hemical Diseases, andDisfiguring Birth Defects
Prenatal Diagnosis: Heredity Disorders, Other Biochemical Diseases, and
Disfiguring Birth Defects
There are over 250 recognized sex-linked diseases, affecting every organ
system. Of these, 95% affect males, (Emery, 1968). Despite these many sex-
linked diseases, at present prenatal diagnosis can specifically be made in fewer
than 40 diseases. (Emery, 1968). These sex-linked diseases are individual rare
and some are named after physicians who described them, for example, Hemophilia
A and B, Duchenne muscular dystrophy, fragile-X syndrome, Fabry disease, Hunter
syndrome, Lesch-Nyhan syndrome, and Menkes steely-hair syndrome. The following
discourse considers the reasons for the importance of prenatal diagnosis,
heredity disorders, and disfiguring birth defects.(Nora,1989).
Fabry disease is a biochemical disorder caused by a missing enzyme.
(Mulinsky, 1989).A complex fatty substance accumulates in the body because of
the missing enzyme which would ordinarily break this compound into
pieces.(Nora,1989). This missing enzyme causes kidney and blood-vessel problems
that lead to high blood pressure, kidney failure and strokes.(Mulinsky, 1989).
After many years of symptoms, most patients have died in their thirties and
forties owing to a lack specific treatment.
A biochemical disorder also caused by a missing enzyme is the Lesch-
Nyhan syndrome, an extremely unpleasant disorder characterized not only by
profound mental retardation and features of brain damage (stiff limbs with
peculiar movements), but also self-mutilation, (Jones, 1988). Given good care
and attention however, these patients may live on many years in their profoundly
retarded state. They often require restraining, tying their hands, to prevent
them from mutilating themselves.
Another Affected children with Menkes steely-hair syndrome have hair
that feels similar to steel wool; in addition, they are retarded. The basic
defect in this condition concerns the way the body handles copper.
Only a few of these sex-linked disorders can now be diagnosed in the
fetus, (Stein, 1994). At the present time, the only recourse parents have in
the case of sex-linked diseases that are not prenatally diagnosable is to
determine the sex of the fetus. If a female fetus is found, the parents can be
reassured that their child will not be affected (a critical exception is
fragile-X). However, if it is determined that there is a male fetus present,
there is a fifty percent chance that it is affected, (Milunsky, 1989). Since
there is no way of being certain, the parents must decide simply on the basis of
high risk weather to take a chance or terminate that pregnancy.
There are some unusual sex-linked diseases that are confined to females.
Disorders of this kind (such as incontinentia pigmenti, a skin disorder
associated with brain damage) can be managed by determining weather the fetus is
a female. In this group, virtually all females will be affected, and the
parents could selective elect to have unaffected boys.
Hemophilia A and Duchenne muscular dystrophy are two of the most common
sex-linked diseases that are familiar to most people. But there are so many
other diseases that great care must be taken by both the doctor and the family
in obtaining an accurate family history. Renpenning syndrome, in which there is
mental retardation without any other physical signs, is confined to males. The
only way to suspect sex-linked inheritance is for the physician to carefully
analyze the family lineage. Tests are preformed to detect female carriers of
such diseases. For example, almost all carriers of hemophilia and Duchenne
muscular dystrophy can now be detected. A muscle enzyme, creatine phosphokinase,
which leaks into the blood is also often measured to give a higher probability
of recognizing a carrier. Unfortunately, because of recombination, the
carrier-detection tests for both hemophilia and muscular dystrophy do not
provide answers in 100 percent of cases. A negative result causes uncertainty
and leaves the question of carrier detection basically unanswered. Fortunately,
carrier-detection tests are steadily becoming possible in more of the sex-linked
and other disorders.
