Genetic Disorders Flashcards
1
Q
The lifetime frequency of genetic diseases is
A
670 per 1000
2
Q
It is estimated
that 50% of spontaneous abortuses during the early months of
gestation have a
A
a demonstrable chromosomal abnormality; there
are, in addition, numerous smaller detectable errors and many
other genetic lesions that are only now coming into view thanks
to advances in DNA sequencing
3
Q
About ________of all newborn infants
possess a gross chromosomal abnormality and serious disease
with a significant genetic component develops in approximately
__________of individuals younger than age 25 years.
A
1%; 5%
4
Q
Disorders related to mutations in single genes with large
effects.
A
These mutations cause the disease or predispose to the
disease and with some exceptions, like hemoglobinopathies, are
typically not present in the normal population. Such mutations and
their associated disorders are highly penetrant, meaning that
the presence of the mutation is associated with the disease in a large proportion of individuals.
5
Q
these diseases are
caused by single-gene mutations, they usually follow the
A
The mendelian pattern of inheritance and are also referred to as Mendelian disorders
6
Q
Chromosomal disorders
A
These arise from structural or
numerical alteration in the autosomes and sex chromosomes.
Like monogenic disease they are uncommon but associated
with high penetrance.
7
Q
Complex multigenic disorders
A
hey are caused
by interactions between multiple variant forms of genes and
environmental factors. Such variations in genes are common
within the population and are also called polymorphisms
8
Q
no single susceptibility gene is necessary or sufficient to
produce the disease. It is only when several such
polymorphisms are present in an individual that disease occurs,
hence the term
A
Multigenic or polygenic
9
Q
Thus, unlike mutant
genes with large effects that are highly penetrant and give rise
to Mendelian disorders
A
each polymorphism has a small effect
and is of low penetrance
10
Q
multifactorial disorders
A
In this category are some of the
most common diseases that afflict humans, including atherosclerosis, diabetes mellitus, hypertension, and
autoimmune diseases. Even normal traits such as height and weight are governed by polymorphisms in several genes
11
Q
Mutations
A
A mutation is defined as a permanent change in the DNA. Mutations that affect germ cells are transmitted to the
progeny and can give rise to inherited diseases.
12
Q
Point mutations within coding sequences
A
A point mutation
is a change in which a single base is substituted with a different
base. It may alter the code in a triplet of bases and lead to the
replacement of one amino acid by another in the gene product.
13
Q
missense mutations
A
these mutations alter the meaning of the sequence of
the encoded protein
14
Q
If the substituted amino acid is biochemically similar to the
original, typically it causes little change in the function of the
protein and the mutation is called a
A
conservative
15
Q
nonconservative
A
mutation replaces the normal amino acid with a biochemically
different one
An excellent example of this type is the sickle
mutation affecting the β-globin chain of hemoglobin (Chapter
14). Here the nucleotide triplet CTC (or GAG in mRNA), which
encodes glutamic acid, is changed to CAC (or GUG in mRNA),
which encodes valine. This single amino acid substitution alters
the physicochemical properties of hemoglobin, giving rise to
sickle cell anemia
16
Q
point mutation
A
change an amino acid codon
to a chain terminator, or stop codon (nonsense mutation).
Taking again the example of β-globin, a point mutation affecting
the codon for glutamine (CAG) creates a stop codon (UAG) if U
is substituted for C (Fig. 5-1). This change leads to premature
termination of β-globin gene translation, and the short peptide
that is produced is rapidly degraded. The resulting deficiency of
β-globin chains can give rise to a severe form of anemia called
β -thalassemia
17
Q
mutations within noncoding sequences.
A
Deleterious effects
may also result from mutations that do not involve the exons.
Recall that transcription of DNA is initiated and regulated by
promoter and enhancer sequences
18
Q
Point mutations
or deletions involving these regulatory sequences may interfere
with binding
A
of transcription factors and thus lead to a marked reduction in or total lack of transcription.]
