Genetic Basis Of Disease

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MEN 2B (multiple endocrine neoplasia 2B)

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mucosal neuromas on tongue and lips
medullary thyroid cancer at 2-3 yrs
pheochromocytoma (tumor of adrenal gland -> release too much epi and Npepi)
hypotonia (low muscle tone), loose joints, long face (marfanoid - resembles Marfan Syndrome)

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2 types of genetic abnormalities

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1) Mendelian Genetics - single gene mutations
2) non-Mendelian Genetics - changes in micro RNA- Teret's syndrome
3) Chromosomal abnormalities

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Mendelian Genetics

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autosomal recessive traits
autosomal dominant traits
x-linked
single gene mutations: missense, nonsense (premature stop codon), frame shift (affects the coding region)

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autosomal recessive

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25% chance of disease transmission
consanguineous (related) mating increases incidence
usually metabolic disorder due to loss of enzyme function

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proband

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anticipated child

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phenylketonuria

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autosomal recessive
common in Skandinavians
Defect in Phenylalanine hydroxylase
fair skin (don't make melanin, secondary to defect in phenylalanine hydroxylase)
eczema (scaly and itchy rashes)
severe mental retardation: 2/3 cannot walk or talk
seizures and neurologic abnormalities (too much phenylpyruvate)

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Maternal PKU

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giving PKU toxic intermediate to their children who don't have the deficiency

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autosomal dominant

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50% chance of having affected offspring if one parent is affected and the other is healthy

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Autosomal dominant disorders

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porphyria
familial hypercholesterolemia
osteogenesis imperfecta
achondroplasia
Marfan syndrome
neurofibromatosis, retinoblastoma, APC

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porphyria

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not enough enzyme activity. normally there's enough enzyme, but under stress condition iron metabolism isn't efficient and you go mad.

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Familial Hypercholesterolemia

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complex metabolic pathway disrupted. accumulation of lipid. 1 defect copy: heart attack in teens. 2 defect copies: heart attack during infancy

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osteogenesis imperfecta

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abnormal subunit of multimeric complex. defects in collagenous fiber; affect bone, tendon and muscle.
brittle bones that are easily broken
collagen I defect
e.g. Dentinogenesis Imperfecta type I

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Dentinogenesis Imperfecta I

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in conjunction with osteogenesis imperfecta
enamel is normal
defect in dentin - opalescent teeth

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Dentinogenesis imperfecta, Shields type II

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locus 4q21.3 (DSPP-dentin sialophosphoprotein): prevent the formation of columnar structure of dentinal tubules
dentinogenesis imperfecta w/o osteogenesis imperfecta
opalescent dentin and teeth: brown-blue or opalescent brown teeth, bulbulous shaped crown, narrow roots, small or obliterated root canals, absent pulp chambers

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Achondroplasia

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gain of function: FGF-3 overproduction; the most mutable gene in the human genome.
cartilage defects: short limbs, trident hand, Genu varum (bowlegs), prominent brow and depressed bridge of nose, Mx hypoplasia, small foramen magnum.
homozygous FGF-3 mutation is not viable

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neurofibromatosis, retinoblastoma, APC

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cancer susceptibility gene

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Marfan Syndrome

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loss of function.
defect in fibrillin 1 or 2
tall, thin stature with long limbs, fingers and toes (not everyone who is tall has Marfan)
narrow and/or sharp-featured face: narrow mouth with a high palate, crowded teeth
off-center lenses in the eye and myopia (ectopia lentis)
scoliosis and loose joints
decreased elasticity of lung tissue, bv, heart valves
prominent stretch marks (due to speedy growth and not elastic skin)
caved-in or pushed-out breastbone
aortic dissection is most serious complication - can die from aneurysm

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hemophilia

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x-linked recessive

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X- linked expressivity in females

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heterozygous carriers
mozaicism:
- lyonization (e.g. striping on the teeth and X linked genes)
- random x-inactivation (e.g. cocalico cat)
- not random if fatal mutant (e.g. ornithine transcarbamylase mutation, no viable offsping in males and mosaic in females)

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Amelogenesis Imperfecta 1E

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x-linked form (14 subtyes)
defect in enamel matrix deposition (hypoplastic): high risk of getting caries and other
small teeth
yellow brown to brown color (males)

Hint 20

lyonization in females

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Non Mendelian Genetic Concepts

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1. mitochondrial inheritance
2. genomic imprinting
3. phenotype/genotype correlation
4. presence of a mutation in a population
5. trinucleotide repeat disease
6. multifactorial inheritance

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1. Mitochondrial inheritance

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vision, nerve and muslce are highly depend on mitochondria
severity depends on # of defective mitochondria inherited - heteroplasmy.
examples are:

Hint 22

Leber Hereditary Optic Neuropathy

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2. Genomic Imprinting

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maternal vs paternal inheritance of an autosome
examples are:

Hint 23

Prader-Willi vs Angelman
Huntington disease
Neurofibromatosis
Myotonic Dystrophies

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Prader-Willi Syndrome

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chromosome 15 deletion inherited from father
hypotonia, obesity, small hands, mild mental retardation, hypogonadism

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Angelman Syndrome

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chromosome 15 deletion inherited from mother
ataxic gait, inappropriate laughter, severe mental retardation and seizure

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3. Genotype/Phenotype Correlation

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- genetic heterogeneity (mutation of different genes cause same disease): i.e.
- variable expressivity: varying degrees of diseases with same gene mutation: i.e.
- penetrence: % of pts with inherited mutation that develop disorder: modifier genes, environment (carcinogens), usually occurs in autosomal dominant disorders - i.e.
- allelic variation: mutation in same gene causes different disease: i.e.

Hint 26

- genetic heterogeneity: familial Alzheimer Disease, Breast Cancer
- variable expressivity: neurofibromatosis 1 (variable # of cafe au lait, learning, skeletal malformations, and cardiac defects)
- penetrence: hereditary nonpolyposis colorectal cancer
- allelic variation: Ret gene

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Ret Gene

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MEN2A (exon 10, 11): pheochromocytoma, MTC
MEN2B (exon 15, 16): pheochromocytoma, MTC, neuroma
familial medullary thyroid carcinoma (exon 10-15)

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4. Presence of a mutation in a population

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1. hyterozygous advantage: i.e.
2. founder effect: suddendecrease in population leaves an increase in mutant

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1. sickle cell anemia and cystic fibrosis
2. Tay Sachs disease in Jews

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5. Trinucleotide repeat diseases

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expansion in the # of 3 nucleotide repeats
low # of repeats are normal
# of repeats above threshold lead to disease
i.e. are:

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Huntington's disease, Fragile X syndrome, Kennedy disease

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6. Multifactorial Inheritance

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aka polygenic
genetic, but no specific gene
family has higher risk than population, non-mendelian
compare concordance between monozygotic and dyzygotic twins
i.e. are

Hint 30

cleft lip/palate, IDDM, NIDDM, epilepsy, hypertension, schizophrenia, manic depression, multiple sclerosis

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Cleft Lip/Palate

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1/700
variable expressivity
RARa, TGFb, folic acid metabolis, fetal alcohol syndrome, malnutrition
Treatments are:

Hint 31

Folate and B6 decrease cleft lip

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Chromosomal Abnormalities

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structurally abnormal
numerically abnormal: autosomal and sex chromosomes
1/200 of newborns have the abnormalities

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Karyotpe

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picture of stained metaphase chromosomes

Hint 33

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Structural Abnormality

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deletion, duplications, insertions, inversions, translocations, isochromosomes (lost one arm and replace it with exact copy of the other arm), inversions, ring chromosomes

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Williams

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microdeletions: at 7q11.23
wide mouth, full lips, small chin, puffy eyes and starburst iris
wide-spaced, small teeth
enamel hypoplasia
thick, curly hair
happy disposition - very social
spatial learning deficit (D of y test)
normal verbal and social
cardiac valve defect

Hint 35

enamel hypoplasia: increased risk of caries, regular dental hygiene visits and good home care, easy to manage pt

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Balanced Translocation

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all genetic material maintained
carrier don't exhibit any signs
fusion of 2 acrocentric chromosomes - Robertsonian Translation during meiosis I, leading to abnormal: i.e.
chromosome # in offspring
problem in gametogenesis

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i.e. Down syndrome

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Abnormal Chromosome #

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aka Aneuploidy
trisomy
extra sex chromosomes
monosomy

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trisomy 13, 18, 21
monosomy: Turners syndrome

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Trisomy 21

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aka Down syndrome
92-95% have 47 chromosomes (3 copies of chromosomes 21) - disjunction during meiosis, high risk to >35 women
incidence increases with maternal age of conception
mental retardation
epicanthic folds and fat facial profile
Simian Crease on the palm
40% have cardiac malformations
increased risk of leukemias and Alzheimer disease

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Abnormal Sex Chromosomes #

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45X to 49XXXXY are viable
XYY or XYYY - normal
Turner Syndrome
Klinefelter Syndrome
Lyon hypothesis, 1 active X

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Turner Syndrome

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45X - abnormal sex chromosomes #
webbed neck
low posterior hairline
widespread nipples
growth retardation
failure to develop secondary sex characteristics
high arched palate
aortic and kidney malformations

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Klinefelter Syndrome

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XXY, XXXY, XXXXY
male hypogonadism
increased body length
testicular atrophy
gynecomastia
sterility
mild mental impairment