Prenatal Studies for Heredity Biochemical Disorders
Many hundreds of different hereditary biochemical disorders of
metabolism are known. About 1 in every 100 children born have one of these
biochemical disorders. (Nora, 1989). Many of these disorders do not cause
mental retardation, or impair the child’s normal development or general health
to any great extent, if at all. Many others, however, cause severe mental
retardation, seizures, stunting of growth, and early death. Close to 150 of
these biochemical disorders can now be diagnosed in the affected fetus early in
pregnancy. (Nora,1989). The first diagnosis of a biochemical disorder in the
fetus while in the womb was made in the late 1960’s; the disorder was Tay-Sachs
disease. (Emery, 1968). Diagnosis such as this are made by obtaining cells from
the amniotic fluid which are placed in small dishes containing a nutrient broth,
and then kept in a special warm, moist incubator. They grow slowly. After a
period of two to three weeks or, occasionally, as long as six weeks, there are
enough cells to work on. Each of the cells having the genetic blueprint will
show the specific biochemical defect ( for example, deficient activity of an
enzyme) thereby enabling a diagnoses to be made. With diagnosis, physicians
can treat the known disorder through the womb.
For a few disorders, such as Rh disease, treatment of the fetus directly
or through the mother has now succeeded. The first prenatal diagnosis of a
biochemical disorder that was treatable in the womb was the rare disorder
methylmalonic aciduria.(Milunsky, 1989). This disorder causes failure to thrive,
vomiting, lethargy, biochemical disturbances, poor muscle tone, and eventually
mental and motor retardation. Treatment of the fetus through the mother during
pregnancy is carried out by giving her intramuscular injections of massive doses
of vitamin B12. This method secures the child’s health at birth, when a special
low-protein diet is started. In this way serious illness, mental retardation
and early death have been averted.
Another considerably more common disorder is congenital adrenal
hyperplasia (CAH). This heredity disorder is inherited equally through a gene
from both parents (autosomal recessive). About 1 in 5,000 to 13,000 whites and
1 in 7550 Japanese are born with CAH – nowhere near the remarkable 1 in 282
among the Yupik Eskimos. (Jones, 1988). Various forms of this disorder occur,
each due to a deficient, though different enzyme along a stepwise pathway that
finally results in the production of “cortisone”. Symptoms of the most common
form of CAH are masculinization of the female genitals, excessive growth, early
appearance of pubic hair, and enlargement of the penis or clitoris. Critically
important in about two-thirds of affected children is the occurrence of a life-
threatening crisis one to four weeks after birth, characterized by vomiting,
diarrhea, and salt loss leading to collapse and even death if not diagnosed and
treated with “cortisone”. Where needed, surgical correction of the female
genitals is possible, and normal growth, puberty and fertility can be achieved
through lifelong medical treatment with cortisone like supplements. Today, both
carrier detection and prenatal diagnosis are possible for most families, using
DNA techniques combined with special blood-group linkage studies.
The very first inherited biochemical disorder found to cause mental
retardation was phenylketonuria.(Koiata, 1995). Since that description in 1934,
it has been learned that PKU (phenylketonuria) occurs in about 1 in 14,000
newborns in the United States and as frequently as 1 in 4,500 in Northern
Ireland.( Nora, 1989). Transmitted by a recessive gene from each parent, all
problems are the result of a deficient liver enzyme. An affected untreated
child will develop irreversible mental retardation. Therefore, in most Western
countries , blood screening of newborns is done to make an immediate diagnosis
and institute the special low-protein diet through which mental retardation can
Despite the availability of effective treatment after birth, prenatal
diagnosis remains a serious option for parents. This option is valuable because
the special low protein diet is tasteless and very restrictive.(Mulinsky, 1989).
Enforcing the diet in early childhood is difficult, and needs to be continued
for as long as possible. (Mulinsky, 1989). The usual practice has been to
discontinue the diet at four to seven years of age. Recent studies show
intellectual deterioration, loss of IQ pionts, learning difficulties, and
behavior problems after the diet has been discontinued. (Jones, 1988). A
steadily increasing number of women with PKU are entering the childbearing years.
