Genetic disorders by liaoqinmei


									Genetic disorders
Know all the mutations listed and some examples
          a.   Point mutations- a single nucleotide base is substituted for another (aka missense)
                SCA is an example of missense/point mutation
          b.   Non-sense mutation occurs when and amino acid codon is changed to terminator
                Beta thalessemia is an example of a non-sense mutation
          c.   Trinucleotide repeat mutations- amplification of sequence of 3 nucleotides (250-4000 repeats)
                Nucleotide repeat mutations- Fragile X syndrome
          d.   Frame-shift mutation occurs when 1 or 2 base pairs are added or deleted altering the reading
                Cystic fibrosis is a frame-shift mutation example
“CATCH 22” problem
     a.   22q11 deletion syndrome
     b.   C- congenital heart defects
     c.   A- Abnormal facies (dysmorphia)
     d.   T- Thymic hypoplasia (T- cell defects)
     e.   C- Cleft palate
     f.   H- Hypocalcemia
     g.   Connected with DiGeorge syndrome

Diseases caused by mutations in receptor/transport proteins
Familial hypercholesterolemia
    Very common (1 in 500 adults)
    FH is due to a mutation in the LDL receptor on the cell surface
    Heterozygotes and homozygotes and their different presentations

                                      Heterozygotes                       Homozygotes
LDL receptor                          Present but low                     Absent
Cholesterol                           High                                Very high
Symptoms                              Cholesterol on tendon sheathes,     Xanthomas in childhood, MI
                                      athersclerosis, CAD                 early (die 15-20 y/o)

Diseases caused by mutations in enzyme proteins
1.   Know that PKU, Galactosemia, Lysosomal storage disease and Glycogen storage disease are all due to
     mutations in enzyme proteins
2.   PKU-
      Lack phenylalnanine hydroxylase (PAH) so they can’t make tyrosine
      Mental retardation, pale skin/hair (little melanin)
      Early diagnosis is essential for avoidance of dietary phenyalanine to prevent mental retardation
3.   Galactosemia-
      Lack to galactos-1-phosphate uridyltransferase (galactose  glucose)
      Children will have hepatomegaly, spelnomegaly, juaundice, hypoglycemia, mental retardation and
4. Lysosomal storage diseases
      Tay- Sach’s- Hexoaminidase A
       a. death by age 2
      Gaucher’s – Glucocerebrosidase
       a. Type 1- adult onset
       b. Type 2- infant onset, deadly
      Niemann- Pick- Sphingomyelinase
       a. death by age 5
      Also know the presence of cherry red spots in the retina causing blindness is seen in Tay- Sach’s
       and Niemann- Pick disease
Glycogenoses (Glycogen storage disorders)
     Von Gierke’s- Glucose-6-phosphatase  glycogen builds up in the liver causing hepatomegaly
      and liver failure
     Mc Ardles- muscle phosphorylase- causing cramps after exercise
     Pompe’s- Glucosidase- cardiomegaly and eventual cardiac failure by age 2
Diseases caused by mutations in proteins that regulate cell growth
     Neurofibromatosis types 1 and 2
     Both are autosomal dominant
     NF1- aka von Recklinghausen’s disease
      Lesions include:
      a. Pedunculated nodules
      b. Multiple neurofibromas
      c. Pigmented skin lesions (Cafe au lait spots)
      d. Pigemented iris harmartomas (Lisch nodules)
      e. Most serious complications is transformation into a tumor called a Neurofibrosarcoma
      f. Due to chromosome 17 defect
     NF2- aka acoustic neurofibromatosis
      a. Chromosome 22 deficiency
      b. Bilateral acoustic neuromas
      c. Neurofibromas
      d. Cafe au lait spots

                      Disease                                         Protein defect
Marfan syndrome                                     Fibrillin
Osteogenesis imperfecti                             Collagen
Ehlers-Danlos syndrome                              Collagen
Familial hypercholesterolemia                       LDL receptor
Cystic fibrosis                                     Transmembrane protien regulator
Tay Sachs disease                                   Hexoaminidase
Phenylkeotonuria                                    Phenylalanine hydroxylase
Galactosemia                                        G1P uridyltransferase
Neruofibromatosis type 1                            Neurofibromin

