•GENETIC DISORDERS
•
•
•
•
•
•
Marfan syndrome
Ehlers-Danlos syndrome
Familial hypercholesterolemia.
Alkaptonuria
Turnes syndrome
Neurofibromatosis
DISEASES
•GENETIC
•ENVIRONMENTAL
•BOTH
MUTATIONS
• PERMANENT change in DNA
GENOME MUTATION: (whole chromosome)
–CHROMOSOME MUTATION: (visible
chromosome change)
–GENE MUTATION: (may, and often, result in
a single base error)
GENE MUTATION
• DELETION OF A SINGLE BASE
• SUBSTITUTION OF A SINGLE BASE
POINT MUTATION
GENE MUTATION
• POINT MUTATION within a coding sequence:
VAL-GLU
• MUTATIONS in NON-coding sequences
defective transcription, regulation
• DELETIONS/INSERTIONS frameshift
mutation, involvement is NOT a multiple of 3
• Tri-nucleotide REPEATS, e.g., CGG repeats
many times in fragile X syndrome
GENE MUTATIONS
•
•
•
•
•
INTERFERE with protein synthesis
SUPPRESS transcription, DNARNA
PRODUCE abnormal mRNA
DEFECTS carried over into TRANSLATION
ABNORMAL proteins WITHOUT impairing
syntheses
GENETIC DISORDERS
• SINGLE gene mutations, following
classical MENDELIAN inheritance
patterns the most
• MULTIFACTORIAL inheritance
• CHROMOSOMAL disorders
DISORDERS WITH MULTIFACTORIAL
INHERITANCE
• Multifactorial (polygenic)
• A multifactorial physiologic or pathologic trait
may be defined as one governed by the
additive effect of two or more genes of small
effect, conditioned by environmental,
nongenetic influences.
• The risk of expressing a multifactorial disorder
is conditioned by the number of mutant genes
inherited.
• The risk is greater in siblings of patients having
severe expressions of the disorder
•
•
•
•
•
•
•
Diabetes mellitus,
Hypertension,
Gout,
Schizophrenia,
Bipolar disorder,
Congenital heart disease,
Some skeletal abnormalities. Hypertension
provides an excellent example of
multifactorial inheritance
• An excellent example of multi factorial
inheritance is
•
Hypertension
MENDELIAN inheritance patterns
• AUTOSOMAL DOMINANT
• AUTOSOMAL RECESSIVE
• SEX-LINKED (recessive), involving
“X” chromosome
AUTOSOMAL DOMINANT
• Disease is in HETEROZYGOTES
• NEITHER parent may have the disease (NEW mut.)
• REDUCED PENETRANCE (env?, other genes?)
• VARIABLE EXPRESSIVITY (env?, other
genes?)
• May have a DELAYED ONSET
• Usually result in a REDUCED PRODUCTION
or INACTIVE protein
AUTOSOMAL DOMINANT
•
•
•
•
•
•
•
•
•
•
•
CNS
HUNTINGTON DISEASE
NEUROFIBROMATOSIS
MYOTONIC DYSTROPHY
TUBEROUS SCLEROSIS
Renal
GIT-----Familial polyposis
POLYCYSTIC KIDNEY
Hematopoietic
HEREDITARY SPHEROCYTOSIS
VON WILLEBRAND DISEASE
Skeletal
•
•
•
•
•
•
•
MARFAN SYNDROME
EHLERS-DANLOS SYNDROMES(some)
OSTEOGENESIS IMPERFECTA
ACHONDROPLASIA
Metabolic
FAMILIAL HYPERCHOLESTEROLEMIA
ACUTE INTERMITTENT PORPHYRIA
AUTOSOMAL DOMINANT PEDIGREE
1) BOTH SEXES INVOLVED
2) GENERATIONS
NOT SKIPPED
AUTOSOMAL RECESSIVE
• Disease is in HOMOZYGOTES
• More UNIFORM expression than AD
• Often COMPLETE PENETRANCE
• Onset usually EARLY in life
• NEW mutations rarely detected clinically
• Proteins show LOSS of FUNCTION
• Include ALL inborn errors of metabolism
• MUCH more common that autosomal dominant
AUTOSOMAL RECESSIVE
•
•
•
•
•
•
•
•
•
•
Metabolic
CF
PKU
GALACTOSEMIA
HOMOCYSTINURIA
LYSOSOMAL STORAGE
Α-1 ANTITRYPSIN
WILSON DISEASE
HEMOCHROMATOSIS
GLYCOGEN STORAGE
DISEASES
hematopoetic
Hgb S
THALASSEMIAS
Endocrine
CONG. ADRENAL HYPERPLASIA
Skeletal
EHLERS-DANLOS (some)
ALKAPTONURIA
nervous
NEUROGENIC MUSC. ATROPHIES
FRIEDREICH ATAXIA
SPINAL MUSCULAR ATROPHYH
AUTOSOMAL RECESSIVE PEDIGREE
1) BOTH SEXES
INVOLVED
2) GENERATIONS
SKIPPED
SEX (“X”) LINKED
•
•
•
•
MALES ONLY
HIS SONS are OK
ALL his DAUGHTERS are CARRIERS
The “Y” chromosome is NOT homologous to
the “X”, i.e., the concept of
dominant/recessive has no meaning here
• HETEROZYGOUS FEMALES have no
phenotypic expression (carriers)….usually,
this means autosomal “recessive”, right?
