GENETIC
DISORDERS
GENETIC ENVIRONMENTAL BOTH
DISEASES
MUTATIONS
PERMANENT change in DNA
GENE MUTATION: (may, and often, result in a
single base error)
CHROMOSOME MUTATION: (visible
chromosome change)
GENOME MUTATION: (whole chromosome)
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
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 (environment?,
other genes?)
VARIABLE EXPRESSIVITY (environment?,
other genes?) May have a DELAYED ONSET Usually result in a REDUCED PRODUCTION or INACTIVE protein
AUTOSOMAL DOMINANT
HUNTINGTON DISEASE NEUROFIBROMATOSIS MYOTONIC DYSTROPHY TUBEROUS SCLEROSIS POLYCYSTIC KIDNEY HEREDITARY SPHEROCYTOSIS VON WILLEBRAND DISEASE
MARFAN SYNDROME EHLERS-DANLOS SYNDROMES (some) OSTEOGENESIS IMPERFECTA ACHONDROPLASIA 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
CF PKU GALACTOSEMIA HOMOCYSTINURIA LYSOSOMAL STORAGE -1 ANTITRYPSIN WILSON DISEASE HEMOCHROMATOSIS GLYCOGEN STORAGE DISEASES Hgb S THALASSEMIAS CONG. ADRENAL HYPERPLASIA EHLERS-DANLOS (some) ALKAPTONURIA NEUROGENIC MUSC. ATROPHIES FRIEDREICH ATAXIA SPINAL MUSCULAR ATROPHY
AUTOSOMAL RECESSIVE PEDIGREE
1) BOTH SEXES INVOLVED
2) GENERATIONS
SKIPPED
SEX (X) LINKED
MALES ONLY HIS SONS are OK, right? 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, sons of affected males are OK 2) GENERATION SKIPPING DOESNT 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. Abraham Lincoln?, Osama bin-Laden
Ehlers-Danlos Syndromes (AD, AR)
Multiple (6?) different types Classical, Hypermob., Vasc., KyphoSc., ArthChal., Derm Various collagen defects Hyperelastic skin, hyperextensible joints
RECEPTOR PROTEIN DEFECTS
FAMILIAL HYPERCHOLESTEROLEMIA
LDL RECEPTOR defect Cholesterol TRANSPORT across liver cell impaired ergo, CHOLESTEROL BUILDUP IN BLOOD
Scavenger System for CHOL kicks in, i.e., MACROPHAGES YOU NOW KNOW THE REST OF THE STORY YOU NOW KNOW WHY MACROPHAGES are FOAMY
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
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
SPHINGOLIPIDOSES
MANY types, Tay-Sachs most often referred to
GANGLIOSIDES are ACCUMULATED Ashkenazi Jews (1/30 are carriers) CNS neurons a site of accumulation CHERRY RED spot in Macula
SULFATIDOSES
MANY types, but the metachromatic leukodystrophies (CNS), Krabbe, Fabry, Gaucher, and Niemann-Pick (A and B) are most commonly referred to SULFATIDES, CEREBROSIDES, SPHINGOMYELIN are the accumulations
NIEMANN-PICK
TYPES A, B, C SPHINGOMYELIN BUILDUP Sphingomyelinase (ASM), is the missing enzyme MASSIVE SPLENOMEGALY ALSO in ASHKANAZI JEWS OFTEN FATAL in EARLY LIFE, CNS, ORGANOMEGALY
GAUCHER DISEASE
GLUCOCEREBROSIDE BUILDUP 99% are type I, NO CNS involvement
ALL MACROPHAGES, liv, spl, nodes, marrow
MUCOPOLYSACCHARIDOSES
HURLER/HUNTER, for I and II, respectively DERMATAN sulfate, HEPARAN sulfate buildup, respectively
coarse facial features clouding of the cornea joint stiffness mental retardation URINARY EXCRETION of SULFATES COMMON
OTHER LYSOSOMAL STORAGE DIS.