Down’s syndrome
     Autosomal disorder and the most common chromosomal disorder
     Trisomy 21
     The most common cause is meiotic nondisjunction. Some scenarios:
      a. 95% of cases 47XX+21/47XY+21
      b. 4% (Roberstonian translocation) t(14;21)
      c. 1-2% (mosaics) 46XX/47XX+21
          i. mosaics show much milder symptoms
Sex chromosome disorders
     Kleinfelter’s-
      a. Male hypogonadism
      b. Most are 47XXY
      c. 15% are some form of mosaic (46XY/47XXY)
      d. Clinical signs include: small testes, infertility, mild retardation
     Turner’s syndrome-
      a. Female hypogonadism
      b. 55% are missing on X chromosome
      c. The remaining 45% are mosaics (46XX/45XO)
      d. Clinical signs include: Poor development of female secondary sex characteristics, broad chest,
          webbed neck , widely spaced nipples, primary amenorrhea due to rudimentary ovaries
Single gene disorders with atypical patterns of inheritance
    Fragile X syndrome
       a. abnormality of the X chromosome
          i. defect localized to Xq27.3 (this is the fragile portion that breaks off)
       b. Clinical features: large mandible, severe retardation, long face, enlarged testicles, This is the
          second most common cause of mental retardation
       c. Due to multiple tandem triplet repeat mutation via a mutation in the FMR-1 gene
    Prader-Willi and Angelman syndromes
       a. PW- mental retardation- with obesity, small hands and feet
       b. AW- mental retardation- with inappropriate laughter (happy puppets)
Leber Hereditary Optic neuropathy- know the symptoms and cause
   a. Caused by a mutation of mitochondrial genes carried in the mother
   b. Expression is variable due to the maternal problems
   c. Causes degenerative neuropathy with progressive bilateral los of central vision and blindness
Genetic screening tests
    a.   Early detection of effected individuals - ie maternal alpha-feto screening for Down’s syndrome
         and newborn screening for PKU
          Alpha feto protein key in detection of DS and neural tube defects
    b.   Carrier detection
             i. Key in Tay-Sach’s disease (in Ashkenazi Jews), use the Hex A test (for hexoaminidase A)
                  because it can help decrease problems associated with the disease by 95%
             ii. Test mothers for AFP, HCG and unconjugated estriol for Down’s syndrome
             iii. Also done in Thalessemias and SCA
Principles in treatment of genetic disease
    a.   The three R’s
           i. Restriction
           ii. Replacement
           iii. Removal
    b.   Restriction- used in PKU (remove dietary phenylalanine), G6PDH deficiency (restrict drugs and
         antimalarials), Familial Hypercholesterolemia (remove dietary choelsterol)
    c.   Replacement- Used in hemophilia A (give pts factor A), Alpha-1-antitrypsin deficiency (give pts
         alpha-1-antitrypsin, liver transplant in familial hypercholesterolemia, SCA/ADA deficiency (add
         bone marrow)
    d.   Removal- In Wilson’s disease (remove excess copper), in familial polyposis (remove the colon
         with polyps in it)

