Flashcards in Bio Chem Enz contd 8-1 Deck (30):
This patient has a history of adrenocortical cancer and now presents with breast cancer based on the pathologic findings of her mass (the image shows high-grade invasive ductal carcinoma with prominent mitotic figures). In addition she has a strong family history (seen in her siblings and her father) of bone, breast, and blood cancers.
This family has Li-Fraumeni cancer syndrome, in which one copy of ?
the p53 tumor suppressor gene carries a mutation. This is an autosomal dominant disorder in which family members have a significantly increased risk of malignancy as children or young adults. Typical cancers include osteosarcomas, soft tissue sarcomas, early-onset breast cancers, adrenocortical tumors, and leukemias.
Mutations in APC would result in early-onset colon cancer. APC is located on chromosome 5 and is implicated in familial adenomatous polyposis coli (FAP), an autosomal dominant disorder. Patients with FAP develop hundreds of colon polyps as teenagers and young adults and are inevitably diagnosed with colon cancer by age 50. Mutations in APC can also cause Gardner syndrome, a subtype of FAP. Patients with this syndrome develop?
colorectal cancer as well as osseous and soft tissue tumors. They are also at increased risk of developing adrenal adenomas, but adrenal malignancy is rare. Gardner syndrome has not been linked to increased risk of the other malignancies seen in this family.
RET is the defective gene in multiple endocrine neoplasia type 2 (MEN2), which can be further categorized as either MEN2A or MEN2B. MEN syndromes are autosomal dominant. Patients with MEN2 syndrome are not at an increased risk of developing breast or ovarian cancer. Both MEN2A and MEN2B can manifest with?
pheochromocytoma and medullary thyroid carcinoma. Note that pheochromocytoma is a catecholamine-secreting neoplasm of the adrenal medulla, not the adrenal cortex. In addition, parathyroid tumors can also present with MEN2A, whereas marfanoid body habitus manifests with MEN2B.
BRCA1 and BRCA2 mutations are well documented familial breast cancer genes that are also associated with an increased risk of ?
early-onset ovarian malignancies. Neither gene has been shown to increase risk of other malignancies, such as the adrenal, bone, and blood cancers that patient and her family members have had.
Based on his clinical presentation of fatigue, shortness of breath, and jaundice after the administration of a new antibiotic, this patient appears to be experiencing an episode of intravascular hemolysis caused by a deficiency of glucose-6-phosphate dehydrogenase (G6PD). Patients with G6PD deficiency are more sensitive to oxidative drugs (eg, sulfa drugs, antimalarial agents) that result in the production of reactive oxygen species (ROS). Normally, when exposed to oxidative stress, red blood cells (RBCs) shunt glucose breakdown through the hexose monophosphate pathway, in which the enzyme G6PD produces reduced nicotinamide adenine dinucleotide phosphate (NADPH) from these products. NADPH allows for?
glutathione reductase to regenerate glutathione, which acts as a sink for ROS and protects hemoglobin and membranes from oxidative damage. However, when there is a G6PD deficiency, RBCs cannot produce enough reduced glutathione, resulting in oxidative damage of proteins and membranes.
Nicotinamide adenine dinucleotide (NAD+/NADH) is not involved in the hexose monophosphate (HMP) shunt. It is easily confused with NADP+/NADPH, which is involved in the HMP shunt.
Glucose-6-phosphate (G6P) is the first intermediate in the HMP shunt. Individuals with G6PD deficiency have a?
reduced ability to use this as a substrate in the HMP shunt, so G6P would be increased in this patient.
Phosphoribosyl pyrophosphate is a crucial precursor for purine nucleotides and may be decreased in patients with G6PD deficiency. However, it does not have clinically significant effects and would not be responsible for this patient’s presentation.
Reactive oxygen species, such as hydrogen peroxide, are produced by oxidizing agents such as sulfa drugs and would most likely be?
elevated, not underproduced, in this patient’s drug reaction.
This patient of African descent has severe pain in his back and legs and bony tenderness on exam, suggestive of vaso-occlusive crisis. His scleral icterus suggests ongoing hemolysis, and his family history of a father with similar symptoms who died of acute chest syndrome would suggest?
sickle cell disease.
