110
U N I T 1
Cell and Tissue Function
Neurofibromatosis-2,which is characterizedby tumors
of the acoustic nerve and multiple meningiomas, is
much less common than NF-1.
10–12
The disorder is often
asymptomatic through the first 15 years of life. The most
frequent symptoms are headaches, hearing loss, and tin-
nitus (i.e., ringing in the ears). There may be associated
intracranial and spinal meningiomas. The condition is
often made worse by pregnancy, and oral contracep-
tives may increase the growth and symptoms of tumors.
Persons with the disorder should be warned that severe
disorientation may occur during diving or swimming
underwater, and drowning may result. Surgery may be
indicated for debulking or removal of the tumors.
Autosomal Recessive Disorders
Autosomal recessive disorders are manifested only when
both members of the gene pair are affected. In this case,
both parents may be unaffected but are carriers of the
defective gene. Autosomal recessive disorders affect
both sexes. The occurrence risks in each pregnancy are
one in four for an affected child, two in four for a carrier
child, and one in four for a normal (noncarrier, unaf-
fected) homozygous child
1–4
(Fig. 6-4).
Consanguineous
mating
(mating of two related individuals), or inbreed-
ing, increases the chance that two people who mate will
be carriers of an autosomal recessive disorder.
With autosomal recessive disorders, the age of onset
is frequently early in life; the symptomatology tends to
be more uniform than with autosomal dominant disor-
ders; and the disorders are characteristically caused by
loss-of-function mutations, many of which impair or
eliminate the function of an enzyme. In the case of a
heterozygous carrier, the presence of a mutant gene usu-
ally does not produce symptoms because equal amounts
of normal and defective enzymes are synthesized. This
“margin of safety” ensures that cells with half their
usual amount of enzyme function normally. By con-
trast, the inactivation of both alleles in a homozygote
results in complete loss of enzyme activity. Although
new mutations for recessive disorders do occur, they are
rarely detected clinically because the affected person is
an asymptomatic heterozygote. Several generations may
pass before the descendants of such a person mate with
other heterozygotes and produce affected offspring.
3
Autosomal recessive disorders include almost all
inborn errors of metabolism. Enzyme disorders that
impair catabolic pathways result in an accumulation
of dietary substances (e.g., phenylketonuria) or cellular
constituents (e.g., lysosomal storage diseases). Other
disorders result from a defect in the enzyme-mediated
synthesis of an essential protein (e.g., the cystic fibrosis
transmembrane conductance regulator in cystic fibrosis
[see Chapter 23]). Two examples of autosomal recessive
disorders that are not covered elsewhere in this book are
phenylketonuria and Tay-Sachs disease.
Phenylketonuria.
Phenylketonuria (PKU, hyperphenyl-
alaninemia) is a metabolic disorder caused by elevated
levels of phenylalanine that are toxic to the brain. The
incidence of PKU and hyperphenylalaninemia is 1 per
10,000 in the white and Asian population, but varies
widely across geographic areas (e.g., 1 per 4500 in Ireland
to less than 1 per 100,000 in Finland).
2
In most cases,
the hyperphenylalaninemia results from a deficiency of
phenylalanine hydroxylase (PAH), a liver enzyme that
converts the amino acid phenylalanine to tyrosine.
1–3,13,14
Phenylalanine is an essential amino acid derived
solely from the diet. In normal children, less than 50%
of the phenylalanine consumed in the diet is used for
protein synthesis. The remainder is converted to tyro-
sine by PAH. When breakdown of phenylalanine is
blocked because of a lack of PAH, other minor meta-
bolic pathways are used, yielding several intermediates
that are excreted in large amounts in the sweat and
urine. These metabolites impart an unpleasant, strong,
musty odor to affected infants. It is believed, however,
that phenylalanine rather than its metabolites contrib-
utes to the brain damage in PKU. The lack of tyrosine,
a precursor of melanin, is responsible for the light color
of the hair and skin.
At the molecular level, approximately 400 mutant
alleles for the PAH gene have been identified, some of
which produce only mild deficiency while others pro-
duce severe deficiency.
3
The severity of hyperphenylal-
aninemia depends on the degree of PAH deficiency and
can be classified as
classic PKU
,
mild PKU
, or
mild
hyperphenylalaninemia
based on blood concentrations
of phenylalanine.
13,14
Infants and children with classic
and mild PKU require dietary protein restrictions to pre-
vent intellectual impairment, microcephaly, and other
signs of impaired neurologic development. Affected
infants are normal at birth but within a few weeks begin
to develop a rising phenylalanine level and signs of
impaired brain development. Seizures, other neurologic
abnormalities, decreased pigmentation of the hair and
skin, and eczema often accompany the mental retarda-
tion in untreated infants.
Because the symptoms of untreated PKU develop grad-
ually andwouldoftengoundetecteduntil irreversible intel-
lectual impairment had occurred, newborns are routinely
screened for abnormal levels of serum phenylalanine.
13–15
FIGURE 6-4.
Simple pedigree for inheritance of an autosomal
recessive trait.The half blue-colored square (male) and circle
(female) represent a mutant gene. When both parents are
carriers of a mutant gene, there is a 25% chance of having
an affected child (full blue-colored circle or square), a 50%
chance of a carrier child, and a 25% chance of an unaffected
or noncarrier child, regardless of sex. All children (100%) of an
affected parent are carriers.
