A.
deficiency of the enzyme glucocerebrosidase, which is a lysosomal enzyme. The
disease is inherited in an autosomal recessive manner. Deficiency of the enzyme
results in the accumulation of glucocerebroside in the cells of the reticuloendothelial
system, especially in the bone marrow, liver, and spleen. Thus, hepatosplenomegaly
is very common.
Summary: A 70-year-old man presents with anemia, hepatosplenomegaly, and
enlarged histiocytes with "wrinkled tissue paper" cytoplasm (Gaucher cells) in
bone marrow.
Most likely diagnosis: Gaucher disease, adult type.
Underlying etiology: Insufficient glucocerebrosidase leading to accumulation
of glucocerebroside in the phagocytic cells of the body and the central
nervous system.

Other clinical features: Hypersplenism (i.e., leukopenia and
thrombocytopenia) and pathologic fractures resulting from bone
involvement.
Gaucher disease, a lysosomal storage disorder, results from mutations in the genes that
encode glucocerebrosidase. As a result of insufficient enzyme, glucocerebroside
accumulates in the phagocytic cells of the body and the central nervous system. Several
types of disease can occur, including a chronic nonneuronopathic variety (type I) that
affects the skeletal regions and the spleen and liver. Bone marrow involvement can lead
to leukopenia and thrombocytopenia. Type 11 usually affects infants and entails
cerebroside accumulation in the brain and abdominal organs. Early death is likely. The
diagnosis is confirmed by decreased glucocerebrosidase levels. Treatment is with
enzyme replacement. Bone marrow transplantation also is being investigated.
PATHOLOGY OF LYSOSOMAL STORAGE DISEASES
Lysosomes are considered key components of intracellular digestion. They contain
hydrolytic enzymes that are capable of breaking down a variety of complex
macromolecules. When one of the lysosomal enzymes is missing, complete breakdown
of the molecule is not possible. This leads to the accumulation of the incompletely
digested molecule within the cell. The Iysosomes and subsequently the cell and the
organ increase in size. Normal cellular function is compromised significantly.
Gaucher disease is the most prevalent lysosomal storage disorder. It is due to the
There are three clinical types. The most common is the adult type (type I or the
chronic nonneuronopathic type), which has an insidious onset of hepatosplenomegaly.
It has a high incidence among Ashkenazi Jews and accounts for 99 percent of all cases
of Gaucher disease. Patients have reduced but detectable levels of glucocerebrosidase
activity. Phagocytic cells become distended with glucocerebroside and are referred to as
Gaucher cells; these cells are enlarged with periodic acid-Schiff (PAS)-positive
cytoplasm with a fibrillary appearance as a result of the stacking of the lipid bilayers in
the Iysosomes. Accumulation of Gaucher cells in the bone marrow may cause bone
deformity or bone destruction, ultimately resulting in pathologic fractures. Life
expectancy in general is normal.
The infantile type, also referred to as type II or acute neuronopathic, is characterized
by progressive central nervous involvement and death at an early age. There is virtually
no detectable glucocerebrosidase activity in the tissues. The third type (type III) has
features intermediate between those of types I and I I.
Other Lysosomal Storage Diseases Niemann-Pick
disease is due to a deficiency of lysosomal sphingomyelinase. Accumulation of
sphingomyelin cholesterol and glycosphyngolipids in the reticuloendothelial
macrophages occurs in organs such the liver, spleen, bone marrow, and lymph nodes.
Mucopolysaccharidoses are a group of disorders caused by a deficiency of the
lysosomal enzymes normally required for the degradation of glycosaminoglycans
(mucopolysaccharides). The glycosaminoglycans are dermatan sulfate, heparan sulfate,
keratan sulfate, and chondroitin sulfate. There are 10 subtypes of this disorder, all but I
of which are transmitted as autosomal recessive.
Tay-Sachs disease is a condition in which there is accumulation of GM2
gangliosides in the nervous system. It is particulary common among Ashkenazi Jews.
Fabry's disease is an X-linked recessive condition in which there is deficiency of
alpha-galactosidase resulting in accumulation of glycosphingolipids. Neurologic and
renal problems dominate the clinical features.
B.
Albinism
Deficiency of tyrosinase
Albinism
(tyrosine is precursor of
melanin synthesis)
341
In glycogen storage disease, there is a hereditary deficiency of one of the enzymes
involved in the synthesis or degradation of glycogen. As in most enzyme deficiencies,
the majority of the subtypes are transmitted as autosomal recessive. In the hepatic forms
of the condition, enzyme deficiency results in organomegaly, prinicipally
hepatomegaly, and impaired glucose release into the circulation, leading to
hypoglycemia. With type I (von Gierke disease), there is deficiency of
glucose-6-phophatase, an enzyme required for the conversion of glucose-6-phophate in
the liver to glucose, which then is released into the circulation. Glucose-6-phosphate
accumulates within the hepatocytes, as does glycogen.
Type V (McArdle disease) is a myopathic form involving muscle phosporylase
deficiency; muscle phosphorylase breaks down glycogen, and the resultant glucose is
used in the glycolytic pathway. This is normally responsible for the breakdown of
muscle glycogen. Muscle cramps and myoglobinuria after exercise are typical features.