Sickle cell anemia (HbSS) is a hemolytic disease of autosomal recessive inheritance caused by a point mutation in the hemoglobin β chain gene.Sickle cell hemoglobin, or hemoglobin S (HbS), is generated when glutamic acid at the sixth position of the β globin gene is replaced with valine. HbS occurs most frequently in populations previously exposed to Plasmodium falciparum malaria (ie, in Africa, India, and the Mediterranean).
Deficiency of the critical red blood cell enzyme glucose-6-phosphate dehydrogenase (G6PD) can lead to acute-onset hemolytic anemia and is typically seen in young men of African descent.
Decreased production of hemoglobin α chains is caused by α-thalassemia, which manifets as?
microcytic anemia. The disease’s effects vary depending on the extent of the defect and range from no symptoms to death.
Decreased production of hemoglobin β chains is caused by β- thalassemia, an inherited anemia typically found in patients of Mediterranean descent. Depending on the extent of the genetic abnormality, patients develop mild hypochromic microcytic anemia or a severe, transfusion-dependent anemia.
Deficiency of the erythrocyte cell membrane protein spectrin causes a ?
normocytic hemolytic anemia most common in patients of northern European descent. The condition, hereditary spherocytosis, would not cause the painful crises experienced by this patient and is uncommon in patients of African descent.
A 2-week-old infant is brought to his pediatrician for a well-baby check-up. His mother is concerned because he has not been feeding well and appears to have lost weight. This is confirmed on his growth chart; he has dropped from the 70th percentile for height and weight at birth to the 30th percentile in the past 2 weeks. His blood is found to contain excess amounts of leucine, isoleucine, and valine.
This infant is most likely to exhibit which of the following additional symptoms?
Maple syrup urine disease is associated with dystonia, which manifests as sustained muscle contractions resulting in twisting and repetitive movements or abnormal fixed postures. This usually manifests by 4 days of age but may not develop until the infant is 4–7 days old, depending on the amount of protein in the infant’s feeding regimen. Additionally, breastfeeding may delay onset into the second week. The mechanism for dystonia is thought to be due to altered levels of dopamine, GABA, and glutamate, and there are also associations with high serum leucine:tyrosine ratios.
Maple syrup urine disease (MSUD) can be associated with hypoglycemia, not hyperglycemia, a result of the body's inability to metabolize the three nonaromatic, nonpolar amino acids (leucine, valine, isoleucine). Hypoglycemia in these patients is most pronounced during times of fasting. Though the mechanism of the hypoglycemia observed in these patients is not completely understood, it is speculated to be ?
secondary to preferential shunting of 3-carbon substrates from amino acids into glutamine. This shunting is thought to lead to decreased oxaloacetate production and subsequently impaired gluconeogenesis. The diagram illustrates the biochemistry of MSUD.
Red urine without visible RBCs is characteristic in rhabdomyolysis, which is a rapid breakdown of skeletal muscles. This condition is associated with excessive myoglobin in the urine, not elevation of three specific amino acids.
Renal stones are associated with?
alkaptonuria, not maple syrup urine disease.
Darkening of urine is classic for alkaptonuria, a disorder of tyrosine and phenylalanine metabolism.
Blood glucose is tightly regulated after a meal by an enzyme found in muscle tissues. This enzyme catalyzes one of the steps in the pathway to convert glucose to glycogen. In addition, this process is subject to feedback inhibition by glucose-6-phosphate.
Which of the following enzymes is being described?
Hexokinase is inhibited by glucose-6-phosphate and is found in all tissues in the body. Although present to some degree in liver and β-pancreatic cells, its function is negligible in these two tissues.
Glucokinase is found in the liver and in pancreatic β cells. It does not undergo feedback inhibition, allowing the liver to take up phosphorylate glucose at higher concentrations than peripheral tissues.
Phosphofructokinase-1 catalyzes the phosphorylation of ?
fructose-6-phosphate to fructose-1,6-bisphosphate in the glycolysis pathway.
Pyruvate dehydrogenase catalyzes the conversion of ?
Pyruvate kinase catalyzes the conversion of phosphoenolpyruvate into pyruvate in the glycolysis pathway.
pyruvate into acetyl-CoA.