Disorders of the Immune system
HLA classes involved in disease
    a.   Ankylosing spondylitis- HLA-B27
    b.   Diabetes mellitus- HLA- DR3/DR4
Hypersensitivity diseases
    a.   Type I hypersensitivity
         1. Examples-
            a. Skin diseases- urticaria, eczema, acute dermatitis and angioneurotic edema,
            b. Anaphylactic shock- ex. penicillin shock, seafood allergy, etc
         2. Basic pathophysiology- IgE activation and degranulation of the mast cells
             Remember normally IgE is protective against parasitic infections
   b.  Type II Hypersensitivity
            a. Know all the subtypes
                 Complement mediated cytotoxicity
                     a. Cause: In this system complement is activated causing cell lysis
                            Hemolytic disease of the newborn (Erythroblastosis fetalis)
                            Goodpasture’s syndrome- Abs against basment membrane of the lung and
                                kidneys causing pneumonitis and glomerulonephritis
                            Autoimmune hemolytic anemia (transfusion reaction)
                 ADCC (Antibody-dependent cell-mediated cytotoxicity)
                     a. Cause: Lysis of Ab coated target cells by killer cells breaking Fc receptors
                           which engage the Fc portion of IgG
                     b. Transplant rejection
                     c. Tumor immunity
                 Antibody-mediated cellular dysfunction
                     a. Cause: Abs deregulate cell function withou producing cell injury
                     b. Grave’s disease- Abs bind TSH receptors causing hyperthyroidism
                     c. Myesthenia gravis- Abs bind ACh receptors blocking neuromuscular
                     d. Hyperthyroidism
                     e. Pernicous anemia
   c. Type III hypersensitivity (immune complex-mediated)
            a. Immune complex deposition is the problem, both local and systemically
            b. Local- Arthus reaction- this is a reaction at the site of antigen injection showing necrosis
                with necrotizing vasculitis
            c. Systemic- Serum sickness, poststreptoccocal glomerulonephritis, SLE, Rheumatiod
                arthritis, polyarteritis nodosa, polymyositis
                 All cause acute inflammation, fibrinoid necrosis (damage of vessels leading to
            d.   ALL OF THESE ARE GLOMERULAR PROBLEMS because immune complexes get
                deposited in the glomerulus
            e. These do not cause pyelonephritis
   d. Type IV hypersensitivity (cell-mediated)
            a.   aka Delayed type hypersensitivity
            b.   The main problems is CD4 T-cell secreting cytokine
            c.   Examples- TB
            d.   Know the tests associtaed with TB
                  Mantoux reaction- erythema and induration following injection of tuberculin is an
                     indication of past TB, or BCG vaccination
                  Granulomatous inflammations
Transplant rejection
   a.   Allographs can cause and immune response (rejection) by types II, II, IV hypersenstivities
         HLA-DR is the most important factor in rejection
   b.   Hyperacute rejections – leads to ischemic infarction of the graft in hyperacute rejection mainly
        due to preformed anti-donor antibodies. Can cause fibrinoid necrosis in very severe cases
   c.   Acute rejection- includes type II,II, and IV hypersensitvities (humoral and cellular rections).
        Most commonly presents with renal failure
         Humoral rejection- due to deposition of Abs. This will cause necrotizing arteritis
         Cellular rejection- Extensinve interstitial mononuclear infiltration. This can cause focal
            tubular necrosis of kidneys
   d.   Chronic rejection- slow with progressive renal failure, no acute changes
   e.   GVH disease- know it happens when immunologically competent cells are transplanted into
        immunologically crippled recipients. CTL will damage recipient’s tissues
         Problems like this occur mostly in the liver, skin and gut mucosa
         Jaundice, skin rashes, diarrhea occur
         CTLs are T-cell infiltrating the organs in GVH disease
Autoimmune diseases
    a.   SLE- systemic lupus erythematosus
          Lots of other diseases will look like this thus all similar diseases are called collagen vascular
