Biochem Disorders Flashcards
Orotic Aciduria
- Children –> FTT, developmental delay
Defect in UMP synthase –> inability to convert orotic acid to UMP (pyrimidine synthesis pathway)
- AR
- megaloblastic anemia refractory to folate and B12
- orotic acid in urine
- NORMAL ammonia (opposed to orthinine transcarbamylase def)
- Rx: uridine monophosphate
Lesch-Nyhan Syndrome
- intellectual disability, self-mutilation, agression, hyperuricemia (orange “sand” sodium urate crystals in diaper), gout, dystonia
Absent HGPRT –> can’t convert hypoxanthine to IMP or guanine to GMP –> defective purine salvage –> excess uric acid production and de novo purine synthesis
- X-linked recessive
- Rx: allopurinol or febuxostat
Adenosine Deaminase Deficiency
No adenosine degradation –> increase in dATP –> toxicity in lymphocytes
- AR SCID
Lynch Syndrome (HNPCC) - Colon cancer
Defective mismatch repair
Xeroderma Pigmentosum
- Increased risk of skin cancer
Defective nucleotide excision repair
- Prevents repair of thymine (pyrimidine) dimers due to UV light exposure
Ataxia Telangiectasia
- Ataxia, poor smooth pursuit with eyes
Defective nonhomologous end joining
- IgA deficiency, elevated alpha fetoprotein
- sensitive to ionizing radiation
Glycolytic Enzyme Deficiency
- hemolytic anemia
Common cause: pyruvate kinase deficiency
- Inability to maintain Na+/K+ ATPase –> cell swelling/lysis –> hemolytic anemia
McArdle Disease (GSD Type V)
- Painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, arrhythmia from electrolyte abnormalities, second-wind phenomenon during exercise (increased muscular blood flow)
Deficient skeletal muscle GLYCOGEN PHOSPHORYLASE
- Blood glucose levels unaffected
- McArdle = Muscle
- Increased glycogen in muscle but muscle cannot break it down –> rhabdomyolysis –> exercise intolerance
VonGierke Disease (GSD Type I)
- 3-4 mo –> FTT
- Gout, hepatomegaly
Deficient GLUCOSE-6-PHOSPHATASE (no G6P to glucose) –> impaired gluconeogenesis and glycogenolysis –> glucose can’t leave liver –> severe fasting hypoglycemia, increased glycogen in liver
- Increased blood lactate
- Increased triglycerides
- Increased uric acid (gout)
- Hepatomegaly
Rx: frequent oral glucose/corn starch, avoid fructose and galactose
Cori Disease (GSD Type III)
- Milder form of VonGierke
Deficient DEBRANCHING ENZYME (alpha-1,6-glucosidase) –> mild hypoglycemia
- Normal blood lactate
- Accumulation of limit dextrin-like structures in cytosol
- Gluconeogenesis is intact
Pompe Disease (GSD Type II)
- Infants: cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, early death (2 yrs)
LYSOSOMAL ALPHA-1,4-GLUCOSIDASE with alpha-1,6-glucosidase activity (acid maltase)
- Pompe trashes the pump
Pyruvate Dehydrogenase Deficiency
- Neuro defects, lactic acidosis
- Infants
No pyruvate –> Acetyl CoA
- Pyruvate can back up and be converted to lactate ( via LDH) or alanine (via ALT)
- X-linked or acquired (arsenic poisoning, B1 def. [alcoholics])
- Increased serum alanine
- Rx: increase intake of ketogenic nutrients (high fat content or high lysine/leucine)
Chronic Granulomatous Disease
- Increased susceptibility to catalase+ organisms
Defect of NADPH OXIDASE –> less ROS and no respiratory burst in neutrophils
- X-linked recessive most common
- Catalase positive organisms (neutralize environmental H2O2): Nocardia, Pseudomonas, Listeria, Aspergillus, Candida, E. coli, Staph, Serratia, B. cepacia, H. pylori
- Abnormal dihydrorhodamine (flow cytometry, green)
- Nitroblue tetrazolium dye reduction test is colorless
G6PD Deficiency
- hemolytic anemia