A young man with muscle aches, fever, a history of intravenous drug use, macular rash, and generalized lymphadenopathy is possibly suffering from ?
acute HIV infection. Western blot is a technique that utilizes protein-antibody hybridization to detect proteins. It can be used to confirm a diagnosis of an HIV infection (following a positive HIV ELISA test).
In a Western blot, protein antigens (in this case, HIV antigens such as gp41, p24 and gp120) are placed in an electrophoretic gel where they are separated by size and charge. Then the separated bands are transferred to a membrane. Finally, labeled probes are added to the membrane for visualization of the desired proteins.
Enzyme-linked immunosorbent assay (ELISA) is a test of antigen-antibody hybridization that is used to detect an antigenic match in a patient’s blood sample to determine if a person’s immune system has encountered a particular antigen. However, the process for ELISA is different from western blot. During ELISA HIV, p24 protein is added to a plate, then the patient’s serum is added and finally labeled probes are added to the plate. An ELISA does not separate proteins by size on an electrophoretic gel.
Ligase chain reaction (LCR) is a technique performed on?
mutant alleles for the purpose of detecting single-point mutations; LCR does not assist in antibody-based detection of specific proteins.
A Northern blot is used to detect RNA through RNA-DNA hybridization; it does not detect proteins.
Polymerase chain reaction (PCR) is a method used to amplify a desired DNA sequence. PCR is not used to detect protein.
A Southern blot is used to detect ?
DNA by DNA-DNA hybridization; it does not detect protein.
A Southwestern blot is used to detect DNA-protein interactions through DNA-protein hybridization. Southwestern blot is not used to detect protein alone as is done in the western blot.
The patient reports substernal chest pain radiating to the back, which is highly suggestive of aortic dissection. A new diastolic murmur in association with severe acute chest pain is a sign of acute aortic regurgitation. This is due to the dissection propagating proximal to the initial tear involving the aortic valve. Clinically, patients with this condition will have a ?
wide pulse pressure, hypotension, and/or heart failure. Acute aortic valve regurgitation occurs in one-half to two-thirds of ascending dissections and is most commonly heard along the right sternal border, unlike aortic regurgitation due to primary aortic valve disease, which is most commonly heard along the left sternal border. There are multiple causes for aortic dissections; however, the description of a tall, slender patient with long arms and fingers indicate Marfan syndrome as the most likely diagnosis.
Marfan syndrome is an autosomal dominant disorder involving the ?
FBN1 gene mutation, located on chromosome 15, resulting in a defect in fibrillin-1 synthesis. Clinical features of this disorder include excessive linear growth of the long bones and joint laxity (except at the elbows where there is decreased extension), pectus carinatum (more specific) or pectus excavatum, arachnodactyly, ectopia lentis, and aortic root disease.
Ectopia lentis is detected on slit-lamp examination after maximal dilatation of the pupil, in which the lens is usually displaced upward. Aortic root disease, leading to aneurysmal dilatation, aortic regurgitation, and dissection, is the main cause of mortality for patients with Marfan syndrome. On histology, the medial layer of the aortic root in patients with Marfan syndrome includes fragmentation of elastic lamellae, cystic medial necrosis, fibrosis, and loss of smooth muscle cells.
Atherosclerosis is associated with aortic dissection in patients over 70 years of age, which is not consistent with this young patient.
Obliterative endarteritis of the vasa vasorum is associated with tertiary syphilis leading to aortic root dilatation and aortic regurgitation; it rarely leads to dissection.
Multiple endocrine neoplasia type 2B patients have ?
“Marfanoid habitus” but do not have ectopia lentis or aortic abnormalities. Ehlers-Danlos syndrome is a defect of type III collagen synthesis, which can lead to an ascending aortic aneurysm and dissection; however, this disease is not associated with tall stature and long arms and fingers.
Homeless people often have poor access to food, especially fresh fruits and vegetables that contain vitamin C, putting them at risk for developing vitamin deficiencies. This homeless patient’s emaciated appearance, poor wound healing, and bleeding gums suggest ?
he has vitamin C deficiency, also called scurvy.
