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Flashcards in Biochem Disorders Deck (33):
1

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

2

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

3

Adenosine Deaminase Deficiency

No adenosine degradation --> increase in dATP --> toxicity in lymphocytes
- AR SCID

4

Lynch Syndrome (HNPCC)
- Colon cancer

Defective mismatch repair

5

Xeroderma Pigmentosum
- Increased risk of skin cancer

Defective nucleotide excision repair
- Prevents repair of thymine (pyrimidine) dimers due to UV light exposure

6

Ataxia Telangiectasia
- Ataxia, poor smooth pursuit with eyes

Defective nonhomologous end joining
- IgA deficiency, elevated alpha fetoprotein
- sensitive to ionizing radiation

7

Glycolytic Enzyme Deficiency
- hemolytic anemia

Common cause: pyruvate kinase deficiency
- Inability to maintain Na+/K+ ATPase --> cell swelling/lysis --> hemolytic anemia

8

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

9

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

10

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

11

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

12

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)

13

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

14

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)

15

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

16

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)

17

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

18

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

19

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

20

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)

21

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

22

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)

23

Hypertriglyceridemia (Type IV Dyslipidemia)
- Hypertriglyceridemia, acute pancreatitis

AD hepatic overproduction of VLDL
- Elevated VLDL, TG
- TG > 1,000

24

Carnitine Deficiency
- weakness, hypotonia, hypoketic hypoglycemia

Inherited defect in transport of LCFAs into mitochondria --> toxic accumulation

25

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

26

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

27

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)

28

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

29

Albinism

- TYROSINASE deficiency or defective tyrosine transport
- No melanin

30

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)

31

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

32

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

33

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