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Chapter 12
Genetics of Metabolism
135
t a b l e
12-6
Metabolic Genetic Disorders Involving Degradation Pathways
Gene/Gene Product
Accumulation
Genetic Disorder
Chromosome
Product
Clinical Features
Mucopolysaccharidosis
IDUA gene/a-L-iduronidase
Heparan sulfate
Infants initially appear normal up to
type I (Hurler , Hurler-
4p16.3
Dermatan sulfate
9 months of age but then develop
Scheie, or Scheie
symptoms; coarsening of facial features,
syndromes)
thickening of alae nasi, lips, ear lobules,
and tongue; corneal clouding; severe
visual impairment; progressive thickening
heart valves leading to mitral and aortic
regurgitation; dorsolumbar kyphosis;
skeletal dysplasia involving all the bones;
linear growth ceases by 3 years of age;
hearing loss; chronic recurrent rhinitis;
severe mental retardation; and zebra
bodies within neurons.
Gaucher disease
GBA gene/
-
Glucosylceramide
Bone disease (e.g., focal lytic lesions,
glucosylceramidase
Other glycolipids
sclerotic lesions, osteonecrosis) is the
1p21
most debilitating pathology of Type I GD;
hepatomegaly; splenomegaly; cytopenia
and anemia due to hypersplenism,
splenic sequestration, and decreased
erythropoiesis; and pulmonary disease
(e.g., interstitial lung disease, alveolar/
lobar consolidation; pulmonary
hypertension); no primary CNS
involvement.
Hexosaminidase A
HEXA gene/
GM2 ganglioside
Infants initially appear normal up to
deficiency (Tay-Sachs)
hexosaminidase
3–6 months of age but then develop
a-subunit
symptoms; progressive weakness and
15q23-q24
loss of motor skills; decreased
attentiveness; increased startled
response; a cherry red spot in the
fovea centralis of the retina; generalized
muscular hypotonia; later, progressive
neurodegeneration, seizures, blindness,
and spasticity occur followed by death
at
2–4 years of age.
Mucopolysaccharidosis
IDS gene/iduronate
Heparan sulfate
Dysostosis multiplex (thickened skull,
type II
2-sulfatase
Dermatan sulfate
anterior thickening of ribs, vertebral
(Hunter syndrome)
Xq27.3-q28
abnormalities, and short/thick long
bones), coarse face, hepatosplenomegaly,
mental retardation, and behavioral
problems.
Mucopolysaccharidosis
SGSH gene/sulfatidase
Heparan sulfate
Dysostosis multiplex (thickened skull,
type III A (Sanfilippo
17q25.3
anterior thickening of ribs, vertebral
A syndrome)
abnormalities, and short/thick long
bones), mental retardation, and
behavioral problems (aggressive
behavior followed by progressive
neurological decline).
Mucopolysaccharidosis
GALNS gene/N-
Keratan sulfate
Short stature, bony dysplasia, and hearing
type IV A (Morquio A
acetylgalactosamine-
Chondroitin-6-
loss.
syndrome)
6-sulfate sulfatase
sulfate
16q24.3
Niemann-Pick type 1A
SMPD1 gene/acid
Sphingomyelin
Hepatosplenomegaly, feeding difficulties,
disorder
sphingomyelinase
and loss of motor skills is seen within
11p15
1–3 months of age; a cherry red spot
in the fovea centralis of the retina; later,
a rapid, profound, and progressive
neurodegeneration occurs followed by
death at
2–3 years of age.
(continued)
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136
BRS Genetics
FIGURE 12-1. (A1, A2, A3) Glycogen storage disease type I (von Gierke). (A1)
Photograph shows a boy 13 years of age with
von Gierke disease. Note the enlarged abdomen. (A2) Light micrograph of a liver biopsy shows hepatocytes with a pale,
clear cytoplasm due to the large amounts of accumulated glycogen that is extracted during histological processing. (A3)
Electron micrograph of a liver biopsy shows hepatocytes filled with glycogen aggregates. (B) Glycogen storage disease
type V (McArdle).
Light micrograph of a skeletal muscle biopsy shows muscle cells with a pale, clear cytoplasm due to the
large amounts of accumulated glycogen that is extracted during histological processing. (C) Maple syrup urine disease.
T2-weighted MRI shows hyperdensity in the brain stem (arrows) indicating neurological deterioration. (D1, D2) Familial
hypercholesterolemia (D1)
Photograph shows xanthomas on the dorsum of the hand. (D2) Photograph shows arcus
lipoides, which represents the deposition of cholesterol around the cornea of the eye. (E) Wilson disease. Photograph
shows a Kayser-Fleischer ring (arrows) caused by the deposition of copper in Descemet membrane and thereby obstructs
the view of the underlying iris. (F) Hemochromatosis. Light micrograph of a liver biopsy stained with Prussian blue shows
hepatocytes with a heavily stained cytoplasm to the large amounts of accumulated iron. (G) Mucopolysaccharidosis type
I (MPS I; Hurler syndrome).
