single-gene disorders

single-gene disorders. Fragile X syndrome is the second most common
genetic cause of mental retardation. It is the most common inherited
form of mental retardation. As is true of other disorders due to sex-linked
recessive genes, more males are affected than are females. The frequency of
fragile X males is about 1 in 1,000; for females, it is about 1 in 2,500. It is estimated
that up to 8 percent of the males in institutions for mental retardation
have a fragile X chromosome. Grant R. Sutherland and John C. Mulley
in 1996 provided a useful review of the characteristics of fragile X syndrome.

Features include a prominent forehead and jaws; prominent, long, and
mildly dysmorphic ears; hyperextensible finger joints; enlarged testes (macroorchidism);
and mitral value prolapse. About 80 percent of fragile X
males have mental retardation. Most of them have moderate retardation,
but some are only mildly retarded. They tend to have better verbal than
spatial abilities. They show speech abnormalities such as echolalia (compulsively
repeating the speech of others). In general, they tend to be hyperactive.
Only about one-half of girls with the fragile X chromosome are affected,
and limited studies of females estimate that perhaps up to 7 percent
of female mental retardation is due to fragile X syndrome. The specific gene
involved in fragile X syndrome has been identified: The syndrome is caused
by an expanded triplet repeat, a form of mutation in which deoxyribonucleic
acid (DNA) nucleotides are repeated a number of times.

Phenylketonuria (PKU) is one of the inborn errors of metabolism that results
in mental retardation if left untreated. PKU is a disorder of amino acid
metabolism in which individuals cannot metabolize normally the amino
acid phenylalanine because they are deficient in the liver enzyme phenylalanine
hydroxylase. As a result, phenylalanine and other metabolites accumulate
in the blood. At birth, children are normal, but clinical features gradually
appear during the first twelve months. Some affected persons have a
“mousy” odor about them because of the excretion of phenylacetic acid.
They tend to have light skin and hair, seizures, mental retardation, and
other neurologic symptoms. PKU occurs in about one in fourteen thousand
births and once accounted for about 1 percent of severely retarded individuals
in institutions. Some interesting variations in the incidence of PKU are
seen among different populations. In Turkey, a very high incidence is seen,
1 in 2,600 births, whereas in Japan the rate is only 1 in 143,000 births. The
disorder is inherited as autosomal recessive, and most of the affected children
are born to parents who are not affected.

PKU represents the prototype of genetic disorders for which newborn
screening can be done: babies with high blood levels of phenylalanine can
be identified, and treatment can begin immediately. Dietary management
of phenylalanine levels does not correct the underlying gene defect, but it
keeps the levels sufficiently low that adverse effects on the brain and nervous
system do not occur, and mental retardation is avoided. It is thought
necessary to maintain the special diet through the adolescent years. It also is
necessary for women with PKU who become pregnant to resume a diet low
in phenylalanine to prevent high intrauterine levels from affecting the developing
fetus, even though the latter may not be genetically “programmed”
to inherit PKU. Untreated patients with PKU have mean IQs around 50,
whereas treated patients will have IQs close to normal.