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 (env?, other genes?)
VARIABLE EXPRESSIVITY (env?, 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
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 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 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
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
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)
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 1
st
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. (gene probes)
greatly enhances G-banding
Fluorescent In-
Situ
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

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*
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
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 (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

Immuno-
Antigen
Proteins

GENES that
MAKE those
PROTEINS