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
Duchenne Muscular Dystrophy
X-Linked disease that is associated with deletions or frame shift mutations of dystrophin gene
Do not present symptoms in infancy
Dystrophin: Provides myofibril stability by binding actin filaments and β-dystroglycan
Defects lead to membrane tears causing calcium influx causing muscle degeneration that is greater than repair which leads to replacement by collagen and fat cells
Duchenne Muscular Dystrophy: Signs and Symptoms
Not seen at birth
Walking is delayed and unstable
Pseudo-hypertrophy of the lower leg
Patients are wheelchair bound by the age of 10
They have a life expectancy of 25-30 years
Eventually succumbing to respiratory insufficiency or heart failure
Cardiomyopathy and arrhythmias develop in older patients
Breathing problems
Cognitive impairment is also seen in patients
Joint contractures and scoliosis
Gower’s Sign- getting up to standing position relying on arms
Duchenne Muscular Dystrophy: Dx
Genetic testing showing a mutation of dystrophin on the X chromosome
Blood tests showing an increased serum creatine kinase
Muscle Biopsy showing muscle degeneration and the presence collagen and fat cells
Duchenne Muscular Dystrophy: Tx
Braces: orthoses that support the foot and ankle or may even extend to the knee
May be required to be worn at night
Standing frames & wheelchairs
Mechanical lifts, shower chairs, & electronic beds
Medications
Corticosteroids to aid in muscle development early on
ACE inhibitors or Beta blockers can be used in cases with heart damage
Therapy
Range of motion & stretching exercise
Low impact aerobics
Breathing aids as respiratory muscles weaken
Tyrosinemia I
Build-up of Fumarylacetoacetate
Defective Enzyme: Fumarylacetoacetate Hydrolase
Transmission: Autosomal Recessive
Tyrosinemia Type 1 deficiency. Characteristic “Cabbage-Like Smell”, jaundice, excessive bleeding
Increased levels of fumarylacetoacetate are toxic to the kidney and liver, and lead to increased risk of hepatocarcinoma development
Tyrosinemia II
Defective Enzyme: Tyrosine Aminotransferase (TAT)
Product Accumulated: Tyrosine
Transmission: autosomal recessive
Early SX:
Photophobia
Skin lesions/yellow tinted calluses on hands and feet
Behavior/coordination changes, neurological defects, ataxia
*Symptoms occur most often after eating
Tyrosinemia III
Defective Enzyme: 4-hydroxyphenylpyruvic acid Dioxygenase (HPD)
Product Accumulated: 4-hydroxylphenylpyruvate
Transmission: Autosomal Recessive
While there are many mutations, some result in the production of a truncated protein.
This causes CNS issues including:
1) Mental Impairment 2) Seizures 3) Ataxia
Alkaptonuria
AKA: Black Urine Disease
Defective Enzyme: Homogentisate-1,2-Dioxygenase
Product Accumulated: Homogentisate
Transmission: Autosomal Dominant
This causes CNS issues including:
1) Black/Ink-Looking Urine
2) After 30 years = weight-bearing joint pain
3) Pigmentation of the sclera and cartilage of the ear
4) Heart Failure
Tyrosinemia/Alkatouria Testing
Neonates have screening tests for various genetic aberrations, including enzymatic deficiencies in the Tyrosine Catabolic Pathway
If testing shows an anomaly, characterized as an “out-of-range” value, the physician will instruct the parents to have confirmatory testing performed such as urine and blood sampling
Cystinuria
Autosomal recessive disorder
Affecting genes SLC3A1 and SLC7A9 on chromosomes 2 and 19 respectively
Causes malabsorption of basic or positively charged amino acids like Arginine, Cystine
Genetic disease resulting in defective transport proteins that reabsorbs cystine into the renal tubular cells
Results in clumping and precipitation of cystine into stones
Cystinuria: Signs and Symptoms
Asymptomatic when no stones
Nausea, vomiting, dull ache, pain that starts and stops abruptly, hematuria (reddish brown urine), hydronephrosis, and pyelonephritis
Severe pain in the flank that radiates around the left side towards the pubic area
Excruciating pain when passing the stone
Cystinuria: Dx
Perform a routine CBC
Blood sugar, urea, and creatinine test
Look in urine for crystals
Cyanide nitroprusside test
Ultrasound and CT can be used, but are not reliable
Genetic analysis to determine which mutation they have
Give contrast by IVP, then use X-ray to determine
Just X-ray gives a fuzzy gray appearance due to the sulfur content
Cystinuria: Tx
Adequate hydration
Alkalization of the urine
Reduce salt and protein intake (especially methionine)
Diet restrictions can prevent them
ESWL (Extracorporeal Shock Wave Lithotripsy)
If this does not work, then surgical removal (large stones)
Phenylketonuria (PKU)
Autosomal Recessive
Defective mutated genes for the enzyme phenylalanine hydroxylase (PAH)
This enzyme is active in the liver, where it converts dietary phenylalanine into tyrosine
If untreated, phenylalanine concentrations build up in the bloodstream and cause permanent damage to the brain
