GENETIC DISORDERS DISEASES GENETIC ENVIRONMENTAL BOTH MUTATIONS PERMANENT

GENETIC DISORDERS DISEASES  GENETIC  ENVIRONMENTAL  BOTH MUTATIONS   PERMANENT

GENETIC DISORDERS 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 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, due to a hexoseaminidase A deficiency 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

MASSIVE SPLENOMEGALY ALSO in ASHKANAZI JEWS OFTEN FATAL in EARLY LIFE, CNS, ORGANOMEGALY GAUCHER DISEASE GLUCOCEREBROSIDE BUILDUP, due to glucocerebrocidase deficiency 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 PHOSPHATASE 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)

NEUROFIBROMATOSIS 1 and 2 1-von Recklinghausen 2- acoustic neurofibromatosis 1 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 I) MULTIFACTORIAL DISORDERS Cleft lip, palate

Congenital heart disease Coronary heart disease Hypertension Gout Diabetes Pyloric stenosis MANY, MANY, MANY MORE, perhaps MOST!

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. (gene probes)

greatly enhances G-banding Fluorescent InSitu Hybridization Uses fluorescent labelled DNA fragments, ~10,000 base pairs, to bind (or not bind) to its complement 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? Why? Chromosome 22q11.2 Deletion Syndrome Because of a DELETION, this cannot be detected by standard karyotyping and needs FISH

Cardiac defects, DiGeorge syndrome, velocardiofacial, CATCH* (Learn the mnemonic) 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

TURNER (XO) 45, X is the proper designation Mosaics common Often, the WHOLE chromosome is not missing, but just part NECK WEBBING, STREAK OVARIES EDEMA of HAND DORSUM CONGENITAL HEART DEFECTS most FEARED

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 (XY) 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 TUMOR DNA in BLOOD H&E tissue structures ImmunoAntigen Proteins (IHC) GENES that MAKE those

PROTEINS

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