Nitrogen Metabolism

Question 1

Most common inborn error of amino acid metabolism

Answer 1

Phenylketonuria (PKU)

Question 2

PKU cause

Answer 2

. Autosomal recessive Mutation in phenylalanine hydroxylase
. Catalyzes the conversion Phe to Tyr
.

Question 3

What happens in PKU

Answer 3

. PAH enzyme defective to Phe and alternative breakdown products (phenylpyruvate, phenyllactatem phenyl acetate) accumulate

Question 4

PKU symptoms and treatment

Answer 4

. Hypopigmentation, developmental delay, intellectual disability, and seizures
. Treatment: avoid Phe in diet but can’t be completely eliminated bc it is essential AA

Question 5

Biopterin defects

Answer 5

. Genetic mutation in gene coding for enzymes in synthesis or recycling of BH4
. Causes impaired function of PAH and accumulation of Phe
. Same manner as PKU

Question 6

Tyrosinemia of newborns

Answer 6

. Seen in preemies
. 4-hydroxyphenylpyruvic acid oxidase immaturity causing lack of Tyr catabolism
. Tyr and Phe accumulate in serum
. Resolves on its own after a few months

Question 7

Maternal PKU syndrome

Answer 7

. High levels blog Phe in pregnant mom w/ PKU is toxic to fetus
. Causes microcephaly and congenital heart defects

Question 8

Enzymes involved in urea cycle that if mutated will cause accumulation of ammonia and encephalopathy

Answer 8

. Carbamoyl phosphate synthetase I (CPSI)
. Ornithine transcarbamylase (OTC): X-linked
. Arginosuccinate synthetase (ASS)
. Arginosuccinate lyase (ASL)
. Arginase (ARG)
. All homozygous recessive except OTC

Question 9

Mutations in genes for what transporters cause urea cycle disorders?

Answer 9

. Ornithine transporter mitochondrial 1 (ORNT1)
. Citrin (mitochondrial Asp transporter)
. N-acetylglutamate synthase (NAGS) can also cause urea cycle disorders, positive effect needed for CPS-1 activity

Question 10

Lab tests for urea cycle disorders

Answer 10

. Blood ammonia level 
. Arterial blood gas
. Plasma amino acid profile 
. Urinary orotic acid 
. Urinary organic acid profile 
. Liver function tests 
. Genetic testing 
. Biopsy for enzyme activity

Question 11

Acute treatment for urea cycle disorders

Answer 11

. Dialysis
. ammonia/nitrogen scavengers
. Replacement therapy for deficient intermediates
. Try to get ammonia levels back to normal

Question 12

Long term treatment for urea cycle disorders

Answer 12

. Dietary protein restriction
. Administration of N/ammonia scavengers and replacement therapy
. Liver transplants if disease is severe

Question 13

Maple syrup urine disorder (MSUD)

Answer 13

. Mutation in gene for branched chain alpha-Keto acid dehydrogenase (BCKD)
. Enzyme catalyzes rate-limiting rxn in Leu, Iso, and Val catabolism (oxidative decarboxylation)
. AA and corresponding alpha-Keto acids build up
. Causes brain damage
. Excreting Leu smells like maple syrup
. Treatment: restricting dietary intake of BCAAs

Question 14

Intermediates in branched chain amino acid catabolism

Answer 14

. Propionyl-CoA, isovaleryl-CoA, and methylmalonyl-CoA

. Genetic mutations in genes coding for enzymes that use these cause accumulation and development of organic acidemias

Question 15

Homocystinuria

Answer 15

. Diseases causing accumulation of homocysteine and its excretion into urine during 1-C metabolism
. Commonly caused by mutation in cystathione beta-synthase (CBS)
. People homozygous have v high levels and develop mental retardation, thrombocytic events, osteoporosis, and lens discoloration
. B6 supplements can help, otherwise avoid dietary Met and administer betaine

Question 16

Tyrosinemia type I

Answer 16

. Mutation in gene for fumarylacetoacetate hydrolase
. Catalyzes conversion of fumarylacetoacetate to fumarate and Acetoacetate in last step of Tyr catabolism
. Most common and most severe
. Diarrhea, vomiting, and failure to thrive from intolerance for dietary protein
. In adults accumulation of toxic compounds can cause liver cancer, liver/kidney failure

Question 17

Tyrosinemia type II and III

Answer 17

. Caused by mutation in gene for Tyr aminotransferase and 4-hydroxyphenylpyruvate dioxygenase

Question 18

Alkaptonuria

Answer 18

. Consequence of accumulation of homogentisic acid that is an intermediate during Tyr catabolism
. Causes homogentisic aciduria, dark urine, and arthritis

Question 19

Albinism

Answer 19

. Type I caused by mutation in tyrosinase
. Catalyzes 1st step in conversion to Tyr to melanin in melanocytes
. Type I is most severe

Question 20

Cystinuria

Answer 20

. Genetic defect in transporter that is unable to reabsorption filtered Cys and dibasic AA (Ornithine, Arg, Lys) in renal proximal tubule
. Causes Cys kidney stones

Question 21

Hartnup disease

Answer 21

. Caused by defective transporter of neutral amino acids (Trp) in kidney and intestine
. Causes pellagra-like symptoms (skin rash)

Question 22

Biopterin function

Answer 22

. Needed to provide reducing equivalents for Phe to Tys reactions

Question 23

Severe neonatal onset of urea cycle disorders

Answer 23

. Complete absence of enzyme
. Severe hyperammonia w/in days of birth
. Poor feeding, lethargy, Tracy pea, hypothermia, irritability, vomiting, seizures, hepatomegaly, sepsis

Question 24

Later-onset urea cycle disorders

Answer 24

. Partial deficiency of enzyme
. Mild hyperammonia: only onset w/ illness/fasting/stress because more ammonia comes in and can’t be detoxified w/ weaker enzyme function
. Nausea, vomiting, altered mental status, migraine headaches, seizures

Question 25

Orotic acid

Answer 25

. Made from carbamoyl phosphate
. Used in pyrimidine synthesis
. High levels in urine w/ OTC deficiency

Question 26

If patient has low citrulline and Ard plasma concentration, what do you suspect?

Answer 26

. Get urine orotic acid
. If low level then CPSI or NAGS (obtain liver biopsy)
. If high it is high get liver biopsy for OTC testing

Question 27

If patient has high citrulline what do you suspect w./ urea disorder?

Answer 27

. ASS if no arginosuccinate (get fibroblast assay)

. If elevated arginosuccinate expect ASL and obtain RBC or fibroblast assay

Question 28

What do you use for CPSI, NAGS, OTC, ASS, ASL, and ARG enzyme essays?

Answer 28

. CPSI, NAGS, OTC: liver biopsy
. ASS, ASL: fibroblasts
. ARG: erythrocytes

Question 29

Reactions involving homocysteine

Answer 29

. Remethylated to Met by B12
. Can form cys through cystathionine (needs folic acid)
. Can be excreted through cystathionine form