Inborn Errors: Amino Acid Metabolism and Urea Cycle Defects Flashcards
Of the disorders discussed in lecture today, which is not on the newborn screening?
Ornithine transcarbamylase deficiency
Who was the first doctor to realize that genes encode enzymes and can be passed down in an autosomal recessive manner?
Archibald Garrod
What is the bacterial inhibition assay for PKU?
Dr. Folling developed bacteria that only grow in response to high levels of phenylalanine. That bacteria can screen for PKU.
Why is Krabbe disease being on the newborn screening disputed?
Because it cannot be reliably treated
What three disorders are not on the Colorado newborn screen that are recommended by the DHHS?
X-linked adrenoleukodystrophy, Pompe, and MPS-1
How many births per year occur in Colorado?
65,000
Phenylketonuria results from ________________.
an autosomal recessive defect in phenylalanine hydroxylase, which normally adds a hydroxyl group to phenylalanine to make it tyrosine
What is the incidence of PKU?
1 : 15,00
What disorder can mimic PKU?
Tetrahydrobiopterin deficiency (which is a cofactor for phenylalanine hydroxylase); this has a more complex phenotype, however.
Why do doctors give small amounts of Phe to kids with PKU at birth?
Because the supplements taste terrible and sometimes kids won’t eat pure non-Phe containing foods
In addition to restricting diet, how should you manage PKU?
Monitor serum albumin levels to ensure that malnutrition is avoided
Some people with PKU respond to __________ (because of an allele), while some do not.
sapropterin
What happens when a woman with PKU gets pregnant?
Phenylalanine has been shown to be a teratogen, so PKU is aggressively managed when women with PKU get pregnant.
What are the three branched-chain amino acids?
Leucine (most elevated in someone with MSUD), isoleucine, and valine
What is the incidence of MSUD?
1 : 150,000 (more common in Amish)
What is opisthotonus?
Severe extension of the muscles, especially neck and arms
In a child with MSUD, ___________ accumulation leads to cerebral edema.
leucine
Symptomatic presentation in a neonate with MSUD can be rapidly reversed with treatment, but it raises the future risk of ____________.
psychiatric diseases
Leucine elevation in combination with lactate and alpha-ketoglutarate elevation suggests a deficiency in _________.
the DLD subunit which is necessary for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched-chain amino acid dehydrogenase
In a person who cannot metabolize a certain protein, it’s important to shut off delivery of that protein from two sources: ___________________.
the diet and catabolism (to turn off catabolism, feed other calories to promote an anabolic state)
A newborn with kidney failure might have a defect in which enzyme?
Fumarylacetoacetate hydrolase, which is downstream in the metabolism of tyrosine (and tyrosinemia type I results in hepatorenal syndrome)
Presence of succinylacetone in the urine is diagnostic of _______________.
tyrosinemia type I; of note, this compound is highly carcinogenic and can cause hepatocellular carcinoma
Tyrosinemia type II is also called ______________.
oculocutaneous tyrosinemia
Defective 4-OH phenylpyruvic acid dehydrogenase results in ______________.
tyrosinemia type II (characterized by stellate lesions in the eye and palmoplantar hyperkeratosis)
The phenocopy (disorder that mimics) homocystinuria is ______________.
Marfan’s
A child with high levels of a serum substance that is pro-thrombotic and with scoliosis likely has a defect in which enzyme?
Cystathionine beta-synthase
What supplement can be given to correct the disturbances of those with homocystinuria?
B6 (which converts homocysteine to cysteine)
The enzyme _____________ converts homocysteine to methionine.
betaine
A lot of people with undiagnosed ____________ will recognize that they feel bad after eating protein and consequently avoid it.
hyperammonemia
What medication can trigger hyperammonemia in undiagnosed people?
Valproate
The most common urea cycle defect is ______________.
ornithine transcarbamylase deficiency
_______________ is curative of ornithine transcarbamylase deficiency.
Liver transplant
There are three lab values that are suggestive of OTC deficiency: ______________.
low citrulline, high glutamine, and orotic acid
How does phenylacetate help with OTC deficiency?
Phenylacetate binds with glutamine and can be excreted in the urine
Generally, blood phenylalanine levels less than _______ are considered safe.
360 uM
In some cases, doctors will give dietary large neutral amino acids (LNAAs) to patients with PKU. Why?
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.
Describe the presentation of MSUD.
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
What three outcomes are typical of untreated tyrosinemia?
- Hepatocellular carcinoma
- Liver failure
- Neurologic crisis
What two treatments can alleviate tyrosinemia?
- Liver transplant (totally curative)
- Nitisone –an inhibitor of one of the enzymes before FAH that prevents accumulation of succinylacetone
What labs are suggestive of urea cycle disorders?
Normal glucose and anion gap with ammonia greater than 150 uM
All of the urea cycle disorders are autosomal recessive with the exception of __________, with is X-linked.
OTC
What enzyme directly produces urea?
Arginase
Severe deficiency or total absence of the first four enzymes in the urea cycle (CPS1, OTC, ASS, ASL) leads to what clinical presentation?
Hyperammonemia in the first few days of life; note, deficiencies in the co-factor producer NAGS also leads to this presentation
What symptoms are suggestive of PKU?
Hypopigmentation Mental retardation Eczema Musty smell Hypomyelination on brain MRI
What disorder of amino acid catabolism is more common in the Amish?
MSUD
What are some acute and chronic signs of hyperammonemia?
Acute:
- encephalopathy (e.g., visual disturbances, ataxia)
- vomiting and loss of appetite
Chronic:
- migraines
- failure to thrive
Why are benzoate and phenylacetate given to those with OTC?
Because both molecules are “ammonia scavengers” that can absorb ammonia and make it excretable