Such is the case in
certain forms of hereditary anemias called thalassemias
19
Q
point mutations within introns may
lead to
A
defective splicing of intervening sequences. This, in
turn, interferes with normal processing of the initial mRNA
transcripts and results in a failure to form mature mRNA.
Therefore, translation cannot take place, and the gene product
is not synthesized.
20
Q
Deletions and insertion
A
Small deletions or insertions
involving the coding sequence can have two possible effects on
the encoded protein.
21
Q
If the number of base pairs involved is
three or a multiple of three,
A
the reading frame will remain
intact, and an abnormal protein lacking or gaining one or more
amino acids will be synthesized (Fig. 5-2). If the number of
affected coding bases is not a multiple of three, this will result
in an alteration of the reading frame of the DNA strand,
producing what is referred to as a frameshift mutation
Single-base deletion at the ABO (glycosyltransferase)
locus, leading to a frameshift mutation responsible for the O allele
22
Q
Cystic Fibrosis is not frame shift, why?
A
: 3 base deletion causes formation of a protein that lacks 508 aa (phenylalanine) this is not a Frameshift mutation
23
Q
Four-base insertion
A
in the hexosaminidase A gene,
leading to a frameshift mutation. This mutation is the major cause
of Tay-Sachs disease in Ashkenazi Jews
24
Q
Trinucleotide-repeat mutations
A
Trinucleotide-repeat
mutations belong to a special category of genetic anomaly.
These mutations are characterized by the amplification of a
sequence of three nucleotides.
25
fragile X
| syndrome
prototypical of this category of disorders, there are
250 to 4000 tandem repeats of the sequence CGG within a gene
called familial mental retardation 1 (FMR1). In normal
populations the number of repeats is small, averaging 29. Such
expansions of the trinucleotide sequences prevent normal
expression of the FMR1 gene, thus giving rise to mental
retardation
26
the distinguishing feature of trinucleotide-repeat mutations
is that they are dynamic (i.e., the degree of amplification increases during gametogenesis). These features,
discussed in greater detail later, influence the pattern of
inheritance and the phenotypic manifestations of the diseases
caused by this class of mutation.
27
three major categories of genetic disorders
```
(1) disorders related
to mutant genes of large effect,
(2) diseases with multifactorial
inheritance
(3) chromosomal disorders
```
28
To these three well-known categories must be added a heterogeneous group of
Single-gene disorders with nonclassic patterns of inheritance.
This group includes disorders resulting from triplet-repeat
mutations, those arising from mutations in mitochondrial DNA
(mtDNA), and those in which the transmission is influenced by
genomic imprinting or gonadal mosaicism.
They don't follow Mendelian inheritance
29
Hereditary disorders
by definition, are
derived from one's parents and are transmitted in the germ line
through the generations and therefore are familial
30
congenital
simply implies “born with.”
31
Some congenital diseases
| are not genetic;
for example, congenital syphilis. Not all genetic diseases are congenital; individuals with Huntington disease, for
example, begin to manifest their condition only after their 20s or 30s.
32
Mendelian Disorders
Virtually all Mendelian disorders are the result of mutations in
single genes that have large effects
33
it is estimated that every individual is a carrier of ________
deleterious genes
five to eight a number originally estimated from studies of
populations that appear to be borne out by genomic sequencing
of normal individuals.
34
Most of these are recessive and therefore
| do not have serious phenotypic effects.
About 80% to 85% of
these mutations are familial. The remainder represents new
mutations acquired de novo by an affected individual.
35
Some autosomal mutations produce partial expression in the
heterozygote and full expression in the homozygotes
36
This is referred to as the
sickle cell trait to differentiate it from full-blown sickle cell
anemia
Sickle cell anemia is caused by the substitution of normal hemoglobin (HbA) by hemoglobin S (HbS). When an individual is homozygous for the
mutant gene, all the hemoglobin is of the abnormal, HbS, type, and even with normal saturation of oxygen the disorder is fully expressed (i.e., sickling deformity of all red cells and hemolytic
anemia). In the heterozygote, only a proportion of the
hemoglobin is HbS (the remainder being HbA), and therefore
red cell sickling occurs only under unusual circumstances, such
as exposure to lowered oxygen tension
37
in some cases both of the alleles of a gene pair
| contribute to the phenotype
codominance.
