•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, DNARNA• 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

hematopoeticHgb STHALASSEMIASEndocrineCONG. ADRENAL HYPERPLASIASkeletalEHLERS-DANLOS (some)ALKAPTONURIAnervousNEUROGENIC MUSC. ATROPHIESFRIEDREICH ATAXIASPINAL 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: G6PDPrimaquine

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