Vitamin C, or ascorbic acid, is a cofactor for the enzymes prolyl-3-hydroxylase, prolyl-4-hydroxylase, and lysyl hydroxylase, which are responsible for the hydroxylation of proline and lysine residues of collagen. Hyrdoxyproline and hydroxylysine are important for stabilizing collagen by cross-linking the propeptides in collagen to form its triple-helical structure. Hence, vitamin C deficiency causes many of its symptoms due to improper collagen formation.
Patients with decreased von Willebrand factor have a tendency to bleed. Decreased von Willebrand factor is associated with an increased partial thromboplastin time (PTT) and bleeding time, both of which are normal in this patient.
Defect in carboxylation of coagulation factors would be seen in vitamin K deficiency. It would result in an increased prothrombin time (PT) and PTT, both of which are normal in this patient.
Dysfunctional platelets may be a result of many factors, including ?
medications (for instance, NSAIDS or aspirin), liver disease, uremia, multiple myeloma, and diabetes mellitus. The characteristic symptom of dysfunctional platelets is mucosal or cutaneous bleeding. This patient has no specific risk factors for dysfunctional platelets, does not take medications, and a normal complete metabolic panel rules out liver disease and uremia.
Mutations of spectrin can lead to a disease called hereditary spherocytosis. Patients with this red blood cell membrane defect typically present with hemolytic anemia, jaundice, and splenomegaly. Bleeding is not a sign of hereditary spherocytosis.
A scientist is performing restriction mapping of various mutant and wild-type genes involved in Drosophila fly wing shape. A specimen of interest is treated with restriction enzymes, pipetted into a well in a gel that contains agarose and ethidium bromide, and subjected to an electric field. The gel is then examined under ultraviolet light.
Which of the following terms best describes this procedure?
The vignette describes gel electrophoresis. Gel electrophoresis uses an electric field to separate molecules based on size. The negatively charged DNA migrates in the electric field toward the positive end. Smaller fragments move more rapidly through the gel. Bands of DNA can be visualized by mixing ethidium bromide, a fluorescent dye, into the agarose gel as it is made.
Enzyme-linked immunosorbent assay (ELISA) is an immunologic technique to determine whether a particular antigen or antibody is present in a sample, such as a patient's blood.
Northern blots are similar to Southern blots except that in Northern blotting, RNA is separated by electrophoresis instead of DNA.
Polymerase chain reaction is a laboratory technique used to ?
produce many copies of a segment of DNA. In this procedure, DNA is mixed with two specific primers, deoxynucleotide triphosphates and a heat-stable polymerase. The solution is heated to denature the DNA and is then cooled to allow reannealing and synthesis. Twenty cycles of heating and cooling amplify the DNA more than a million times.
Sequencing is a laboratory technique that uses dideoxynucleotides to randomly terminate growing strands of DNA. Gel electrophoresis is used to separate the varying lengths of DNA. The DNA sequence can then be read based on the position of the bands on the gel.
In a Southern blot, DNA is separated with ?
electrophoresis, denatured, transferred to a filter, and hybridized with a labeled DNA probe. Regions on the filter that base pair with the labeled DNA probes can be identified when the filter is exposed to film that is sensitive to the radiolabeled probe.
In a Western blot, a protein sample is separated by electrophoresis and labeled antibodies are used as a probe. This technique can be used to detect the existence of an antibody to a particular protein.
The patient’s presentation of small size, jaundice, corneal clouding, hepatomegaly, and vomiting after milk feedings of any kind points to a diagnosis of classic galactosemia. Classic galactosemia is an autosomal recessive inherited disease caused by a deficiency of ?
galactose-1-phosphate uridyltransferase. Without this enzyme, phosphorylated galactose cannot be converted to UDP-galactose, an intermediate in the eventual conversion of galactose to glucose. As a result, galactose-1-phosphate and galactitol accumulate in various organs in the body, including the central nervous system, liver, and eyes. Long-term consequences of continued feeding with milk include cataracts and intellectual disability. Galactose and lactose (found in milk) should be avoided by patients with this condition.
Galactokinase converts galactose to galactose-1-phosphate. Deficiency results in symptoms such as infantile cataracts and developmental delay, which are associated with a milder form of galactose metabolism dysfunction.
Aldolase B deficiency causes fructose intolerance, causing ?
accumulation of fructose-1-phosphate. This results in signs of hypoglycemia, jaundice, cirrhosis, and vomiting. It does not present with infantile cataracts.