Photograph shows an infant with coarsening of facial features; thickening of alae nasi, lips,
ear lobules, and tongue; dorsolumbar kyphosis; and skeletal dysplasia involving all the bones. (H) Gaucher disease. Light
micrograph of a bone marrow aspirate smear shows the typical Gaucher cells with an abundant cytoplasm filled with fib-
rillarlike material. (I) Tay-Sachs disease. Electron micrograph shows central nervous system neurons filled lysosomes
(Lys) containing whorls of membranelike material due to the large amounts of accumulated GM2 ganglioside. N
nucleus
of neuron.
t a b l e
12-6
(continued)
Gene/Gene Product
Accumulation
Genetic Disorder
Chromosome
Product
Clinical Features
Fabry disorder
GLA gene/a-
Globotriaosyl-
In classically affected males, symptoms
galactosidase A
ceramide
begin in childhood or adolescence;
Xq22
severe neuropathic or limb pain
precipitated by stress, extreme heat or
cold, and physical exertion;
telangiectasias, angiokeratomas in the
groin, hip, and periumbilical regions;
asymptomatic corneal deposits; retinal
vascular tortuosity; in adulthood, end
stage renal disease, cardiac involvement,
and cerebrovascular involvement leading
transient ischemic attacks and strokes.
Krabbe disorder
GALC gene/
Galactosylceramide
Developmental delay, limb stiffness,
galactocerebrosidase
hypotonia, absent reflexes, optic atrophy,
14q31
microcephaly, and extreme irritability
within 1–6 months of age; later, seizures
and tonic extensor spasms associated
with light, sound, or touch stimulation
occur; a rapid regression to the
decerebrate condition followed by death
at
2 years of age.
Metachromatic
ARSA gene/
Cerebroside sulfate
Regression of motor skills, gait difficulties,
leukodystrophy
arylsulfatase A
ataxia, hypotonia, extensor plantar
22q13.3-qter
responses, and optic atrophy within
6 months to 2 years of age; later,
peripheral neuropathy occurs followed
by death at
5–6 years of age;
metachromatic lipid deposits in neurons
is pathognomic
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Chapter 12
Genetics of Metabolism
137
A1
A2
A3
E
F
G
C
B
H
I
Lys
N
D1
D2
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138
1.
In metabolic genetic diseases, heterozy-
gotes are generally normal. Which of the fol-
lowing is the most likely explanation for this
observation?
(A)
Heterozygotes have compound muta-
tions.
(B)
Heterozygotes produce enough enzymes
for normal metabolic function.
(C)
Heterozygotes produce defective
enzymes that are repaired by the normal
allele.
(D)
Heterozygotes produce defective
enzymes that are spliced to normal
enzymes.
2.
In hereditary hemochromatosis, some
affected individuals are not homozygous for
either of the two common mutations, C282Y
and H63D, which cause the disease. Which
one of the following causes the disease in
these individuals?
(A)
high hepatic concentration of copper
(B)
heterozygosity for C282Y
(C)
heterozygosity for H63D
(D)
compound heterozygosity for the two
common mutations
3.
Familial hypercholesterolemia is caused
by which one of the following?
(A)
autosomal recessive inheritance of a
mutation in the LDL receptor gene
(B)
homozygosity or heterozygosity for a
mutation in the LDL receptor gene
(C)
a mutation in the mitochondria
(D)
multifactorial inheritance
4.
Most genetic metabolic diseases are
caused by mutations in which one of the
following?
(A)
mitochondrial genes
(B)
DNA repair genes
(C)
genes that code for structural proteins
(D)
genes that code for enzymes
5.
Which of the following is a genetic meta-
bolic disease involving degradation path-
ways?
(A)
glycogen storage disease
(B)
maple syrup urine disease
(C)
mucopolysaccharidosis
(D)
galactosemia
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1. The answer is (B).
Because most metabolic diseases are inherited in an autosomal recessive
fashion, heterozygotes have a normal allele and usually produce enough enzymes for nor-
mal metabolic function.
2. The answer is (D).
Heterozygotes for either C282Y or H63D are normal, but when both
mutations are present in the heterozygous state in an individual that individual is affected.
This is called compound heterozygosity.
3. The answer is (B).
Familial hypercholesterolemia is caused by autosomal dominant inheri-
tance of a mutation in the low density lipoprotein receptor (LDLR) gene. Because it is an
autosomal dominant disease, both heterozygous and homozygous individuals are affected.
Most cases of hypercholesterolemia in the population are multifactorial in origin.
4. The answer is (D).
Metabolic reactions within biochemical pathways require enzymes to
facilitate the reactions. Most metabolic diseases are caused by mutations in the genes that
encode the enzymes in a biochemical pathway.
5. The answer is (C).
Mucopolysaccharidosis is due to lysosomal enzyme deficiencies that
result in the lack of complete degradation of glycosaminoglycans, resulting in the buildup of
incomplete degradation products in cells.
139
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