          Other collagen vascular diseases include: Rheumatoid arthritis, systemic sclerosis,
          Criteria for SLE: remember a few major ones: ANA antibodies, renal disease, butterfly rash
          Not all autoimmune diseases are collagen vascular consider: Hashimoto’s thyroiditis, Grave’s
            disease, Myasthenia gravis, Ulcerative colitis (all are non-collagen vascular
          HLA-DR2/3 are important with connection to SLE
          Damage to tissue occurs via type II and III hypersensitivity
            a. Fibrinoid necrosis of small arteries
          Death most commonly due to kidney disease- glomerular diseases such as
            glomerulonephritis due to Ab deposition on the glomerular basement membrane
          Associated conditions: Libman-Sack’s endocarditis, and other nephritis’
          Occurs mostly in females 1:10 ratio
          ANA Ab’s are detected in virtually all patients, the most specific test for SLE is anti-double
            stranded DNA
Immunodeficiency diseases
    Read thru them all
    Primary immunodeficiency
    a. Bruton’s disease- problem of agammaglobulinemia
           X-linked trait
           Absence of B-cells leads to recurrent bacterial infections
    b. Swiss-type/ combined immunodeficiency- both B and T lymphocytes are gone
           Caused by an ADA deficiency
           Young death (~2 y/o)
    c. Thymic hypoplasia- lack of T-cells (aka DiGeorge’s syndrome)
           22q11 deletion syndrome closely related to DiGeorge’s
           Failure of the thymus to develop
           Disabled CMI: viral, fungal and mycobacterial disease
    d. Most common primary immunodeficiency disease is isolated IgA deficiency
           Pulmonary and GIT infections common
           1:700 develop this
    Secondary immunodeficiency
    a. AIDS is 4th leading cause of death between 15 and 54
           3 methods of transmission: sexual, parenteral and mother to child
           Window period- 3-7 weeks for Abs to develop
           Test for HIV is ELISA- will not detect all HIV-2 infections
           Attacks immune and nervous system
              a. Attacks CD4 T-cells by binding with GP120
              b. Normal CD4:CD8 ratio is 2:1, but it will drop to 1:1 in AIDS
              c. >200 CD4/mL then diagnose full blown AIDS
              d. Read the box on page 12 and know the phases of AIDS
         Stage                                           Signs/Symptoms
Early acute               Decreased CD4 cells, viremia, and widespread seeding of lymphoid tissues
                          Seroconversion occurs after the window period
                          Non-specific symptoms (sorethroat, diarrhea, etc) which resolve in 3-6
Middle chronic            Group II-Asymptomatic
                          Group III- Possible general lymphadenopathy and low level HIV replication,
                              may last 7-10 years
Final crisis phase        Pneumonia, Diarrhea, multiple opportunistic infections, Kaposi’s sarcoma,
                              AIDS dementia, lymphomas common
      This is a disease in which amyloid, a pathologic proteinaceous substance is deposited
      extracellularly in a variety of tissues and organs producing pressure atrophy
       Some immune system problems underlie this disease
  b. Most common amyloidosis in the US- multiple myeloma causing primary amyloidosis and
      expressing the protein AL (amyloid light chains)
 Multiple myeloma will excrete Ig in the urine or light chains known as Bence-Jones proteins (causing
  c. ATTR- A prealbumin that is associated with Senile cardiac amyloidosis and hereditary
  d. B2 microglobulin- seen in patients with chronic renal failure getting dialysis. This cannot be
      removed and gets accumulated giving rise to carpal tunnel syndrome
  e. Secondary amyloidosis- seen in chronic infections such as TB, osteomylitis, and rheumatoid
  f. Organs effected by amyloidosis
       Kidney- most common site of damage and death
           a. amyloid in the glomeruli casues destruction
       Spleen- 2 patterns of deposition
           a. Small nodular deposits in spelnic follicles called Sago Spleen
           b. Large map like areas of deposits in the splenic pulp called Laraceous spleen
       Heart- becomes enlarged due to amyloid deposition leading to pressure atrophy
           (cardiomyopathy and CHF).

