February 1, 2001

Genetics and Mental Retardation

V. Reid Sutton, M.D.
Dr. Sutton is Assistant Professor, Department of Molecular & Human Genetics, Baylor College of Medicine, Houston.

There are many causes of mental retardation, including genetic and chromosomal disorders, infections during pregnancy, drug and alcohol use during pregnancy, problems with the birth or delivery, prematurity and low family IQ in general. Despite advances in medical diagnosis, the cause of MR in many individuals is unknown.

While for every newborn baby there is at a small risk of MR, babies born into a family which already has a child with MR are much more likely also to develop MR. This suggests a genetic component that is not, at present, fully understood. I'd like to review the current knowledge about risk factors for and causes of MR in order to help people with concerns about the risks make better informed decisions.

MR Basics
The American Psychiatric Association defines MR as the combination of (1) tested IQ at or under 70, (2) problems with learning and social adaptation and (3) symptoms that begin before 18 years of age. MR is further subdivided into two categories: mild (IQ 50-70) and moderate-severe (IQ under 50). While there are great differences between these subcategories, genetics plays at least some role in both. MR is a common problem, affecting as much as 2% of the world's population.

For many individuals and families, the cause of mental retardation is not yet known. One reason for the uncertainty is that mental retardation covers a number of different problems with different causes.

Looking for a Cause
Many studies have attempted to find out how and why MR occurs. Unfortunately, most were done in the 1980s or earlier, before the recent advances in our ability to identify and test for certain genetic and chromosomal disorders. Chromosomes are the materials within human cells that contain our genes. Damaged or abnormal genes, and extra or missing chromosomes, are known to be a prime cause of MR.

It appears that the more severe the MR, the more likely the cause is to be genetic.

It appears that the more severe the MR, the more likely the cause is to be genetic. In mild MR, a specific risk factor has been identified in about 43% of the cases studied. Only 24% of those cases yield a fairly clear or convincing diagnosis. Of those, 14% are classified as genetic and 10% environmental. With moderate-severe MR, a cause is determined in up to 64% of cases with 45% of those being linked to genetic causes and 19% to environmental factors.

The seemingly lesser role of genetics in milder retardation may have something to do with the fact that some who fall into the mild MR category may simply represent the low end of the normal range of human intelligence. In other words, their low IQ may be the result of low family IQ, not a genetic problem or other specific cause. Those in the moderate-severe category, however, are much more likely to be there because of an environmental or genetic problem that has disrupted normal development.

Genetic Disorders
The most common genetic disorders that have been shown to cause MR are Trisomy 21, which causes Down's syndrome, deletions or duplications of the ends (telomeres) of chromosomes, and Fragile X syndrome. Normal individuals have 46 chromosomes, arranged in 23 pairs, with a parent contributing one chromosome of each pair. In Trisomy 21, the affected child inherits three chomosome 21's.

Down's syndrome accounts for 5% of mild MR cases and 30% of severe MR cases, telomere deletions or duplications account for about 7.5% of MR, while Fragile X is seen in 5% of both mild and moderate-severe MR. The fact that more than 500 other genetic diseases, mostly very rare, have also been associated with MR suggests that we may someday learn that genetics are responsible for all, or nearly all, of the MR cases whose cause is currently in the "unknown" category.

Studies have shown that a number of environmental factors can cause or contribute to MR. These can be broken down into the following categories:

Pregnancy problems, including high blood pressure, multiple pregnancy, infections (rubella, toxoplasmosis, herpes, syphilis), physical injury and drug or alcohol abuse.

Problems during or shortly after birth, including prematurity, breathing problems, jaundice, high blood sugar, brain bleeds and thyroid problems.

Childhood diseases, including infections (meningitis, encephalitis, pertussis, varicella), lead poisoning, head injury, brain tumor, heart problems and breathing problems.

Psychosocial factors, including poverty and parental neurosis or other mental health problem.

Other Illnesses Associated with MR
Studies have also found definite links between MR and a number of medical problems, chiefly epilepsy, cerebral palsy, blindness and deafness (Table 1). What we do not know for sure is whether these diseases and MR have a common genetic cause or whether the MR is the byproduct of an underlying medical problem (Table 2). The following are the results from a large, recent study that was done using the records of the British Columbia health service in Canada:

Table 1.
Features Associated With MR
Feature Mild MR Moderate-severe MR
Seizures 12% 35%
Cerebral Palsy 9% 20%
Blindness 1% 15%
Deafness 7% 10%

Table 2.
Features Associated With MR+

MR only
Cerebral Palsy
+Listed separately because the study did not divide the cases into mild and moderate-severe groups for this analysis.

It is clear from these tables that conditions such as seizures and cerebral palsy are strongly connected with MR. We do not know exactly why this is. It could be that some undetected trauma or infection caused both the medical condition and the MR. Another possibility is that in some cases, complications from seizures caused the MR. A third possibility is that a single genetic cause may be responsible for both the MR and the accompanying condition. Finally, the answer may be a combination of two or even all three of these possibilities.

The Recurrence Question
There is no question that MR runs in families. All studies on the subject have found that the MR risk for the brother or sister of someone with MR is much higher than that of the general population. A couple who has had one child with MR is ten times more likely to have another.

The question is whether this is the result of genetics or environment. The fact that most families share both makes this is a difficult area to study. This is made even more complicated by the fact that most studies will include parents who also have MR. It can be hard to determine if the children inherited MR from their parents or whether the cause was something in the family environment.

Some light has been shed on this subject by studies of identical twins. Identical twins, of course, share identical genetic material, but not necessarily the same environment.

Unfortunately, no studies have yet been done of MR in twins reared apart. According to our best current thinking, while some individuals with mild MR are simply at the lower end of the intelligence spectrum, most cases of MR have a specific medical or genetic cause, whether it is identified or not. This is supported not only by the demonstrated recurrence risks for MR with parents of normal intelligence but also by the presence of genetic causes that we can identify, including Trisomy 21 and Fragile X, in both the moderate-severe and mild MR groups.

We know from studies of both mild MR and moderate-severe MR that while outside factors such as disease, injury and social environment play some role in determining IQ, genetics are a significant, if not the most significant, cause of MR. Exactly how significant is a question that may be settled in the near future, as medical science continues to extend our knowledge of human genetics.

A careful history and physical examination, along with family history and laboratory testing may often reveal a cause for mental retardation. Knowledge of the cause for MR can empower parents to make informed decisions about testing other family members or testing a pregnancy for genetic causes of MR. Parents concerned about having a second child with MR should attempt to attain a diagnosis and then seek prenatal counseling with a clinical geneticist or genetic counselor.
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