Biochemistry disorders

Question 1

What is maple syrup urine disease? (Cause, enzyme defect, transmission type, symptoms, treatment)

Answer 1

Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine)
Decreased alpha-ketoacid dehydrogenase (B1).
Increased alpha-ketoacids in the blood, especially those of leucine.
Symptoms: severe CNS defects, intellectual, disability, and death
Autosomal recessive.
Urine smells like maple syrup/burnt sugar
Tx: restriction of leucine, isoleucine, and valine in diet + thiamine supplementation

Question 2

What is glycogen phosphorylase and how is it regulated?

Answer 2

It cuts glucose-1-P off of chains until it is 4 residues from a branch point. it is regulated by glycogen phosphorylase kinase (phosphorylating it activates it) which is activated by epinephrine and glucagon.

Question 3

What are the four glycogen storage disorders?

Answer 3

Very Poor Carbohydrate Metabolism:
Von Gierke Disease (Type I)
Pompe Disease (Type II)
Cori disease (Type III)
McArdle Disease (Type V)

Question 4

What is Von Gierke disease?

Answer 4

Type I.
Severe fasting hypoglycemia, A lot of increased glycogen in liver, increased blood lactate, hepatomegaly.
Deficient enzyme: Glucose-6-phosphatase
Autosomal recessive.
Treatment: frequent oral glucose/cornstarch; avoidance of fructose and galactose.

Question 5

What is Pompe disease?

Answer 5

Type II.
Cardiomyopathy and systemic findings leading to early death.
Deficient enzyme: Lysosomal alpha-1,4-glucosidase (acid maltase)
Autosomal recessive.
Pompe trashes the pump (heart, liver, muscle).

Question 6

What is Cori disease?

Answer 6

Type III. 
Milder form of type I with normal blood lactate levels. 
Deficient enzyme: debranching enzyme.
Autosomal recessive. 
Gluconeogenesis is intact.

Question 7

What is McArdle Disease?

Answer 7

Type V.
Increased glycogen in muscle, but cannot break it down, leading to painful muscle cramps, myglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities.
Deficient enzyme: skeletal muscle glycogen phosphorylase (myophosphorylase).
Autosomal recessive.
McArdle = muscle.

Question 8

What is Fabry disease?

Answer 8

Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease
Deficient enzyme: alpha-galactosidase A
Accumulated substrate: Ceramide trihexoside
X-recessive

Question 9

What is Gaucher disease?

Answer 9

Most common.
Hepatosplenomegaly, pancytopenia, aseptic necrosis of femur, bone crises, Gaucher cells (lipid laden macrophages resembling crumpled tissue paper);
treatment: recombinant glucocerebrosidase
Deficient enzyme: Glucocerebrosidase (B-glucosidase)
Accumulated substrate: Glucocerebroside
Autosomal recessive

Question 10

What is Niemann-Pick disease?

Answer 10

Progressive neurodegeneration, hepatosplenomegaly, “cherry-red” spot on macula, foam cells (lipid-laden macrophages).
Deficient enzyme: sphingomyelinase
Accumulated substrate: sphingomyelin
Autosomal recessive
No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase)

Question 11

What is Tay-Sachs disease?

Answer 11

Progressive neurodegeneration, developmental delay, "cherry-red" spot on macula, lysosomes with onion skin, no hepatoslenomegaly used for differentiating between Niemann-Pick.
Deficient enzyme: hexosaminidase A
Accumulated substrate: GM2 ganglioside 
Autosomal recessive
Tay SaX lacks heXosaminidase.

Question 12

What is Krabbe disease?

Answer 12

Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Deficient enzyme: galactocerebrosidase
Accumulated substrate: galactocerebroside, psychosine (buildup destroys myelin sheath)
Autosomal recessive

Question 13

What is metachromatic leukodystrophy?

