Learning disabilityLucy Raymond has found genetic mutations that cause learning difficulties in human males |
A child’s intellectual development is a fascinating and delightful process. Soaking up experiences like a sponge, the child learns, becomes able to solve problems, think abstractly, make sense of the world, and so on.
For children with learning disabilities, development may be slower and they never attain the same learning abilities. Although the causes are often clear, in about 40 per cent of cases the underlying cause – whether environmental, genetic or both – remains mysterious.
Unknown genetic factors are the focus of Dr Lucy Raymond’s research at the University of Cambridge.
In 2001 she established the Genetics of Learning Disability (GOLD) study, and has collected samples from more than 400 affected families from around the world.
As affected males outnumber females, Dr Raymond’s focus is on the X chromosome (unlike females, males have only one X chromosome, and a single mutation can knock out the function of a gene completely). Indeed, the most common single gene cause of learning disorder is fragile X, which may account for about 3 per cent of learning disorders in males.
“It’s clear that there are many genes involved in learning disability,” says Dr Raymond, “and there is good evidence that as many as 70 genes on the X chromosome may be responsible. There are more than 700 genes on the X chromosome, any of which could be the culprit. For each gene that has been identified so far, the numbers of people affected are few as the mutations are rare. We therefore need to look at lots of genes, in a high-throughput manner, and as each mutation is rare, we need very accurate detection. A single base-pair change in the DNA can have a big effect.”
Dr Raymond has therefore teamed up with Mike Stratton’s group, the Cancer Genome Project at the Wellcome Trust Sanger Institute, who are searching for the genetic mutations that underlie cancer. “We share an interest in the technology although the questions are different,” she says. The idea is to use DNA sequencing to examine the base pairs in large numbers of X chromosome genes, and to compare them to the reference human genome sequence – a Herculean task.
Linking genes to learning
Proof that the strategy works comes from a family in which four males with moderate to severe learning disability were found to have a mutation in a gene called DLG3, as did the unaffected carrier females who had passed on the mutation. Dr Raymond then looked at the DLG3 gene in more than 300 other affected families, and found that three more families had mutations in the same gene, but each family’s mutation was different.
“For one branch of the first family, the finding had particular significance,” says Dr Raymond. “Three daughters had held off reproductive decisions, because of the family history of learning disability. We found that their mother was not a carrier, so they did not have the mutation.”
The gene itself is also of interest, for the protein it produces, called SAP102, is found at the junctions between nerves and binds to a molecule crucial to learning and memory, the NMDA receptor. And it is closely related to a gene (PSD95) that Professor Seth Grant’s team had inactivated in mice a few years previously, resulting in mice with severe learning deficits (see Genes and cognition).
“We’re in a very interesting situation,” says Dr Raymond. “We find a new gene that has a direct impact on several families, in particular because it gives a reason for the learning disability. But it is also very important to the idea that intellectual disability can be due to the incorrect function of NMDA receptors. This is the first concrete example in humans that shows the hypothesis to be true.”
IQ
The average IQ (intelligence quotient) of the population is often taken to be 100, and an IQ of less than 70 to indicate intellectual impairment or learning disability. In about 2–3 per cent of the population, this learning disability is mild to moderate (IQs 50–70), and in about 0.5 per cent it is severe (IQs less than 50).
The French psychologist Alfred Binet, who published the first intelligence test in 1905, aimed to identify students who could benefit from extra help in school. His assumption was that lower IQ indicated the need for more teaching, not an inability to learn.
Learning about the family
Many genetic disorders have profound impact on people’s lives – not only those affected by the disorder but also other family members. Relationships can be strained, discussions of the disorder can be difficult, hard choices may have to be made about reproduction, and so on. The situation is even more complicated if the cause of the disorder is unknown.
While such issues have been explored extensively in a few inherited conditions such as Huntington’s disease, little research has been carried out on the impacts of learning disabilities on families. Professor Martin Richards, Nina Hallowell and Helen Statham at the Centre for Family Studies, University of Cambridge have been interviewing families involved in Lucy Raymond’s GOLD study.
“We are interested in the impact of genetic disorders on families, and of course families can be affected in many different ways,” says Professor Richards. “The GOLD study gives us the chance to look at different groups: families with an affected son and with or without a sister of the affected boy or boys, and families before or after a mutation has been found.”
The impact on the families, who have been keen to take part, is profound – as the interviews have shown. “The families feel a great sense of responsibility towards the affected son or sons and rally round,” says Nina. “But it can be very isolating and difficult for the families and put tremendous strains on their relationships.
For the sisters of affected boys, there can be difficult emotions: while they love their siblings, they may have had a difficult childhood, and may be caring for their brother in their adult life.”
Taking part in the GOLD study brings the chance of a diagnosis. Although most families realise this is far from certain, many are optimistic that one will be found, and many just want to have an explanation. For others, there may be more immediate needs, such as help with reproductive decisions.
The provision of support services also appears to vary markedly. Many parents soon notice that there is something wrong, but only when a son enters education do services become available. “Of course, in the 1930s, say, there was no support for people with learning disabilities – they were seen as untreatable,” says Nina. “Today, special schools are available, but care services are often poor.”
For Professor Richards and colleagues, the study will grow as more genes underlying learning disability are, hopefully, uncovered. “For the families, that’s just the start of the story,” says Helen. “They have to know what it means, and it may change how they perceive the disorder and how they deal with it.”