Inborn Errors: Amino Acidopathies

Question 1

SIgns & Symptoms of PKU

Answer 1

• Microcephaly
• Epilepsy
• Mentally delayed → Severe intellectual disability
• Mischevious → Behavior problems.
• Musty body odor / eczema caused by excretion of excessive Phe and metabolites.
• ↓ Myelin formation
• ↓ Monoamines: derived from Phe → Tyr → DOPA →

Question 2

General appraoches to treating PKU

Answer 2

1. Restrict dietary phenylalanine (Phe)
2. Supplement with BH₄ (cofactor for PAH)
3. Supplement w/large neutral amino acid (LNAA) transporters

Question 3

Characteristics of dietary phenylalanine restriction

Answer 3

• Normalization of [Phe] and [Tyr] in the blood prevent above deficits.
• Initiate diet ASAP after birth and continue into adolescence or perhaps whole life.
• use Phe-free medical formula ==> normal nutritional status + acceptable plasma [Phe]
  
  • low protein food available, but unpalatable/expensive
• Ensure adequate calories, protein, vitamins, minerals
• Have to reduce but NOT eliminate Phe in diet. It is still an essential AA and necessary for growth.

Question 4

Characteristics of BH₄ supplementation in PKU

Answer 4

• Synthesis and recycling of BH4 can also cause PKU - trial injection is used to test efficacy/response
• The majority of individuals with mild or moderate PKU may be responsive to BH4
• Up to 10% of individuals with classic PKU show a response

Question 5

Characteristics of LNAA transporter supplementation in PKU

Answer 5

• At the blood-brain barrier, phenylalanine shares a transporter with other LNAA.
• Some individuals have been shown to exclude excess phenylalanine because of throughput variation in LNAA transporter capacity across BBB.
• LNAA supplementation ==> reduced brain Phe concetration via competitive inhibition.
• In non-compliant adults, this may help to protect the brain from acute toxic effects of phenylalanine.

Question 6

Maternal PKU syndrome definition

Answer 6

• Maternal HPA/PKU syndrome is the result of fetal exposure to high maternal plasma [Phe].
  
  • High Phe ==> hostile intrauterine environement
• Risks are congenital heart disease, intrauterine and postnatal growth retardation, microcephaly, and intellectual disability.
• Liklihood depends on severity of maternal HPA and effectiveness of dietary management.

Question 7

Rationale for newborn screening

Answer 7

• Goal = Dx of inborn errors of metabolism is based on the detection of characteristic substances in the blood or urine.
• allows pre-symptomatic detection of some inborn errors of metabolism, allowing early treatment and reduction of morbidity and mortality in some cases.
• There is NOT reliable detection of ALL inborn errors and urea cycle defects on newborn screen; nor are all disorders on the screen reliably detected

Question 8

Amino acids elevated in maple syrup urine disease (MSUD)

Answer 8

• Leucine, Isoleucine, Valine

Question 9

Changes in biochemical intermediates in homosystinuria

Answer 9

• Homocystinuria caused by cystathionine β-synthase (CBS) deficiency.
• ==> elevated homocysteine + methionine

Question 10

Signs & symptoms of classic homocystinuria (connective tissue/MSK)

Answer 10

• Ectopia lentis and/or severe myopia
• Skeletal abnormalities → excessive height and length of the limbs, osteoporosis, scoliosis
• Marfanoid habitus
• Thromboembolism → PE, stroke
• Athrosclerotic Disease → highest cause of mortality

Question 11

Signs/sx of classic homocystinuria (neurologic)

Answer 11

• Developmental delay/intellectual disability
• Seizures
• Psychiatric problems
• Extrapyramidal signs such as dystonia, hypopigmentation, malar flush, livedo reticularis, and pancreatitis.

Question 12

Tx approach in classic homocystinuria

Answer 12

• In neonates maintain normal or near-normal plasma homocysteine concentrations
• Protein-restricted and methionine-restricted diets (challenging diet)
• Possibly use Betaine
• Folate and vitamin B12 supplementation.
• B6 (pyridoxine) therapy if responsive

Question 13

Betaine MOA/use

Answer 13

• drug that drives Homocysteine to Methionine
• sometimes used in neonates w/classic homocystinuria
• often used in children w/classic homocystinuria

Question 14

Clinical sx of tyrosinemia type 1

Answer 14

• Liver dysfunction, hepatomegaly, jaundice
• Renal tubular dysfunction → growth failure and rickets
• Peripheral neuropathy
• no tx ==> children w/neurologic crises/change in mental status, abdominal pain and/or respiratory failure requiring mechanical ventilation ==> death by age 10

Question 15

Pathognomonic compound in Tyrosinemia Type 1

Answer 15

• Fumarylacetoacetate hydrolase deficiency → biochemical marker of disease
• Nitisinone (NTBC) blocks the down stream production of fumarylacetoacetate by blocking tyrosine conversion by p-HPPD