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Classification of Genetic Disorders
  1. Related to Mutant Genes of Large Effect: Single gene (uncommon disorders)
  2. Multifactorial (polygenic) inheritance, genes of small effect (Environment plays large role)
  3. Genomic or Chromosomal muetations: Cytogenic; # or structural changes in chromosomes
  4. Single-Gene disorders w/ Nonclassic patterns of inheretance: triplet repeat mutations, mDNA mutations, genomic imprinting
Mendelian Disorders (single gene disorders)
Every person carries 5-8 deleterious genes (but most are recessive, so no problem)

85% mutations are familial, some autosomal

Autosomal Dominant, Autosomal recessive, X-linked inheretance
Autosomal Dominant
  • Mendelian Disorders
Heterozygous state

Every gen. affected
50% chance offspring affected

adult onset usually

Variation of effect: penetrance & expressivity
  • Mendelian Disorders
Frequency with which the abnormal gene produces disease

explanation for why there is variation of defects (wide range)
  • Mendelian Disorders
Degree of abnormality seen in different individuals

explanation for why there is variation of defects (wide range)
Single Gene disorders transmitted by Autosomal Dominance
  • Neurofibromatosis
  • Familial Hypercholesterolemia
  • Marfans
  • Ehlers-Danlos syndrome
Autosomal Recessive
  • Mendelian Disorders
manifested in homozygous state

every generation affected
Heterozygous parents: 1/4 chance of passing
Childhood onset
Single Gene diseases transmitted through Autosomal Recessive
Most inborn errors of metabolism & storage diseases
  • Cystic Fibrosis
  • Galactosemia
  • PKU
  • Lysosomal Storage Diseases: Tay-Sachs, Gaucher's, Neimann-Pick's
  • Glycogen storage disesases: von gierke, mc ardle, pompe's
X-linked Disorders
  • Mendelian Disorders
All X-linked, no Y-linked found yet

Almost all are recessive
Dominant = vitamin D-resistant rickets

Transmitted by female carriers & expressed in males

Lack of male-to-male transmission = hallmark
Single gene diseases tranmitted by X-linked
  • Fragile X syndrome
  • Hunter Syndome: mucopolysaccharide
  • Hemophilia A & B
  • Chronic Granulomatous Disease
  • Dominant = Vit-D resistant rickets
  • G6PD deficiency
  • Duchenne muscular dystophy
  • Diabetes insipidus
Diseases caused by mutations in structural proteins
  • Marfans syndrome
  • Ehlers-Danlos syndome: think contortionists
Marfan Syndrome
  • what's the defect
  • what does that mean
  • clinical features
  • Defect = Fibrillin
  • Fibrillin typically serves as a scaffold for deposit of collagen & elastin
  • Chromosome 15q21.1
  • Clinical:
Skeletal abnormalities; long extremities, high palate, hyperextensible joints, pectus excavatum
Eyes: bilateral dislocation of lens, retinal detachment
CV issues:(most serious) dissecting aneurysm (usually cause of death)-->aortic rupture, Floppy valve syndrome, MV prolapse
Ehlers-Danlos Syndrome
  • what's the defect
  • clinical
Defect = collagen synthesis (10 subtypes)

Clinical = hypermobile joints, hyperelastic & fragile skin, weak blood vesssel walls --> hemorrhage

Diseases caused by mutations in receptor/transport proteins
Familial Hypercholsterolemia (FH)
1 of most common AD disorders

Defect = LDL receptor-->overproduction & accumulation of cholesterol in plasma

Heterozygotes: cholesterol deposist along tendon sheaths --> premature atherosclerosis--> CAD

zygotes: Xanthomas in childhood--> death from MI (15-20 yoa)
Diseases caused by Mutations in Enzyme Proteins
defective enzyme-->metabolic block-->absent normal protein & accum. of substrates/intermediate products that can be toxic to body
  1. PKU
  2. Galactosemia
  3. Lysosomal Storage diseases
  4. Glycogen storage diseases
Phenylketonuria (PKU)
  • Single gene, mutations in proteins
  • Problem is because of accumulation of substrates
1 of most common inborn errors of metabolism (N. european descent)

Deficient: PAH (liver enzyme the converts Phe-->Tyr)

