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Flashcards in AA disorders Deck (8)
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1
Q

Classical PKU

A
  • Phenylalanine Hydroxylase def.
  • elevation of serum phenylalanine & reduction in Tyr
  • Tyr becomes essential a.a.
  • Phenylalanine Hydroxylase requires BH4 as cofactor
    • mutation may reduce enzyme affinity for BH4
    • typically mild or moderate forms of disease
    • Rx: Sapropterin (synthetic BH4)
  • AR
  • Sx:
    • “mousey” odour of urine
    • Phe metabolized to phenylpyruvate, phenylacetate, phenyllactate
    • hypo-pigmentation
    • CNS sx: mental retardation, delayed development, due to inhibition of NT synthesis & competition interaction of Phe with other brain AA transport systems
  • Test for Phe
    • Guthrie bacterial inhibition assay
    • Tandem Mass Spec
    • Heel prick baby (~5 days old to avoid maternal Phe clearance)
  • Rx:
    • maintain blood [Phe] at nl range by diet low in Phe, feeding synthetic AA preps low in Phe, avoiding Aspartame, Tyr supplements
      *
2
Q

Maternal PKU syndrome

A
  • High maternal blood Phe (Teratogen) leads to fetal defects:
    • microcephaly
    • mental retardation
    • congenital heart defects
  • fetus usually has nl Phe Hydroxylase activity
3
Q

PKU II (malignant PKU)

A
  • Hyperphenylalaninemia can also be caused by deficiencies in enzymes required to BH4 or Dihydrobiopterin Reductase (BH2/BH4)
  • Sx:
    • Much more severe CNS sx; worse than Type I
    • decreased NT synthesis (5-HT, DA, catecholamines; also dependent on BH4)
  • Rx includes:
    • Low Phe diet
    • dietary supplements of biopterin
    • precursors of NT
4
Q

Alkaptonuria

A
  • Homogentisate Oxidase def.
  • Accumulation of Homogentisic acid deposited in cartilage & CT and excreted in urine
  • Sx:
    • joint arthritis
    • Ochronosis: discoloration of cartilage & CT
5
Q

Tyrosinosis (Tyrosinemia Type I)

A
  • Fumarylacetoacetate Hydrolase def. (catalyses last step in Tyr degradation)
  • manifestations are severe & usually fatal
  • Sx:
    • accumulation of fumarylacetoacetate causes liver & kidney damage
    • death due to liver failure within 1st year
  • Rx:
    • Dietary restriction of Phe & Tyr may be tried but difficult to accomplish as Tyr essential for NT synthesis
6
Q

Maple Syrup Urine Disease (MSUD)

A
  • Branched-Chain alpha-Ketoacid Dehydrogenase (BCKD); TLCFN
  • accumulation of BCAA and associated alpha-ketoacids
  • Sx:
    • Maple syrup odour urine
    • Ketosis
    • Sx develop in neonates aged 4-7 days
    • presents with poor feeding, vomiting, poor weight gain & increasing lethargy
    • Neurological signs develop rapidly (ex. alternating muscular hypotonia & hypertonia, seizures, encephalopathy
    • coma & death of child in early infancy
  • Rx:
    • dietary restriction of BCAA
    • improves neurological sx
  • problems of Rx:
    • very difficult to Rx
    • BCAA very abundant in most proteins sources
    • 3 BCAA are all essential
    • catabolic states mobilize tissue protein which then releases aa to metabolism
  • Thiamine supplement may be useful in Pt that have enzyme with low coenzyme affinity
7
Q

Methylmalonic Aciduria

A
  • Methylmalonyl CoA Mutase def.
  • Sx:
    • metabolic acidosis
    • seizures
    • encephalopathy
  • Methylmalonyl CoA Mutase requires B12
    • enzyme with reduced affinity for B12 results in milder form
    • Rx: B12 supplement
  • Methylmalonyl-CoA also sometimes used instead of malonyl-CoA for FA synthesis 27 -> branched FA incorporated into membranes
  • Rx:
    • Gastrostomy tube for feeding at regular intervals
    • special diets low in BCAA
8
Q

Homocysteinuria

A
  • Cystathionine-beta-synthase def.
    • requires PLP
  • accumulating Homocysteine binds to CT & disrupts protein structure
  • Sx:
    • Marfan-like habitus: ectopic lentis, skeletal abnormalities, premature arterial disease
    • mental retardation
    • homocysteine can have other effects: lipid oxidation & platelet aggregation -> leads to fibrosis & calcification of atherosclerotic plaques
  • Rx: dietary restriction of methione
    • some Pt respond to oral Vit B6 (pyridoxine); required for PLP
    • milder form due to low coenzyme affinity
    • B12 & folate supplement