SEX (“X”) LINKED
•
•
•
•
•
•
•
•
DUCHENNE MUSCULAR DYSTROPHY
HEMOPHILIA , A and B
G6PD DEFICIENCY
AGAMMAGLOBULINEMIA
WISKOTT-ALDRICH SYNDROME
DIABETES INSIPIDUS
LESCH-NYHAN SYNDROME
FRAGILE-X SYNDROME
SEX LINKED PEDIGREE
1) MALES ONLY
2) GENERATION SKIPPING DOESN’T MATTER
SINGLE GENE DISORDERS
• ENZYME DEFECT (Most of them, e.g., PKU)
– Accumulation of substrate
– Lack of product
– Failure to inactivate a protein which causes damage
• RECEPTOR/TRANSPORT PROTEIN DEFECT (Familial
Hypercholesterolemia)
• STRUCTURAL PROTEIN DEFECT (Marfan, Ehl-Dan)
– Structure
– Function
– Quantity
• ENZYME DEFECT WHICH INCREASES DRUG
SUSCEPTIBILITY: G6PDPrimaquine
STRUCTURAL PROTEIN DEFECTS
• Marfan Syndrome
– Fibrillin-1 defect (not -2 or -3)
– Tall, dislocated lens, aortic arch aneurysms, etc.
• Ehlers-Danlos Syndromes (AD, AR)
– Multiple (6?) different types
– Classical, Hypermob., Vasc., KyphoSc., ArthChal., Derm
– Various collagen defects
– Hyperelastic skin, hyperextensible joints
Marfan Syndrome
• It is a connective tissue disorder manifest in
skeleton, eyes and CVS.
• 70 to 80% are familial and A.D inheritance
• Pathogenesis
• Inherited defect in extracellular glycoprotein
FIBRILLIN-1( component of mircrofibril)
• Microfibril more widely distributed in aorta,
ligaments, ciliary zones.
• Two froms are Fibrilin 1 and 2
• Microfibril regualte the TGF beta lack of this
protein leads to defect in smooth muscle
chamges in the vascular system
Morphology
• Skeletal system
• Tall long extremities,
• Tapering fingers and toes,Hyperextensible
thumb upto the wrist joint
• Kyphosis scoliosis
• Pectus excavatum
• Ectopia
lentis(subluxation of the
lens)
• ocular change is bilateral
dislocation, or subluxation,
of the lens owing to
weakness of its suspensory
ligaments
CVS
• TGF beta signaling contribute to the aortic
dilation,
• Weakening of the media,intimal tear
• MVP(loss of connective tissue support)
• Aortic incompetence,
• Histologically cystic medial necrosis of the
media
Ehlers-Danlos Syndromes
• Ehlers-Danlos syndromes (EDSs) are
characterized by defects in collagen synthesis
or structure
• tissues rich in collagen, such as skin,
ligaments, and joints, are frequently involved
in most variants of EDS. Because the abnormal
collagen fibers lack adequate tensile strength,
skin is hyperextensible and joints are
hypermobile
• Deficiency of the enzyme lysyl hydroxylase
• Deficient synthesis of type III collagen resulting
from mutations affecting the COL3A1 gene.
This variant (vascular typeIV)
• Defective conversion of procollagen type I to
collagen, resulting from a mutation in two
type I collagen genes (COL1A1 and COL1A2) in
arthrochalasia-type EDS
• The skin is extraordinarily stretchable,
extremely
• fragile, and vulnerable to trauma
• Minor injuries produce gaping defects, and
surgical repair
• The basic defect in connective tissue may lead
to serious internal complications, including
rupture of the colon and large arteries.
RECEPTOR PROTEIN DEFECTS
• FAMILIAL HYPERCHOLESTEROLEMIA
– LDL RECEPTOR defect
– Mutations in the gene encoding the LDL
receptors which is involved in the transport and
metabolism of the cholesterol.
– There is loss of feed back control and elevated
levels of cholesterol that induce premature
atherosclerosis and increased risk of MI.
familial hypercholesterolemia
• Mutations in the LDL receptor
gene impair the intracellular
transport and catabolism of LDL,
resulting in accumulation of LDL
cholesterol in the plasma.
