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Pyruvate kinase deficiency
- Most common glycolytic enzyme deficiency
- Causes hemolytic anemia, since inability to maintain Na/K pump leads to RBC swelling and lysis
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Pyruvate dehydrogenase deficiency
- Inability to synthesize acetyl CoA from pyruvate and alanine causes buildup of substrates, and lactic acidosis
- Seen in alcoholics, due to B1 (thiamine) deficiency
- Neurological deficits
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G6PD deficiency
- Hemolytic anemia, due to oxidative stress (antimalarials, sulfonamides, infection)
- X-linked
- Oxidized Hb precipitates in RBCs, and forms Heinz bodies
- Bite cells on peripheral smear
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Fructose intolerance
- Aldolase B deficiency
- Accumulation of fructose-1P inhibits glycogenolysis and gluconeogenesis
- Symptoms include hypoglycemia, jaundice, cirrhosis, and vomiting
- Appears in babies, when they start eating fructose
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Essential fructosuria
- Fructokinase deficiency
- Fructose appears in blood and urine
- Benign
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Classic galactosemia
- Galactose 1P uridyltransferase deficiency
- Toxins accumulate in eye and neurons
- Symptoms include failure to thrive, jaundice, hepatomegaly, infantile cataracts, and retardation
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Ornithine transcarbamoylase deficiency
- Most common defect in the urea cycle
- X-linked
- Excess carbamoyl phosphate is converted into orotic acid, which builds up in the blood and urine
- Decreased BUN
- Ammonia intoxication
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Phenylketonuria
- Phenylalanine hydroxylase or tetrahydrobiopterin deficiency
- Phenylalanine cannot be converted into tyrosine, making tyrosine and essential AA
- Presents with mental retardation, growth retardation, seizures, albinism (lack of melanin), eczema, and a musty body odor
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Alkaptonuria
- Homogentisic acid oxidase deficiency causes impaired tyrosine degradation
- Findings include dark CT, pigmented sclera, urine that blackens in the air
- Arthralgias
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Sorbitol accumulation
Aldose reductase converts glucose to sorbitol, which accumulates in cells and causes osmotic damage (re: cataracts, retinopathy, peripheral neuropathy, seen in diabetes)
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Albinism
Can be due to a tyrosinase deficiency (tyrosine is converted to melanin) or a failure of neural crest cells to migrate
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Homocystinuria
- Can be due to a deficiency in B6, B12, or folate
- Can be due to a mutation in cystathione synthase or homocysteine methyltransferase
- Causes mental retardation, osteoporosis, kyphosis, lens subluxation, and atherosclerosis
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B12 deficiency
- B12 is needed to activate folate and to convert methylmalonyl CoA to succinyl CoA
- Lack of active folate causes megaloblastic anemia
- Buildup of methylmalonyl CoA causes peripheral neuropathy
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Cystinuria
- Caused by an AR defect in the renal cysteine transporter
- Cystine buildup precipitates as stones
- Treat with acetazolamide to alkalinize urine (since cystine is more soluble at high pH)
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Maple syrup urine disease
- Due to a defect in branched amino acid dehydrogenase
- Buildup of isoleucine, leucine, and valine
- Severe CNS defects and death
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Hartnup disease
- Defective tryptophan reabsorption in urine
- Causes pellagra like symptoms (diarrhea, dermatitis, dementia), since tryptophan is used to make niacin
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Von Gierke's disease (type I)
- Deficient glucose 6 phosphataseSevere fasting hypoglycemia and hepatomegaly
- Doll-like facies
- Hyperlipidemia
- Increased blood lactate
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Pompe's disease (type II)
- Deficient lysosomal a-1,4 glucosidase
- Cardiomegaly
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Cori's disease (type III)
- Deficient debranching enzymeGlycogen looks abnormal under a microscope, but little or no hypoglycemia
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McArdle's disease (type V)
- Deficient glycogen phosphorylase in skeletal muscleCramps and myoglobinuria after exercise
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Hers disease (type VI)
- Deficient glycogen phosphorylase in the liverHepatomegaly
- Mild hypoglycemia (gluconeogenesis is intact)
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Fabry's disease
- Deficient a-galactosidase A
- XR
- Peripheral neuropathy
- Angiokeratomas
- Cardiovascular and renal disease
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Gaucher's disease
- Deficient B-glucocerebrosidase
- Hepatosplenomegaly
- Aseptic necrosis of head of femur
- Crumpled tissue paper macrophages
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Neimann-Pick disease
- Deficient sphingomyelinase
- Progressive neurodegeneration
- Hepatosplenomegaly
- Cherry-red spot on macula
- Foam cells
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Tay-Sachs disease
- Deficient hexosaminidase A
- Progressive neurodegeneration
- Cherry-red spot on macula
- NO hepatomegaly
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Krabbe's disease
- Deficient galactocerebrosidase
- Peripheral neuropathy
- Optic atrophy
- Globoid cells
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Metachromatic leukodystrophy
- Deficient arylsulfatase A
- Central and peripheral demyelination, with ataxia and dementia
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Hurler's syndrome
- Deficient a-L-iduronidase
- Gargoylism
- Airway obstruction
- Corneal clouding
- Hepatosplenomegaly
- (Hunter's syndrome is like Hurler's, but more mild, and XR, with no corneal clouding)
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Abetalipoproteinemia
- Inability of enterocytes to form chylomicrons
- Decreased TGs, cholesterol, and FAs
- Acanthocytes
- Steatorrhea
- Night blindness
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Type I hyperchylomicronemia
- Defective lipoprotein lipase or ApoC-II (activates LPL
- Pancreatitis, hepatosplenomegaly, xanthomas
- NO increased risk for atherosclerosis
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Type II familial hypercholesterolemia
- Deficient LDL receptors
- AD
- Accelerated atherosclerosis (homozygotes die of heart failure by 20)
- Corneal arcus
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Type IV hypertriglyceridemia
- Hepatic overproduction of VLDLs
- Pancreatitis
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