Clinical Correlations Flashcards
Errors during these processes can lead to dysfunctional proteins
Replication
Transcription
Translation
Mode of action of Streptomycin
mRNA is misread so no inititiation complex is made
Mode of action of tetracycline
Inhibition of binding of aminoacyl-tRNA to the A site
What is the mode of action of chloramphenicol?
Inhibition of peptidyl transferase activity so elongation is affected
Mode of action of Erythromycin
Inhibition of translocation of the peptidyl-tRNA to the P site
Mode of action of neomycin/gentamycin
Mistranslation of the mRNA codon so incorrect aa-tRNAs incorporated and effects initiation
What is gray baby syndrome?
An adverse reaction to chloramphenicol where mitochondrial ribosomes are mistakenly attacked over the procaryotic ribosomes. Leads to ashen grey skin, blue lips, and blue nail beds.
What does diptheria toxin target and what are the symptoms?
Targets eukaryotic elongation factor 2 (eEF-2) by ADP-ribosylation
Lesions in upper respiratory tract cause necrotic injury to epithelial cells
Targets 28S rRNA and cleaves adenine base from it. Cleavage impacts N-glycosidase activity and a loss of binding of elongation factors to large ribosomal subunit. Protein synthesis is off
Ricin
Disorder in collagen processing. Mutations in ATPase copper transporting gene and impacts lysine hydroxylase. Patients present with depigmented hair and hypotonia
Menkes Disease
I-cell Disease
Transfer of a phosphate to mannose during post translational modification of lysosomal enzymes is impaired. Lysosomal enzymes are unable to enter the lysosome and are secreted in serum. Lysosomes are dysfunctional
Patients present with inclusion bodies in fibroblasts, coarse facial features, and bone fractures and slow motor abilities
Cystic Fibrosis
Mutations in gene encoding chloride channel membrane protein (CFTR) which causes disorder in N-linked glycosylation and misfolding of CFTR.
Stickiness of fluids. Symptoms are cough, repeated lung infections, and damaged pancreas
Alpha 1 Antitrypsin Deficiency
Alpha 1 Antitrypsin is expressed in liver. Deficiency results in mutations of gene encoding alpha 1 antitrypsin protein, which causes misfolding of the protein and aggregations of it in the ER. This damages the liver cell. Parents with M allele do not develop the disease
Symptoms are liver cyrrhosis and chronic pulmonary disease due to lack of alpha1-antitrypsin
Alcohol Tolerance
Prolonged alcohol or barbiturate use lead to increase of SER which means more enzymes and faster metabolism. Need more alcohol or drugs to get same effect
Proton Leak
Protons re-enter mitochondrial matrix without contributing to ATP synthesis. In most cells it is problematic and wastes energy and creates free radicals (ROS) that damage mitochondria and cell.
Intentional proton leak in brown fat cells, mediated by uncoupling protein called thermogenin to drive non-shivering thermogenesis
Tay-Sachs Disease
Lysosomal Storage Disease. Enzyme required for break down of gangliosides is malformed so gangliosides accumulate in CNS neurons.
Zellweger Syndrome
Mutation in gene encoding receptor for peroxisomal targeting signal. Shipping label to peroxisome is correct but receptor in peroxisomal membrane can’t read it.
Results in severe neurologic dysfunction and craniofacial abnormalities and liver dysfunction
Patient presents with pellagra (dermatitis, diarrhea, dementia) and does not have eat beans, milk, eggs, or enriched flour. Patient also has alcohol use disorder. What are they deficient in?
Niacin - Vitamin B3
Patient presents with sore mouth. Smooth, swollen, magenta tonuge with stomatitis and cheilosis. What are they deficient in?
Riboflavin - Vitamin B2
Hemoglobin A1c
Early glycation product. Measures the amount of glucose attached to hemoglobin in red blood cells.
Why can bacteria digest polysaccharides like cellulose?
Bacteria can break the Beta 1,4 linked glucose
Lactose Intolerance
Lactase non-persistance.
Patient will present with recurring abdominal pain for duration of 4 months and occurs when they eat at favorite ice cream shop. After lactose ingestion, pt does not have rise in blood sugar, H2 detectable in breath, and they have acidic stool
Raffinose
Rich in legumes. Has alpha 1,6 galactosidic bond and can’t be digested. Supplements for galactosidase can help
How does a patient present with a glycolytic disorder?
Hemolytic anemia
Jaundice
Enlarged spleen
Rare congenital disorders
Occurs because red blood cells rely exclusively on glycolysis
Mutations in genes for enzymes specialized for glycolytic degradation
Inherited Errors of Metabolism
Disorder present at birth and manifest when offending substance ingested. IEM impede development and need to be addressed early to prevent disability
Essential Fructosuria
Fructokinase deficiency, fructose excreted in urine. Benign
Hereditary Fructose Intolerance
Aldolase B deficiency
Fructose-phosphate accumulates in liver
Depletes liver phosphate pools and impairs glycogen mobilization - hypoglycemia
Liver damaged with accumulation of glycogen and lack of phosphate for synthesis of ATP - jaundice
Treat by avoiding fructose and sucrose
Galactosemia
Galactose Metabolism Disorder
Many types
- Galactose 1 phophate uridyl transferase deficiency
- UDP galactose epimerase deficiency
- Galactokinase deficiency
Affected newborns present with milk intolerance and signs of liver failure (jaundice)
Thiamine deficiency
Common in alcoholic patients because alcoholism inhibits thiamine uptake and conversion to TPP.
