W01_01 Intro to metabolic disease

Question 1

what is phenylketonuria?

Answer 1

autosomal recessive due to mutations in the phenylalanine hydroxylase (PAH) gene. the result is higher phenylalanine (toxic) and decreased tyrosine.

Question 2

what do increased phenylalanine levels cause?

Answer 2

competes with brain’s amino acid transporter, so there’s lower concentration of other AAs

Question 3

low tyrosine and low tryptophan leads to low levels of what?

Answer 3

dopamine and serotonin

Question 4

what’s the final result of PKU in the brain?

Answer 4

defective myelination, cognitive problems, seizures, small brain

Question 5

how can PKU cause fair skin/hair?

Answer 5

low tyrosine = low melanin

Question 6

what’s the dietary treatment for PKU?

Answer 6

reduce intake of phenylalanine with special diets

reduce protein intake

Question 7

what’s the medical treatment for PKU?

Answer 7

1) large neutral amino acid therapy, to compete for phenylalanine and prevent its uptake;
2) sapropterin BH4: PAH enzyme enhancer;
3) phenylalanine lyase (PAL) alternative metabolism of phenylalanine to cinnamic acid

Question 8

which molecule is a common congregation of the protein/carb/lipid metabolic pathways?

Answer 8

acetyl-CoA

Question 9

what’s glycogen storage disease type 1?

Answer 9

glucose-6-phosphatase doesn’t work, so can’t get glucose from glycogen

Question 10

what happens if you give a GSD1 patient glucagon?

Answer 10

they’ll produce G6P, but instead of getting glucose, they’ll make lactic acid and triglycerides and uric acid

Question 11

what are clinical features of GSD1?

Answer 11

massive hepatomegaly;
hypoglycemia;
high triglycerides;
high uric acid

Question 12

what’s the management of GSD1?

Answer 12

take cornstarch throughout the day to replenish the glucose supplies;
treat other symptoms of triglycerides and uric acid

Question 13

note: there are emerging neonatal gene therapies for GSD1, and hepatocyte transplantation techniques

Answer 13

ok

Question 14

what are clinical features of organelle diseases?

Answer 14

correlation to the organs where complex molecules accumulate; OR
correlation to specific organs where the organelles are preferentially utilized (e.g. mitochondria in the muscles, brain, heart)

Question 15

what is lysosomal storage disease?

Answer 15

a deficiency of one or more of the many lysosomal hydrolases

Question 16

what are the 3 big mucopolysaccharides we discussed in class?

Answer 16

heparan sulfate (accumulates in brain);
dermatan sulfate (accumulates in brain);
keratan sulfate (accumulates in bone)

Question 17

how to molecularly diagnose MPS?

Answer 17

thin-layer chromatography

Question 18

clinical features of hurler syndrome? (MPS I)

Answer 18

chronic runny nose + recurrent otitis media;
umbilical and inguinal hernias;
coarse facies;
corneal clouding;
large liver+spleen;
developmental slowiing by year 2
increase in dermatan, keratan, heparan sulfates

Question 19

what causes MPS I?

Answer 19

defect in iduronidase enzyme

Question 20

what’s the treatment for MPS I?

Answer 20

enzyme replacement therapy (aldurazyme);
bone marrow transplant;
symptomatic management

Question 21

what has aldurazyme shown as treatment results?

Answer 21

better joint RoM;
smaller liver;
improvements in cardiac, pulmonary function

Question 22

limitations of ERT?

Answer 22

allergic reactions;
can’t cross BBB;
expensive

Question 23

note: bone marrow transplantation can fix brain issues in LSD if given early enough (< 2 years, and IQ > 70%)

Answer 23

ok