GENETIC DISEASES
-human
diseases
can
be
either
genetically
determined,
environmentally determined, or both
first category is represented by disorders of genetic origin
-HEREDITARY - means derived from one or both parents
-FAMILIAL - occurs in families
-CONGENITAL - implies present at birth- may be genetic or nongenetic
genetic disorders my arise
1) from chromosomal abberations
-include disorders resulting from numerical or structural
abnormalities of chromosomes- most of them are congenital
2) be related to single-gene disorder
-include relatively rare conditions, most of them are hereditary
and familial (storage diseases)
3) have multifactorial (polygenic) inheritance
-include some of the most common disorders, such as
hypertension and DM
1) CYTOGENETIC DISORDERS
aberrations underlying cytogenetic disorders may take the form of
-abnormal number of chromosomes
-structural alterations of one or more chromosomes
chromosomal abnormalities are more frequent than is generally
appreciated- 1 in 200 newborn infants have some type of chromosomal
abnormalities
- more than a half of first trimester abortions are due to lethal
chromosomal abnormalities
NUMERICAL ABNORMALITIES OF CHROMOSOMES
normal number of chromosomes in human is 46 = diploid number
46 XX - for the female
46 XY - for the male
23 = haploid number
euploid - any exact multiple of haploid number
aneuploid - if an error occurs in mitosis and the cell has chromosomal
number which is not exact multiple of 23- the most common cause of
aneuploidy is meiotic nondisjunction
STRUCTURAL ABNORMALITIES OF CHROMOSOMES
structural changes in chromosomes result from chromosome breakage
and loss of some genetic material or chromosomal rearrangment which
may have several forms:
1- translocation - implies a transfer of a part of one
chromosome to another chromosome, fragments may be exchanged
between two chromosomes
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2- deletion - means a loss of a part of chromosome
a single break deletes a terminal fragment, two breaks result in a loss
of the central fragment
3- inversion - occurs when two interstitial breaks devide a
chromosome and the segments reunite after complete turnaround
4- ring chromosome - following the loss of both terminal
fragments, the ends of chromosome unite to form a ring
In most chromosomal disorders the parents are normal and the risk of
recurrence in siblings is low
1) AUTOSOMAL DISORDERS - resulting from abberations of
autosomes
2) SEX CHROMOSOME DISORDERS - resulting from abberations of
sex chromosomes
AUTOSOMAL DISORDERS
DOWN’s SYNDROME
-is the most common of autosomal disorders
affected persons have trisomy of 21 chromosome- karyotype shows
chromosome count of 47
-average incidence is 1 in 700 births, very strong influence of
maternal age
Down’s syndrome occurs once in 25 live births for mothers older than
45 years! (for young mothers the incidence is low)
Clinical features of Down’s syndrome:
-severe mental retardation (IQs lower than 80)
-additional congenital malformations, including cardiac malformations
-high susceptibility to infections
-increased risk of developing of acute leukemias
-epicanthic folds
-simian crease on palms
-abundant neck skin folds and umbilical hernias
SEX CHROMOSOME DISORDERS
Include:
KLINEFELTER SYNDROME
most patients have karyotype 47, XXY - results from nondisjunction of
sex chromosome X during meiosis (sometimes more extra XX)
The extra X chromosome may be of maternal or paternal origin
clinical manifestation:
-patients are phenotypically males, there is marked testicular atrophylower serum testosteron levels
- sterility - due to impaired spermatogenesis or total azoospermia
-gynecomastia
-may be associated with mental retardation but not always
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TURNER SYNDROME
are phenotypically females, disorder results from partial or total
monosomy of short arm of X chromosome, or X chromosome is totaly
missing- karyotype 45,X
clinical features:
-significant growth retardation (abnormally short stature)
-lymphedema of hands and feet, webbing of the neck, low hairline
-various congenital malformations, including coarctation of aorta and
renal malformations
affected patients fail to develop secondary sex characteristics,
genitalia remain infantile, -breasts are undeveloped, there is primary
amenorrhea
-low levels of estrogens
MALES OF XYY KARYOTYPE
results from nondisjunction at the second meiotic division
-most of the affected persons are phenotypically normal, but they have
been reported to display anusual aggressive behavior
2) DISEASES CAUSED BY SINGLE-GENE DEFECTS (MUTATIONS)
Diseases caused by single-gene defect are sometimes referred to as
mendelian disorders, because they follow mendelian patterns of
inheritance
mutations of single gene may follow one of the three possible patterns:
1) autosomal dominant disorders (AD)
2) autosomal recessive disorders (AR)
3) X-linked
1. AUTOSOMAL DOMINANT DISORDERS
AD are manifested in heterozygotous state, so at least one parent is
affected and every child of affected person has one chance in two of
having disease
both males and females are affected, both can transmit the condition
Clinical features are modified by „reduced penetrance“, and
phenotypically normal persons can transmit the disease
MARFAN SYNDROME
-is AD disorder of connective tissues, principal clinical features are
related to skeleton, eyes, cardiovascular system
-skeletal abnormalities include abnormally long legs and arms, long
fingers (arachnodyctyly) and hyperextensibility in joints
-occular changes - bilateral subluxation of lens due to weakness of
suspensary ligaments
-cardiovascular changes - most important and include fragmentation
of elastic fibers in media of aorta = medionecrosis cystica Erdheim result very often in aneurysmal dilatation and aortic dissection
death of aortal rupture may occur at any age (most cases in 3rd and
4th decade)
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FAMILIAR HYPERCHOLESTEROLEMIA
-the most common mendelian disorder - incidence 1: 500 in the
general population
