Amino Acid and Nucleic Acid Metabolism and Disorders

Question 1

Phenylketonuria (PKU)

1. main presentation
2. symptoms
3. enzymatic defect/Mechanism
4. diagnosis made on
5. MOI
6. Treatment

Answer 1

• not frequent bc of newborn screening
• need to be careful during pregnancy: untreated PKU mothers can have babies born w microcephaly, cardiac lesion and mental retardation
• PKU treatment = lifelong baby formula

1. cognitive impairment,
2. hypopigmentation, developmental problems, hyperactivity, poor growth, seizure, musty urine/body odor
3. phenylalanine hydroxylase (which converts Phe to Tyrosine) or the cofactor (tetrahydrobiopterin=BH4). Phenylalanine accumulates and is converted to phenylketones (toxic) which combine w Fe to make a colored precipitate
4. Phe concentration (mass spec from blood spots). Normal: 2-3 mg/kg. PKU: 20 mg/kg; 420-600µmol/dL
5. AR
6. Low Phe, high Tyr diet; 25-30% respond to treatment with cofactor (BH4, brand name = KUVAN; Large neutral amino acids compete with Phe for BBB transporters; in trials: Phenylalanine ammonia lyase treatment: modifies Phe to something less toxic/blocks conversion

Question 2

Tyrosine makes:

Answer 2

• neurotransmitters

Question 3

Tyrosinemia I:

1. Enzymatic Defect/Mechanism
2. Main Presentation
3. Symptoms
4. Diagnosis
5. MOI
6. Treatment

Answer 3

1. defect/deficiency in fumarylacetoacetate (FAH), which converts acetyl-CoA fumarate –> fumarate + acetoacetate). Results in buildup fo fumarylacetoacetate which is metabolized to accumulate succinylacetone
2. Liver faliure
3. damage to liver, hepatomegaly, edema b/c of low albumin in liver, kidneys, neurologic crises, no hypoglycmia or acidosis; Tyr and Methionine high in blood
4. Check urine and fine succinyl acetone (an inhibitor of heme synthesis) (normal urine would not have this); high Tyr and Met in blood
5. AR
6. NTBC prevents production of homogentisate, which is one step above FAH. This increases tyrosine levels, but attenuates liver and kidney disease. avoid tyorsine; liver transplant

Question 4

Maple Syrup Urine Disease (MSUD):

1. Mechanism
2. Main Presentation
3. Symptoms
4. MOI
5. Treatment:
6. Diagnosis:

Answer 4

1. Defect in mitochondrial Branched-Chain alpha-keto-acid dehydrogenase, so Leu, Iso, and Val aren’t broken down, so alpha-keto-acid intermediates accumulate in serum and urine
2. metabolic encephalopathies
3. born healthy, urine smells like maple syrup, ketoacidosis, neurodegeneration, faliure to thrive, coma, seizures, mild hypoglycemia, mild metabolic acidosis, ketonuria (ataxia= gait disturbance with acute late onset pts); untreated/late treated pts have hypomyelination; cerebral edema
4. AR
5. Avoid Isoleucine, Leucine, and Valine (I Love Vermont maple syrup from trees with branches). If mutation in E2 subunit (there are 4 subunits), then addition of cofactor thiamine might be helpful.
6. Ketoacids of Ile, Leu, and Val in the urine (?)

*

Question 5

Homocystenuria

1. Mechanism
2. Symptoms
3. Treatment
4. MOI
5. Diagnosis

Answer 5

1. Defect/Deficiency in CBS/Vit B6 which converts homocysteine to cystathionine. Buildup of homocysteine and Methionine
2. Tall, slender, glasses, scoliosis, Dislocation of lens, skeletal malformations, thromboembolism (clotting disorder)
3. Vitamin B6 (cofactor of CBS) can be given- 50% are responsive; Low Methionine diet
4. AR
5. plasma and urine presence of homocysteine (typically not present); high plasma Methionine

Question 6

Ornithine Transcarbamylase (OTC) deficiency

1. Mechanism
2. Symptoms
3. Main Presentation
4. MOI
5. Treatment
6. Diagnosis

Answer 6

1. Urea cycle defect in which ornithine is not converted into citruline (only part of urea cycle in mitochondria). Ammonia accuulates because NH3 isn’t converted to urea
2. Low blood urea nitrogen (BUN), high blood ammonia, coma, death,
3. Unexplained encephalopathy in children and adults
4. XLR including random X inactivation (other urea cycle defects are autosomal recessive). Most pts women bc men w/it die early
5. Dialysis to remove NH3, Limit protein intake, arginine/citruline supplementation, liver transplant is curative, Use of scavengers to remove nitrogen waste product (benzoic acid, Na Phenylburate). Avoid steroids (which stimulate AA catabolism)
6. high levels of orotic acid in the urine

