Genetic Disorders 2 Flashcards
Lysosomal Storage Diseases
Lysosomes are key components of the “intracellular digestive
tract.” They contain a battery of hydrolytic enzymes, which have
two special properties. First, they function in the acidic milieu of
the lysosomes. Second, these enzymes constitute a special
category of secretory proteins that are destined not for the
extracellular fluids but for intracellular organelles. This latter
characteristic requires special processing within the Golgi
apparatus
Similar to all other secretory proteins, lysosomal enzymes (or
acid hydrolases, as they are sometimes called) are synthesized
in the
ER
The phosphorylated mannose
residues serve as an
“address label” that is recognized by
specific receptors found on the inner surface of the Golgi
membrane.
n inherited deficiency of a
functional lysosomal enzyme gives rise to two pathologic consequences (
Catabolism of the substrate of the missing enzyme remains
incomplete, leading to the accumulation of the partially
degraded insoluble metabolite within the lysosomes.
Since lysosomal function is also essential for autophagy,
impaired autophagy
, leading to the accumulation of the partially
degraded insoluble metabolite within the lysosomes. This is
called
“primary accumulation”.
impaired autophagy gives rise to
“secondary accumulation” of
autophagic substrates such as polyubiquinated proteins and old
and effete mitochondria. The absence of this quality control
mechanism causes accumulation of dysfunctional mitochondria
with poor calcium buffering capacity and altered membrane
potentials. This can trigger generation of free radicals and
apoptosis.
Tay-Sachs Disease (GM2
Gangliosidosis:
Hexosaminidase α-Subunit Deficiency)
GM2 gangliosidoses are a group of three lysosomal storage
diseases caused by an inability to catabolize GM2 gan‐
gliosides. Degradation of GM2 gangliosides requires three
polypeptides encoded by three distinct genes
The phenotypic
effects of mutations affecting these genes are fairly similar,
because they result from accumulation of GM2 gangliosides. The
underlying enzyme defect, however, is different for each
the most common form of GM2 gangliosidosis,
results from mutations in the α-subunit locus on chromosome 15
that cause a severe deficiency of hexosaminidase A.
Tay Sachs
This disease
is especially prevalent among
Jews, particularly among those of
Eastern European (Ashkenazic) origin, in whom a carrier rate of
1 in 30 has been reported.
ganglioside
glycosphingolipid ith one or mote sialic acids on the sugar chain
Complex lipids in the brain
cell-cell recognition, adhesion, transductiom
degraded by ceramides and sequential removal of sugar units in oligosaccharide
The hexosaminidase A is absent from virtually all the
tissues, so GM2 ganglioside accumulates in many
tissues
heart, liver, spleen, nervous system), but
the involvement of neurons in the central and
autonomic nervous systems and retina dominates
the clinical picture
histologic examination
neurons are ballooned with cytoplasmic vacuoles,
each representing a markedly distended lysosome
filled with gangliosides (Fig. 5-11A). Stains for fat
such as oil red O and Sudan black B are positive. With
the electron microscope, several types of cytoplasmic
inclusions can be visualized, the most prominent
being whorled configurations within lysosomes
composed of onion-skin layers of membranes (Fig. 5-
11B).
A cherry-red spot thus appears in the
macula, representing accentuation of the normal
color of the macular choroid contrasted with the pallor
produced by the swollen ganglion cells in the
remainder of the retina (Chapter 29). This finding is
characteristic of Tay-Sachs disease and other storage
disorders affecting the neurons.
Clinical Features of TS
The affected infants appear normal at birth but begin to
manifest signs and symptoms at about age 6 months. There is
relentless motor and mental deterioration, beginning with motor
incoordination, mental obtundation leading to muscular
flaccidity, blindness, and increasing dementia.
cherry-red spot appears in the macula of the
eye in almost all patients. Over the span of 1 or 2 years a
complete vegetative state is reached, followed by death at age 2
to 3 years. More than 100 mutations have been described in the
α-subunit gene; most affect protein folding. Such misfolded
proteins trigger the “unfolded protein” response (Chapter 1)
leading to apoptosis
Niemann-Pick Disease Types A and B
Niemann-Pick disease types A and B are two related
disorders that are characterized by lysosomal
accumulation of sphingomyelin due to an inherited
deficiency of sphingomyelinase.
