C h a p t e r 6
Genetic and Congenital Disorders
111
Infants with hyperphenylalaninemia are treated with
a special diet that restricts phenylalanine intake. The
results of dietary therapy of children with PKU have been
impressive. The diet can prevent intellectual impairment
as well as other neurodegenerative effects of untreated
PKU. However, dietary treatment must be started early in
neonatal life to prevent brain damage. Infants with ele-
vated phenylalanine levels should begin treatment by
7 to 10 days of age, indicating the need for early diagno-
sis. The duration of the dietary restriction remains con-
troversial. Women with PKU who wish to have children
require careful attention to their diet, both before concep-
tion and during pregnancy, as a means of controlling their
phenylalanine levels.
Tay-Sachs Disease.
Tay-Sachs disease is a variant of a
class of lysosomal storage diseases, known as the gan-
gliosidoses, in which there is failure of lysosomes to
break down the GM
2
ganglioside of cell membranes.
Tay-Sachs disease is inherited as an autosomal reces-
sive trait and is predominantly a disorder of Eastern
European (Ashkenazi) Jews, in whom a carrier rate of
1 in 30 has been reported.
1–3
The GM
2
ganglioside accumulates in the lysosomes
of all organs in Tay-Sachs disease, but is most promi-
nent in the brain neurons and retina. Microscopic
examination reveals neurons ballooned with cytoplas-
mic vacuoles, each of which constitutes a markedly dis-
tended lysosome filled with gangliosides. In time, there
is progressive destruction of neurons within the brain
substance, including the cerebellum, basal ganglia,
brain stem, spinal cord, and autonomic nervous system.
Involvement of the retina is detected by ophthalmos-
copy as a cherry-red spot on the macula.
Infants with Tay-Sachs disease appear normal at birth
but begin to manifest progressive weakness, muscle flac-
cidity, and decreased attentiveness at approximately 6 to
10 months of age. This is followed by rapid deteriora-
tion of motor and mental function, often with develop-
ment of generalized seizures. Retinal involvement leads
to visual impairment and eventual blindness. The disease
is invariably fatal, and death usually occurs before 4 to
5 years of age. Although there is no cure for the disease,
analysis of the blood serum for the lysosomal enzyme
hexosaminidase A, which is deficient in Tay-Sachs dis-
ease, allows for accurate identification of genetic carriers
for the disease.
X-Linked Disorders
Sex-linked disorders are almost always associated with
the X, female, chromosome, and the inheritance pattern
is predominantly recessive.
1–4
Because of the presence
of a normal paired X gene, female heterozygotes rarely
experience the effects of a defective gene, whereas all
males who receive the gene are typically affected. The
common pattern of inheritance is one in which an unaf-
fected mother carries one normal and one mutant allele
on the X chromosome. This means that she has a 50%
chance of transmitting the defective gene to her sons,
and her daughters have a 50% chance of being carriers
of the mutant gene (Fig. 6-5). When the affected son
procreates, he transmits the defective gene to all of his
daughters, who become carriers of the mutant gene.
Because the genes of the Y chromosome are unaffected,
the affected male does not transmit the defect to any of
his sons, and they will not be carriers or transmit the
disorder to their children. X-linked recessive disorders
include glucose-6-phosphate dehydrogenase deficiency
(see Chapter 13), hemophilia A (see Chapter 12), and
X-linked agammaglobulinemia (see Chapter 16).
Single-Gene Disorders with Atypical
Patterns of Inheritance
Several genetic disorders do not follow the mendelian
pattern of inheritance. These include diseases caused by
genomic imprinting, triplet repeat mutations, and muta-
tions in mitochondrial genes.
3
Genomic Imprinting
According to the mendelian pattern of inheritance, a
mutant allele of an autosomal gene is equally likely to
be transmitted from a parent to an offspring of either
sex; similarly, a female is equally likely to transmit a
mutated X-linked gene to either sex.
2
Originally, little
attention was paid to whether the sex of the parent
had any effect on expression of the genes each parent
transmits. It is now known that in some genetic disor-
ders, such as Prader-Willi and Angelman syndromes, the
expression of the disease phenotype depends on whether
the mutant allele was inherited from the father or the
mother, a phenomenon known as
genomic imprint-
ing
. Both syndromes exhibit intellectual disability as a
common feature, and both involve the same deletion in
chromosome 15. However, when the deletion is inher-
ited from the mother, the infant presents with Angelman
FIGURE 6-5.
Simple pedigree for inheritance of an X-linked
recessive trait. X-linked recessive traits are expressed
phenotypically in the male offspring. A small blue-colored
circle represents the X chromosome with the defective gene in
the female and the larger blue-colored square represents the
affected male.The affected male passes the mutant gene to all
of his daughters, who become carriers of the trait and have a
50% chance of passing the gene to their sons and daughters,
who in turn have a 50% chance of being carriers of the gene.
