AAAP Today

Diversity in genotype underlies diversity on the surface

Lirio S. Covey, PhD.

Source: Jonathan Chang, Sarah R Gilman, Andrew H Chiang, Stephan J Sanders, Dennis Vitkup. “Genotype to phenotype relationships in autism spectrum disorders”. NatureNeuroscience, published online 22 December 2014.

Has it struck you that persons with autism whom you have met are so different from one another? Indeed, many of us in the autism community are very familiar with the theme of – different, not less.

True, there are commonalities – a tendency towards compulsive and repetitive behaviors, problematic adjustment to change, inability to sense other people’s feelings, awkwardness in social settings.

But there is also a broad range of differences – in language capacity, emotional stability, mental strength, functioning skills, including physical appearance. (Unlike persons with Down’s syndrome or Rett’s disorder who show physical features characteristic of their respective condition).

A recent study conducted by researchers at Columbia University in New York indicates that such differences, apparent on the surface and referred to as phenotypical differences, relate to broad heterogeneity on the genetic level. These differences can be traced to diverse mutations occurring to any or combinations of hundreds of genes found to increase the risk of autism. Gene mutations are alterations in the DNA sequence, usually rare and different from what occurs in most people. Different mutations can lead to different features of ASD.

The diversity in genetic mutations is thought to underlie the broad range in severity of ASD impairments and in the large male to female ratio of ASD (4:1). More active mutations relate to greater severity of ASD symptoms. Thus, milder mutations characterize high functioning ASD persons, whereas greater mutation activity characterizes greater impairment such as low-verbal or nonverbal IQ.

The threshold for damaging gene mutations also appears to be higher in girls than boys, consistent with the lower prevalence of ASD in girls than boys. However, when mutated genes occur in girls they have greater activity than in boys, consistent with the observation that ASD symptoms, when they occur, are more severe in females than in males with autism.

These findings have implications for ASD management and treatment. According to the senior author, Dr. Vitkup, “through understanding of the relationships between genetic mutations and phenotypical features of ASD we may be able to use patients’ genetic profiles to develop diagnostic and prognostic tools and perhaps personalize treatment”.

PATERNAL OBESITY AND INCREASED RISK FOR AUTISM IN OFFSPRING

Another incentive for managing weight when planning for family?

By Lirio Sobrevinas-Covey, Ph.D.

Obesity – having a basal metabolism index (BMI) over 30 was implicated as a risk factor for autism spectrum disorder (ASD) in children in a recent well controlled study conducted in Norway. (BMI is calculated by dividing weight in kilograms by height in meters squared).

The study used the DSM-IV typology of autism. Paternal obesity was associated with autistic disorder and Asperger’s syndrome, but not with pervasive developmental disorder.

Obesity in fathers, not in mothers, significantly increased risk of autism in children. This finding had been unexpected since a prior research had implicated mothers’ obesity as an autism risk factor. (1) That study, however, did not include fathers’ obesity among the variables to be examined.

In this study by Suren and colleagues (2), whereas mothers’ obesity had appeared to be a risk factor when assessed by itself, once both mothers’ and fathers’ obesity were considered simultaneously, it was only fathers’ obesity that showed statistical independence. The significant effect of paternal obesity and lack of effect of maternal obesity remained after controlling for potential modifiers of the association: parental age, parental smoking, parental education, parental psychiatric history, as well as the children’s year of birth, and the number of mother’s children. (Prior research has also implicated increased father’s and mother’s age as autism risk factors).

This study had several strengths including – its longitudinal design (children were followed from 4-13 years after first screening), recency (children born from 1999 to 2009 and processed by December, 2012), use of a large sample (92,909 children from a population-based mother and child cohort study), careful measurement of the Autism diagnoses following DSM-IV criteria, and estimation of odds ratios and 95% confidence intervals from logistic regression models.

Knowledge of risk factors can lead to understanding of the underlying etiology and mechanisms, all essential to effective prevention. Knowledge of maternal risk factors can give rise to hypotheses regarding intrauterine exposures. Evidence regarding paternal influences suggests the additional importance of investigating for genetic and epigenetic risk factors of autism.

References:

(1) Krakowiak P, Walker CK, Bremmer AA et al, Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012; 129 (5).

(2) Suren P, Gunnes N, Roth C, et al. Parental Obesity and Risk of Autism Spectrum Disorder. Pediatrics 2014; 133:e1128-e1138.

PULMONARY DISEASE AND AUTISM SPECTRUM DISORDER

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Autism and lung diseases ARHerradura AAAP Sept 13 2014.pptx