Accumulation: Phenylalanine (2nd wk of life)

Clinical: mental retardation, mouse odor, psycho behavior, tremors, rashes, pale skin & hair,
  • Single gene, mutations in proteins
  • Problem is because of accumulation of substrates
Deficient: galactose-1-phosphate uridyltransferase

Accumulates: Galactose & its metabolites --> galactosuria

Infants fed milk-->hepatosplenomegaly (liver & spleen), jaundice, hypoglycemia, cataracts (eye), retardation (brain)

Liver--> steatosis-->Cirrhosis (6months)
Diseases caused by Mutations in proteins that regulate cell growth
Neurofibromatosis Types 1 & 2: AD

Type 1, Chrom. 17 = Von Recklinghausen disease (90%) Multiple fibromas, cafe au lait spots, iris hamartomas (Lisch nodules) could have malignant transformation

Type 2, Chrom. 22: bilateral acoustic neuromas, peripheral neurofibromas, cafe au lait spots
Lysosomal Storage
    characterized by accumulation of abnormal amount of lipids
    1. Tay-Sach
    2. Gaucher
    3. Niemann-Pick

    • Lysosomal storage disease

    hexosaminidase:Gm2-ganglioside:brain,retina (cherry red spot)

    death by 2-3 yoa
    Gaucher Disease
    • Lysosomal storage disease
    Gaucher- glucocerebrosidase: cerebrosidase in RE cells:brain, retina, liver, spleen, bone marrow

    Type 1: adults, no brain involvement, normal life-span

    Type 2: infants, death at young age
    Neimann-Pick disease
    • Lysosomal storage disease
    sphingomyelinase:sphingomyelin in phagocytes & neurons:brain, liver, spleen, retina (cherry red spot), bone marrow, lymph nodes

    death usually by 5 yoa
    • diseases caused by mutations in enzyme proteins
    1. Von Gierke disease
    2. Mc Ardle Syndrome
    3. Pompe disease
    Von Gierke disease
    • Glycogenoses

    glucose-6-phosphatase:glycogen:enlarge liver & kidney, hypoglycemia

    50% mortality
    Mc Ardle Syndrome
    • glycogenoses
    musle phosphorylase:glycogen:skeletal muscle-->cramps after exercise
    Pompe Disease
    • glycogenoses
    glucosidase:glycogen in heart:heart-->cardiomegaly-->cardiac failure by age 2

    most severe of glycogenoses
    Review of Disease & Defect: Single Gene Diseases

    FH: LDL receptor
    Vit. D resistant rickets: Vit D. receptor
    Cystic Fibrosis: transmem. regulator
    PKU: phenylalanine hydroxylase
    Galactosemia: G1P uridyltransferase
    Neurofibromatosis Type 1: Neurofibromin
    Diseases with multifactorial (polygenic) inheritance
    Action of several genes @ different foci

    Ex. of characterists: height, weight, hair color, blood pressure

    Genetic + environmental factors

    1st degree relatives of affected = 5-10%

    Diabetes mellitus, HTN, coronoary heart disease, gout, schizophrenia, manic depression, congenital malformation
    Cytogenic Disorders
    numerical or structural change in chromosome
    1. Down syndrome (Trisomy 21)
    2. Kleinfelter syndrome
    3. Turner syndrome
    Down Syndrome (Trisomy 21)
    • Most common autosomal chromosomal disorder
    most common cause --> meiotic nondisjunction
    95% = trisomy (47XX+21 or 47XY+21)
    4% = robertsonian t (14;21)
    1-2% = mosaics

    Mom > 45 = 1 in 25 births
    avg. 1:700 births

    Clinical: upward-slanting eyes, prominent epicanthal folds, congenital malformations (heart defects: VSD), mental retardation: leading cause of retardation

    + susceptible to infections & acute leukemias

    80% w/o heart disease live 30 yrs

    Middle age -> alzeheimer eventually
    Sex Chromosome Disorders: Kleinfelter & Turner
    autosomes are normal
    Kleinfelter: male hypogonadism; most 47XXY, some mosaics
    Small testes, impaired spermatogenesis-->infertile, mild retardation, reduced hair, gynecomastia, +FSH & +LH