Phenylketonuria (PKU): Signs and Symptoms
Eczema (skin rash) Mental retardation Hyperactivity Seizures Tremors Autism Delayed mental and social skills Unusual positioning of the hands Jerking movements of the arms or legs Mousy or musty odor of breath, skin, and urine Lighter skin, hair, eyes than brothers or sisters without the disease
PKU: Dx
Guthrie Test in newborns
High levels of Phe in the blood sample overcome the inhibition, and allow the bacteria to grow. If an elevated level of Phe is detected, the child is placed on a phenylalanine-restricted diet for the first several years
PKU: Tx
Avoid high Phe foods: fish, dairy, diet soda, wheat, eggs, nuts/legumes, and meat
Eat low Phe foods: vegetables, fruit, sugars, low protein foods, special breads/cookies/crackers
Extra BH4 (Kuvan) cofactor helps stabilize protein folding in some cases Phenylalanine ammonia lyase: bacterial enzyme for breaking down Phe Large neutral amino acids: competitors for Phe transporters in the brain
Osteogenesis Imperfecta
Autosomal Dominant
Most common mutations site are within the helical structure itself at the COL1A1 or COL1A2 genes
Mutation may result in either a change in the structure of type 1 collagen or in the number of collagen molecules made
Mutation location dictates severity of OI
Other possible gene mutations: CRTAP and P3HI (autosomal recessive)
Osteogenesis Imperfecta: Characteristics
Short stature Muscle weakness Scoliosis Bleeding (hematoma) Hearing loss Breathing problems Discoloration of sclera
Osteogenesis Imperfecta: Dx
No definitive OI diagnostic exam Occurrence of fractures Common characteristics Differential DX of child abuse Quality/quantity of Type 1 collagen DNA sequencing COL1A1 and COL1A2
Osteogenesis Imperfecta: Mild Form Histology
Osteoporotic bone present
Thick osteoid seams and reduced intercellular matrix
Osteoclasts and osteocytes are normal
Bone trabecullae are thin and disorganized
Lamellar bone in diaphysis and metaphysis
On electron microscopy → Osteoblasts show distended rough ER
Collagen fibers are reduced in diameter
Osteogenesis Imperfecta: Severe Form Histology
Severe form:
Reveals hyperosteocytosis and increased vascular channels
Reduced cortical bone thickness
Lack of normal cortical bone formation
Disorganization of the growth plate
Give “popcorn calcification” appearance
Woven bone is seen, with minimal osteoid bone and no lamellar bone
Osteogenesis Imperfecta: Types
Types I-IV: dominant mutation in gene coding for type I collagen
Types V-VI: unknown mutation; no type I collagen mutation
Types VII-VIII: Recessive mutation in two genes that affect collagen
Most severe Type II (early death) Type III (usually wheelchair bound)
Least severe Type I (Most common
Junctional Epidermolysis Bullosa (JEB)
Also known as butterfly children, cotton wool babies, and crystal skin children
Mutations in adhesion proteins
Autosomal recessive
Two different types:
Herlitz JEB = more severe
Non-Herlitz JEB = very mild
Diagnosis: skin biopsy, genetic screening for implicated genes
JEB: Signs and Symptoms
Blistering over large regions of the body
Scarring and red, bumpy patches of granulation tissue
Serious infections
Loss of proteins, minerals, fluids
Buildup of granulation tissue in airway
Weak, hoarse cry and difficulty breathing
Abnormalities of fingers and toes
Malformed fingernails and toenails
Alopecia
Irregular tooth enamel
Non-Herlitz JEB has milder symptoms, conditions improve after newborn period
Herlitz JEB has very severe symptoms involving multiple organ systems
JEB: Pathology
Non-functional adhesion proteins
The epidermal layers easily detach from the dermis leaving it exposed to the external environment
Accumulation of fluid/mucus causing blisters
High risk of bacterial infections
Lesions are non-healing or very slow to heal
Affects all areas where epithelial tissues are present
Airway
GI tract
JEB Tx
Manage the symptoms Drain and dress wounds appropriately Antibiotics for infection antibacterial for prevention Monitor fluid loss. Surgery C-section: reduces trauma to infant
Can be fatal in severe JEB
Retinoblastoma
Rare type of eye cancer that develops in early childhood caused by mutated RB1 gene
Hereditary (40%): occurs when a defective RB1 allele is inherited from one or both parents
In the case of inheriting one defective RB1 allele, the other “good” allele must eventually undergo mutation for retinoblastoma to develop
One or both eyes can be affected and increased risk for developing other secondary cancers
Non-Hereditary (60%): arises from a mutation of both RB1 alleles within the cells of the eye
Usually only one eye is affected
No increased risk of developing secondary cancers in other areas of the body since the rest of the body has normal RB1 function
No risk of passing on to children
Retinoblastoma: Signs and Symptoms
Leukocoria, “cats eye”.