Histocompatibility and blood group antigens are good examples
of codominant inheritance.
38
A single mutant gene may lead to many end effects, termed
pleiotropism; conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity)
Sickle cell
anemia is an example of pleiotropism.
39
mom, blood type OO, father also O can A be produced?
yES
40
In this hereditary disorder
not only does the point mutation in the gene give rise to HbS,
which predisposes the red cells to hemolysis, but also the
abnormal red cells tend to cause a logjam in small vessels,
inducing
splenic fibrosis, organ infarcts, and bone
changes. The numerous differing end-organ derangements are
all related to the primary defect in hemoglobin synthesis.
41
profound childhood deafness
an apparently
the homogeneous clinical entity results from many different types of
autosomal recessive mutations
42
Transmission Patterns of Single-Gene
| Disorders
Mutations involving single genes typically follow one of
three patterns of inheritance: autosomal dominant,
autosomal recessive, and X-linked
43
Autosomal Dominant Disorders
Autosomal dominant disorders are manifested in the
heterozygous state, so at least one parent of an index case
is usually affected; both males and females are affected, and
both can transmit the condition. When an affected person
marries an unaffected one, every child has one chance in two of
having the disease.
44
Many new mutations seem to occur in
| germ cells of
relatively older fathers
45
Clinical features can be modified by variations in penetrance
and expressivity
Some individuals inherit the mutant gene but
are phenotypically normal. This is referred to as incomplete
penetrance.
46
Penetrance
is expressed in mathematical terms.
Thus, 50% penetrance indicates that 50% of those who carry
the gene express the trait
47
In contrast to penetrance, if a trait is
seen in all individuals carrying the mutant gene but is
expressed differently among individuals
the phenomenon is
called variable expressivity. For example, manifestations of
neurofibromatosis type 1 range from brownish spots on the skin
to multiple skin tumors and skeletal deformities.
48
the phenotype of a patient with sickle cell anemia
(resulting from mutation at the β-globin locus) is influenced by
the genotype at the α-globin locus,
because the latter
| influences the total amount of hemoglobin made
49
autosomal dominant
disorders depend upon the nature of the mutation and the
type of protein affected
The biochemical mechanism
50
Many autosomal
dominant diseases arising from deleterious mutations fall into
one of a few familiar patterns
1. Those involved in regulation of complex metabolic pathways
that are subject to feedback inhibition.
2. Key structural proteins, such as collagen and cytoskeletal
elements of the red cell membrane (e.g., spectrin)
Less common than loss-of-function mutations are gain-of-function mutations
51
Those involved in regulation of complex metabolic pathways
| that are subject to feedback inhibition.
Membrane receptors
such as the low-density lipoprotein (LDL) receptor provide one
such example; in familial hypercholesterolemia, discussed later,
a 50% loss of LDL receptors results in a secondary elevation of
cholesterol that, in turn, predisposes to atherosclerosis in
affected heterozygotes
52
Key structural proteins, such as collagen and cytoskeletal
| elements of the red cell membrane (e.g., spectrin).