Deficient GLUCOSE-6-PHOSPHATE DEHYDROGENASE –> can’t make NADPH –> can’t keep glutathione reduced –> can’t detoxify free radicals and peroxides –> hemolytic anemia due to poor RBC defense against oxidizing agents
- Oxidizing agents: fava beans, sulfonamides, primaquine, dapsone, chloroquin, nitrofurantoin, antituberculosis drugs
- Also precipitated by infection (most common cause) –> inflammatory response produces free radicals that diffuse into RBCs
- X-linked recessive
- Most common human enzyme deficiency
- More prevalent among AA (malarial resistance)
- Heinz bodies (denatured Hb due to oxidative stress)
- Bite cells (from splenic macs)
Essential Fructosuria
- benign, asymptomatic
Defect in FRUCTOKINASE (no fructose to F1P) –> can still metabolize fructose by converting to F6P via hexokinase –> pyruvate and glycogen
- AR
- Fructose appears in blood and urine
Fructose Intolerance
- hypoglycemia, jaundice, cirrhosis, vomiting following consumption of fruit, juice, honey
Defect in ALDOLASE B (no F1P metabolism) –> F1P builds up –> metabolic sink (P gets trapped) –> no ATP for glycolysis or ATP synthase –> inhibits glycogenoysis and gluconeogenesis –> severe hypoglycemia
- Urine dipstick will be negative (only tests for glucose)
- Reducing sugar detected in urine
- Rx: decrease intake of fructose and sucrose (glucose + fructose)
Galactokinase Deficiency
- Infants start feeding, infantile cataracts, failure to track objects, failure to develop social smile
Deficiency of GALACTOKINASE –> no galactose to galactose-1-P –> more galactose to galactitol (via aldose reductase)
- AR
- Sx begin when infant begins feeding (lactose present in breast milk and formula)
- Galactosemia, galactosuria, infantile cataracts
Classic Galactosemia
- FTT, jaundice, hepatomegaly, infantile cataracts, intellectual disability
Deficiency of GALACTOSE-1-PHOSPHATE-URIDYLTRANSFERASE –> no galactose-1-P to glucose-1-P –> accumulation of toxic substances (including galactitol)
- Can lead to E. coli sepsis in neonates
- Rx: exclude galactose and lactose (galactose + glucose) –> strikingly alters course of DZ
Lactase Deficiency
- Bloating, cramps, flatulence, osmotic diarrhea
Insufficient LACTASE –> no brush border digestion of lactose into glucose and galactose –> osmotic diarrhea, bacteria produce gas
- Primary: age-dependent decline after childhood (Asian, African, NA)
- Secondary: loss of brush border due to gasteroenteritis (rotavirus), AI DZ
- Congenital: rare
- Stool –> decreased pH
- Breath –> increased hydrogen
- NORMAL MUCOSA
- Rx: avoid dairy, add lactase pills
Abetalipoproteinemia
- steatorrhea, ataxia, nightblindness
- Deficient ApoB-48 and ApoB-100
- AR mutation in MTP gene –> decreased chylomicron and VLDL synthesis and secretion
- Decreased absorption of fat soluble vitamins
- Bx: enterocytes swollen with triglycerides
- Peripheral smear: acanthocytosis of RBCs (“spikes”) due to alteration in membrane lipids
- Rx: Vit E (restores lipoproteins)
Hyperchylomicronemia (Type I Dyslipidemia)
- Pancreatitis, hepatosplenomegaly, eruptive/pruritic xanthomas
AR defect in LIPOPROTEIN LIPASE or APO-CII
- Elevated chylomicrons, TGs, cholesterol
- NO RISK FOR ATHEROSCLEROSIS
- Creamy layer in supernant
Familial Hypercholesterolemia (Type IIa Dyslipidemia) - Hyperlipidemia, MI before age 20, tendon xanthomas (Achilles), corneal arcus
AD absent/defective LDL RECEPTORS (bind Apo-B100)
- Elevated LDL and cholesterol
- Heterozygotes –> cholesterol = 300
- Homozygotes –> cholesterol = 700
- ACCELERATED ATHEROSCLEROSIS (MI before age 20)
