Exam V: Genetic Diseases Flashcards
Sickle Cell Anemia
Autosomal Recessive
Heterozygotes: advantage because little side effects of having one mutated allele, but have resistance to malaria caused by Plasmodium falciparum
A mutated gene results in RBCs that are deficient in O2 transport protein (Hb) causing them to develop a sickle/crescent shape
Sickle cells are stiff and sticky and therefore tend to block blood flow in the blood vessels of the limbs and organs (ISCHEMIA, PAIN, NECROSIS)
Healthy red blood cells typically function for 2-3 months, but sickled cells only last 10–20 days (ANEMIA)
Sick Cell Anemia: Signs and Symptoms
Symptoms don’t appear in infants until they are 4 months old
First sign can be swelling on the back of the hands and feet (hand-foot syndrome)
Most common symptom is anemia (severe fatigue) and pain.
Sickle cell crisis (sudden pain throughout the body) can affect many parts of the body and cause many complications
Hereditary Spherocytosis
Caused by intrinsic defects in the RBC membrane skeleton altering the shape to be spherical and prone to splenic sequestration/destruction via macrophages
An Autosomal Dominant Inheritance Pattern is seen in 75% cases.
Mutations in spectrin, ankyrin, band 4.2, or band 3 cause cells to adopt a spherical shape
Hereditary Spherocytosis: Signs and Symptoms
Most Specific: Spherocytosis Reticulocytosis Marrow Erythoid Hyperplasia Mild Jaundice Cholelithiasis Moderate splenomegaly Increased sensitivity to osmotic lysis aka lyse faster than normal RBCs Increased mean cell Hb concentration due to dehydration
Hereditary Spherocytosis: Treatment
Splenectomy- corrects for the anemia, but the membrane defect remains
Supportive Care
Folic Acid
Blood Transfusion/Erythropoietin
Hematopoietic cell transplantation
Ornithine Transcarbamylase Deficiency(OTC Deficiency)
X Linked Recessive
Breakdown of amino acids generates NH4+, which needs to be eliminated from the body
Without OTC:
Carbamyl Phosphate can’t enter the urea cycle
Ammonia builds up in the blood (hyperammonemia)
OTC Deficiency: Signs and Symptoms
Elevated ammonia levels causes cerebral edema and consequential brain damage
Seizures, developmental delays, ADHD, intellectual deficiencies
Increased extracellular potassium levels causes increased frequency of seizures
Liver failure from increased levels of liver enzymes and coagulopathy
Symptoms depend on early or late onset
OTC Deficiency: Dx
Severe neonatal-onset disease:
Plasma amino acid analysis (PAA)
High glutamine & low citrulline indicates OTC deficiency
Males & females of all ages:
Urine organic acid analysis (UOA)
Elevated acid concentration indicates OTC deficiency
Confirming the diagnosis
Mutation in OTC gene
Decreased OTC enzyme activity in liver
Pedigree analysis
G6PD Deficiency
X Linked Recessive
Triggered by bacteria, viral infection, certain drugs (malaria medication) or eating fava beans
Newborns are screened for this deficiency in the hospital routinely ONLY in 2 states (PA & DC)
Accumulation of reactive 02 species= damage RBC’s
Leads to formation of Heinz bodies
G6PD Deficiency: Signs and Symptoms
Symptoms:
Hemolytic Anemia
Low red blood cell count, low Hb, paleness, jaundice, Dark colored urine, fatigue, shortness of breath, rapid HR, RBC with Heinz bodies
If left untreated can lead to kidney failure & death
Most people have no signs or symptoms
Patients recover quickly in about 8 days ( when new RBCs are created they have normal G6PD activity)
Hemochromatosis: Types
Excessive iron absorption deposited in parenchymal organs such as liver, pancreas, heart, joints, endocrine organs
Primary: Hereditary hemochromatosis
Excess Iron accumulation due to gene mutation
Secondary: Parenteral administration of iron
Blood transfusions causing hemolysis due to underlying condition (i.e. Beta Thalassemia)
excessive iron release from lysed RBC’s
Hemochromatosis: Pathogenesis
Autosomal Recessive
Higher penetrance in Caucasians and Males (Celtic Disease)
Abnormal regulation of intestinal absorption
Iron accumulation toxic to liver
Reversible → not fatally injured
Hepcidin (HAMP gene) secreted by liver Main regulator for decreasing iron absorption Lowers plasma iron levels Deficiency → iron overload Mutation in the HFE gene
Hemochromatosis: Signs and Symptoms
Two most common: Chronic fatigue and joint pain
Other symptoms: Lack of energy Diabetes Mellitus (glucose intolerance) Abdominal pain Memory fog Loss of sex drive Heart flutters Irregular heart beat Pain in the knuckles of the pointer and middle finger, collectively called “The Iron Fist,” is the only sign or symptom specific to hemochromatosis.