Question 7

_____ is the only organ that makes urea.

Answer 7

Liver

Question 8

AAs broken down and nitrogen is carried by ____ in the blood b/c it is not stored

Answer 8

glutamine

Question 9

Functions of nucleotides:

Answer 9

1. energy
2. chemical signaling
3. enzyme cofactors
4. DNA and RNA

Question 10

____ is a building block for other purines

Answer 10

IMP: inosinate

Question 11

Synthesis of nucleotides happens:

2.

Answer 11

1. de novo using AAs, ribose-5-phosphate, CO2, NH3
2. Salvage Pathways: recycling of free bases and nucleosides from NA breakdown

Question 12

Gout

1. Mechanism
2. Symptoms
3. Diagnosis
4. MOI
5. Treatment

Answer 12

1. Excess purine consumption or production( partial HGPRT deficiency): leading to accumulation of uric acid. Uric acid (pretty insoluble) builds up in joints, crystallizes and gives crystal arthritis and kidney stones
2. Hyperuricemia, deposition of uric acid crystals –> arthritic changes, kidney stones
3. shadows on xray, joint fluid milky w crystals
4. varies with dx
5. Rasburicase eliminates buildup of uric acid by making allantoid (souluble in water). Allopurinol inhibits xanthine oxidase, the enzyme that makes uric acid from xanthine. Treat with anti-inflammatory for acute crises

• This can be genetic or caused simply by diet (overconsumption), underexcretion by kidneys, undergoing chemotherapy, etc. “Rich Persons Disease” = lots of meat

Question 13

Lesch-Nyhan Syndrome

1. Mechanism
2. Symptoms
3. MOI
4. Treatment

Answer 13

1. HGPRT (Hydroxanthine-Guanine Phosphoribosyl Transferase) defect leads to no purine salvage happening. This gives increased serum uric acid–> gout and behavioral symptoms
2. neurological problems, uncontrolled self-bitin, gouty arthritis
3. XLR (almost all cases male)
4. reduced purine intake; allopurinol (?) doesn’t help much

• “He’s Got Purine Recovery Trouble”
• very poor prognosis, even with treatment

Question 14

Severe Combined Immune Deficiency (SCID)

Answer 14

1. Adenosine Deaminase deficiency (Adenosine–> inosine) deficiency leads to toxic amounts of dATP, which inhibits: ribonucleotide reductase, deoxyribonucleotide production, de novo nucleotide synthesis.
2. Both B and T cells rely on de novo nucleotide synthesis. Reduced B and T cells leads to immunodeficiency.
3. AR or XLR
4. ERT, bone marrow transplant, gene therapy in trials

Question 15

Neonates of PKU mothers are abnormal because:

Answer 15

a. A toxic product crosses the placenta
b. Too much phenylalanine crosses the placenta
c. Phenylalanine blocks the uptake of other aminoacids at blood brain barrier.

Question 16

PKU ____ tyrosine levels and tyrosinemia ___ tyrosine levels

Answer 16

PKU decreases, tyrosinemia increases

Question 17

PKU children are often light-colored because:

Answer 17

PKU leads to low tyrosine, and tyrosine is the precursor to melanin

Question 18

The two NH3 in urea derive from

Answer 18

Aspartate
Citrulline

Question 19

long term diseases of childhood related to AA metabolism:

short term/emergency diseases of childhood related to AA metabolism:

Answer 19

• homocysteinuria (a disease of adolescents) and tyrosinemia are more long term, not necessarily emergency
• PKU and urea cycle defects depend on feeding and represent emergencies (ie: baby not feeding well)

Question 20

OTC deficiency causes high _____ and low___

Answer 20

OTC causes high orotic acid, NH3, and ornithine, low citrulline (made from ornithine by OTC)

Question 21

allopurinol is a molecular mimic of:

Answer 21

hypoxanthine

Question 22

defects in HGPRT are predicted to:

Answer 22

inhibit rate of synthesis of nucleoside monophosphates

Question 23

OTC results in low levels of ___________ and high levels of ____.

Answer 23

• lowe levels arginine and urea
• high levels of NH3 and glutamine (and orotic acid, etc.)