A type of glycogen storage disease that is considered a lysosomal storage disease is type
II (Pompe disease), in which acid maltase is lacking. Acid maltase breaks down
glycogen directly to glucose.
Other inborn errors of carbohydrate metabolism are summarized in Table 45-1.
Table 45-1
Table 45-1 (continued)
SELECTED LIST OF INBORN ERRORS OF METABOLISM
NAME OF DISEASE
ENZYME DEFICIENCY
CLINICAL SYNDROME
Alkaptonuria
Deficiency of homogentisate
Accumulation of
oxidase, which impairs
conversion of homogentisate
to maleylacetoacetate
homogentisate leads to
urine darkening on
standing and deposition
in cartilage, resulting in
joint damage
Deficiency of cystathionine
Mental retardation,
Homocysteinuria
synthetase; homocysteine is
converted to cystathionine
by cystathionine synthetase
Martfan-like habitus, and •
dislocation of lens
Maple syrup urine
Deficiency of branched-chain
Accumulation of the
disease
alpha-ketoacid dehydrogense
corresponding alphaketoacids, leading to
neurologic problems
Fanconi syndrome
Two types: congenital
Hypophosphatemic
(De Toni-Fanconi syndrome)
and acquired (e.g., due to
drugs, heavy metal poisoning)
Tubular reabsorption of amino
rickets and low
bicarbonate (with
resultant metabolic
acidosis)
SELECTED LIST OF INBORN ERRORS OF METABOLISM
NAME OF DISEASE
ENZYME DEFICIENCY
CLINICAL SYNDROME
Galactosemia
Galactose-I-phosphate
Mental retardation,
Uridyl transferase (interferes
with conversion of galactose
failure to thrive, cataract
acid, glucose, phosphate
Cysteinuria
to glucose)
Hereditary fructose
Deficiency of aldolase
intolerance
leading to accumulation of
fructose-I-phosphate,
Hartnup disease
which is toxic
Phenylketonuria
Deficiency of phenylalanine
hydroxylase
Neurologic features
Defective tubular reabsorption
Cysteine stones in
of cysteine, ornithine, arginine,
and lysine (COAL)
kidneys
Defective reabsorption of
Pellagra (if dietary niacin
tryptophan (because tryptophan
is converted to niacin, low
is insufficient)
niacin results)
C.
C. Liver cells
D. Lymph nodes
E. Skeletal muscle
Comprehension Questions
[45.1] A 71-year-old man presents with signs of anemia and is found to have an
enlarged liver and spleen along with peripheral pancytopenia. Sections from
bone marrow reveal numerous macrophages with a fibrillar appearance of the
cytoplasm that resembles wrinkled tissue paper. What enzyme deficiency does
this individual most likely have?
D. Acid maltase
E. Arylsulfatase A
F. Glucocerebrosidase
G. Homogentisate oxidase
H. Phophphorylase
[45.2] A 2-year-old girl of Ashkenazi Jewish descent is being evaluated for mental
retardation, seizures, and ataxia. Physical examination finds enlargement of
the liver, spleen, and several lymph nodes. A bone marrow biopsy reveals
aggregates oflipid-laden macrophages (foam cells). These cells contain
excessive amounts of sphingomyelin and cholesterol. Further workup finds a
deficiency of the enzyme sphingomyelinase. What is the best diagnosis?
A.
B.
C.
D.
E.
Fabry disease
Gaucher disease
Niemann-Pick disease
Sandhoff disease
Tay-Sachs disease
[45.3] A familial deficiency of glucose-6-phosphatase is most likely to be associated
with the abnormal accumulation of glycogen in which of the following
locations?
A. Basal ganglia
B. Cardiac muscle
[45.1] C. Gaucher disease is the most common lysosomal storage disorder.
This autosomal recessive disorder results from a deficiency of the enzyme
glucocerebrosidase. As a result, glucocerebroside accumulates in the cells of
the reticuloendothelial system, such as the bone marrow, liver, and spleen.
The most common type of Gaucher disease is the adult type, which has a high
incidence in the Ashkenazi Jewish population. In addition to
hepatosplenomegaly, features of the adult type of Gaucher disease include
hypersplenism and pathologic fractures.
[45.2]
C. Niemann-Pick disease is an autosomal recessive disorder that results from
a deficiency of the lysosomal enzyme sphingomyelinase. As a result,
sphingomyelin accumulates in the cytoplasm of macrophages in the liver,
spleen, bone marrow, and lymph nodes. These lipid-filled macrophages are
called foam cells. The most common type of Niemann-Pick disease is the
infantile type, which is characterized by mental retardation, seizures, ataxia,
and death by age 3.
[45.3]
C. The glycogen storage diseases result from hereditary deficiencies
involving any of the enzymes involved in the synthesis or degradation of
glycogen. Type I glycogen storage disease (von Gierke disease) results from
a deficiency of glucose-6-phosphatase, an enzyme that is necessary for the
conversion of glucose-6-phosphate to glucose in the liver. This deficiency
results in the accumulation of glycogen in the cytoplasm of hepatocytes.
Symptoms of this disorder result from recurrent severe fasting hypoglycemia
and include dizziness, sweating, and convulsions.