LESSON 7 : CYTOGENETICS

• Genetic Disorder : It is a disease caused by abnormalities in an individual’s genetic material (genome).
• Four Types of Genetic Disorder :

  • Single-gene
  • Multifactorial
  • Chromosomal
  • Mitochondrial
• Single-Gene : Also called Mendelian or monogenic ; Caused by a changes that occur in the DNA sequence of one gene resulting to production of protein that can no loner carry out its normal function giving rise to a disorder.
• Examples of Single-Gene GD :

  • Cystic Fibrosis
  • Sickle Cell Anemia
  • Marfan Syndrome
  • Huntington’s Disease
  • Herditary Hemochromatosis
• Multifactorial : Also called Complex or Polygenic ; Caused by a combination of environmental factors and mutations in multiple genes.
• Examples of Multifactorial GD :

  • Breast cancer susceptibility havE been found on chromosomes 6, 11, 13, 14, 15, 17 and 22.
  • Heart Disease
  • Alzheimer’s Disease
  • Arthritis
  • Diabetes
• Chromosomal : Abnormalities in chromosome structure as missing or extra copies or gross breaks and rejoining (translocations) can result in disease.
• Examples of Chromosomal GD :

  • Down Syndrome
  • Patau Syndrome
• Mitochondrial : A relatively rare type of genetic disorder caused by mutations in the nonchromosomal DNA of mitochondria.
• Mutations at high levels cause mitochondrial dysfunction, which will have consequences on ATP levels and other cellular process.
• Mitochondrial Myopathy : a disorder which can cause muscle weakness, fatigue and difficulty with motor skills due to impaired function of mitochondria in muscle.
• 1. Achondroplasia : Short limbs relative to trunk, prominent forehead, low nasal root, redundant skin folds on arms and legs.
  2. Gene / Defect : Fibroblast Growth Factor Receptor 3 (FGR3) – constitutively active (gain of function).
  3. Inheritance : Autosomal Dominant
• 1. Cystic Fibrosis : Persistent pulmonary infection, pancreatic insufficiency, and elevated sweat chloride levels ; A hereditary disorder characterized by lung congestion and infection.
  2. Gene / Defect : Cystic Fibrosis Transmembrane Regulator (CFTR) – impaired chloride ion channel function.
  3. Inheritance : Autosomal Recessive
• Multifactorial Complications of Cystic Fibrosis :

  • Antimicrobial Allergy
  • Increased Arterial Stiffness
  • Gastrointestinal Malignancy
  • Renal Failure
  • Female Subfertility
  • Osteoporosis
  • Lymphoma
  • Urinary Incontinence
  • Musculoskeletal Abnormalities
  • Dyspepsia
  • Anxiety and Depression
  • Hearing Impairment
• 1. Duchenne Muscular Dystrophy : Gradual degeneration of skeletal muscle, impaired heart and respiratory musculature.
  2. Gene / Defect : Dystrophin - deletions
  3. Inheritance : X-Linked Recessive
• 1. ( G6PD ) Glucose 6-Phosphate Dehydrogenase Deficiency : Anemia (due to increased hemolysis) induced by oxidizing drugs, sulfonamide antibiotics, sulfones (e.g. dapsone), and certain foods (e.g. favabeans)
  2. Gene / Defect : B-Glucosidase
  3. Inheritance : Autosomal Recessive
• What to avoid when have G6PD?

  • Fava Beans & All Legumes
  • Blueberries
  • Any Medicine
  • Tonic Water
  • Napthalene
  • Red Wine
• 1. Huntington Disease : Also called as Huntington Chorea ; Disorder is characterized by progressive motor, cognitive and psychiatric abnormalities.
  2. Gene / Defect : Huntingtin - CAG repeat expansion within exon 1 (expansion occurs in father).
  3. Inheritance : Autosomal Dominant
• Chorea : no repetitive involuntary jerks – is observed in 90% of patients.
• Huntington's Disease : Rare condition that is inherited ; Has a 50% risk of being passed down to every offspring of someone with the disease ; Degenerates nerve cells in brain areas responsible for movement and thinking ; Onset is between the ages of 30 and 50.
• Stages of Huntington Disease :

  • Stage 0 : Preclinical Stage
  • Stage 1 : Early Stage
  • Stage 2 : Early Intermediate Stage
  • Stage 3 : Late Intermediate Stage
  • Stage 4 : Early Advanced Stage
  • Stage 5 : Advanced Stage
• 1. Marfan Syndrome : Abnormalities of the skeleton (disproportionate tall stature, scoliosis), heart (mitral valve prolapse, aortic dilatation, dissection of the ascending aorta), pulmonary system, skin (excessive elasticity), and joints (hypermobility). A frequent cause of death is congestive heart failure.
  2. Gene / Defect : 5p-, deletion of the long arm of chromosome 5
  3. Inheritance : Autosomal Dominant
• Marfan Syndrome Features : MARFANS