Hemochromatosis: Fully Developed
Micronodular cirrhosis → all patients
Golden yellow hemosiderin granules of hepatocyte cytoplasm
Can use Prussian Blue Stain for Iron
Diabetes Mellitus → 75%-80%
Bronze Diabetes: preferential iron deposition on pancreatic beta cells leading to death
Abnormal skin pigmentation → 75%-80%
Joints: Synovitis
Hemochromatosis: Treatment
Blood donation/Therapeutic Phlebotomy:
Regular blood donation → every 8 weeks
A person with severe iron overload → as much as 8 times in a single month
Iron Chelation Therapy: increase excretion of iron
Dietary Changes:
Avoid Iron supplements
Limit Vitamin C and Alcohol intake
Avoid Uncooked Shellfish
Wilson’s Disease
Autosomal Recessive or spontaneous mutation
Women affected to 2:1 ratio compared to men
Genetic defect: ATP7B, which encodes metal transporting ATPase causing reduced excretion of copper
Systemic accumulation of copper in liver, brain, kidneys, cornea, heart, pancreas and joints
Wilson’s Disease: Signs and Symptoms
Manifests at ages 6 - 40
Movement disorders, tremors, involuntary movements, drooling, dystonia, seizures, migraines
Insomnia depression, personality change, psychosis, jaundice, bruising
Scarring of liver, liver failure, persistent neurological problems, kidney problems, psychological problems
Kayser-Fleischer Rings- copper build up in eyes
Wilson’s Disease Testing
Genetic testing: look for Autosomal recessive inheritance
Blood test and urine test to measure high copper levels
Diffucult to diagnose- symptoms match other liver diseases such as hepatitis
Eye exam- look for copper deposits/sunflower cataracts
Liver Biopsy
Wilson’s Disease: Treatment
Chelation therapy drugs to bind copper and increase its urinary excretion = Penicillamine, Trientine, Zinc Acetate
Successful treatment requires lifelong adherence to drug regimen and avoidance of foods high in copper
Liver, shellfish, mushrooms, nuts, chocolate
Severe liver damage would require a liver transplant
Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD Deficiency)
Autosomal recessive disorder
Gene involved: ACADM where Lys is replaced by glutamic acid
MCADDis a disorder of fatty acid oxidationthat impairs the body’s ability to break down medium-chain fatty acidintoacetyl-CoA
When the MCAD enzyme deficient, the body cannot use fat for energy, and must rely solely on glucose. Since limited glucose available, the body tries to use fat
This leads to hypoglycemia, and to the build up of harmful substances in the blood causing damage to brain, liver, and other organs
MCAD Deficiency: Signs and Symptoms
Hypoglycemia Excessive vomiting Lethargy Common flu-like symptoms Seizures Coma Sudden Infant Death Syndrome (SIDS) is also possible
MCAD Deficiency: Pathology
Accumulation of lipids in organs dependent upon fatty acid oxidation such as liver, heart, kidney, and skeletal muscle fibers, which can lead to liver failure
Accumulation of lipids may disappear without any damage once homeostasis is restored
Increased levels of intermediate metabolites of medium chain fatty acids associated with MCADD
Octanoylcarnitine (C8) is the primary MCADD marker
MCAD Deficiency: Tx
Simple carbohydrates by mouth
IV glucose to reverse catabolism and sustain anabolism
Avoid fasting
Low fat diet
L-carnitine supplements
Always monitor and inform physician during cases of poor appetite, low energy or excessive sleepiness, vomiting, diarrhea, infection, & fever
Galactosemia
Autosomal recessive disorder characterized by the deficiency of enzymes involved in the galactose metabolic pathway
Type I: Galactose-1-phosphate uridylyltransferase deficiency (classic galactosemia, the most common and most severe form); GALT mutation
Type II: Galactokinase deficiency; GALK1 mutation
Type III: Galactose-6-phosphate epimerase deficiency; GALE mutation
Galactosemia: Signs and Symptoms
Cataracts Liver cirrhosis Jaundice Mental retardation Kidney damage Lethargy Failure to thrive Death (if galactose present in diet)
Galactosemia: Newborn Screening
Urine or blood test (heel stick) that checks for enzymes needed to change galactose into glucose. If these enzymes are lacking there will be high levels of galactose in the blood and urine.
Blood Test Levels for GALT
Prenatal: Amniocentesis or Chronic Villus Sampling
Galactosemia: Tx
Avoiding all products containing lactose or galactose
Alternative diets for babies: meat based formula or soy based formula along with calcium supplement
Avoid this:
Dairy products, puddings, cookies, food coloring, instant potatoes, some canned or frozen foods (if lactose is listed as an ingredient)
Hemophilia A
X Linked Recessive
Low Factor VII levels = easily bruised/bleed internally
Signs/Symptoms: cola urine, tarry stools, coffee ground emesis
Dx: Medical health history, evaluate clotting factor assays
CBC, PTT, PT, fibrinogen tests
Tx: Prophylactic treatment or Amicar