Beri Beri
Thiamine Deficiency
Patients present with pain and paresthesia. Wet form present with symptoms of congestive heart failure. Dry form presents with symmetric peripheral neuropathy
Wernicke Encephalopathy
Thiamine deficiency in chronic alcoholism patient.
CNS impacted via mental impairment, cerebellar ataxia, horizontal nystagmus, and opthalmoplegia.
Treat with administration of thiamine.
Can progress to Wernicke-Korsakoff syndrome
Pyruvate dehydrogenase deficiency
Patient present with unexplained metabolic acidosis. Homozygous mutation in PDHX gene which encodes the E3 binding protein. The binding protein is important for the function of PDH.
Patient placed on high fat diet and limit carbohydrates
Most common mutations impact pyruvate decarboxylase (E1)
Fumarase deficiency
Elevated urinary fumarate because fumarase converts fumarate to malate.
Very rare
DNP
Potent uncoupling agent used for dieting. Works by collapsing proton gradient and bypassing ATP synthase.
What are inhibitors of electron transport chain?
Anoxia - no oxygen, no oxidative phosphorylation
Rotenone - inhibits complex I so e- can be moved from NADH to coenzyme Q
Antimycin A - inhibits complex III so electrons not transferred from coenzyme Q to cytochrome c
Cyanide - Inhibits complex IV and binds heme iron. Blocks transfer of electrons from cytochrome c to oxygen
Mitochondrial Encephalomyopathies
Defects in oxidative phosphorylation
MERRF - Associated with ragged red fibers. Due to point mutations in mitochondrial tRNA for lysine
MELAS - Mutation in mitochondrial gene encoding tRNA for leucine.
Combined oxidative phosphorylation deficiency 1 - mutation in mitochondrial elongation factor 1 gene
Combined oxidative phosphorylation deficiency 2 - mutation in mitochondrial ribosomal protein S16
Leber hereditary optic neuropathy
Mutation in genes that affect complex I of respiratory chain
Optic nerve dies and pt has sudden onset loss of vision.
Gluconeogenesis Disorder
Example: Fructose 1,6 bisphosphatase deficiency
Patient presents with fasting hypoglycemia
Metabolic acidosis
Abnormal glucagon response - no sign. increase in blood glucose
Liver stores fat instead of carbs
How will a patient with a Pentose Phosphate Pathway Disorder present?
Hemolytic anemia - red blood cells lack NADPH
Jaundice
Enlarged spleen
Glucose 6-Phosphate Dehydrogenase Deficiency
Most common in Mediterranean and African Americans. Affects more males (X-linked)
Depletes RBCs of NADPH which lowers radical stress resistance.
Hemolytic anemia
Glycogen Storage Diseases
Liver and muscle can have glycogen phosphorylase defects
Liver can have glucose 6 phosphatase deficiency
All tissues can have alpha-glucosidase defect since all tissues perform autophagy
Patient present with muscle pain, fever and dark urine. They have exercise intolerance and muscles show hypertrophy and elevation levels of glycogen and absent glycogen phosphorylase activity. No production of lactate in exercise.
Patient cannot mobilize intracellular glucose reserves during exercise.
Glycogen Storage Disease affecting the liver and is glucose 6-phosphatase deficiency
Type 1: Von Gierke
Patient presents with fasting hypoglycemia and enlarged liver. Glucose 6-phosphate builds up,
glycogen storage disease affecting all tissues. Involves acid maltase (lysosomal alpha glucosidase deficiency)
Type II: Pompe
Lysosomal storage disease that causes enlarged liver and heart.
Glycogen Storage Disease affecting muscle only. Involves muscle glycogen phosphorylase deficiency.
Type V: McArdle
Muscle unable to mobilize glycogen and results in exercise intolerance. Muscle cramps, fatigue, and burgundy urine.
What metabolic reactions occur with epinephrine?
Increase muscle ATP production
Signaling through cAMP and calcium
Liver gluconeogenesis and glycogenolysis increases
Muscle glycolysis also increases
What metabolic reactions occurs with increased cortisol?
Increase glucose supply.
Change gene transcription.
Liver gluconeogenesis and glycogen synthesis increase
Glucose deposition in adipose tissues decreases
How does a patient with alcohol use disorder present?
Fasting hypoglycemia
Metabolic Acidosis
Fatty liver - impairs uptake and storage of vitamins of carb metabolism (wernicke korsakoff and beri beri)
Hunter Syndrome
Mucopolysaccharidoses
X-linked disorder and patient presents with skeletal abnoramalities and intellectual disability
Hurler-Scheie Syndrome
Mucopolysaccharidoses
Elevated urine glycosaminoglycan.
Defective alpha iduronidase enzyme. Inability to degrade dermatan and heparan sulfate. Results in skeletal abnormalities and intellectual disability.
Sanfilippo Syndrome
Mucopolysaccharidoses
Mild defects
What will low UDP-UGT activity result in?
Patient will have inability to transfer glucuronic acid which causes buildup of molecules like bilirubin.
Bilirubin UGT defects cause non-hemolytic jaundice
Gilbert Syndrome - most common
Crigler Najjar Syndrome - severe
