Other Metabolic Diseases

Question 1

what does increased NADH/NAD+ ratio when consuming ethanol cause?

Answer 1

1. lactic acidosis (pyruvate -> lactate)
2. inhibits gluconeogenesis -> fasting hypoglycemia
3. increase TG synthesis -> hepatosteatosis
4. decrease TCA cycle -> increase acetyl coA for lipogenesis (hepatosteatosis) and ketogenesis (ketoacidosis)

Question 2

what is fomepizole?

Answer 2

drug that inhibits ADH + antidote for methanol/ethylene glycol poisoning

Question 3

what is disulfram?

Answer 3

drug that inhibits ALDH -> increases acetaldehyde when alcohol is consumed -> increases super sick feeling

Question 4

what happens with Pyruvate DH complex deficiency?

Answer 4

increased pyruvate -> shunted to lactate (LDH) or Ala (ALT) -> get lactic acidosis, increased serum Ala, neuro defects

Question 5

inhibitors of ETC and what they inhibit?

Answer 5

• rotenone: complex I
• antimycin A: complex III
• CO, CN: complex IV
• oligomycin: complex V (ATPase)

Question 6

what are uncoupling agents?

Answer 6

• increase membrane permeability
• stop ATP synthesis but ETC continues -> generate heat
• 2,4-DNP, aspirin overdose, thermogenin

Question 7

where is G6phosphatase NOT found?

Answer 7

muscle

Question 8

what happens with fructokinase deficiency?

Answer 8

fructosuria

• autosomal recessive
• fructose in blood and urine
• otherwise asymptomatic

Question 9

what happens with aldolase B deficiency?

Answer 9

fructosemia/fructose intolerance

• F1P accumulates, lowers phosphate, inhibits glycogenolysis and gluconeogenesis
• symptoms appear after fruit, juice, or honey consumption
• get reducing sugar in urine
• hypoglycemia, jaundice, cirrhosis, vomiting

Question 10

what happens with galactokinase deficiency?

Answer 10

• galactitol accumulates
• galactose in urine, blood
• infant cataracts
• initial presentation: failure to track objects

Question 11

what happens with gal-1-uridyltransferase deficiency?

Answer 11

galactosemia

• autosomal recessive
• damage due to accumulation of toxins (galactitol)
• failure to thrive, jaundice, hepatomegaly, infant cataracts, low IQ
• can lead to E. coli sepsis in neonates

Question 12

what is sorbitol?

Answer 12

alcohol version of glucose - another way to trap glucose inside a cell

• via aldose reductase (uses NADPH)
• some then proceed to turn sorbitol into fructose via sorbitol DH (uses NAD+)

Question 13

what can intracellular sorbitol accumulation cause?

Answer 13

osmotic damage -> cataracts, retinopathy, peripheral neuropathy

(seen in diabetes)

Question 14

different types of lactase deficiency

Answer 14

• primary: age-dependent decline - no lactase persistent allele
• secondary: loss of brush border due to gastroenteritis, etc.

all result in low stool pH, breath with increased H2 gas, bloating, cramps, flatulence, osmotic diarrhea

Question 15

what happens with hyperammonemia and how do you treat it?

Answer 15

increased NH4+ -> decreased alpha-KG -> inhibits TCA

treat w/ benzoate or phenylbutyrate

Question 16

symptoms of ammonia intoxication

Answer 16

• tremor (asterixis)
• slurring of speech
• somnolence
• vomiting
• cerebral edema
• blurring of vision

Question 17

what happens with NAG deficiency?

Answer 17

hyperammonemia (needed for CPSI)

-presents same as CPSI deficiency, but increased ornithine w/ normal urea cycle enzymes

Question 18

what happens with OTC deficiency?

