Biomedical subjects

Sarah J Spence

Publications and source records attributed to Sarah J Spence.

6 recordsLinked to original sources

PubMed2006

Stratification based on language-related endophenotypes in autism: attempt to replicate reported linkage.

The identification of autism susceptibility genes has been hampered by phenotypic heterogeneity of autism, among other factors. However, the use of endophenotypes has shown preliminary success in reducing heterogeneity and identifying potential autism-related susceptibility regions. To further explore the utility of using language-related endophenotypes, we performed linkage analysis on multiplex autism families stratified according to delayed expressive speech and also assessed the extent to which parental phenotype information would aid in identifying regions of linkage. A whole genome scan using a multipoint non-parametric linkage approach was performed in 133 families, stratifying the sample by phrase speech delay and word delay (WD). None of the regions reached suggested genome-wide or replication significance thresholds. However, several loci on chromosomes 1, 2, 4, 6, 7, 8, 9, 10, 12, 15, and 19 yielded nominally higher linkage signals in the delayed groups. The results did not support reported linkage findings for loci on chromosomes 7 or 13 that were a result of stratification based on the language delay endophenotype. In addition, inclusion of information on parental history of language delay did not appreciably affect the linkage results. The nominal increase in NPL scores across several regions using language delay endophenotypes for stratification suggests that this strategy may be useful in attenuating heterogeneity. However, the inconsistencies in regions identified across studies highlight the importance of increasing sample sizes to provide adequate power to test replications in independent samples.

Autistic Disorder↗

PubMed2005

beta2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins.

Gestational and genetic factors can contribute to autism during infancy and early childhood through their effects on fetal brain development. Previous twin studies have shown strong genetic components for the development of autism, a disorder that can have multiple causes. We investigated the effects of prenatal overstimulation of the beta2-adrenergic receptor in dizygotic twins who were exposed to terbutaline, a selective beta2-adrenergic receptor agonist used to treat premature labor, as a gestational factor. As a possible genetic mechanism, we studied two beta2-adrenergic receptor polymorphisms in twins from whom DNA was available: glycine substitution at codon 16 (16G) and glutamic acid substitution at codon 27 (27E), which show diminished desensitization in vivo compared with the wild-type receptor. Continuous terbutaline exposure for 2 weeks or longer was associated with increased concordance for autism spectrum disorders in dizygotic twins (relative risk = 2.0), with a further increase in the risk for male twins with no other affected siblings (relative risk = 4.4). A significant association was found between the presence of 16G and 27E polymorphisms in autistic patients compared with population controls (P = .006). Prenatal overstimulation of the beta2-adrenergic receptor by terbutaline or by increased signaling of genetic polymorphisms of the beta2-adrenergic receptor that have diminished desensitization can affect cellular responses and developmental programs in the fetal brain, leading to autism.

Autistic Disorder↗

PubMed2004

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.

Adolescent↗

PubMed2004

Autism spectrum disorder: screening, diagnosis, and medical evaluation.

Autism spectrum disorder (ASD) are a group of behaviorally defined neurodevelopmental disabilities with core deficits in socialization, communication, and behavior, although the presentation can be extremely variable. This article describes the core deficits in ASD, as well as the differential diagnosis and the more commonly associated comorbid disorders. The importance of early diagnosis is emphasized, and screening and assessment tools are reviewed. Finally, the role of the pediatric neurologist is discussed with regard to specific components of the evaluation, including history, physical examination, and ancillary testing.

Autistic Disorder↗

PubMed2004

The genetics of autism.

Autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric disorders. Discovery of autism susceptibility genes has been the focus of intense research efforts over the last 10 years, and current estimates suggest that 10 to 20 different interacting genes are involved. Evidence from twin and family studies demonstrates increased risk in family members not only for autistic disorder, but also for a milder constellation of similar symptoms referred to as the broader phenotype. In addition, several genetic syndromes and chromosomal anomalies have been associated with ASD. Large family studies using linkage-analysis techniques have demonstrated several chromosomal regions thought to harbor genes related to the disorder. Finally, specific candidate genes based on function and location have been explored; these studies are reviewed here.

Autistic Disorder↗

PubMed2003

A genomewide screen of 345 families for autism-susceptibility loci.

We previously reported a genomewide scan to identify autism-susceptibility loci in 110 multiplex families, showing suggestive evidence (P <.01) for linkage to autism-spectrum disorders (ASD) on chromosomes 5, 8, 16, 19, and X and showing nominal evidence (P <.05) on several additional chromosomes (2, 3, 4, 10, 11, 12, 15, 18, and 20). In this follow-up analysis we have increased the sample size threefold, while holding the study design constant, so that we now report 345 multiplex families, each with at least two siblings affected with autism or ASD phenotype. Along with 235 new multiplex families, 73 new microsatellite markers were also added in 10 regions, thereby increasing the marker density at these strategic locations from 10 cM to approximately 2 cM and bringing the total number of markers to 408 over the entire genome. Multipoint maximum LOD scores (MLS) obtained from affected-sib-pair analysis of all 345 families yielded suggestive evidence for linkage on chromosomes 17, 5, 11, 4, and 8 (listed in order by MLS) (P <.01). The most significant findings were an MLS of 2.83 (P =.00029) on chromosome 17q, near the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), and an MLS of 2.54 (P =.00059) on 5p. The present follow-up genome scan, which used a consistent research design across studies and examined the largest ASD sample collection reported to date, gave either equivalent or marginally increased evidence for linkage at several chromosomal regions implicated in our previous scan but eliminated evidence for linkage at other regions.

Autistic Disorder↗