Inborn Errors Flashcards
List the signs and symptoms of phenylketonuria (PKU).
- Microcephaly
- Epilepsy
- Severe intellectual disability
- Behavioral problems
- Musty odor
- Eczema and other skin conditions
- Decreased skin and hair pigmentation
- Exaggerated DTRs
- Tremor
- Paraplegia or hemiplegia
- Decreased myelin formation
- Decreased dopamine, Norepinephrine and serotonin production
Describe the three approaches to treating a patient with PKU/hyperphenyalanemia
- Low protein diet, Phe-free formula for babies and Phe-free protein supplementation for older children and adults. Supplementation of BH4
- Supplementation with large neutral amino acids, which competes with Phe at the blood brain barrier transporter
- Oral use of enzyme phenylalanine ammonia lyase
Define maternal PKU symptoms
Can still contain high levels of plasma Phe. Tetatogenic to developing fetus. Babies with maternal PKU syndrome often have congenital heart disease, growth retardation, microcephaly and intellectual disability.
Describe the original rational for newborn screening
Originally instituted for PKU
Know the three amino acids elevated in maple syrup urine diease
Leucine (usually the most)
Isoleucine
Valine
Caused by deficiency of branched chain ketoacid dehydrogenase
Describe the biochemistry of classic homocystinuria
Autosomal recessive disorder caused by mutations that affect the metabolism of methionine to homocysteine or cysteine. Most common mutation is a deficiency of cythathionine-B-Synthase (CBS). CBS uses Vitamin B6 as a coenzyme
Describe the approach to treating a patient with classic homocystinuria
Protein-restricted diet with methionine restrictions.
Give B6 orally for a week to see if is it a B6 responsive variant
Betaine, which helps promote conversion of homocysteine back to methionine.
Folate and B12 supplementation
Describe the clinical symptoms of tyrosinemia type 1
Presents in young infants with severe liver involvement, including hepatic failure, cholestatic jaundice or cirrhosis with renal tubulopathy
Late in infancy this can present with Rickets and growth failure
When untreated, children will have repeated neurologic crisis that can change mental status, cause abdominal pain, peripheral neuropathy and respiratory failure.
Liver failure, hepatocellular carcinoma and neurogenic crisis typically cause death before age 10 if untreated
Name the pathogenic compound of tryrosinemia type 1
Caused by mutation in the FAH gene which codes for the enzyme fumarylacetoacetate hydrolase (FAH). Results in increased succinylacetone concentrations in the blood and urine.
Tyrosine, Methionine and Phenylalanine are elevated in the plasma
List three symptoms of hyperammonemia
Altered mental status
Vomiting
Seizures
(Also lethargy and progressive obdundation»_space; coma»_space; death)
Describe the age of presentation for severe and mild urea cycle disorders
Can manifest at ANY AGE
Most severe defect present in the newborn period (hyperammonemia)
Name the amino acids that comprise the urea cycle
There are 4 amino acids that are the backbone of the Urea Cycle:
- Ornithine
- Citrulline
- Argininosuccinate
- Arginine
These amino acids accept ammonia and release urea
Name the urinary compound elevated in early urea cycle disorders
What you see in the urine depends on where the problem (block) is.
- Problem with Arginosuccinate Synthase → Build-up of citrulline, ammonia
- Problem with Arginosuccinate Lyase → Build-up of arginosuccinate
- Problem with Arginase → Build-up of arginine
- OTC deficiency → Build-up of Ornithine (decreased citrulline, increased orotic acid & ammonia)
- Problem with Carbamoyl Phosphatase 1 → Build-up of ammonia (eep, really bad!)
- Problem with N-Acetylglutamate Synthase → Build-up of, ammonia (also really bad!)
Illustrate why glutamine is elevated in hyperammonemia
The brain must expend energy to detoxify and to export the ammonia it produces. This is accomplished in the process of producing adenosine diphosphate (ADP) from ATP by the enzyme glutamine synthetase, which is responsible for mediating the formation of glutamine from an amino group. Synthesis of glutamine also reduces the total free ammonia level circulating in the blood; therefore, a significant increase in blood glutamine concentration can signal hyperammonemia
Describe how ammonia scavenging medications work
Ammonia scavenging medications conjugate amino acids into more soluble compounds so they can be excreted in urine to get rid of ammonia in the absence of a normally functioning urea cycle.
- Sodium Benzoate: conjugates glycine to benzoate → Hippurate for excretion
- Sodium Phenylacetate: conjugates phenylacetate to glutamine → phenylacetylglutamine for excretion