• Familial hypercholesterolemia is an
autosomal dominant disease.
• Heterozygotes have a two- to
threefold elevation of plasma
cholesterol levels, Homozygotes may
have in excess of a fivefold elevation.
• Absence of LDL receptors on liver
cells also impairs the transport of
IDL into the liver, and hence a
greater proportion of plasma IDL
is converted into LDL.
• Two-thirds of the resultant LDL
particles are metabolized by
the LDL receptor pathway, and
the rest is metabolized by a
receptor for oxidized LDL
(scavenger Receptors)
• The LDL receptor binds to
apolipoproteins B-100 and E
and hence is involved in the
transport of both LDL and IDL.
•IDL is the immediate
and major source
for LDL
• The receptor-mediated transport of LDL
involves binding to the cell surface receptor,
followed by endocytotic internalization Within
the cell, the endocytic vesicles fuse with the
lysosomes, and the LDL molecule is
enzymatically degraded, resulting ultimately in
the release of free cholesterol into the
cytoplasm.
NEUROFIBROMATOSIS TYPE 1 AND 2
• Neurofibromatoses compromise two
autosomal dominant disorders 100,00 people
in USA.
• Type 1 Neurofibromatosis is also called as
VON RECKLING HAUSEN disease and
• Type 2 neurofibromatosis is also called as
ACOUSTIC NEURROFIBROMATOSIS.
NEUROFIBROMATOSIS
• 1 and 2
• 1-von Recklinghausen
• 2- “acoustic” neurofibromatosis
• 1
– Neurofibromas, café-au-lait, Lisch nodules
• 50% of the patients with
definite family history and
remainder with new
mutations.
CLINICAL FEATURES
• 1.Multiple neural tumors present in
or on the body.
• 2.Numerous pigmented skin lesions
called Café au lait spots
• 3. Pigmented iris hamartomas. called
as Lisch nodules.
Morphology
• Neurofibromatoisis type 1
• 3 types of neurofibromas are found in
individuals with type 1
• 1. Cutaneous,
• 2. subcutaneous and
• 3. plexform lesions.(thickened tortuous
nerves)
Microscopic
• Proliferation of all the elements
in the peripheral nerves,
including neurites, schwann cells,
fibroblasts.
• Plexform neurofibromas become
malignant in 5% of the patients.
• Cutaneous pigmentations is second major
component which is present in more than 90%
of the patients.
• They are light brown café au lait macules with
smooth borders.
• Lisch nodules are iris hamartomas which helps
in diagnosis but remain harmless.
Café au lait spots
Cutaneous
Subcutaneous type
LISCH NODULES
Neurofibromatosis type 2
• It is a autosomal dominant disorder where
bilateral acoustic shwannomas and multiple
meningiomas are commonly present.
• Café au lait spots are present but Lisch
nodules are absent.
• It is less common compared to type 1.
NEUROFIBROMATOSIS
• 1 and 2
• 1-von Recklinghausen
• 2- “acoustic” neurofibromatosis
• 2
– Bilateral acoustic neuromas and multiple meningiomas
ENZYME DEFICIENCIES
• BY FAR, THE LARGEST KNOWN
CATEGORY
– SUBSTRATE BUILDUP
– PRODUCT LACK
– SUBSTRATE could be HARMFUL
• LYSOSOMAL STORAGE DISEASES
comprise MOST of them
LYSOSOMAL STORAGE DISEASES
•
•
•
•
•
•
GLYCOGEN STORAGE DISEASES
SPHINGOLIPIDOSES (Gangliosides)
SULFATIDOSES
MUCOPOLYSACCHARIDOSES
MUCOLIPIDOSES
OTHER
– Fucosidosis, Mannosidosis, Aspartylglycosaminuria
– WOLMAN, Acid phosphate deficiency
•
•
•
•
Lack of enzyme activator
Lack of subtrate activator protein
Lack of transport protein
Enzyme replacement therapy is the current
use of treatment
NIEMANN-PICK
• TYPES A, B, C(inherited deficiency of
spingomyelinase)
• SPHINGOMYELIN BUILDUP
• MASSIVE SPLENOMEGALY
• ALSO in ASHKANAZI JEWS
• OFTEN FATAL in EARLY LIFE, CNS, ORGANOMEGALY
TYPE A
• Sever infantile form with
extensive neurological
involvement,
• Progressive wasting
• Death in early life with in 3
years of life.
TYPE B
•
•
•
•
Organomegaly
But no CNS involvement
Genetic inheritence
The spingomyelinase gene on chromosome
11p5.4
• Missense mutation in TYPE A
• Diagnosis spingomyelinase activity by liver
and bone marrow biopsy
TYPE C
•
•
•
•
•
•
Primary defect in the lipid transport
Mutation in NPC1 and NPC2 gene.
