Amino Acidopathies

Question 1

What is the most common clinically encountered inborn error or AA metabolism?

Answer 1

PKU

prevalence: 1: 15,000

Question 2

What causes PKU?

Answer 2

Caused by elevated levels of phenylalanine (10x normal), phenylpyruvate, phenyllactate, phenylacetate in blood and urine.
This can happen due to mutation in Phenylalanine Hydroxylase. Over 100 mutations identified. Severity of PAH deficiency depends on type of mutation.

Can also be due to mutations in enzymes associated with formation of BH4 or conversion of BH2 to BH4 (dihydropteridine reductase)

BH4 is involved in other metabolic processes. Can also lead to problems in catecholamine and serotonin synthesis.

Question 3

What are the symptoms of PKU?

Answer 3

Symptoms: Hypopigmentation due to inhibition of tyrosinase, intellectual disability, developmental delay, microcephaly, seizures

Question 4

What is the treatment for PKU?

Answer 4

Screening at birth. Restrict phenylalanine in diet

Question 5

What is Maple Syrup Urine Disease?

Answer 5

autosomal recessive
partial or complete deficiency of branched chain alpha-keto acid dehydrogenase. Accumulation of alpha keto acids and their AA precursors: Leucine Valine Isoleucine
Brain function interference, especially by Leucine and its alpha keto acid: alpkaketoisocaproic acid.

Question 6

What are the symptoms of MSUD?

Answer 6

urine smells like maple syrup due to Isoleucine; feeding problems, vomiting, ketoacidosis, changes in muscle tone, neurologic problems that can result in coma.
Fatal if left untreated.
If treatment is delayed, intellectual disability.

Question 7

What is the treatment for MSUD?

Answer 7

synthetic formula free off BCAAs but supplemented with limited amounts to allow for normal growth without producing toxic levels.

Question 8

What is Albinism?

Answer 8

Results from absent or defective copper-requiring tyrosinase. 1: 30,000 and is primarily autosomal recessive

Question 9

What are the symptoms of albinism?

Answer 9

pink eyes, white hair, pale skin that is sunlight sensitive, impaired vision, photophobia

Question 10

What is the treatment for albinism?

Answer 10

protection from UV exposure

Question 11

How do you make melanin? How many types of melanin are there?

Answer 11

From tyrosine
Eumalanin: black/brown
Pheomelanin: red/blonde

Question 12

What is malignant melanoma?

Answer 12

most serious form of skin cancer. 10,000 deaths in 2014 with 30-40% 5 year survival rate. Incurable but some drugs are used to prolong life: sabrafenib, trametinib

Largely due to mutations in B-RAF protein kinase ~ 70% of cases
Most pts have mutation to glutamic acid V600E
Thus, BRAF is constituently active, does not depend on growth factors or activated RAS

Question 13

What is Homocystinuria?

Answer 13

Rare group of disorders involving defects in metabolism of homocysteine
derived from the metabolism of methionine

Symptoms: Lens dislocation, skeletal abnormalities (long limbs and fingers), intellectual disability and greater risk of developing blood clots.

Treatment: reduce methionine in the diet and supplement with Vitamins B6 and B12 to drive homocysteine to form non-toxic products (B-12 :methionine and B6: cysteine)

Question 14

What is alkaptonuria?

Answer 14

Deficiency of homogentisic acid oxidase results in accumulation of homogentisic acid (2,5 dyhydroxyphenyl), derived from tyrosine metabolism.
Symptoms: urine is oxidized when exposed to oxygen and turns black. Connective and collagenous tissue is pigmented black. Large joint arthritis can be severely crippling.
Treatment: reduce phenylalanine and tyrosine in the diet

Question 15

How is Nitric Oxide formed?

Answer 15

Through the metabolism of Arginine + O2 (nitric oxide synthase)-> citrulline + NO

Question 16

How many types of NO are there?

Answer 16

Three
eNOS- endothelial
nNOS- neural
iNOS- inducible

have coenzymes FMN, FAD, heme and tetrahydrobiopterin

eNOS and nNOS require ca2+-calmodulin

Question 17

What are the actions of NO?

Answer 17

Vasodilator- relaxes smooth muscles

Prevents platelet aggregation

Functions as NT

Mediates tumoricidal and bactericidal actions of macrophages

Question 18

What is the pathway by which NO relaxes arterial smooth muscle?

Answer 18

Ach bind Ach GPCR (G protein coupled receptor) on endothelium -> activates phospholipase C -> Ca2+-calmodulin -> NO synthase catalyzes reaction arginine to citrulline forming NO. NO diffuses past endothelial membrane into smooth muscle and binds NO receptor which is activated by GTP -> cGMP + PPi. This ultimately activate protein kinase G causing smooth muscle relaxation.

Question 19

What does viagra target?

Answer 19

it inhibits phosphodiesterase-5 which is responsible for the degradation of cGMP=> GMP. Inhibition causes more cGMPs in the smooth muscle increasing the chance that an erection will last longer.