Pathology_Unit 5A

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21 terms · Developmental (Part 2)

Does everyone with autosomal recessive disorders have UNIFORM penetrance AND expression?

Yes!

A mutation in the gene coding for what often leads to an autosomal recessive disorder?

Mutation in gene coding for an enzyme

LYSOSOMAL STORAGE DISEASE (LSD):
-Autosomal dominant or recessive?
-What is the mechanism of action behind lysosomal storage disease?
-What are common clinical findings with LSD?
-How are LSDs classified?
-How are individual diseases classified?

-Autosomal recessive
-Enzymes are usually degraded in the lysosome by lysosomal enzymes into small diffusable end products; however if one or more of the degradative enzymes inside of the lysosome is missing, there is a build up of enzyme inside of the lysosome which causes the lysosome to distend
-1) CNS dysfunction, 2) Bone dysplasia, 3) Hepatosplenomegaly, 4) Death in childhood
-Classification is by the type of substrate that accumulates
-Individual diseases is classified by the enzyme that is missing

MNEMONIC: the huge LYSOSOME began to LYSE the STORE that had BONY (bone dysplasia) children with HEPATOSPLENOMEGALY by cutting out their BRAINS leading to a lot of DEAD children everywhere

MUCOPOLYSACCHARIDOSES (AKA GAGs):
-What enzyme is deficient?
-Where are GAGs found?
-What are 4 common GAGs?
-What is the prognosis of mucopolysaccharidoses?
-All types of mucopolysaccharidoses are autosomal recessive except for which type?

-The enzyme needed to break down GAGs (glycosaminoglycans)
-GAGs are found in the ECM
-GAGs: 1) Dermatan sulfate, 2) chondroitin sulfate, 3)heparin sulfate, 4) keratan sulfate
-Progressive degeneration (start off normal than began to get 1) mental retardation, and 2) Dysostosis (Bone and Joint Disease=>stiff joints) Multiplex)
-Type II is X-linked (Hunter's Syndrome)
-Clinical: Clouded cornea, course facial features, mental retardation, skeletal and joint dysplasia, cardiac valve sclerosis and subendothelial coronary artery deposits

MNEMONIC:
1) most hunters are men (hunter's syndrom is x-linked)
2) mucous (MUCOPOLYSACCHARIDOSES) in my eye CLOUDS (cloudy cornea) my vision and i accidentally drink too much alcohol during my hard COURSE (coarse facial features) leading to MENTAL RETARDATION and problems with my JOINTS AND BACK (joint and skeletal dysplasia). i hope that i dont break my mother's HEART with the bad news since she does eat a lot of fatty foods leading to CORONARY ARTERY DEPOSITS AND CORONARY VALVE SCLEROSIS

Glycogenosis Type II (Pompe Disease):
-What is unique about Glycogenosis Type II? (Pompe Disease)
-What enzyme is deficient?
-What results from an increase in glycogen in cells?

-Only type of glycogenosis with a deficiency of an enzyme within the lysosome; the other types of glycogenolysis have enzyme deficiencies within the cytoplasm
-Lysosomal Acid Maltase
-Hepatomegaly, Cardiomegaly, Hypotonia, Death in infancy and childhood

MNEMONIC:
If there is excess FAT (glycogen) around your HEART AND LIVER, you may DIE YOUNG from lack of TONE (hypotonia) and never have a chance to be a Pom Pom (POMPE) girl

GAUCHER DISEASE:
-What enzyme is deficient?
-Where would the substrate accumulate?
-What is the name of the distended cell?
-What is the appearance of the cytoplasm in Gaucher cells?
-Clinical Presentation?
-Treatment?
-Affect on CNS?

-Deficiency in glucocerebroisidase which cleaves glucose from ceramide in membranes during turnover
-Macrophages
-Gaucher cells
-The cytoplasm is like wrinkled tissue paper
-Hepatosplenomegaly and pancytopenia (decr. in WBCs) due to hypersplenism and Gaucher cells in spleen, liver, lungs, nodes, and marrow
-Treatment: Enzyme Replacement
-does NOT affect CNS; therefore enzymes for not have to cross BBB

MNEMONIC:
oh my GOSH (gaucher disease), it is a magic trick, because as he pats his LIVER AND SPLEEN they began to ENLARGE and WBC'S leave the spleen (pancytopenia) and go into his black MAC (macrophage) cane and NOT into his BRAIN. hopefully he'll REPLACE the ENZYMES that he took toMORROW (marrow) so that i wont LOOSE MY BREATH (lungs)

TAY SACHS (GM2 GANGLIOSIDOSIS):
-What enzyme is deficient?
-What substrate accumulates? Where?
-What ethnic background is TS common in?
-Clinical Presentation?

