UWorld 3.17.16 Flashcards
Discuss Hartnup disease
-intestinal and renal absorption of tryptophan defective
-essential amino acid and precursor for nicotinic acid, serotonin, melatonin
-niacin deficiency since trp precursor to niacin
-most children with Hartnup are a symptomatic, but some experience:
Photosensitivity, pellagra-like rashes
*neurologic involvement- ataxia
-neurologic and skin symptoms wax and wane during course of disease
Lab finding: aminoaciduria restricted to neutral amino acids (alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine)
-proline, hydroxyproline and arginine unchanged => differentiates Hartnup from generalized aminoaciduria such as Fanconi syndrome
Tx: treatment with nicotinic acid or nicotinamide and high protein diet => improvement in symptoms
Discuss the clinical relevance of the following supplements:
- thiamine
- riboflavin
- folic acid
- pyridoxine
- tocopherol
- ascorbate
- Thiamine- cofactor for transketolase in pentose phosphate, alpha-KG DH, Pyruvate DH; maximal use in accelerated carbohydrate metabolism
- Riboflavin-flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)- prosthetic groups of enzymes for electron transport. Both from riboflavin (B2); deficiency => cheilosis [perleche], glossitis, keratitis, conjunctivitis, photophobia, lacrimation, marked corneal vascularization, seborrheic dermatitis
- Folic acid- deficiency => megaloblastic anemia, but no neurological manifestations as B12 deficiency [subacute combined degeneration of posterior and lateral columns]
- Pyridoxine B6- converted to pyridoxal-5-P => coenzyme in decarboxylation and transamination of amino acids; deficiency => anemia, peripheral neuropathy, dermatitis
- Tocopherol = Vit E => fat soluble vitamin- scavenger of free radicals (antioxidant); deficiency is rare => myelopathy or neurologic dysfunction
A 46 yo chronic alcoholic comes in with recurrent epistaxis, swollen gums, scattered ecchymoses, hyper keratosis. Also has chronic ulcer on lower left extremity that does not appear to be infected. Which mechanism accounts for this patient’s exam findings?
- Abnormal oxidative decarboxylation of keto acids
- abnormal proline hydroxylation
- abnormal transamination
- deficient methionine synthesis
- diminished synthesis of purines
Vit C deficiency => scurvy- most often seen in severely malnourished individuals [homeless, alcohol, drug abusers]
Symptoms from decreased connective tissue strength
Capillary walls fragile => easy bruising, mucosal bleeding, peri follicular petechial hemorrhages
-periodontal disease- gum swelling, loosening of teeth, infection
-poor wound healing
-hyper keratitis follicles with corkscrew hairs
-much more severe in children => hemorrhages, bony deformities, sub periosteal and joint hematomas
Need Vit C for hydroxylation of proline and lysine during collagen synthesis- prolyl and lysyl hydroxylases with Vit C as reducing agent
-hydroxyproline and hydroxylysine essential for cross-linking collagen molecules
If there is abnormal oxidative decarboxylation of keto acids, what vitamin deficiency are you thinking?
Thiamine- B1- coenzyme in decarboxylation reactions by DH enzymes
- pyruvate to acetyl CoA
- alpha-KG to succinyl CoA
- Peripheral neuropathy + heart failure [beriberi]
- CNS dysfunction [Wernicke Korsakoff]
If there is abnormal transamination, what vitamin deficiency are you thinking of?
Pyridoxine B6- cofactor in reactions involving amino acids- transamination, decarboxylation, deamination
- seborrheic dermatitis
- glossitis
- peripheral neuropathy
- cheilosis, stomatitis
If there is deficient methionine synthesis, what vitamin deficiency are you thinking of?
Cobalamin B12- synthesis of methionine from homocysteine [methyltransferase], and succinyl CoA from methylmalonyl CoA [isomerase]
Deficiency => megaloblastic anemia and subacute combined degeneration of spinal cord
If there is diminished synthesis of purines, what vitamin deficiency are you thinking of?
Folate B9- purine and thymidine synthesis with folate deficiency. Decreased ability of erythropoietic cells to form DNA => megaloblastic anemia
[hydroxymethyl/formyl carrier]
-neural tube defects- fetus
Talk about the primary function and deficiency issues with:
- B2
- B3
B2- riboflavin- mitochondrial hydrogen carrier- FMN, FAD- angular cheilosis, stomatitis, glossitis, normocytic anemia
B3- Hydrogen acceptor (NAD/NADH)- pellagra- dermatitis, dementia, diarrhea
21 yo male with vision impairment has bilateral lens opacities, a symptomatic, no specific diet; labs show urinary excretion of large amounts of galactose.
bilateral cataracts with excretion of galactose => galactokinase deficiency- galactosemia- benign disorder- no hepatocellular manifestations
- elevation of galactose levels; excess circulating => galactitol via aldose reductase, and galactonic acid by galactose oxidase [metabolized by HMP shunt], galactitol accumulates in cells => responsible for cataracts with galactokinase
- Tx: dietary restriction of lactose improve symptoms of all forms of galactosemia
Vs. Classic galactosemia - galactose-1-P uridyl transferase deficiency- most common form
GALT deficiency- vomiting, lethargy, failure to thrive after feeding begins; impaired liver function, hyper choleric metabolic acidosis, aminoaciduria- severe symptoms after initiation of breast feeding
78 yo suffers nausea, anorexia, fatigue, skin rash on her legs; she is mildly demented, severe malnutrition; organic aciduria. Suspect biotin deficiency. What would be impaired?