The
biochemical mechanisms by which a 50% reduction in the
amounts of such proteins results in an abnormal phenotype are
not fully understood. In some cases, especially when the gene
encodes one subunit of a multimeric protein, the product of the
the mutant allele can interfere with the assembly of a functionally
normal multimer
53
Even with a single mutant collagen chain, normal
collagen trimers cannot be formed, and hence there is a marked
deficiency of collagen. In this instance, the mutant allele is called
dominant-negative, because it impairs the function of a normal
allele. This effect is illustrated by some forms of osteogenesis
imperfecta, characterized by a marked deficiency of collagen and
severe skeletal abnormalities
54
gain-offunction mutations, which can take two forms
Some mutations
result in an increase in a protein’s normal function, for example,
excessive enzymatic activity. In other cases, mutations impart a
wholly new activity completely unrelated to the affected
protein’s normal function. The transmission of disorders
produced by gain-of-function mutations is almost always
autosomal dominant, as illustrated by Huntington disease
55
Nervous system dominant dominant
Huntingtins
neurofibromatosis
myotonic dystrophy
tuberous sclerosis
56
Urinary DominanT dominant
PCKD
57
Gastrointestinal dominanat
Familial polyposis coli
58
Hematopoetic Dominant
Heriditary spherocytosis
| vwf disease
59
Skeletal Dominant
Marfan
Ehlers-dahnlos
Osteogenesis imperfecta
achondroplasia
60
Metabolism Dominant
Falina; hypercholesterolemia
| Acute intermittent porphyria
61
Autosomal Recessive Disorders
Autosomal recessive traits make up the largest category of
Mendelian disorders. They occur when both alleles at a
given gene locus are mutated. These disorders are
characterized by the following features:
(1) The trait does not usually affect the parents of the affected individual, but siblings may show the disease;
(2) siblings have one chance in four of
having the trait (i.e., the recurrence risk is 25% for each birth);
(3) if the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected
individual (proband) is the product of a consanguineous marriage.
62
features generally apply to most
autosomal recessive disorders and distinguish them from
autosomal dominant diseases
• The expression of the defect tends to be more uniform than in
autosomal dominant disorders.
* Complete penetrance is common.
* Onset is frequently early in life.
• Although new mutations associated with recessive disorders do
occur, they are rarely detected clinically. Since the individual
with a new mutation is an asymptomatic heterozygote, several
generations may pass before the descendants of such a person
mate with other heterozygotes and produce affected offspring.
• Many of the mutated genes encode enzymes. In heterozygotes,
equal amounts of normal and defective enzyme are synthesized.
Usually the natural “margin of safety” ensures that cells with
half the usual complement of the enzyme function normally.
63
Autosomal Recessive Disorders examples
Metab: CF, PKU, Galactosemia, Homocystenuria, Lysosomal stroagre disease, a1 antitrypsin, Wilsons, hemochromatosis, Glycogen storage
Hematopetic: SCA, Thalsemmia
Endocrine- Congenital adrenal hyperplasia
Skeletal- Ehlers dahnos syndrome, Alkaptonuria
Nervous- Neurogenic musciular atrophy
Freidrich ataxia, SMA
64
X-Linked Disorders
All sex-linked disorders are X-linked, and almost all are
recessive. Several genes are located in the “male-specific
region of Y”; all of these are related to spermatogenesis. Males
with mutations affecting the Y-linked genes are usually infertile,
and hence there is no Y-linked inheritance
65
X-linked recessive inheritance
accounts for a small number of
well-defined clinical conditions. The Y chromosome, for the most
part, is not homologous to the X, and so mutant genes on the X
do not have corresponding alleles on the Y. Thus, the male is
said to be hemizygous for X-linked mutant genes, so these
disorders are expressed in the male
66
An illustrative condition is glucose-6-phosphate dehydrogenase
(G6PD) deficiency.