-Deficient in hexosiminidase A
-Accumulation of GM2 GANGLIOSIDES in neurons
-Eastern European Ashkenazi Jewish
-Clinical Presentation: Progressive mental and motor deterioration, ataxia, blindness, dementia, death by 3 yrs., cherry red spot on macula by retina

MNEMONIC: this guy named TAYLOR (tay sachs) must be DEMENTED b/c he claims that he's SACKED (tay sachs) 6 girls in our class, but they said he has PROGRESSIVE MOTOR AND MENTAL deterioration, b/c he cannot get an erection and when he finally does he is so DISORIENTED (ataxia) that he cums in girls' eyes making them BLIND and DEAD within 3 yrs. If he keeps lying, a GANG (gangliosides) will ACCUMULATE and definitely BUST HIS CHERRY (cherry red spot on retina at the macula)

NIEMANN-PICK DISEASE:
-What is deficient?
-What accumulates?
-Where is it commonly found (which organs)?
-With which ethnicity is this prominent?

-Sphingomyelinase deficiency
-Zebra bodies (sphingomyelin) accumulates in fixed tissue macrophages and neurons
-Found in liver, spleen, lungs, nodes, bone marrow, brain
-Ashkenazi Jewish
-Clinical: severe as an infant: failure to thrive, psychomotor deterioration, massive hepatosplenomegaly

MNEMONIC: the MAN PICKED (niemann-pick disease) a branch from the tree to make a SLINGshot (SPHINGOmyelinase) that can shoot a MILE (sphingoMYELINASE) to kill the MAC (macrophages) INFANT zebras in the BRAIN (neurons ) for ACCUMULATING all of the branches and preventing him from making slingshots

What are 5 possible treatments for LSDs?

1) Gene therapy
2) Enzyme Replacement Therapy
3) Bone Marrow Transplant
4) Supportive care
5) Substrate Reduction Therapy

CYSTIC FIBROSIS (CF):
-What secretions are hindered?
-What gene is mutated and what effects does that have?
-Describe the MOA behind salty sweat.
-Describe the MOA behind dehydrated mucous in the airways
-What are secondary effects of thick mucous in the airways?
-What are 4 microbes that may cause CF?
-How does CF present clinically?
-6 Possible treatments?

-Exocrine glands, epithelium of respiratory, GI, reproductive tract
-CFTR gene is mutated which hinders the transport of Cl- across the epithelial membrane via the CFTR channel
-Salty sweat occurs when there is a mutation in CFTR gene preventing the utilization of CFTR as a transmembrane channel allowing Cl- into the cell. The CFTR channel and the Na+ channel work together, so if no Cl- gets into the cell, no Na+ gets into the cell. This causes increase salt in sweat.
-In the airways, CFTR normally allows Cl- out of the airway and has an inhibitory affect on Na+ (and consequently H2O) coming into the cell from the airway. If CFTR is not functioning properly, Cl- will stay in the cell (unable to escape) and Na+ and H2O will loose their inhibition and instead flood into the cell. If all of the water goes into the cell, there is none left to moisturize the mucous in the airway which leads to dry mucous membranes
-Thick mucous in the airways causes airway obstruction and possible infections. The incr. in infection will lead to an incr. in neutrophil response
-1) S. aureus, 2) H. influenzae, 3) P. aeruginosa, 4) Burkholderia Cepacia
-Pancreatic insufficiency (exocrine atrophy, endocrine is fine with the islets), malabsorption (fatty stinky stool), malnutrition, abdominal distension, poor weight gain, biliary cirrhosis due to bile inspissation, intestinal obstruction, block epididymis, azospermia, meconium ileus (baby's first bowel movement is blocking the small intestine b/c of impacted vicid mucin causing a distended abdomen)
-Treatments:1) CFTR modulation, 2) gene therapy, 3) restore airway surface liquids, 4) mucous alteration, 5) anti-inflammatory, anti-infectious, 6) transplantation

MULTIFACTORIAL DISORDERS:
-What is the recurrence risk for multifactoral disorders as compared to the general population? Compared to monogenic disorders?
-What % of siblings get the disorder if 1 sibling is affected?
-What % of siblings get the disorder if 2+ sibling is affected?
-What are 4 multifactorial disorders?