it is caused by mutation in the gene that specifies the receptor for lowdensisty lipoprotein (the form in which most of the cholesterol is
transported)
in familiar hypercholesterolemia - accumulation of LDL cholesterol in
plasma, the absence of LDL receptors on the liver cells also impairs
the transport of LDL into the liver
heterozygotes have two or three-fold elevation of plasma cholesterol
level, but homozygotes may have fivefold and more - these may dye of
myocardial infarction in childhood
NEUROFIBROMATOSIS
includes at least two AD disorders, one od them is NF-1 (von
Recklinghausen disease), the other is NF-2 ( bilateral acoustic NF)
NF-1 is much more common, has two major clinical features
multiple neurofibromas- nodules in the skin, internal organs or large
plexiform neurofibromas- both are benign tumors derived from
Schwann cell and fibroblasts
pigmented skin lesions- café au lait spots
neurofibromas may become malignant transformation- to neurogenic
sarcoma
2. AUTOSOMAL RECESSIVE DISORDERS
-in this pattern of inheritance the disease appears only if both alleles
in a given site are affected
thus, siblings have one chance in four of being affected (the
recurrence risk in 25 per cent for each birth)
the expression of the defect is common
-onset is frequently at birth or in early life
-heterozygotes are asymptomatic
CYSTIC FIBROSIS
incidence 1: 2000 live births- most common lethal genetic disorder
fundamental defect - in the transport of chloride ions through
epithelia- widespread -defect in the secretory process of all exocrine
glands with abnormally thick mucus secretion
characteristic feature - high levels of sweat sodium chloride
clinical features:
pancreatic abnormalities appear in most patients- include
accumulation of mucus, cystic dilatation of ducts with atrophy and
abundant fibrotic stroma = fibrotic disease of pancreas
pulmonary lesions- is the most important aspect of the disease
retention of abnormally viscid mucus results in repeated pulmonary
infections - chronic bronchitis, bronchiectasias, lung abscesses
obstruction of small intestine in newborns - meconium ileus
PHENYLKETONURIA (PKU)
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-lack of phenylalanine hydroxylase, results in hyperphenyl
alaninaemia and PKU (Phenylketonuria), because phenylalanine is not
converted to tyrosin
-babies are normal at birth- untreated children develop severe mental
retardation
-treatment: total restriction of phenylalanine of diet prevents clinical
consequences
ALBINISM
-is a heterogenous group of inherited disorders characterized by
inability to synthesize melanin
- most of them are transmitted as AR disorders
major clinical manifestation- hypopigmentation of skin, hair and eyes
(oculocutaneous form) or just the eyes (ocular albinism)
GLYCOGEN STORAGE DISEASES
- hepatic form, myopathic form, generalized form
LYSOSOMAL STORAGE DISEASES - Gaucher disease, Niemann-Pick
disease, Tay-Sachs disease
3. X-LINKED DISORDERS
sex-linked or more exactly X-chromosome-linked disorders are
transmitted by -heterozygotous women to their sons, who are always
hemizygotous for X-chromosome
-heterozygotous daughters do not express defect phenotypically owing
to the presence of intact second allele
-affected men do not transmit the disorder to sons, but all their
daughters are carriers the most important X-linked diseases are:
HEMOPHILIA A
-the most common X-linked hereditary diseaes associated with serious
bleeding
-it is caused by decreased activity of factor VIII of clotting system
- affected person- are either heterozygotous men or homozygotous
women, almost always affected males
clinical manifestation:
massive hemorrhage following trauma or operations and frequent
spontaneous hemorrhages encountered wherever, most commonly
recurrent spontaneous hemorrhages in joints = hemarthros
3) DISORDERS WITH MULTIFACTORIAL (POLYGENIC)
INHERITANCE
-this type of inheritance is involved in majority of human features
including physiologic characteristics, such as hair color, heigh, blood
pressure, stc.
-multifactorial disorders are transmitted in families (family members
share many genes but also some environmental factors)
first degree relative (sons, daughters) of affected person - have some 5
to 10 per cent risk of developing the disease
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this form of inheritance probably underlie many common diseases,
such as DM, hypertension, gout, etc
GOUT
-is a genetic or acquired disorder in metabolism of uric acid
it leads to hyperuricamia and consequent acute and chronic arthritis
the recurrent attacks of arthritis are caused by precipitation of
monsodium urate crystals into the joints major clinical features:
1) acute arthritis
monosodium urate crystals are present in synovial fluid and activate
acute inflammatory response
synovial membranes are congested and heavily infiltrate with
leukocytes, macrophages, lymphocytes and plasma cells
marked predilection of acute gout attyck for perpheral joints, such as
toe- related to the lower temperature at the peripheral joints
2) chronic arthritis
evolves from continuous precipitation of urates in recurrent attacks of
acute arthritis
3) formation of tophus (tophi)
tophus results from large aggregation of urates in soft tissues usually
in vicinity of joints
- tophus is a mass composed of amorphous or crystalline urates
surrounded by an intense inflammatory reaction, including
macrophages lymphocytes fibroblasts, large foreign-body giant cells
around crystalline salts are prominet
-tophi are likely to develop in periarthricular ligaments, tendons,
connective tissue in the vicinity of joints- result in secondary
osteorthritis
less frequently- tophi in kidney, aorta, heart, etc
4) involvement of kidney
there are thre types of lesions in the kidney
1- the most common- urate nephropathy- resulting from
deposition of urates in the interstitial tissue
2- less common- renal failure due to intratubular deposition of
free uric acid crystall- more often as a result of excessive breakdown
of nuclei following chemotherapy of hematologic malignancies
3- uric acid stones are formed and followed by purulent
pyelonephritis
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