A whitening/cloudiness of the eye is usually the first sign noticed by parents.
Photographic “red eye” present in only one eye may be a sign
Complaints of poor vision
Strabismus: deviation of one or both eyes either inward or outward.
Complaints of pain in the affected eye(s) due to increased intraocular pressure as the tumor grow
Retinoblastoma: Dx
Diagnosis by physical examination (fundoscopic).
Confirmation and further classification/staging by imaging.
MRI is the preferred imaging modality, but ultrasound and CT may also be used
Retinoblastoma: Pathology
Grossly appears as a white elevated mass with fine surface vessels.
Microscopically appears as small, round-cell tumor.
Flexner-Wintersteiner rosettes- characteristic finding in retinoblastoma
Circular arrangement of cuboidal or short columnar tumor cells surrounding a central lumen. Nuclei displaced away from lumen
Hereditary Non-Polyposis Colorectal Cancer (Lynch Syndrome)
Autosomal Dominant: effects mismatch repair genes and leads to accumulation of genetic damage
Dx: MRI or IHC of tumor tissue, + gene test, or blood test
Screening: colonoscopy, barium enema, stool hemocult tests
MERRF
Myoclonic Epilepsy with Ragged Red Fibers
Mitochondrial disorder that primarily affects the muscle and nervous system
Caused by point mutation in the tRNA genes of mitochondrial DNA (mtDNA)
Without functioning tRNA, proteins essential for oxidative phosphorylation cannot be synthesized and the mitochondria cannot create ATP
Has largest effect on cells with the highest energy requirements
MERRF Testing and Tx
Testing
Lactic acidosis in blood and CSF (increased lactate and pyruvate)
Elevated CSF protein concentration
Muscle biopsy, genetic testing
Treatment
Coenzyme Q10 and L-Carnitine given in an attempt to improve mitochondrial function
No actual cure for the disease
Treatment for management of symptoms
MERRF: Signs and Symptoms
Main Symptoms:
Myoclonus (muscle twitches)
Generalized epilepsy
Ataxia (difficulty coordinating movements)
Ragged-red fibers (in muscle biopsy) or mtDNA pathogenic variant identification
Other symptos: myopathy (weakness) and spasticity (stiffness), exercise intolerance, short stature, hearing loss, optic atrophy and poor night vision, peripheral neuropathy (loss of sensation in extremities), dementia (deterioration of intellectual function), lactic acidosis
β-Thalassemia
A relatively common genetic blood disorder involving reduced production of hemoglobin
Major symptoms: anemia and predisposition to abnormal blood clotting
Two Main Types:
Thalassemia Major (aka Cooley’s Anemia)
Thalassemia Intermedia
Genetics: HBB Gene; Beta knot (no beta chains) and beta + (reduced beta chains)
Autosomal Recessive
Reduced production of adult hemoglobin (HbA) due to reduced or no synthesis of beta chains
Leads to reduced red blood cell formation (erythropoiesis)
β-Thalassemia Major
The more severe form of the disease
Signs & Symptoms Appear within first 2 years of life Development of life-threatening anemia Failure to thrive Jaundice Enlarged spleen, liver, and heart Misshapen bones Delayed puberty
β-Thalassemia Intermedia
A milder form of the disease
Signs & Symptoms:
Can appear early in in childhood or later in life
Mild to moderate anemia
Possible slow growth and bone abnormalities
Diagnosis generally between 6 and 12 years of age
β-Thalassemia: Dx and Tx
Dx: Blood tests, CBC, DNA tests, blood smears, family history
Hemoglobin Tests – check for types present
Tx:
Blood transfusion- required for survival in cases of Thalassemia Major, and improves quality of life in Thalassemia Intermedia
Complications: buildup of iron in body over time leading to heart, liver, and hormone problems
Chelation therapy to get rid of excess iron
Folic Acid Supplements
Bone Marrow transplant
Future treatments: induce production of different types of hemoglobin
β-Thalassemia: Histology
Red blood cell abnormalities in size and shape
Target cells
Basophilic stippling
Fragmented red cells
Nucleated immature red cells in periphery
CPS I Deficiency
CPS 1 Deficiency is an autosomal recessive metabolic disorder mutation in the CPS 1 gene
Disorder results in a shortage of Carbamoyl Phosphate Synthetase 1, a key enzyme in the urea cycle
Inability for nitrogenous waste to be properly metabolized
Leads to a buildup of ammonia within the body
In healthy individuals
CPS I Deficiency: Signs and Symptoms
Lethargy, hypotonia, vomiting, seizures
Labs: high levels of ammonia, glutamine, and glutamate
The blood work indicated an underperforming liver
Genetic testing also ordered
A liver biopsy would show pale, swollen hepatocytes
CPS I Deficiency: Tx
Reduced protein intake
A special ammonia reducing medication= Sodium Benzoate
Recommends a special low protein formula
