Inborn Errors: Amino Acid Metabolism and Urea Cycle Defects Flashcards Preview

DEMS EXAM 3 > Inborn Errors: Amino Acid Metabolism and Urea Cycle Defects > Flashcards

Flashcards in Inborn Errors: Amino Acid Metabolism and Urea Cycle Defects Deck (47)
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1
Q

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

A

Ornithine transcarbamylase deficiency

2
Q

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

A

Archibald Garrod

3
Q

What is the bacterial inhibition assay for PKU?

A

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

4
Q

Why is Krabbe disease being on the newborn screening disputed?

A

Because it cannot be reliably treated

5
Q

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

A

X-linked adrenoleukodystrophy, Pompe, and MPS-1

6
Q

How many births per year occur in Colorado?

A

65,000

7
Q

Phenylketonuria results from ________________.

A

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

8
Q

What is the incidence of PKU?

A

1 : 15,00

9
Q

What disorder can mimic PKU?

A

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

10
Q

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

A

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

11
Q

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

A

Monitor serum albumin levels to ensure that malnutrition is avoided

12
Q

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

A

sapropterin

13
Q

What happens when a woman with PKU gets pregnant?

A

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

14
Q

What are the three branched-chain amino acids?

A

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

15
Q

What is the incidence of MSUD?

A

1 : 150,000 (more common in Amish)

16
Q

What is opisthotonus?

A

Severe extension of the muscles, especially neck and arms

17
Q

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

A

leucine

18
Q

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

A

psychiatric diseases

19
Q

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

A

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

20
Q

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

A

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

21
Q

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

A

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

22
Q

Presence of succinylacetone in the urine is diagnostic of _______________.

A

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

23
Q

Tyrosinemia type II is also called ______________.

A

oculocutaneous tyrosinemia

24
Q

Defective 4-OH phenylpyruvic acid dehydrogenase results in ______________.

A

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

25
Q

The phenocopy (disorder that mimics) homocystinuria is ______________.

A

Marfan’s

26
Q

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

A

Cystathionine beta-synthase

27
Q

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

A

B6 (which converts homocysteine to cysteine)

28
Q

The enzyme _____________ converts homocysteine to methionine.

A

betaine

29
Q

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

A

hyperammonemia

30
Q

What medication can trigger hyperammonemia in undiagnosed people?

A

Valproate

31
Q

The most common urea cycle defect is ______________.

A

ornithine transcarbamylase deficiency

32
Q

_______________ is curative of ornithine transcarbamylase deficiency.

A

Liver transplant

33
Q

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

A

low citrulline, high glutamine, and orotic acid

34
Q

How does phenylacetate help with OTC deficiency?

A

Phenylacetate binds with glutamine and can be excreted in the urine

35
Q

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

A

360 uM

36
Q

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

A

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.

37
Q

Describe the presentation of MSUD.

A

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

38
Q

What three outcomes are typical of untreated tyrosinemia?

A
  • Hepatocellular carcinoma
  • Liver failure
  • Neurologic crisis
39
Q

What two treatments can alleviate tyrosinemia?

A
  • Liver transplant (totally curative)

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

40
Q

What labs are suggestive of urea cycle disorders?

A

Normal glucose and anion gap with ammonia greater than 150 uM

41
Q

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

A

OTC

42
Q

What enzyme directly produces urea?

A

Arginase

43
Q

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

A

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

44
Q

What symptoms are suggestive of PKU?

A
Hypopigmentation
Mental retardation
Eczema
Musty smell
Hypomyelination on brain MRI
45
Q

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

A

MSUD

46
Q

What are some acute and chronic signs of hyperammonemia?

A

Acute:

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

Chronic:

  • migraines
  • failure to thrive
47
Q

Why are benzoate and phenylacetate given to those with OTC?

A

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