Hypertriglyceridemia (Type IV Dyslipidemia)
- Hypertriglyceridemia, acute pancreatitis
AD hepatic overproduction of VLDL
- Elevated VLDL, TG
- TG > 1,000
Carnitine Deficiency
- weakness, hypotonia, hypoketic hypoglycemia
Inherited defect in transport of LCFAs into mitochondria –> toxic accumulation
Phenylketonuria
- intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor
Decreased PHENYLALANINE HYDROXYLASE or TETRAHYDROBIOPTERIN COFACTOR (no Phe –> Tyr)
- Tyrosine becomes essential
- Increased Phe –> excess phenylketones in urine (phenylacetate, phenyllactate, phenylpyruvate)
- Screened 2-3 d after birth
- Rx: decreased Phe and increased Tyr, BH4 supplementation, avoid aspartame
- Lack of proper dietary therapy during pregnancy –> microcephaly intellectual disability, growth retardation, congenital heard defects
Ornithine Transcarbamylase Deficiency
- Lethargic, unwilling to eat, poorly controlled RR and body temp, seizures
- First few days of life
- Most common urea cycle disorder
- X-linked recessive
- Can’t do urea cycle –> buildup of nitrogen and ammonia in the body –> orotic acid in blood and urine
- BUN decreased (can’t make urea)
- Hyperammonemia
Hyperammonemia
- slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
Acquired (liver disease) or hereditary (urea cycle enzyme deficiencies)
- Excess NH3 –> depletes alpha-KG –> inhibition of TCA cycle
- Rx: limit protein, lactulose (acidify GI tract and trap NH4), rifaximin (wipe out colonic ammoniagenic bacteria), benzoate/phenylacetate/phenylbutyrate (bind NH4 and lead to excretion)
Alkaptonuria
- bluish-black CT and sclerae (ochronosis), urine turns black on prolonged exposure to air, debilitating arthralgias
- Congenital deficiency in HOMOGENTISATE OXIDASE
- Can’t degrade tyrosine to fumarate –> pigment forming homogentisic acid accumulates in tissue
- AR
- Usually benign
Albinism
- TYROSINASE deficiency or defective tyrosine transport
- No melanin
Homocystinuria
- intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, atherosclerosis (stroke and MI)
- AR
- CYSTATHIONE SYNTHASE deficiency –> no homocysteine to cystathione (supplement cysteine/B12/folate, reduce methionine in diet)
- Decreased affinity of cystathione synthase for pyridoxal phosphate (Rx: supplement B6 and cysteine)
- METHIONINE SYNTHASE deficiency –> no homocysteine to methionine (rx: supplement methionine)
Cystinuria
- Recurrent precipitation of hexagonal cystine stones
Hereditary defect of renal PCT and intestinal AA transporter than prevents reabsorption of CYSTINE, ORNITHINE, LYSINE, and ARGININE (COLA)
- Rx: urinary alkalinization (potassium citrate, acetazolamide), chelating agents (penicillamine)
- AR
- Urinary cyanide-nitroprusside test to dx
Maple Syrup Urine Disease
- Severe CNS defects, intellectual disability, death
- Vomiting, poor feeding, urine smells like maple syrup/burnt sugar
Deficiency in BRANCHED-CHAIN ALPHA-KETOACID DEHYDROGENASE –> can’t degrade branched AA (isoleucine, leucine, valine) –> increased alpha-ketoacids in blood (esp. leucine)
- Rx: restriction of isoleucine, leucine, and valine; thiamine supplementation
- AR
Hartnup Disease
- Diarrhea, dementia (and hallucinations), dermatitis (“broad collar” rash, hyperpigmentation of sun exposed limbs)
- AR deficiency of neutral AA transporters in proximal renal tubular cells and on enterocytes –> neutral aminoaciduria and decreased absorption from gut –> decreased tryptophan for conversion to niacin (B3) –> pellagra = DERMATITIS, DIARRHEA, DEMENTIA
- Rx: high-protein diet, nicotinic acid