  M : Mitral Valve Prolapse / Medical Necrosis of Aorta

  A : Aortic Aneurysm

  R : Retinal Detachment

  F : Fibrilin Defect

  A : Arachnodactyly

  N : Negative Nitroprusside Test

  S : Subluxated Lense
• Marfan Syndrome Features : MDRED

  M : Malar Hypoplasia

  D : Dolicocephaly

  R : Retrognathia

  E : Enopthalmos

  D : Down-slanting palpebral fissures
• 1. Cri du Chat Syndrome : Cry of the cat. Severe mental retardation, microcephaly, catlike cry. Low birth-weight, roundface, hypertelorism (wide-set eyes), low-set ears, epicanthal folds.
  2. Gene / Defect : 5p-, deletion of the long arm of chromosome 5
  3. Inheritance : Chromosomal
• 1. Down Syndrome (Trisomy 21) : Most common cause of mental retardation. Will see epicanthal folds, simian crease, brushfield spots in eyes. Associated syndromes : congenital heart disease, leukemia, premature Alzheimer's disease (same morphological changes).
  2. Gene / Defect : Familial form (no age-associated risk) is translocation t (21, X) in a minority of cases.
  3. Inheritance : Chromosomal
• 1. Edward’s Syndrome (Trisomy 18) : Mental retardation, micrognathia, rocker-bottom feet, congenital heart disease, flexion deformities of fingers. Death by 1 year old.
  2. Gene / Defect : Trisomy 18
  3. Inheritance : Chromosomal
• 1. Klinefelter's Syndrome (XXY) : Hypogonadism, tall stature, gynecomastia. Mild mental retardation. Usually not diagnosed until after puberty. One Barr body seen on buccal smear.
  2. Gene / Defect : Non-disjunction of the sex chromosome during Anaphase I of meiosis ------> Trisomy (47, XXY)
  3. Inheritance : Chromosomal (Sex Chromosome)
• 1. Turner Syndrome ( X- ) : Streak gonads, primary amenorrhea, webbed neck, short stature, coarctation of Aorta, infantile genitalia. No mental retardation. No Barr bodies visible on buccal smear.
  2. Gene / Defect : Non-disjunction of the sex chromosome during Anaphase I of meiosis – Monosomy ----> (45, X)
  3. Inheritance : Chromosomal ( Sex Chromosome )
• 1. Chronic Myeloid Leukemia : An uncommon type of cancer of the bone marrow.
  2. Gene / Defect : Philadelphia (Ph) chromosome - the result of a translocation—or exchange of genetic material—between the long arms of chromosomes 9 and 22.
  3. Inheritance : Somatic Mutation
• 1. Hemophilia A ( Factor VIII Deficiency ) : Hemorrhage, hematuria, hemarthroses. Prolonged PTT.
  2. Gene / Defect : Factor VIII deficiency
  3. Inheritance : X-Linked Recessive
• Symptoms of Internal Bleeding :

  • Bleeding on the skin, gums, eye or mouth
  • Bruises, nosebleed, abdominal pain
  • Join pain or swelling
  • Blood in stool, urine, vomit, or when coughing
  • Extreme headaches
  • Feeling weak, numb
  • Vision Problems
• Symptoms of Hemophilia A :

  • Nosebleeds
  • Bleeding gums or mouth
  • Swollen & stiff joints
  • Bruises
  • Coughing and vomiting blood
  • Blood in urine and stool
  • Heavy menstrual bleeding
• 1. Hemophilia B ( Factor IX Deficiency ) : Milder than Hemophilia A. Hemorrhage, hematuria, hemarthroses. Prolonged PTT.
  2. Gene / Defect : IX deficiency
  3. Inheritance : X-Linked Recessive
• Christmas Disease A.K.A. Hemophilia B : Symptoms (SNUG)

  S : Skin bruising

  N : Nosebleeds

  U : Urinary Tract bleeds

  G : Gastrointestinal Tract bleeds
• 1. Chronic Granulomatous Disease : Failure of phagocytes leads to susceptibility to infections, especially Staph Aureus and Aspergillus spp. B and T cells usually remain normal T.
  2. Gene / Defect : NADPH Oxidase deficiency ---> no formation of peroxides and superoxides ---> no oxidative burst in phagocytes.
  3. Inheritance : X-Linked or Autosomal Recessive
• Clinical Features of Klinefelter's Disease :

  • Gynecomastia
  • Tall Stature
  • Small Testes
  • Micropenis
  • Infertility
  • Behavioral Problems
• What is the laboratory findings in Klinefelter's Disease?

  • Low testosterone
  • High FSH / LH
• Increased risk malignancies in Klinefelter's Disease?

  • Breast Cancer
  • Testicular Cancer
• What is the most effective treatment for Klinefelter's Disease?

  Testosterone Replacement Therapy