Type A
severe infantile
form with extensive neurologic involvement, marked visceral
accumulations of sphingomyelin, and progressive wasting and
early death within the first 3 years of life
Type B
disease patients have organomegaly but generally no central
nervous system involvement. They usually survive into
adulthood. As with Tay-Sachs disease, Niemann-Pick disease
types A and B are common in Ashkenazi Jews. The gene for acid
sphingomyelinase maps to chromosome 11p15.4 and is one of
the imprinted genes that is preferentially expressed from the
maternal chromosome as a result of epigenetic silencing of the
paternal gene
Although, this disease is
typically inherited as an autosomal recessive,
those
heterozygotes who inherit the mutant allele from the mother can
develop Nieman Pick Disease. More than 100 mutations have
been found in the acid sphingomyelinase gene and there seems
to be a correlation between the type of mutation, the severity of
enzyme deficiency, and the phenotype.
Morphology of NEIP
In the classic infantile type A variant, a missense
mutation causes almost complete deficiency of
sphingomyelinase. Sphingomyelin is a ubiquitous
component of cellular (including organellar)
membranes, and so the enzyme deficiency blocks
degradation of the lipid, resulting in its progressive
accumulation within lysosomes, particularly within
cells of the mononuclear phagocyte system. Affected
cells become enlarged, sometimes to 90 µm in
diameter, due to the distention of lysosomes with
sphingomyelin and cholesterol
Innumerable small
vacuoles of relatively uniform size are created
imparting foaminess to the cytoplasm
In frozen sections of fresh tissue
the vacuoles stain for
fat. Electron microscopy confirms that the vacuoles
are engorged secondary lysosomes that often contain
membranous cytoplasmic bodies resembling
concentric lamellated myelin figures, sometimes
called “zebra” bodies
The lipid-laden phagocytic foam cells are
widely
distributed in the spleen, liver, lymph nodes, bone
marrow, tonsils, gastrointestinal tract, and lungs. The
involvement of the spleen generally produces
massive enlargement, sometimes to ten times its
normal weight, but the hepatomegaly is usually not
quite so striking.
In the brain
the gyri are shrunken and the
sulci widened. The neuronal involvement is diffuse,
affecting all parts of the nervous system. Vacuolation
and ballooning of neurons constitute the dominant
histologic change, which in time leads to cell death
and loss of brain substance. A retinal cherry-red
spot similar to that seen in Tay-Sachs disease is
present in about one third to one half of affected
individuals.
Clinical manifestations in type A disease
may be present at
birth and almost invariably become evident by age 6 months.
Infants typically have a protuberant abdomen because of the
hepatosplenomegaly. Once the manifestations appear, they are
followed by progressive failure to thrive, vomiting, fever, and
generalized lymphadenopathy as well as progressive
deterioration of psychomotor function. Death comes, usually
within the first or second year of life
Niemann-Pick Disease Type C
Although previously considered to be related to types A and B,
Niemann-Pick disease type C (NPC) is distinct at the
biochemical and genetic levels and is more common than types
A and B combined. Mutations in two related genes, NPC1 and
NPC2, can give rise to NPC,
NPC1
being responsible for
95% of cases. Unlike most other storage diseases, NPC is due to
a primary defect in nonenzymatic lipid transport. NPC1 is
membrane bound whereas NPC2 is soluble. Both are involved in
the transport of free cholesterol from the lysosomes to the
cytoplasm. NPC is clinically heterogeneous
It may present as (NPC}
hydrops fetalis and stillbirth, as neonatal hepatitis, or, most
commonly, as a chronic form characterized by progressive
neurologic damage. The latter presents in childhood and is
marked by ataxia, vertical supranuclear gaze palsy, dystonia,
dysarthria, and psychomotor regression.
Gaucher Disease
Gaucher disease refers to a cluster of autosomal recessive
disorders resulting from mutations in the gene encoding
glucocerebrosidase. It is the most common lysosomal storage
disorder
The affected gene encodes glucocerebrosidase
an enzyme that normally cleaves the glucose residue from
ceramide. As a result of the enzyme defect, glucocerebroside
accumulates principally in phagocytes but in some subtypes also
in the central nervous system
Glucocerebrosides are continually
formed from the catabolism of glycolipids
derived mainly from
the cell membranes of senescent leukocytes and red cells
pathologic changes in Gaucher disease are
caused not just by the burden of storage material but also by
activation of macrophages and the consequent secretion of
cytokines such as IL-1, IL-6, and tumor necrosis factor (TNF)
type I GD
r the chronic nonneuronopathic form. In this type, storage of
glucocerebrosides is limited to the mononuclear phagocytes
throughout the body without involving the brain. Splenic and
skeletal involvements dominate this pattern of the disease. It is
found principally in Jews of European stock. Individuals with
this disorder have reduced but detectable levels of
glucocerebrosidase activity. Longevity is shortened but not
markedly.