- pyruvate to alanine
- pyruvate to oxaloacetate
- glucose to ribose-5-P
- Pyruvate to acetyl-CoA
- Succinate to oxaloacetate
-pyruvate to oxaloacetate
Biotin CO2 carrier on surface of carboxylase enzyme
*acetyl-CoA carboxylase
*pyruvate carboxylase
*propionyl carboxylase
*beta-methylcrotonyl CoA carboxylase
-carb and lipid metabolism
-in people deficient in biotin => pyruvate converted to lactic acid instead of oxaloacetate => metabolic acidosis
-propionyl CoA builds up, metabolized into surplus of odd-chain fatty acids
-secondary to poor diet, excessive raw egg white consumption (avidin), congenital disorders
Resection of the pituitary gland in a lab rat shows decreased production of epinephrine by the adrenal medulla. Decreased activity by which enzyme would most likely be responsible for this?
- COMT
- dopa decarboxylase
- dopamine beta-hydroxylase
- MAO
- Phenylalanine hydroxylase
- Phenylethanolamine-N-methyltransferase
- Tyrosine hydroxylase
Catecholamine synthesis:
Phenylalanine –> Tyrosine [phenylalanine hydroxylase, liver] –> DOPA [tyrosine hydroyxlase] –> dopamine [dopa decarboxylase] –> norepinephrine [dopamine beta-hydroxylase] –> epinephrine [PNMT- phenylethanolamine-N-methyltransferase]
*PNMT is positively regulated by cortisol –> pituitary resection reduces ACTH, which stimulates cortisol
3 yo boy recently immigrated to US, has not begun to walk or speak. Severe intellectual disability. Dies 6 months later from refractory seizures => respiratory failure
Autopsy- pallor of the substantial nigra, locus ceruleus, Vagal nucleus dorsalis. Underlying condition most likely caused by deficiency of which enzyme?
-branched-chain ketoacid dehydrogenase
-dopamine hydroxylase
-homogenous if acid oxidase
-phenylalanine hydroxylase
-Tyrosinase
Severe intellectual disability, history of seizures, abnormal pallor of catecholaminergic brain nuclei => phenylketonuria (PKU)
- inability to convert phenylalanine into tyrosine- normally catalyze do by phenylalanine hydroxylase- requires BH4 [tetrahydrobiopterin], regenerated from dihydrobiopterin [BH2] by dihydropteridine reductase
- most cases of neonatal hyperphenylalaninemia caused by phenylalanine hydroxylase
- excess phenylalanine and metabolites [phenyllactate, phenylacetate] => brain damage
- hypo pigmentation- skin, hair, eyes, catecholaminergic brain nuclei [dark pigment, neuromelanin]- inhibitory effects of excess phenylalanine on melanin synthesis
- musty/mousy body odor- accumulation of abnormal phenylalanine metabolites
14 mo old boy evaluated for failure to thrive, developmental delay. At 12 mo, barely lift his head, difficulty sitting unsupported. Toddler has not started babbling or forming words. Labs: Hemoglobin: 8.6g/dL MCV: 114fL Relics: 1% Ammonia, plasma: 42ug/dL normal: 40-80ug/dL Urine specimens- large amounts of orotic acid crystals. What can you supplement? -ascorbic acid -folic acid -guanine -iron -pyridoxine -uridine
Uridine- hereditary orotic aciduria- rare aut rec disorder of de novo pyrimidine synthesis => physical and mental retardation [low height/weight, delayed developmental milestones], megaloblastic anemia [MCV increased, low retics], elevated urinary orotic acid
[compare to ornithine transcarbamylase deficiency: increased orotic acid, failure to thrive, hyper monetize encephalopathy within first few weeks of life due to impaired urea synthesis]
Hereditary orotic aciduria- defect in UMP synthase- orotate phosphoribosyltransferase, OMP decarboxylase => catalyze a final conversion of orotic acid to UMP; deficiency in enzyme => excretion of orotic acid in urine
Uridine supplementation => bypass enzymatic defect and improve symptoms as uridine converted to UMP via nucleoside kinases
Pyridoxine- indicated supplement during treatment with isoniazid- cofactor in transamination, deamination, decarboxylation, condensation reactions
DNA replication in eukaryotes v prokaryotes
Junk Key steps in both are similar
15 yo boy can’t weightlift with his friends even if he tries hard. Severe muscle cramping and urine discoloration after periods of intense straining. Exercise tolerance can be improved by drinking oral glucose solution before beginning a strenuous activity. What is the enzyme deficiency and disease?
McArdle, type V glycogen storage disease. Deficiency is myophosphorylase => decreased breakdown of glycogen during exercise => poor exercise tolerance, muscle cramps, rhabdomyolysis. Good prognosis, improved by consuming simple sugars before beginning physical activity
- weakness and fatigue with exercise
- no rise in blood lactate levels after exercise