Answer 13

Central and peripheral demyelination with ataxia, dementia.
Deficient enzyme: Arylsulfatase A
Accumulated substrate: Cerebroside sulfate (leads to impaired production of myelin sheath)
Autosomal recessive.

Question 14

What is Hurler Syndrome?

Answer 14

Mucopolysaccharidoses.
Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly.
Deficient enzyme: alpha-L-iduronidase.
Accumulated substrate: Heparan sulfate, dermatan sulfate.
Autosomal recessive.

Question 15

What is Hunter syndrome?

Answer 15

Mucopolysaccharidoses.
Mild Hurler + aggressive behavior, no corneal clouding.
Deficient enzyme: Iduronate sulfatase
Accumulated substrate: Heparan sulfate, dermatan sulfate.
X-recessive.
Hunter’s see clearly (no corneal clouding) and aggressively aim for the X.

Question 16

Which Lysosomal storage disorders occur more frequently with Ashkenazi Jews?

Answer 16

Tay Sachs, Niemann-Pick, Gaucher disease

Question 17

What is Type 1 hyperchylomicronemia?

Answer 17

Increased Chylomicrons, TG, cholesterol.
Autosomal recessive.
Lipoprotein lipase deficiency or altered apolipoprotein C-II cause pancreatitis, hepatosplenomegaly and eruptive /pruritic xanthomas (no increased risk for atherosclerosis).

Question 18

What is type IIa - familial hypercholesterolemia?

Answer 18

Increased LDL, cholesterol.
Autosomal dominant.
Absent or defective LDL receptors.
Heterozygotes (1:500) have cholesterol + 300mg/dL; homozygotes have very high cholesterol ~ 700. Causes accelerated atherosclerosis (May have MI before age 20), tendon (Achilles) xanthomas, and corneal arcus.

Question 19

What is type IV - hypertriglyceridemia?

Answer 19

Increased VLDL, TG.
Autosomal dominant.
Hepatic overproduction of VLDL. Causes pancreatitis.

Question 20

What is type III - familial dysbetalipoproteinemia?

Answer 20

Increased cholesterol, TGs.
ApoE3/E4 defect
Xanthomas. Premature coronary/vascular disease.

Question 21

What are the mnemonics for all the lysosomal disorders?

Answer 21

All are autosomal recessive except Fabry and Hunter XR. Hunger pointing gun to X target. Hurler is like Hunter (both mucopolysaccharidoses), but Hurler can’t hunt well because of corneal clouding. Both Hunter and Hurler accumulates Heparan Sulfate (and dermatan sulfate). Hurler is alpha-iduronidase deficiency (remember that and the other one should be easy - iduronate sulfatase)

No man picks his nose with his Sphinger “Nieman Pick - Sphingomyelinase “

Gaucher-Glucocerebrosidase-Glucocerebroside 3G… have you Got your iPhone 3G. Gaucher Cells are crumpled tissue paper macrophages.

Cherry-red spot is hyphenated and so is Nieman Pick and Tay-Sach

Ashkenazi Jews have Gaucher, Niemann-Pick, and Tay-Sachs

Angiokeratoma is a Fabric of Vessels and Galaxy of skin spots. Angiokeratoma is seen in Fabry disease in which there is a Galactosidase deficiency and epidermal keratosis. Ceramide trihexoside accumulates (fabric of vessels through brain…think cerebral..which is ceramide trihexoside).

Tay-Sachs..Tay is a kid who crashes his GM car…GM2 ganglioside accumulates.

Question 22

What is abetalipoproteinemia?

Answer 22

It’s a defect in Apo B synthesis (decreased). Problem secreting chylomicrons and VLDL into bloodstream and so fat accumulates into enterocytes. Mutation in microsomal triglyceride transfer protein (MTP). ApoB-100 is VLDL and ApoB-48 is for chylomicrons.
Symptoms are failure to thrive, steatorrhea, acanthocytosis, ataxia and night blindness (these last two are from lack of Vitamin E).