Type II GD
acute neuronopathic Gaucher disease, is the
infantile acute cerebral pattern. This form has no predilection
for Jews. In these patients there is virtually no detectable
glucocerebrosidase activity in the tissues. Hepatosplenomegaly
is also seen in this form of Gaucher disease, but the clinical
picture is dominated by progressive central nervous system
involvement, leading to death at an early age
type III GD
intermediate between types I and II.
These patients have the systemic involvement characteristic of
type I but have progressive central nervous system disease that
usually begins in adolescence or early adulthood
Morphology of GD
distended phagocytic cells, known as Gaucher cells, are found in the
spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer patches. Similar cells may be found in both the alveolar septa and the air spaces in
the lung.
n contrast to other lipid storage diseases
Gaucher cells rarely appear vacuolated but instead
have a fibrillary type of cytoplasm likened to crumpled
tissue paper (Fig. 5-13). Gaucher cells are often
enlarged, sometimes up to 100 µm in diameter, and
have one or more dark, eccentrically placed nuclei.
Periodic acid–Schiff staining is usually intensely
positive. With the electron microscope the fibrillary
cytoplasm can be resolved as elongated,
distended lysosomes, containing the stored lipid in
stacks of bilayers.
In type I disease, the spleen is enlarged
sometimes up to 10 kg. The lymphadenopathy is
mild to moderate and is body-wide. The accumulation
of Gaucher cells in the bone marrow occurs in 70% to
100% of cases of type I Gaucher disease. It produces
areas of bone erosion
Bone destruction occurs due to
he secretion of cytokines by activated macrophages.
In patients with cerebral involvement, Gaucher cells
are seen in the Virchow-Robin spaces, and arterioles
are surrounded by swollen adventitial cells. There is
no storage of lipids in the neurons, yet neurons appear
shriveled and are progressively destroyed. It is
suspected that the lipids that accumulate in the
phagocytic cells around blood vessels secrete
cytokines that damage nearby neurons
Clinical Features of GD
In type I, symptoms and signs first appear in adult life
and are related to splenomegaly or bone involvement. Most
commonly there is pancytopenia or thrombocytopenia secondary
to hypersplenism. Pathologic fractures and bone pain occur if
there has been extensive expansion of the marrow space.
Although the disease is progressive in the adult, it is compatible
with long life
In types II and III, central nervous system
dysfunction, convulsions, and progressive mental deterioration
dominate, although organs such as the liver, spleen, and lymph
nodes are also affected. The diagnosis of homozygotes can be
made by measurement of glucocerebrosidase activity in
peripheral blood leukocytes or in extracts of cultured skin
fibroblast
Mucopolysaccharidoses (MPS)
The MPSs are a group of closely related syndromes that
result from genetically determined deficiencies of enzymes
involved in the degradation of mucopolysaccharides
(glycosaminoglycans)
Chemically, mucopolysaccharides are
long-chain complex carbohydrates that are linked with proteins
to form proteoglycans. They are abundant in the ground
substance of connective tissue. The glycosaminoglycans that
accumulate in MPSs are dermatan sulfate, heparan sulfate,
keratan sulfate, and chondroitin sulfate.
Several clinical variants of MPS, classified numerically
MPS I to MPS VII, have been described, each resulting from the
deficiency of one specific enzyme.
All the MPSs except one are
inherited as autosomal recessive traits
the exception, Hunter
syndrome, is an X-linked recessive trait. Within a given group
(e.g., MPS I, characterized by a deficiency of α-l-iduronidase),
subgroups exist that result from different mutant alleles at the
same genetic locus
Morphology of MPS
The accumulated mucopolysaccharides are
generally found in mononuclear phagocytic cells,
endothelial cells, intimal smooth muscle cells,
and fibroblasts throughout the body. Common sites
of involvement are thus the spleen, liver, bone
marrow, lymph nodes, blood vessels, and heart.
Microscopically, affected cells are MPS
distended and
have apparent clearing of the cytoplasm to create so-called balloon cells. Under the electron microscope,
the clear cytoplasm can be resolved as numerous
minute vacuoles. These are swollen lysosomes
containing a finely granular periodic acid–Schiff–
positive material that can be identified biochemically
as mucopolysaccharide.
Similar lysosomal changes are
found in the neurons of those syndromes
characterized by central nervous system involvement.
however, some of the lysosomes in
neurons are replaced by lamellated zebra bodies
similar to those seen in Niemann-Pick disease.
common threads that
run through all of the MPSs
Hepatosplenomegaly, skeletal deformities,
valvular lesions, and subendothelial arterial
deposits, particularly in the coronary arteries,
and lesions in the brain
In many of the more
protracted syndromes, coronary subendothelial
lesions lead to myocardial ischemia. Thus, myocardial
infarction and cardiac decompensation are important
causes of death.
