Platelet studies in autism spectrum disorder patients and first-degree relatives.

BACKGROUND: Platelets have been proven to be a useful cellular model to study some neuropathologies, due to the overlapping biological features between neurons and platelets as granule secreting cells. Altered platelet dense granule morphology was previously reported in three autism spectrum disorder (ASD) patients with chromosomal translocations that disrupted ASD candidate genes NBEA, SCAMP5, and AMYSIN, but a systematic analysis of platelet function in ASD is lacking in contrast to numerous reports of elevated serotonin levels in platelets and blood as potential biomarker for ASD. METHODS: We explored platelet count, size, epinephrine-induced activation, and dense granule ATP secretion in a cohort of 159 ASD patients, their 289 first-degree relatives (103 unaffected siblings, 99 mothers, and 87 fathers), 45 adult controls, and 65 pediatric controls. For each of the responses separately, a linear mixed model with gender as a covariate was used to compare the level between groups. We next investigated the correlation between platelet function outcomes and severity of impairments in social behavior (social responsiveness score (SRS)). RESULTS: The average platelet count was increased in ASD patients and siblings vs. controls (ASD 320.3 × 10(9)/L, p = 0.003; siblings 332.0 × 10(9)/L, p < 0.001; controls 283.0 × 10(9)/L). The maximal platelet secretion-dependent aggregation response to epinephrine was not significantly lower for ASD patients. However, secondary wave responses following stimulation with epinephrine were more frequently delayed or absent compared to controls (ASD 52 %, siblings 45 %, parents 53 %, controls 22 %, p = 0.002). In addition, stimulated release of ATP from dense granules was reduced in ASD patients, siblings, and parents vs. controls following activation of platelets with either collagen (ASD 1.54 µM, p = 0.001; siblings 1.51 µM, p < 0.001; parents 1.67 µM, p = 0.021; controls 2.03 µM) or ADP (ASD 0.96 µM, p = 0.003; siblings 1.00 µM, p = 0.012; parents 1.17 µM, p = 0.21; controls 1.40 µM). Plasma serotonin levels were increased for ASD patients (n = 20, p = 0.005) and siblings (n = 20, p = 0.0001) vs. controls (n = 16). No significant correlations were found in the different groups between SRS scores and count, size, epinephrine aggregation, or ATP release. CONCLUSIONS: We report increased platelet counts, decreased platelet ATP dense granule secretion, and increased serotonin plasma levels not only in ASD patients but also in their first-degree relatives. This suggests that potential genetic factors associated with platelet counts and granule secretion can be associated with, but are not fully penetrant for ASD.

Measuring quantitative autism traits in families: informant effect or intergenerational transmission?

Autism spectrum disorders (ASD) have a high degree of heritability, but there is still much debate about specific causal genes and pathways. To gain insight into patterns of transmission, research has focused on the relatedness of quantitative autism traits (QAT) between family members, mostly using questionnaires. Yet, different kinds of bias may influence research results. In this paper, we focus on possible informant effects and, taking these into account, on possible intergenerational transmission of QAT. This study used multiple informant data retrieved via the Social Responsiveness Scale from 170 families with at least one member with ASD. Using intraclass correlations (ICCs) and mixed model analyses, we investigated inter-informant agreement and differences between parent and teacher reports on children and between self- and other-reports on adults. Using structural equation modelling (SEM), we investigated the relatedness of QAT between family members in ASD families. Parent-teacher agreement about social responsiveness was poor, especially for children with ASD, though agreement between parents was moderate to strong for affected and unaffected children. Agreement between self- and other-report in adult men was good, but only moderate in women. Agreement did not differ between adults with and without ASD. While accounting for informant effects, our SEM results corroborated the assortative mating theory and the intergenerational transmission of QAT from both fathers and mothers to their offspring.

Quantitative autism traits in first degree relatives: evidence for the broader autism phenotype in fathers, but not in mothers and siblings.

Autism spectrum disorder (ASD) symptoms are present in unaffected relatives and individuals from the general population. Results are inconclusive, however, on whether unaffected relatives have higher levels of quantitative autism traits (QAT) or not. This might be due to differences in research populations, because behavioral data and molecular genetic research suggest that the genetic etiology of ASD is different in multiplex and simplex families. We compared 117 unaffected siblings and 276 parents of at least one child with ASD with 280 children and 595 adults from the general population on the presence of QAT using the Social Responsiveness Scale (SRS). Mean SRS scores for siblings, control children, parents and control adults were 25.4, 26.6, 33.7 and 32.9. Fathers of children with ASD showed significantly higher levels of QAT than controls, but siblings and mothers did not. We could not detect a statistically significant difference in SRS scores between relatives from simplex and multiplex families. These results do not support the theory of differential (genetic) etiology in multiplex and simplex families and suggest that a carried genetic risk is generally not expressed phenotypically in most relatives, except in fathers.

What's new in autism?

This review on autism spectrum disorder (ASD) focusses on recent insights in the clinical picture, such as continuity of the phenotype and the concept of broader phenotype, on epidemiology and on clinical issues relevant to physicians, including new methods for early screening and diagnosis, psychiatric and somatic co-morbidity, and the expansion of so-called complementary and alternative treatments. ASD is a disorder with mainly genetic causes and recent insights show that a variety of genetic mechanisms may be involved, i.e. single gene disorders, copy number variations and polygenic mechanisms. Technological advances in genetics have lead to a number of promising findings, which, together with other lines of fundamental research, suggest that ASD may be a disorder of connectivity in the brain, at least in a subgroup of patients. It is possible that part of the genetic load in autism actually reflects gene-environment interaction, but there is no evidence for purely environmental causes in a substantial number of cases. Clinical research suggests that ASD may be a multi-system disorder in at least a subgroup of subjects, affecting the gastro-intestinal (GI) tract, the immune system and perhaps other systems. Behavioural treatments remain the cornerstone of management, and are mainly aimed at stimulation of the domains of impaired development and reducing secondary behaviours. These treatments are constantly being refined, but the main progress in this area may be the increase of research on effectiveness.

No aggression in a 4-year-old boy with an androgen-producing tumour: case report.

BACKGROUND: The androgen testosterone plays a critical role in many aspects of sexual differentiation. Also, it is thought to induce aggressive behaviours or to play a role in social dominance. CASE PRESENTATION: In this case report a 4-year-old boy is described whose testosterone and dehydroepiandrosterone sulphate (DHEA-S) levels were raised to pubertal levels due to a testosterone producing testis tumour. This provided the unique opportunity to examine the effects of elevated levels of androgens on levels of aggression or on social dominance before the onset of puberty. CONCLUSION: The present case report does not support the hypothesis of a causal relationship between testosterone and aggression or between testosterone and social dominance in young children.