(Jones, 1988). If they become pregnant, the chemical products that accumulate
in their blood damage the fetal brain and other developing organs. Their risk
of having a retarded child or one with a heart defect or microcephaly approaches
an incredible 100 percent. (Koiata, 1995). Only a mere handful of cases are
known in which the diet was adhered to strictly before conception and a healthy
child is born. Today, new DNA techniques have made both carrier detection and
prenatal diagnosis of PKU possible for most families and therefore an important
Galactosemia is another treatable hereditary biochemical disease where
prenatal diagnosis is possible. If the fetus is affected, special lactose-free
dietary treatment of the mother started early enough will almost always avert
early death or mental retardation, cataracts, and liver damage.(Jones, 1988).
There are a few other very rare disorders where prenatal diagnosis and early
treatment may be critical to save life or prevent mental retardation or other
consequences. Some of these diseases are: tyrosinemia, homocystinuria, maple-
sirup urine disease, and propionicacidemia. (Jones, 1988). A few other
disorders are now being conquered by early diagnosis and treatment in the womb.
(Jones, 1988). Continued support for medical research will undoubted provide
more and more opportunities for early treatment or prevention, reducing the need
for abortion, which is a major option and issue today. Progress in actual
prenatal treatment for genetic disorders can be anticipated, provided that fetal
research is not interdicted by state legislation. (Nora, 1989).
The fact that mental retardation is more common in males has been a
known fact for about a century. (Emery, 1968). The major reason for this excess
became clear in the mid-1970’s, when studies from Australia focused attention on
an unexpectedly common disorder with striking features: the fragile -X syndrome.
(Nora, 1989). This disorder, caused by a single defective gene on the X
chromosome, has highly variable signs that usually include mental retardation
and distinctive facial features. (Milunsky, 1989). Special studies have
revealed the location of the defective gene on the X chromosome: a vulnerable
spot that tends to break, hence, the term “fragile-X syndrome.” (Milunsky, 1989).
Because of the remarkable variability of the physical, behavioral, and
developmental features of fragile-X syndrome and the delayed appearance of some
major features, definitive recognition of this disorder eluded researchers for
many years. (Milunsky, 1989). Confusion was also generated by the fact that
although males were primarily affected, within the same families mildly affected
females were also observed. It is now known that about 1 in 1,060 males are
born with fragile-X syndrome, and that the disorder accounts for about 25
percent of all male cases of mental retardation and about 10 percent of mild to
moderate mental retardation in females.(Nora,1989). The main signs of this
disorder are on Table 1.
Transmission of the fragile-X disorder was initially thought to conform
to other sex-linked disorders. Quite unexpectedly, a unique pattern that does
not conform exactly to sex-linked inheritance has been discovered only recently.
The current knowledge, as studied by Dr. Milunsky, allows certain risk
1. An intellectually normal female who inherits the fragile-X gene from
her carrier mother has a 50 percent risk of having an affected son, whose risk
of being retarded is 40 percent . Half her daughters will carry the gene, but
only 16 percent will be retarded.
2. If such a daughter is retarded, her risk of having an affected and
retarded son is 50 percent. If she has a daughter herself, the risk is 28
percent that the will also be mentally impaired.
3. Men who are seemingly entirely normal and do not even show the
fragile-X chromosome when tested may nevertheless transmit the gene to all their
daughters. These females are usually intellectually normal. However, when they
reproduce, 50 percent of their sons will be affected, and 40 percent will be
retarded. Half their daughters will be carriers, among 16 percent will be
4. Normal-but-transmitting males may account for 20 percent of all cases
of the fragile-X syndrome. Unfortunately, they will remain undetectable until
new technology revels their ominous burden or until one of their children or
grandchildren is diagnosed as having this fateful flaw.
5. Curiously, women carriers who bear a son who is a normal-but-
transmitting male have a 50 percent risk of having an affected male, who has
only a 9 percent risk of being retarded. This carrier female also has a 50
percent risk of having carrier daughters, and these girls have only a 5 percent
risk of being intellectually impaired.
Further research inth this devistating disorder and it’s complex
heridaty pattern may significantly reduce the amount of congenital mental
Heredity, biochemical and other disfiguring birth defects must be a top
priority with expectant parents. A knowledge of these concerns will alolow them
to make wise decisions regarding prenatal diagnosis and decisions and
availability of treatment to prevent birth defects, thereby saving lives.