Hurler syndrome, also
called MPS I-H,
Results from a deficiency of α-l-iduronidase. It is
one of the most severe forms of MPS. Affected children appear
normal at birth but develop hepatosplenomegaly by age 6 to 24
months. Their growth is retarded, and, as in other forms of MPS,
they develop coarse facial features and skeletal deformities.
Death occurs by age 6 to 10 years and is often due to
cardiovascular complications.
Hunter syndrome,
also called MPS
II, differs from Hurler syndrome in mode of inheritance (Xlinked), absence of corneal clouding, and milder clinical course.
Glycogen Storage Diseases (Glycogenoses)
he glycogen storage diseases result from a hereditary
deficiency of one of the enzymes involved in the synthesis
or sequential degradation of glycogen. Depending on the
tissue or organ distribution of the specific enzyme in the normal
state, glycogen storage in these disorders may be limited to a
few tissues, may be more widespread while not affecting all
tissues, or may be systemic in distribution.
A phosphoglucomutase then transforms the glucose-6-phosphate
to glucose-1-phosphate, which, in turn, is converted
uridine diphosphoglucose. A highly branched, large polymer is then built
(molecular weight as high as 100 million), containing as many as
10,000 glucose molecules linked together by α-1,4-glucoside
bonds. The glycogen chain and branches continue to be
elongated by the addition of glucose molecules mediated by
glycogen synthetases.
Hepatic forms
The liver is a key player in glycogen
metabolism. It contains enzymes that synthesize glycogen for
storage and ultimately break it down into free glucose, which is
then released into the blood. An inherited deficiency of hepatic
enzymes that are involved in glycogen degradation therefore
leads not only to the storage of glycogen in the liver but also to
a reduction in blood glucose concentrations (hypoglycemia)
Deficiency of the enzyme glucose-6-phosphatase
(von Gierke disease, or type I glycogenosis) is a prime example
of the hepatic-hypoglycemic form of glycogen storage disease
Other examples include deficiencies of liver
phosphorylase and debranching enzyme, both involved in the
breakdown of glycogen (Fig. 5-15). In all these disorders
glycogen is stored in many organs, but
hepatic enlargement
and hypoglycemia dominate the clinical picture
Myopathic forms
In the skeletal muscles, as opposed to the
liver, glycogen is used predominantly as a source of energy
during physical activity. ATP is generated by glycolysis, which
leads ultimately to the formation of lactate
If the
enzymes that fuel the glycolytic pathway are deficient
glycogen
storage occurs in the muscles and is associated with muscular
weakness due to impaired energy production.
McArdle disease
type V glycogenosis
Muscle
phosphofructokinase
(type VII glycogen storage disease)
individuals with the myopathic forms
present with
muscle cramps after exercise and lactate levels in
the blood fail to rise after exercise due to a block in glycolysis.
Glycogen storage diseases associated with (1) deficiency of αglucosidase (acid maltase) and (2) lack of branching enzyme
Glycogen storage diseases associated with (1) deficiency of αglucosidase (acid maltase) and (2) lack of branching enzyme
Disorders Associated with Defects in
Proteins That Regulate Cell Growth
Normal growth and differentiation of cells are regulated by two
classes of genes; proto-oncogenes and tumor suppressor genes,
whose products promote or restrain cell growth (Chapter 7). It is
now well established that mutations in these two classes of
genes are important in the pathogenesis of tumors. In the vast
majority of cases, cancer-causing mutations
In approximately 5%
of all cancers,
however, mutations transmitted through the germ
line contribute to the development of cancer. Most familial
cancers are inherited in an autosomal dominant fashion, but a
few recessive disorders have also been described. This subject is
discussed in Chapter 7.
Complex Multigenic Disorders
such disorders are caused by
interactions between variant forms of genes and environmental
factors. A gene that has at least two alleles, each of which
occurs at a frequency of at least 1% in the population, is
polymorphic, and each variant allele is referred to as a
polymorphism. According to the common disease/common
variant hypothesis, complex genetic disorders occur when many
polymorphisms, each with a modest effect and low penetrance,
are co-inherited.
Two additional facts that have emerged from
studies of common complex disorders, such as
type 1 diabetes,
are:
• While complex disorders result from the collective inheritance
of many polymorphisms, different polymorphisms vary in
significance.