FUCOSIDOSIS MANNOSIDOSIS ASPARTYLGLYCOSAMINURIA WOLMAN (CHOL., TRIGLYCERIDES) ACID PHOSPHATE DEFICIENCY (PHOS. ESTERS)
ALCAPTONURIA
NOT a LYSOSOMAL ENZYME DISEASE FIRST ONE TO BE DESCRIBED HOMOGENTISIC ACID HOMOGENTISIC ACID OXIDASE
BLACK URINE BLACK NAILS (OCHRONOSIS), SKIN BLACK JOINT CARTILAGE (SEVERE ARTHRITIS)
1 and 2 1-von Recklinghausen 2- acoustic neurofibromatosis
1
NEUROFIBROMATOSIS
Neurofibromas, caf-au-lait, Lisch nodules
NEUROFIBROMATOSIS
1 and 2 1-von Recklinghausen 2- acoustic neurofibromatosis
2
Bilateral acoustic neuromas and multiple meningiomas
MULTIFACTORIAL INHERITANCE
Multi-FACTORIAL, not just multi-GENIC SOIL theory Common phenotypic expressions governed by multifactorial inheritance
Hair color Eye color Skin color Height Intelligence Diabetes, type II
FEATURES of multifactorial inheritance
Expression determined by NUMBER of genes Overall 5% chance of 1st degree relatives having it Identical twins >>>5%, but WAY less than 100% This 5% is increased if more children have it
Expression of CONTINUOUS traits (e.g., height) vs. DISCONTINUOUS traits (e.g., diabetes)
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 G(iemsa)-banding, 500 bands per haploid recognizable Short (p-etit) arm = p, other (long) arm = q
More KARYOTYPING info
A,B,C,D,E,F,G depends on chromosome length
A longest G shortest
Groups within these letters depend on the p/q ratio
ARMREGIONBANDSub-BAND,
numbering from the centromere progressing distad
F.I.S.H.
Fluorescent InSitu Hybridization
Uses fluorescent labelled DNA fragments, ~10,000 base pairs, to bind (or not bind) to its complement
(gene probes)
greatly enhances G-banding
FISH
SUBTLE MICRODELETIONS COMPLEX TRANSLOCATIONS AND TELOMERE ALTERATIONS
TRIPLE CHROMOSOME #20
A DELETION in CHROMOSOME #22
SPECTRAL KARYOTYPING
CYTOGENETIC DISORDERS
DEFINITIONS:
EUPLOID
ANEUPLOID (NOT AN EXACT MULTIPLE OF 23)
MONOSOMY, AUTOSOME OR SEX TRISOMY, AUTOSOME OR SEX DELETION BREAKAGE
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 Gods children
Because of a DELETION, this cannot be detected by standard karyotyping and needs FISH Cardiac defects, DiGeorge syndrome, velocardiofacial, CATCH*
Chromosome 22q11.2 Deletion Syndrome
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 Xs 47, XXY 82% of the time L----O----N----G legs, atrophic testes, small penis
45, X is the proper designation Mosaics common Often, the WHOLE chromosome is not missing, but just part NECK WEBBING EDEMA of HAND DORSUM CONGENITAL HEART DEFECTS most FEARED
TURNER (XO)
HERMAPHRODITES
GENETIC SEX is determined by the PRESENCE or ABSENCE of a Y chromosome, but there is also, GONADAL (phenotypic), and DUCTAL sex TRUE HERMAPHRODITE: OVARIES AND TESTES, often on opposite sides (VERY RARE) PSEUDO-HERMAPHRODITE:
MALE: TESTES with female characteristics (Y-) FEMALE: OVARIES with male characteristics (XX)
SINGLE GENE, NON-Mendelian Triplet repeats
Fragile X (CGG) Others: ataxias, myotonic dystrophy
Mitochondrial Mutations: (maternal)
(LEBER HEREDITARY OPTIC NEUROPATHY)
Genomic IMPRINTING: (Inactivation of
maternal or paternal allele, contradicts Mendel)
Gonadal MOSAICISM: (only gametes have
mutated cells)
MOLECULAR DX by DNA PROBES
BIRTH DEFECTS, PRE- or POST- NATAL TUMOR CELLS CLASSIFICATIONS of TUMORS IDENTIFICATION of PATHOGENS DONOR COMPATIBILITY PATERNITY FORENSIC
H&E tissue structures ImmunoAntigen Proteins GENES that MAKE those PROTEINS