Transmitted on the X chromosome, this
enzyme deficiency, which predisposes to red cell hemolysis in
patients receiving certain types of drugs (Chapter 14), is
expressed principally in males. In the female, a proportion of
the red cells may be derived from precursors with inactivation
of the normal allele. Such red cells are at the same risk for
undergoing hemolysis as are the red cells in the hemizygous
male. Thus, the female is not only a carrier of this trait but also
is susceptible to drug-induced hemolytic reactions
67
X linked Recessive MSCK
DMD
68
Blood
HEmophilia A, B, CGD, G6PD
69
Immune
Agammaglobulinema, Wisclott-aldrich
70
Metabloic
Diabetes insipidus, Lesh-nacyh
71
Nervous
Fragile X
72
X-linked dominant conditions
They are
caused by dominant disease-associated alleles on the X
chromosome. These disorders are transmitted by an affected
heterozygous female to half her sons and half her daughters and
by an affected male parent to all his daughters but none of his
sons, if the female parent is unaffected. Vitamin D–resistant
rickets is an example of this type of inheritance
73
Biochemical and Molecular Basis of
| Single-Gene (Mendelian) Disorders
Mendelian disorders result from alterations involving
single genes. The genetic defect may lead to the formation
of an abnormal protein or a reduction in the output of the
gene product
74
For this
discussion, the mechanisms involved in single-gene disorders
can be classified into four categories
(1) enzyme defects and
their consequences; (2) defects in membrane receptors and
transport systems; (3) alterations in the structure, function, or
quantity of nonenzyme proteins; and (4) mutations resulting in
unusual reactions to drugs
75
Mutations may result in the synthesis of an enzyme with
| reduced activity or a reduced amount of a normal enzyme
In either case, the consequence is a metabolic block. Figure 5-5
provides an example of an enzyme reaction in which the
substrate is converted by intracellular enzymes, denoted as 1, 2,
and 3, into an end product through intermediates 1 and 2. In
this model the final product exerts feedback control on enzyme
1. A minor pathway producing small quantities of M1 and M2
also exists
76
Accumulation of the substrate
depending on the site of block,
may be accompanied by accumulation of one or both
intermediates. Moreover, an increased concentration of
intermediate 2 may stimulate the minor pathway and thus lead
to an excess of M1 and M2. Under these conditions tissue
injury may result if the precursor, the intermediates, or the
products of alternative minor pathways are toxic in high
concentrations. For example, in galactosemia,
77
Excessive accumulation of complex substrates within the
| lysosomes as a result of deficiency of degradative enzymes
responsible for a group of diseases generally referred to as
| lysosomal storage diseases
78
An enzyme defect can lead to a metabolic block and a
decreased amount of end product that may be necessary for
normal function
For example, a deficiency of melanin may
result from lack of tyrosinase, which is necessary for the
biosynthesis of melanin from its precursor, tyrosine, resulting in
the clinical condition called albinism
79
Lesch-Nyhan syndrome
the deficiency of the end product may permit
overproduction of intermediates and their catabolic products,
some of which may be injurious at high concentrations
80
Failure to inactivate a tissue-damaging substrate
est
exemplified by α1
-antitrypsin deficiency. Individuals who have
an inherited deficiency of serum α1
-antitrypsin are unable to
inactivate neutrophil elastase in their lungs. Unchecked activity
of this protease leads to destruction of elastin in the walls of
lung alveoli, leading eventually to pulmonary emphysema
81
Defects in Receptors and Transport Systems
A genetic defect in a receptor-mediated transport system is exemplified by familial hypercholesterolemia, in which
reduced synthesis or function of LDL receptors leads to defective transport of LDL into the cells and secondarily to excessive cholesterol synthesis by complex intermediary mechanisms
82
In cystic fibrosis the transport system for chloride
ions in exocrine glands, sweat ducts, lungs, and pancreas is
defective.
By mechanisms not fully understood, impaired
chloride transport leads to serious injury to the lungs and
pancreas
83
Alterations in Structure, Function, or Quantity of
| Nonenzyme Proteins
Genetic defects resulting in alterations of nonenzyme proteins
often have widespread secondary effects, as exemplified by
sickle cell disease. The hemoglobinopathies, sickle cell disease
being one, all of which are characterized by defects in the
structure of the globin molecule, best exemplify this category
Osteogeneis imperfecta, Heridatry spherocytosis, Muscular dystrophies
84
Genetically Determined Adverse Reactions to Drugs
Certain genetically determined enzyme deficiencies are
unmasked only after exposure of the affected individual to
certain drugs.