Amyloidosis seen                     Disease caused by                    Proteins seen
Primary amyloidosis                  Multiple myeloma                     AL
Secondary amyloidosis                Chronic inflammation                 AA
Hereditary/Senile cardiac            Familial amyloid                     ATTR
amyloidosis                          polyneuropathies
Hemodyalisis associated              Chronic renal failure                B2-microglobulins

13. Infectious diseases
a.   Chlamydial infection
              Causes urethritis and cervicitis (also prostatitis in males)
              Most frequent STD disease in the US with 3 million new cases (second to Gonorrhea)
              Mostly caused by C. trachomatis
              Newborns infected with it can also get inclusion conjunctivitis
b.   Keratoconjunctivitis due to chlamydial infections
      One of the leading causes of blindness
      Causes scarring and ulceration of the conjunctiva
c.   Lymphogranulmoa venereum (LGV)-
              STD
              Not common
              Lesions at the penis, vagina, cervix
              Occurs in 3 stages
         1. Small ulcer at site of infection
         2. Granulomatous lymphadenitis (buboes) and pus discharge
         3. Elephantiaisis, esthiomene
d.   Rickettsial diseases
              Typhus is a louse borne disease caused by Rickettsia prowazekii
         a. a typhus nodule is a small vessel lesion of the brain and other organs showing focal leukocytic
         infiltration and microglial proliferatoin
              Rocky mountain spotted fever is a tick borne infection
          1.Rocky mountain spotted fever (ricketsia ricketsii)
            a. Hallmark is the eschar (a rash)
            b. Meningitis may occur
e.   Mycoplasma-
      These are tiny organisms also called PPLOs or Eaton agents
      M. pneumonia accounts for 10-30% of all primary interstitial pneumonias
      Produces cold agglutinins
      Common in military recruits and institutions (prisons)
Bacterial infections
      remember gram positive and gram negative can both cause severe septicemia and shock
      Gram positive can cause Toxic shock syndrome (vaginal tampons)
      Streptococcal infections
       Have 2 patterns of disease: spreading of suppurative infections, and poststrep. hypersensitivity
           (causing glomerulonephritis, rheumatic fever, and erythema nodosum)
  d. Menigococal infections
 Severe septicemia
 Death
 DIC and hemorrhages in the adrenals causing a severe shock called Waterhouse-Friderichsen
     e. Gonococcal infections
 Causes sterility in males and females.
 PID leading to sterility (due to tubo-ovarian abscesses) in females and ectopic pregnancy
 Causes destruction of the epididimis in males causing sterility
 Can cause right upper quadrant pain around the liver called Fitz-Hugh-Curtis-Syndrome
  f. Gram negative rods cause:
 Endotoxic shock- a hypotensive shock due to bacterial endotoxins
 Nosocomial infections
 Remeber Legionella infections
          a. Caused by L. pneumophilia
          b. Causes DIC, shock, renal failure and most commonly respiratory failure
          c. Pontaic fever- a mild form, usually self limiting
     g. Legionella infections
           These are commonly respiratory infections caused by L. penumophilia and others
           The bugs are found in cooling systems
           2 disease presentations
            a. Pontaic fever- mild, self-limited febrile disease
            b. Legionnaire’s disease- severe pneumonia with a 15-20% fatality rate
           Legionnaire’s presents with dry cough, slow pulse, chest and abdominal pain. Eventually
            respiratory failure, shock, DIC and renal failure can occur
           May present as lobular pneumonia or confluent bronchopneumonia
Infectious diarrheas
     a.Typhoid fever
        Typhoid carriers are asymptomatic humans, they can develop the disease if they become
            compromised. Remember humans are the only reservoir
 It causes, toxic coagulation of the cardiac muscle,
 Neutropenia occurs due to bone marrow suppression
 Rose spots develop on the chest
  b. Lyme disease
        Tick borne infection (Borrelia burgdorferi)
        It is a spirochete
            a. Other spirochete infections include: Relapsing fever, syphilis, and Weil’s disease
        3 stages
            1. ECM- erythema chronicum migrans
            2. Chorea, myocarditis
              3.     Chronic debilitating arthritis
Sexually transmitted diseases
     a.   Syphilis

      Stage                                Symptoms                           Complications/resolution
Primary syphilis             Chancre- painless, eroded and indurated      Heals in 3-12 weeks
                              occur on penis, labia or cervic
                             Painless lymphadenopathy
Secondary syphilis           1-3 months post chancre
                             Well or with malaise
                             Skin rashes which are bilateral,
                             May show retinitis, meningitis

Tertiary syphilis            Cardiovascular- aortic aneurysm, aortic      Gummatous necrosis of the liver,
                              incompetance and narrowing of the            bones and testes.
                              coronary ostia
                             Neurosyphilis- tabes dorsalis and GPI
                              (general paresis)
                             Gummas

b.   Congenital syphilis
      Contracted via the placenta
      Causes late abortion, stillbirth
c.   Tuberculosis
      Caused by Mycobacterium tuberculosis
          a. transmitted by inhalation, ingestion or skin inocculation
    Identified by Ziehl-Neelsen Stain
    Causes infective granulomas called tubercles (w/Langhans giant cells)
    Primary infection is mediated by a type IV cell-mediated hypersensitivity reaction, this plays a major
     role in caseating tissue destruction (large cavities in the lung)
    What is primary TB
      a. Granulomas called Ghon foci and enlarged hilar lymph nodes, together called Ghon complex are
         found subpleurally
    What is secondary TB
      a. Seen in people who have been previously infected, via a recativation
      b. Coin lesions with hemoptysis
    Some possible outcomes of TB
      a. May induce amyloidosis
      b. If the tubercle bacilli gain access to the blood they can form yellow-white lesions in distant organs
          such as the eye, bone marrow, spleen and liver. This is called miliary TB

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