It might be seen in
Hydrops fetalis
Neonatal hepatitis
And still births
•
•
•
•
•
Clinicla features
Ataxia
Supranuclear gaze palsy
Dystonia
Psychomotor regression
GLYCOGEN STORAGE DISEASES
• MANY TYPES (at least 10)
• Type 2 (Pompe), von Gierke, McArdle, most
studied and discussed, and referred to
• Storage sites: Liver, Muscle, Heart
MUCOPOLYSACCHARIDOSES
• HURLER/HUNTER, for I and II, respectively
• DERMATAN sulfate, HEPARAN sulfate
buildup
– coarse facial features
– clouding of the cornea
– joint stiffness
– mental retardation
– URINARY EXCRETION of SULFATES COMMON
ALCAPTONURIA
• It is autosomal recessive disorder
• HOMOGENTISIC ACID metabolism defect
DEFICIENCY OF HOMOGENTISIC OXIDASE
• Clinically become evident after 30 years.
BLACK URINE
–BLACK NAILS (OCHRONOSIS), SKIN
–BLACK JOINT CARTILAGE (SEVERE ARTHRITIS)
• Homogentisic acid binds to collagen cartilages
and ligaments ,imparting to these tissues
black color(Ochronosis) most evident in ears
,cheeks and nose.
• Because of pigmentation the cartilage looses
its resilience and become brittle.
• The vertebral column(intervertebral discs)
mainly involved next knee and shoulders
involved.
complications
• Severe crippling
• Osteoarthritis in elderly
persons.
• Alkaptonuria arthropathy in
early age.
“MULTIFACTORIAL” DISORDERS
•
•
•
•
•
•
•
•
Cleft lip, palate
Congenital heart disease
Coronary heart disease
Hypertension
Gout
Diabetes
Pyloric stenosis
MANY, MANY, MANY, MANY MORE
KARYOTYPING
• Defined as the study of CHROMOSOMES
• 46 = (22x2) + X + Y
• Conventional notation is “46,XY” or “46,XX”
MORE DEFINITIONS
COMMON CYTOGENETIC DISEASES
• AUTOSOMES
– TRISOMY-21 (DOWN SYNDROME)
– 8, 9, 13 (Patau), 18 (Edwards), 22
– 22q.11.2 deletion
• SEX CHROMOSOMES
–KLINEFELTER: XXY, XXXY, etc.
–TURNER: XO
TRISOMY-21
TRISOMY-21
• Most trisomies (monosomies, aneuploidy) are
from maternal non-disjunction
• (non-disjunction or anaphase lag are BOTH
possible)
• #1 cause of mental retardation
• Maternal age related
• Congenital Heart Defects, risk for acute leukemias,
GI atresias
• Most LOVABLE of all God’s children
SEX CHROMOSOME DISORDERS
• Problems related to sexual development and
fertility
• Discovered at time of puberty
• Retardation related to the number of X
chromosomes
• If you have at least ONE “Y” chromosome,
you are male
KLINEFELTER (XXY, XXXY, etc.)
• Hypogonadism found at puberty
• #1 cause of male infertility
• NO retardation unless more X’s
• 47, XXY 82% of the time
• L----O----N----G legs, atrophic testes,
small penis
TURNER (XO)
• 45, X is the “proper”
designation
• Complete or partial
monosomy of the X
chromosome charcteised by
hypogonadism in females.
• Three types of karyotyping abnormalities in
turners syndrome.
• 1.57% missing the entire X chromosome result
in 45X.
• 2.14% have structural abnormalities of the X
chromosomes.
• 3.29% are mosaics.
In infants and Children
• The most severely affected patients present
since infancy with lymph edema dorsum of
the hand and foot.
• Swelling of the nape of the neck.(Cystic
hygroma)
• Bilateral neck webbing
• Congenital coarctation of the aorta and
biscupid valve.
Adults
• Failure to develop normal 2ry sexual
characteristics.
• The genitralia infantile underdeveloped
breasts and little pubic hair.
• Single most important cause for primary
Amenorrhea.
• Hypothyroidism and insulin resistance.
STREAK OVARIES
• In Turner syndrome the fetal ovaries develop
early in embryogenesis but due to absence of
X chromosome leads to acclerated loss of
oocytes which completes by 2nd year.
• Menopause occurs before menorche.
• Ovaries are reduced and atrophic fibrous
strands devoid of ovarian follicle called as
STREAK OVARIES.
• SHORT STATURE HOMEOBOX
gene.
• Haploinsufficiency in this gene
gives rise to short stature.
MOLECULAR DX by DNA PROBES
•
•
•
•
•
•
•
BIRTH DEFECTS, PRE- or POST- NATAL
TUMOR CELLS
CLASSIFICATIONS of TUMORS
IDENTIFICATION of PATHOGENS
DONOR COMPATIBILITY
PATERNITY
FORENSIC