Inborn Errors: Amino Acid Metabolism and Urea Cycle Defects

Question 1

Of the disorders discussed in lecture today, which is not on the newborn screening?

Answer 1

Ornithine transcarbamylase deficiency

Question 2

Who was the first doctor to realize that genes encode enzymes and can be passed down in an autosomal recessive manner?

Answer 2

Archibald Garrod

Question 3

What is the bacterial inhibition assay for PKU?

Answer 3

Dr. Folling developed bacteria that only grow in response to high levels of phenylalanine. That bacteria can screen for PKU.

Question 4

Why is Krabbe disease being on the newborn screening disputed?

Answer 4

Because it cannot be reliably treated

Question 5

What three disorders are not on the Colorado newborn screen that are recommended by the DHHS?

Answer 5

X-linked adrenoleukodystrophy, Pompe, and MPS-1

Question 6

How many births per year occur in Colorado?

Answer 6

65,000

Question 7

Phenylketonuria results from ________________.

Answer 7

an autosomal recessive defect in phenylalanine hydroxylase, which normally adds a hydroxyl group to phenylalanine to make it tyrosine

Question 8

What is the incidence of PKU?

Answer 8

1 : 15,00

Question 9

What disorder can mimic PKU?

Answer 9

Tetrahydrobiopterin deficiency (which is a cofactor for phenylalanine hydroxylase); this has a more complex phenotype, however.

Question 10

Why do doctors give small amounts of Phe to kids with PKU at birth?

Answer 10

Because the supplements taste terrible and sometimes kids won’t eat pure non-Phe containing foods

Question 11

In addition to restricting diet, how should you manage PKU?

Answer 11

Monitor serum albumin levels to ensure that malnutrition is avoided

Question 12

Some people with PKU respond to __________ (because of an allele), while some do not.

Answer 12

sapropterin

Question 13

What happens when a woman with PKU gets pregnant?

Answer 13

Phenylalanine has been shown to be a teratogen, so PKU is aggressively managed when women with PKU get pregnant.

Question 14

What are the three branched-chain amino acids?

Answer 14

Leucine (most elevated in someone with MSUD), isoleucine, and valine

Question 15

What is the incidence of MSUD?

Answer 15

1 : 150,000 (more common in Amish)

Question 16

What is opisthotonus?

Answer 16

Severe extension of the muscles, especially neck and arms

Question 17

In a child with MSUD, ___________ accumulation leads to cerebral edema.

Answer 17

leucine

Question 18

Symptomatic presentation in a neonate with MSUD can be rapidly reversed with treatment, but it raises the future risk of ____________.

Answer 18

psychiatric diseases

Question 19

Leucine elevation in combination with lactate and alpha-ketoglutarate elevation suggests a deficiency in _________.

Answer 19

the DLD subunit which is necessary for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain amino acid dehydrogenase

Question 20

In a person who cannot metabolize a certain protein, it’s important to shut off delivery of that protein from two sources: ___________________.

Answer 20

the diet and catabolism (to turn off catabolism, feed other calories to promote an anabolic state)

Question 21

A newborn with kidney failure might have a defect in which enzyme?

Answer 21

Fumarylacetoacetate hydrolase, which is downstream in the metabolism of tyrosine (and tyrosinemia type I results in hepatorenal syndrome)

Question 22

Presence of succinylacetone in the urine is diagnostic of _______________.

Answer 22

tyrosinemia type I; of note, this compound is highly carcinogenic and can cause hepatocellular carcinoma

Question 23

Tyrosinemia type II is also called ______________.

Answer 23

oculocutaneous tyrosinemia

Question 24

Defective 4-OH phenylpyruvic acid dehydrogenase results in ______________.

Answer 24

tyrosinemia type II (characterized by stellate lesions in the eye and palmoplantar hyperkeratosis)

Question 25

The phenocopy (disorder that mimics) homocystinuria is ______________.

Answer 25

Marfan’s

Question 26

A child with high levels of a serum substance that is pro-thrombotic and with scoliosis likely has a defect in which enzyme?

Answer 26

Cystathionine beta-synthase

Question 27

What supplement can be given to correct the disturbances of those with homocystinuria?

Answer 27

B6 (which converts homocysteine to cysteine)

Question 28

The enzyme _____________ converts homocysteine to methionine.

Answer 28

betaine

Question 29

A lot of people with undiagnosed ____________ will recognize that they feel bad after eating protein and consequently avoid it.

Answer 29

hyperammonemia

Question 30

What medication can trigger hyperammonemia in undiagnosed people?

Answer 30

Valproate

Question 31

The most common urea cycle defect is ______________.

Answer 31

ornithine transcarbamylase deficiency

Question 32

_______________ is curative of ornithine transcarbamylase deficiency.

Answer 32

Liver transplant

Question 33

There are three lab values that are suggestive of OTC deficiency: ______________.

Answer 33

low citrulline, high glutamine, and orotic acid

Question 34

How does phenylacetate help with OTC deficiency?

Answer 34

Phenylacetate binds with glutamine and can be excreted in the urine

Question 35

Generally, blood phenylalanine levels less than _______ are considered safe.

Answer 35

360 uM

Question 36

In some cases, doctors will give dietary large neutral amino acids (LNAAs) to patients with PKU. Why?

Answer 36

LNAAs pass through the BBB through the same channel as phenylalanine, so giving high doses of LNAAs lowers the amount of phenylalanine in the brain.

Question 37

Describe the presentation of MSUD.

Answer 37

Complete deficiency of BCKAD:

• Ketonuria and poor feeding in the first three days of life
• Spasming and lethargy in days 4-5 of life
• Coma and central respiratory failure by day 10

Partial BCKAD deficiency:
- metabolic disturbances in catabolic states

Question 38

What three outcomes are typical of untreated tyrosinemia?

Answer 38

• Hepatocellular carcinoma
• Liver failure
• Neurologic crisis

Question 39

What two treatments can alleviate tyrosinemia?

Answer 39

• Liver transplant (totally curative)

- Nitisone –an inhibitor of one of the enzymes before FAH that prevents accumulation of succinylacetone

Question 40

What labs are suggestive of urea cycle disorders?

Answer 40

Normal glucose and anion gap with ammonia greater than 150 uM

Question 41

All of the urea cycle disorders are autosomal recessive with the exception of __________, with is X-linked.

Answer 41

OTC

Question 42

What enzyme directly produces urea?

Answer 42

Arginase

Question 43

Severe deficiency or total absence of the first four enzymes in the urea cycle (CPS1, OTC, ASS, ASL) leads to what clinical presentation?

Answer 43

Hyperammonemia in the first few days of life; note, deficiencies in the co-factor producer NAGS also leads to this presentation

Question 44

What symptoms are suggestive of PKU?

Answer 44

Hypopigmentation
Mental retardation
Eczema
Musty smell
Hypomyelination on brain MRI

Question 45

What disorder of amino acid catabolism is more common in the Amish?

Answer 45

MSUD

Question 46

What are some acute and chronic signs of hyperammonemia?

Answer 46

Acute:

• encephalopathy (e.g., visual disturbances, ataxia)
• vomiting and loss of appetite

Chronic:

• migraines
• failure to thrive

Question 47

Why are benzoate and phenylacetate given to those with OTC?

Answer 47

Because both molecules are “ammonia scavengers” that can absorb ammonia and make it excretable