Answer 18

increased carbamoyl phosphate -> make orotic acid

• x linked recessive
• increased orotic acid in blood/urine, decreased BUN, symptoms of hyperammonemia but no megaloblastic anemia

*most common urea cycle disorder

Question 19

PKU: cause and what happens

Answer 19

phenylalanine hydroxylase deficiency or BH4 deficiency

• makes Tyr essential
• increased phenylketones in urine
• low IQ, growth retardation, seizures, fair skin, eczema, musty BO

must avoid aspartame

Question 20

what is maternal PKU

Answer 20

lack of proper diet therapy during pregnancy

-infant -> microcephaly, low IQ, growth retardation, congenital heart defects

Question 21

alcaptonuria: cause and what happens

Answer 21

aka ochronosis = deficiency of homogentisate oxidase

• autosomal recessive
• dark CT, brown sclera, urine turns black in air
• may have debilitating arthralgias

Question 22

homocystinuria: cause and what happens

Answer 22

can be due to:

• cystathione synthase deficiency
• decreased affinity of cystathione synthase for PLP
• homoCys methyltransferase/Met synthase deficiency

all cause increased homoCys in urine, low IQ, osteoporosis, tall stature, kyphosis, lens subluxation, thrombosis, atherosclerosis

Question 23

what is cystinuria?

Answer 23

defect of renal PCT and intestinal aa transporters for Cys, ornithine, Lys, Arg

• autosomal recessive
• urinary cyanide-nitroprusside test = diagnostic

Question 24

what is maple syrup urine disease?

Answer 24

blocked degradation of BCAA -> due to decreased alpha-ketoacid DH (needs B1)

• increased a-ketoacids in blood
• severe CNS defects, low IQ, death
• urine smells like like maple syrup/burnt sugar

Question 25

von Gierke's disease

Answer 25

deficient G-6-phosphatase (liver only) - severe fasting hypoglycemia - increased glycogen in liver - increased blood lactate - hepatomegaly - autosomal recessive

Question 26

Pompe disease

Answer 26

deficient acid maltase/lysosomal a-1,4-glucosidase - cardiomyopathy and systemic findings leading to early death - autosomal recessive

Question 27

Cori disease

Answer 27

deficient debranching enzyme (a-1,6-glucosidase) | -milder form of von Gierke's with normal blood lactate levels

Question 28

McArdle's disease

Answer 28

deficient skeletal muscle glycogen phosphorylase - increased glycogen in muscle, but can't break it down - painful muscle cramps w/ exercise - red urine (myoglobinuria) - arrhythmia from electrolyte abnormalities

Question 29

Fabry disease

Answer 29

deficient alpha-galactosidase A - accumulate ceramide - x linked - peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease

Question 30

Gaucher disease

Answer 30

deficient glucocerebrosidase (B-glucosidase) - accumulate glucocerebroside - most common lysosomal storage disease ** - hepatosplenomegaly, pancytopenia, aseptic necrosis of femur, bone crises, Gaucher cells (crumpled tissue macrophages)

Question 31

Niemann-Pick disease

Answer 31

deficient sphingomyelinase - accumulate sphingomyelin - progressive neurodegeneration, hepatosplenomegaly, cherry red spots on macula, foam cells

Question 32

Tay-Sachs disease

Answer 32

deficient hexosaminidase A - accumulate GM2 ganglioside - progressive neurodegeneration, developmental delay, cherry red spots on macula, lycosomes with onion skin , NO HEPATOSPLENOMEGALY

Question 33

Krabbe disease

Answer 33

deficient galactocerebrosidase - accumulate galactocerebroside - peripheral neuropathy, developmental delay, optic atrophy, globoid cells

Question 34

metachromatic leukodystrophy

Answer 34

deficient arylsulfatase A - accumulate cerebroside sulfate - central and peripheral demyelination with ataxia, dementia

Question 35

Hurler syndrome

Answer 35

deficient alpha-iduronidase - accumulate heparan sulfate, dermatan sulfate - developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly

Question 36

Hunter syndrome

Answer 36

deficient iduronate sulfatase - x linked - accumulate heparan sulfate, dermatan sulfate - mild Hurler + aggressive behavior, no corneal clouding

Question 37

carnitine deficiency

Answer 37

inability to transport LCFAs into mitochondria -> toxic accumulation -> weakness, hypotonia, hypoketotic hypoglycemia

Question 38

acyl-coA DH deficiency

Answer 38

increased dicarboxylic acids, decreased glucose and ketones