-The recurrence risk for multifactoral disorders is higher than risk in general population, but lower than the risk for monogenic disorders
-2-7% of siblings get the disorder if 1 sibling has it
-9% of siblings get the disorder if 2+ siblings has it
1) Congenital heart malformations 2) Cleft lip/cleft palate 3) Pyloric stenosis 4) Neural Tube Defect

PYLORIC STENOSIS:
-Which nationality has higher incidence?
-How is it treated?

-1/250 Caucasians
-Projectile vomiting/palpable olive
-Treat with pyloromyotomy

SMALL FOR GESTATIONAL AGE; INTRAUTERINE GROWTH RESTRICTION (IUGR):
-What is SYMMETRIC IUGR?
*Which organs are affected?
*What are some fetal causes of symmetric IUGR?
-What is ASYMMETRIC IUGR?
*Which organs are affected?
*What are some fetal causes of symmetric IUGR?

-Symmetric: small head and small abdomen
*Affects all organ systems equally
*Fetal causes: trisomy, infections, malformations
-Asymmetric: normal head and small abdomen
*Brain is spared relative to the viscera
*Placental or maternal causes

LARGE FOR GESTATIONAL AGE:
-What are 2 causes?

-2 causes: 1) maternal obesity, 2) maternal diabetes

MATERNAL DIABETES:
-What can be seen a few hours after delivery?
-How is hyperinsulinemia displayed in the histology of the fetus? In the organs, fat, and muscle?
-What 4 things is the fetus at an increased risk for?
-What is a key word for a physical finding of infants with maternal diabetes?

-Hypoglycemia, b/c while in utero, the fetus develops hyperinsulinemia to combat the hyperglycemic levels of its mother, but when it is delivered and removed from the mother's circulation, it's glucose levels drop, but the insulin levels remain high. This large amount of insulin removes lots of needed glucose from the blood resulting in hypoglycemia.
-Hyperplasia/hypertrophy in the islets of the pancreas along with organomegaly and increased fat and muscle
-Increased risk of: 1) malformations, 2) fetal demise 3) RDS (respiratory distress syndrome; hyaline membrane disease), 4) Birth Trauma
-Caudal Regression Syndrome

What are 2 main causes of premature births?

1) Chorioamnionitis
2) Premature membrane rupture

What are 3 organs that are most affected by premature births? How?

Lungs => Hyaline Membrane Disease
Brain =>Germinal matrix; intraventricular hemorrhage
Gut => Necrotizing enterocolitis

HYALINE MEMBRANE DISEASE (HMD):
-How does it present clinically?
-What is the correlation between gestational age and incidence of hyaline membrane disease?
-What is the MOA behind HMD?

-Respiratory distress, cyanosis, "ground glass" appearance of x-ray
-They are inversely proportional (increase in gestational age = smaller incidence of HMD)
-Type II pneumocytes are not capable of producing surfactant (reduces alveolar surface tension, so less pressure needed to keep alveolar open) until after week 32-34. This causes atelectasis (collapse of all or part of lung) leading to hypoxia and CO2 retention => acidosis => pulmonary vasoconstriction => pulmonary hypoperfusion => endothelial and epithelial damage =>plasma protein leak into alveoli => fibrin and cell debris (aka: hyaline membrane)

SURFACTANT:
-What causes an increase in surfactant (4 things)?
-What causes a decrease in surfactant (2 thing)?

-Increase: steroids, labor, thyroxine, fetal stress
-Decrease: Premature, high insulin levels (seen in babies born from diabetic mothers)

INTRAVENTRICULAR HEMORRHAGE:
-What is the MOA?

-The vessels around the germinal matrix receive a lot of blood flow, but they are very fragile. In a situation of prematuration, there is hypoxia and increased venous pressure leading to rupturing of the vessels. This blood pools into the intraventricular space.

NECROTIZING ENTEROCOLITIS:
-How does it present clinically?
-Under what weight is this common?
-What is treatment for NE?
-What are 3 common causes of NE?
-What part of the bowel does NE most commonly affect?

-Clinically: abdominal distension, gas in the bowel wall (pneumatosis), shock, bloody stools
-<1500g
-Treatments: Antibiotics, support surgery
-Enteral feeding + Ischemia + Immature mucosa
-Most commonly affects: Right colon, cecum, and terminal ileum

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