    Turner: female hypogonadism, 55% monosomy (45X), 45% mosaics (45X & 46XX)
    Short stature, webbed neck, broad spaced nipples, lymphedema, congenital malformations: coarcation of aorta, horseshoe kidneys
    Primary amenorrhea, rudimentary ovaries, +FSH, +LH
    Single gene disorders with atypical patterns of inheretance
    1. Fragile X Syndrome
    2. Leber hereditary optic neuropathy
    3. Prader-Willi & Angelman syndromes
    Fragile X-syndrome
    • X-linked recessive
    • Atypical pattern of inheretance
    Multiple tandem triplet repeat mutation in FMR-1 gene
    constriction of long arm (q) of X-chromosome-->fragility

    M>F, 50% carrier females affected

    Clinical: mod-->severe mental retardation, long face, large mandible, large everted ears, enlarged testes
    get worse with each generation

    Common causes of mental retardation
    1. Downs
    2. Fragile X
    1. Fetal alcohol syndrome
    Principles of Teratology
    • developmental disorders
    Teratology = study of developmental anomalies

    Teratogens = chemical, physcial, biologic agents that cause developmental anomalies

    • Individual susceptibility
    • Susceptibility of developmental stages: 1st trimester most susceptible
    • Mechanism of teratogenesis
    • Dose-response relationship: Dose dependent
    • Outcome of teratogenic influences
    Proven teratogens
    • Cytotoxic drugs
    • Alcohol
    • Some antiepileptic drugs
    • heavy metals
    • thalidomide
    Errors of Morphogenesis
    for normal development you need activation & repression of certain genes

    Most genes in early zygote are inactive & individual genes are activated/inactivated as the zygote enters clevage stage

    Formation of primordial organ systems =
    most susceptible stage
    failure of organ to develop
    failure to form a lumen of a tubular structure
    failure of an organ to get to normal size

    If in pairs, and 1 organ is normal sized, it will begin to hypertrophy
    Range of major-minor effects of fetus
    If in early embryonic cells --> death of embryo

    1st trimester--> usually major effects of morphogenesis

    after 1st trimester--> rarely major effect
    Neural Tube defects (Dysraphic States)
    impaired closure of the dorsal aspect of the vertebral column
    1. Anencephaly
    2. Spina bifida
    • neural tube defect
    congenital abscence of cranial vault, cerebral hemispheres can be completely missing

    Genetic component
    M:F = 1:2 (only one thats more F than M)

    2/3 die in utero
    live births die w/in a week

    screen pregos for serum-alpha-fetoprotein & ultrasound, can reduce occurance w/ folic acid supplementation
    Spina Bifida
    neural tube closes in craniocaudad direction-->abnormalities of the vertebral column usually in lumbar region

    mildest dysraphic defect of CNS
    Occulta: asymptomatic, tuft of hair
    Meningocele: hernial protrusion of meninges through defect
    Myelomeningocele: spinal cord herniates through defect
    Thalidomide Induced Malformation
    Thalidomide: Europe, used for morning sickness

    --> phocomelia (arms short & malformed)
    Fetal Alcohol Syndrome
    usually born to chronic alcoholics, heavy consumption in 1st trimester

    mental retardation, dysfunction of CNS, facial dysmorphology

    mechanism & harmful dose unknown

    possible most common cause of acquired mental retardation
    signs & symptoms assoc. w/ fetal or neonatal infection w/
    T: toxoplasmosis
    O: other, syphilis, TB, EBV
    R: rubella
    C: CMV
    H: HSV
    TORCH effects
    clinical & pathological findings vary, few present with multisystem disease
    ALL TORCH can affect:
    • Brain (serious!)-->lesions: acute encephalitis & calcification: microcephaly, hydrocephaly, abnormal gyri & sulci
    • Eyes: particularaly in rubella, cataracts & microphthalmus
    • Heart: rubella, patent ductus arteriosus & vasrious septal defects
    Congenital Syphillis
    T. palladium transmitted from mother-->fetus @ any time , typically during 1st & 2nd stages of disease

    Untreated: 40% die in utero

    Still birth, hepatomegaly, pneumonitis
    Live: chronic rhinitis, mucocutaneous lesions

    If untreated for 2 years-->notched incisors, interstitial keratitis, deafness, saddle-nose deformity
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