In recent years, there has been an explosion in the number of children diagnosed with autism. There is seemingly one in every classroom, most of them boys; some are quiet and nerdy, others may be disruptive and aggressive. Most have normal intelligence, and can be educated in mainstream schools. Parents of such children question why one child is affected when often their siblings develop perfectly normally. We have few answers, but most research shows that genetic inheritance plays by far the largest role.
Genetic influences on the risk of autism are complex. There is no clear biological or symptomatic boundary between people with the formal diagnosis – which is based on arbitrary criteria designating a degree of severity – and the presence of mild symptoms or traits in the general population. Recognition of this 'spectrum' of risk led autism to be renamed Autism Spectrum Disorder (ASD) a few years ago.
A small proportion of the most severe cases are caused by serious genetic anomalies – sometimes inherited, but usually new mutations. Older fathers' sperm is particularly likely to contain such mutations, which will be passed on. In the majority of cases, however, ASD results from a multiplicity of tiny genetic risk factors - hundreds, possibly thousands - inherited from both parents, which acquire causal significance only in combination.
The role of the environment in enhancing risk is even less well understood, but a novel discovery has recently been made by a group of researchers studying a birth cohort of children in Bristol through the Avon Longitudinal Study of Parents and Children (ALSPAC) [Golding et al, 2017]. Their report concerns the purported genetic transmission of enhanced risk from maternal grandmothers who smoked during their pregnancy (see BioNews 898).
The idea that behaviour during pregnancy of maternal grandmothers could increase the risk of their grandchildren having ASD initially sounds implausible. Yet there is a potential explanation: during the grandmother's pregnancy, eggs were developing in the female fetus. Those eggs, maturing in her daughter as she reaches puberty, would eventually provide around 50 percent of the genetic makeup of a maternal grandchild. It is astonishing to realise that the eggs from which we developed originally grew in our mother whilst she was a fetus. They were thus susceptible to environmental influences during her own mother's pregnancy.
In a sense, we each inherit two genomes from our mother: one is half of a genome that manages virtually all developmental processes, found in the nuclei of our cells (and is equivalent to the paternal contribution). The other genome, passed on only through maternal eggs, is found within our mitochondria. These are minute organelles that exist in each cell in our body, but lie outside the nucleus. They are often described as the 'powerhouses' of the cell: if they malfunction, very serious conditions can ensue, many of which are neurological in character.
The paternal contribution to offspring has no equivalent to the mitochondria. Paternal grandmothers do not influence the development of their son's sperm. Brand new sperm were created by our father throughout his post-pubertal life, but no new eggs were created by our mother: a girl seems to be born with all the eggs she will ever possess.
Professor Jean Golding and her colleagues knew that the risk of a woman having a child with autism could be increased if she smoked during pregnancy. They reasoned that if the products of smoking circulating in the blood could influence the developing fetus, they might also influence the mitochondria of the developing eggs in female fetuses. Fortunately, they had a way of testing that hypothesis. ALSPAC is a remarkable and influential survey of all children born in the city of Bristol over a year or so, 1990-91. Families were recruited during pregnancy and followed up into adult life, and information about their social, educational and medical histories was collected throughout.
Of over 14,000 children in ALSPAC, 273 were eventually diagnosed with an ASD. Helpfully, given our current understanding of the condition as a spectrum, the study also gathered measures of autistic traits. In the recent paper, Golding et al discuss the evidence that the risk conferred to her grandchildren, by a maternal grandmother's smoking in pregnancy, has an impact on mild autistic-like symptoms as well as on the probability of an ASD diagnosis.
When the ALSPAC study was conceived in 1988, autism was still regarded as a very rare phenomenon; the ALSPAC development team's decision to measure 'autistic traits' was condemned by some experts as maverick, even unscientific. We now know that at least one of the instruments they used – a parent-rated Social Communication Disorders Checklist (SCDC) – measures a set of traits that are influenced by the very same set of genes that influence the risk of developing autism itself. That has been extremely valuable in evaluating the evidence that the maternal grandmother's smoking habits somehow influence the risk of her grandchild developing autistic traits or an ASD diagnosis.
The SCDC was administered repeatedly over the period seven to 16 years: recent analyses have suggested that traits in females increase dramatically in adolescence to equal those of boys. For many years, it has been assumed that boys are much more susceptible to autistic traits than girls. Yet the evidence from ALSPAC indicates overt autistic traits become more evident during adolescence in girls, and that girls are relatively more susceptible to the negative impact of a maternal grandmother's smoking habits, especially on their social communication skills.
The mechanism by which inter-generational transmission of an environmental risk occurs remains speculative. This intriguing study will undoubtedly stimulate the debate about why we are seeing a burgeoning prevalence of ASD in recent years, and it provides more than a hint of a plausible preventive strategy.