85
The classic example of drug-induced injury in the genetically susceptible individual is associated with a deficiency of the enzyme G6PD
Under normal conditions glucose-6 phosphatedehydrogenase (G6PD) deficiency does not result in disease, but
on administration, for example, of the antimalarial drug
primaquine, a severe hemolytic anemia results
86
Marfan Syndrome
Marfan syndrome is a disorder of connective tissues, manifested principally by changes in the skeleton, eyes,
and cardiovascular system.
Its prevalence is estimated to be 1
in 5000.
Approximately 70% to 85% of cases are familial and transmitted by autosomal dominant inheritance.
The remainder
are sporadic and arise from new mutations
87
Pathogenesis.
| Marfan syndrome
results from an inherited defect in an
extracellular glycoprotein called fibrillin-1. There are two
fundamental mechanisms by which loss of fibrillin leads to the
clinical manifestations of Marfan syndrome: loss of structural
support in microfibril rich connective tissue and excessive
activation of TGF-β signaling
88
Fibrillin is the major component of microfibrils found in the
extracellular matrix (Chapter 1). These fibrils provide a
scaffolding on which tropoelastin is deposited to form elastic
fibers. Although microfibrils are widely distributed in the body,
they are particularly abundant in the aorta, ligaments, and the
ciliary zonules that support the lens; these tissues are
prominently affected in Marfan syndrome
Fibrillin occurs in
two homologous forms, fibrillin-1 and fibrillin-2, encoded by two
separate genes, FBN1 and FBN2, mapped on chromosomes
15q21.1 and 5q23.31, respectively. Mutations of FBN1 underlie
Marfan syndrome
89
congenital contractural
| arachnodactyly
an autosomal dominant disorder characterized
by skeletal abnormalities. Mutational analysis has revealed
more than 600 distinct mutations of the FBN1 gene in
individuals with Marfan syndrome. Most of these are missense
mutations that give rise to abnormal fibrillin-1. These can
inhibit the polymerization of fibrillin fibers (dominant-negative
effect). Alternatively, the reduction of fibrillin content below a
certain threshold weakens the connective tissue (haploinsufficiency).
90
clinical manifestations of Marfan syndrome can be
| explained by
changes in the mechanical properties of the
extracellular matrix resulting from abnormalities of fibrillin,
several others such as bone overgrowth and myxoid changes in
mitral valves cannot be attributed to changes in tissue
elasticity. Recent studies indicate that loss of microfibrils gives
rise to abnormal and excessive activation of transforming
growth factor-β (TGF-β), since normal microfibrils sequester
TGF-β and thus control the bioavailability of this cytokine.
91
Excessive TGF-β signaling has deleterious effects on vascular
smooth muscle development and it also increases the activity of
metalloproteases, causing loss of extracellular matrix. This
schema is supported by two sets of observations. First, in a
small number of individuals with clinical features of Marfan
syndrome (MFS2), there are no mutations in FBN1 but instead
gain-of-function mutations in genes that encode TGF-β
receptors. Second, in mouse models of Marfan syndrome
generated by mutations in Fbn1, administration of antibodies to
TGF-β prevents alterations in the aorta and mitral valves
92
Skeletal abnormalities are the most striking
| feature of Marfan syndrome.
most striking
feature of Marfan syndrome. Typically the patient
is unusually tall with exceptionally long extremities
and long, tapering fingers and toes. The joint
ligaments in the hands and feet are lax, suggesting
that the patient is double-jointed; typically the thumb
can be hyperextended back to the wrist. The head is
commonly dolichocephalic (long-headed) with bossing
of the frontal eminences and prominent supraorbital
ridges. A variety of spinal deformities may appear,
including kyphosis, scoliosis, or rotation or slipping of
the dorsal or lumbar vertebrae. The chest is classically
deformed, presenting either pectus excavatum (deeply
depressed sternum) or a pigeon-breast deformity.
