Inborn Errors: Amino Acidopathies Flashcards Preview

DEMS: Unit IIb > Inborn Errors: Amino Acidopathies > Flashcards

Flashcards in Inborn Errors: Amino Acidopathies Deck (15)
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SIgns & Symptoms of PKU

  • 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 →


General appraoches to treating PKU

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


Characteristics of dietary phenylalanine restriction

  • 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.


Characteristics of BH4 supplementation in PKU

  • 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


Characteristics of LNAA transporter supplementation in PKU

  • 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.


Maternal PKU syndrome definition

  • 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.



Rationale for newborn screening

  • 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 


Amino acids elevated in maple syrup urine disease (MSUD)

  • Leucine, Isoleucine, Valine


Changes in biochemical intermediates in homosystinuria

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


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

  • 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


Signs/sx of classic homocystinuria (neurologic)

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


Tx approach in classic homocystinuria

  • 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


Betaine MOA/use

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


Clinical sx of tyrosinemia type 1

  • 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


Pathognomonic compound in Tyrosinemia Type 1

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