16 February 2011

Mutations and Mental Retardation and IQ

The genetic forces that make people smart turn out to be quite different from the genetic forces that cause extremely low IQ, i.e. mental retardation.

As of 2008, the cause of about 20% of mental retardation cases was understood, some environmental (e.g. shortage of oxygen at birth, lead exposure) and sometimes genetic:

Scientists estimate that, in about 30% of the patients, a defect on the X-chromosome is the underlying cause. This is called X-linked mental retardation (XLMR). In over half of the XLMR patients, the gene responsible has not yet been identified.

But, the generalized source for about three-quarters of the remaining cases appears to be new mutations appearing for the first time in the child.

The majority of mental retardation is caused by spontaneous mutations in paternal sperm or maternal egg cells. . . . The researchers read the genetic code of all 20,000 genes for 10 patients with mental retardation. A similar analysis was performed for their healthy parents. By comparing the genetic codes obtained, differences in genes between parents and child could be precisely determined.

For nine out of ten children, the researchers indeed found such changes, each time in a different gene. For three children, the change identified was irrelevant to their disorder. But more important, for the remaining six children, they found two changes that are definitely relevant to their disorder and the four other changes are most likely related to their disorder. Geneticist Joris Veltman: "Apparently, the mental retardation observed in six of these ten children can be explained by a novel genetic change, a de novo mutation. . . .

In the world of medical genetics, mental retardation reflects an intriguing paradox. Individuals with mental retardation seldom have children themselves; as such, they do not pass their impairment on to the next generation. Nonetheless, the frequency of mental retardation in the general population balances and remains around two percent. How can this be possible? . . .

Veltman and Brunner now offer a surprising resolution for this paradox. A majority of mental retardation occurred by chance; by novel mutations in the genetic code of the children. It is expected that approximately 1,000 of all 20,000 genes can cause mental retardation. When a de novo mutation hits one of these genes, it will result in mental retardation. . . .

In addition, we can now determine the recurrence risk for those families in which a de novo mutation caused the mental retardation. This risk will be only marginally increased compared to the general population. For many parents this is a reassuring message which may play a role in their decision making process for additional children. . . .

On average, one new mutation will appear during the process that copies all parental genes to their child. With 1,000 of all 20,000 genes potentially playing a role in mental retardation, the chance of having a child with mental retardation is relatively high. A similar scenario is likely to be true for other diseases in which a large number of genes play a role, such as schizophrenia and autism. The concept of de novo mutations might be equally important for these diseases. . . .

Veltman: "So far, mental retardation was thought to be caused by an interaction of multiple genes. We describe this as complex genetics. Indeed, in the general population mental retardation can be caused by as many as thousand genes. But on an individual level, each case -- as we now found -- is caused by a mutation in a single gene. This newly generated mutation can be readily identified by reading the genetic code of the parents and their child, because there is only one distinguishing factor, which is the causative mutation.

From Science Daily (December 7, 2010).

The genes involved appears to be, unsurprisingly, a subset of genes associated with the nervous system that are increasingly well defined.

Obviously, a ten person sample is too small to produce a statistically significant estimate that the percentage of severe mental retardation cases caused by spontaneous mutations is precisely 60% (the margin of error is roughly +/- 31%). But, simply knowing that this accounts for a very large share of all cases is itself a breakthough.

One way to imagine the situation is that the baseline set of genetic allelles necessary to produce an IQ within the normal range are fixed in human populations. Almost every allelle present in the gene pool for at least a couple of generations is consistent with IQ within the normal range. It takes a whole set of genes to produce a normal range IQ phenotype and a single mutation is enough to bring the entire system tumbling down. Overwhelmingly, new mutations anywhere in this group of genes are bad news.

This also suggests that the notion of mental retardation as simply the low end of a Bell Curve distribution of IQ may be fundamentally flawed. Instead, there is a normal range that includes 97%-98% of the population (perhaps a very few high IQ people are outside it as well), and then a chasm between people within the normal range and the 2% who are mentally retarded.


Anonymous said...

I have a severely mentally retarded/autistic son who is 8 but developmentally, maybe 3. The anguish is sometime truly unbearable. I am terrified,that when my Wife and I die, he will be all alone in a grungy facility somewhere, banging his head against a wall. I don't understand why he can't develop, why he is so "stuck", it breaks my heart every single day. I love him for who he is, but he can't survive in this world alone. How is it that someone who has a been shot in the head can somehow recover, but my son who had an oxygen problem at birth cannot.

Andrew Oh-Willeke said...

You face a very difficult situation, and as so often is the case, one in which life is not fair. I've worked on custody cases involving children with these kinds of challenges, so I am familiar the anguish these challenges can provide for parents. My experience has been that the challenges often become greater as a child's physical development grows more and more advanced relative to his mental development.

Even as we are increasingly starting to understand the root causes of autism/mental retardation in terms of genetic mutations v. oxygen shortages v. other causes, there has been virtually no progress in treatment, the social safety net in the United States is feeble, and we don't have the same kinds of strong extended families that provided backup for parents in the days before there was a social safety net.

We also don't have a real good way of even thinking about how to fit someone who is severely mentally retarded/autistic into our society. A world increasingly designed around voluntary consent and incentives that provides more freedom and choice to the able, doesn't necessarily do those who lack ability and judgment any favors. And, one needs to be wealthy indeed to afford the kind of care that seems to really afford people receiving it the kind of dignity that they deserve as human beings.

I wish I had answers. I don't.