93
ocular changes
Most
characteristic is bilateral subluxation or dislocation
(usually outward and upward) of the lens, referred to
as ectopia lentis. This abnormality is so uncommon in
persons who do not have this disease that the finding
of bilateral ectopia lentis should raise the suspicion of
Marfan syndrome
94
Cardiovascular lesions
are the most life-threatening features of this disorder. The two most
common lesions are mitral valve prolapse and, of greater importance, dilation of the ascending aorta due to cystic medionecrosis. Histologically the
changes in the media are virtually identical to those found in cystic medionecrosis not related to Marfan
syndrome
95
Loss of medial support results
in progressive dilation of the aortic valve ring and the
root of the aorta, giving rise to severe aortic
incompetence. In addition, excessive TGF-β signaling
in the adventitia may also contribute to aortic dilation.
Weakening of the media predisposes to an intimal tear,
which may initiate an intramural hematoma that
cleaves the layers of the media to produce
aortic
dissection. After cleaving the aortic layers for
considerable distances, sometimes back to the root of
the aorta or down to the iliac arteries, the hemorrhage
often ruptures through the aortic wall. Such a
calamity is the cause of death in 30% to 45% of these
individuals.
96
The clinical
| diagnosis of Marfan syndrome is currently based on
“revised Ghent criteria.” These take into account family history,
cardinal clinical signs in the absence of family history, and
presence or absence of fibrillin mutation. In general, major
involvement of two of the four organ systems (skeletal,
cardiovascular, ocular, and skin) and minor involvement of
another organ is required for diagnosis
97
The mainstay of the medical treatment is Marfan
administration of β
blockers which likely act by reducing heart rate and aortic wall
stress. In animal models inhibition of TGF-β action by use of
specific antibodies has been found useful. Since lifelong use of
such antibodies in humans is not feasible, other strategies to
block TGF-β signaling are being tested. Blockade of angiotensin
type 2 receptors accomplishes this effect in humans and several
preliminary studies are very promising
98
Ehlers-Danlos Syndromes (EDS
EDSs comprise a clinically and genetically heterogeneous
group of disorders that result from some defect in the
synthesis or structure of fibrillar collagen. Other disorders
resulting from mutations affecting collagen synthesis include
osteogenesis imperfecta (Chapter 26), Alport syndrome (Chapter
20), and epidermolysis bullosa
99
EDS cladssification
study table
100
As might be expected, tissues rich in collagen, such as
| skin, ligaments, and joints, are frequently involved in
variants of EDS. Because the abnormal collagen fibers lack
adequate tensile strength, skin is hyperextensible, and the joints
are hypermobile. These features permit grotesque contortions,
such as bending the thumb backward to touch the forearm and
bending the knee forward to create almost a right angle.
101
Perhaps the best characterized is the
| kyphoscoliosis type
the most common autosomal recessive form
of EDS. It results from mutations in the gene encoding lysyl
hydroxylase, an enzyme necessary for hydroxylation of lysine
residues during collagen synthesis. Affected patients have
markedly reduced levels of this enzyme. Because hydroxylysine
is essential for the cross-linking of collagen fibers, a deficiency
of lysyl hydroxylase results in the synthesis of collagen that
lacks normal structural stability
102
The vascular type of EDS results from
abnormalities of type III
collagen. This form is genetically heterogeneous, because at
least three distinct types of mutations affecting the COL3A1
gene encoding collagen type III can give rise to this variant.
Some affect the rate of synthesis of pro-α1 (III) chains, others
affect the secretion of type III procollagen, and still others lead
to the synthesis of structurally abnormal type III collagen. Some
mutant alleles behave as dominant negatives (see discussion
under “Autosomal Dominant Disorders”) and thus produce
severe phenotypic effects
103
Familial Hypercholesterolemia
Familial hypercholesterolemia is a “receptor disease” that
is the consequence of a mutation in the gene encoding the
receptor for LDL, which is involved in the transport and
metabolism of cholesterol
