and ASD in the cohort study, but the combined underlying mechanisms through which paternal and maternal age impact ASD risk do not seem to act synergistically. The results of the sibling analysis suggest that the association between parental age and ASD found in the cohort study cannot be accounted for by common genetic and environmental factors.

A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands

The involvement of genetic factors in the etiology of autism has been clearly established. We undertook a genome-wide search for regions containing susceptibility genes for autism in 12 subjects with childhood autism and related pervasive developmental disorders (PDDs) and 44 controls from the relatively isolated population of the Faroe Islands. In total, 601 microsatellite markers distributed throughout the human genome with an average distance of 5.80 cM were genotyped, including 502 markers in the initial scan. The Faroese population structure and genetic relatedness of cases and controls were also evaluated. Based on a combined approach, including an assumption-free test as implemented in CLUMP, Fishers exact test for specific alleles and haplotypes, and IBD0 probability calculations, we found association between autism and microsatellite markers in regions on 2q, 3p, 6q, 15q, 16p, and 18q. The most significant finding was on 3p25.3 (PT1=0.00003 and PT4=0.00007), which was also supported by other genetic studies. Furthermore, no evidence of population substructure was found, and a higher degree of relatedness among cases could not be detected, decreasing the risk of inflated P-values. Our data suggest that markers in these regions are in linkage disequilibrium with genes involved in the etiology of autism, and we hypothesize susceptibility genes for autism and related PDDs to be localized within these regions.

Medical Disorders Among Inpatients with Autism in Denmark According to ICD-8: A Nationwide Register-Based Study

Possible associations between autism and specific medical disorders have been suggested, and this could be of relevance in the clinical examination and treatment of patients and may help to identify factors involved in the etiology or pathophysiology of autism. Two population-based Danish registers were used to investigate the occurrence of medical disorders in patients with autism according to ICD-8 and in a matched control sample. A total of 29 of the 244 patients (11.9%) diagnosed with autism had one or more medical disorders. In contrast to previous studies, we did not find an increased occurrence of almost any medical disorders. A highly significant increased frequency of congenital malformations was found, which may indicate abnormalities in embryogenesis in the etiology of autism.

Time Trends Over 16 Years in Incidence-Rates of Autism Spectrum Disorders Across the Lifespan Based on Nationwide Danish Register Data

This study investigated time trends and associated factors of incidence rates of diagnosed autism spectrum disorders (ASD) across the lifespan from 1995 to 2010, using data from the Danish Psychiatric Central Research Registry. First time diagnosis of childhood autism, atypical autism, Asperger’s syndrome, or pervasive developmental disorder—unspecified (PDD-NOS) were identified, incidence rates were calculated, and data were fitted using non-linear least squares methods. A total of 14.997 patients were identified and incidence rates for ASD increased from 9.0 to 38.6 per 100,000 person years during the 16-year period. The increases were most pronounced in females, adolescents, adults, and patients with Asperger’s syndrome and PDD-NOS.

Use of early intervention for young children with autism spectrum disorder across Europe

Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities.

Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders

Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C > T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.

A systematic review and meta-analysis of the long-term overall outcome of autism spectrum disorders in adolescence and adulthood.

A systematic review and meta‐analysis of studies reporting on the overall outcome in terms of a global measure of adjustment in children with autistic disorders followed up in adolescence and adulthood.