AA disorders

Question 1

Classical PKU

Answer 1

• 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
    *

Question 2

Maternal PKU syndrome

Answer 2

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

Question 3

PKU II (malignant PKU)

Answer 3

• 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

Question 4

Alkaptonuria

Answer 4

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

Question 5

Tyrosinosis (Tyrosinemia Type I)

Answer 5

• 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

Question 6

Maple Syrup Urine Disease (MSUD)

Answer 6

• 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

Question 7

Methylmalonic Aciduria

Answer 7

• 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

Question 8

Homocysteinuria

Answer 8

• 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