STEPTRACKERBIOCHEMISTRY + PEDIATRICS + NEPHROLOGY | AMINO ACID METABOLISM | HIGH-YIELD REVIEW

Homocystinuria, MSUD & Other Aminoacidopathies

Sulfur and branched-chain amino acid defects, the organic acidemias that cause newborn acidosis, and two transporter defects in the gut and kidney.

FOCUS ON
Homocystinuria: cystathionine β-synthase ↓ (or methionine synthase/MTHFR) → ↑ homocysteine → marfanoid, lens down and in, ID, thrombosis. MSUD: branched-chain α-ketoacid DH ↓ (B1) → ↑ Isoleucine, Leucine, Valine → sweet urine, encephalopathy. Propionic/methylmalonic acidemia → anion gap acidosis + hyperammonemia + hypoglycemia. Cystinuria: COLA transporter → hexagonal cystine stones. Hartnup: neutral amino acids lost → pellagra.
DISORDER
DEFECT
FEATURES
CLUE · TREATMENT
Homocystinuria — CBS type
most common · AR
Cystathionine β-synthase (B6) → can't make cystathionine → ↑ homocysteine, ↑ methionine
Marfanoid habitus, ectopia lentis (down/in), ID, osteoporosis, arterial and venous thrombosis
↓ Met, ↑ Cys diet, B6 (responsive forms), betaine, B12/folate
Homocystinuria — remethylation types
Methionine synthase (B12) or MTHFR ↓
↑ Homocysteine with ↓ methionine
Give B12, folate, betaine
Maple syrup urine disease
AR
Branched-chain α-ketoacid dehydrogenase (TPP, lipoate…) → ↑ Leu, Ile, Val and their α-ketoacids
Days after birth: poor feeding, vomiting, alternating hypertonia/hypotonia, seizures, cerebral edema; urine smells of maple syrup/burnt sugar
Leucine is the most neurotoxic · restrict BCAA, give thiamine
Propionic acidemia
Propionyl-CoA carboxylase (biotin) ↓
Neonatal vomiting, lethargy, anion gap metabolic acidosis, hyperammonemia, hypoglycemia
Restrict precursors: Val, odd-chain FA, Met, Ile, Thr
Methylmalonic acidemia
Methylmalonyl-CoA mutase (or B12 metabolism) ↓
Same neonatal picture as propionic acidemia; ↑ MMA
B12-responsive forms exist
Cystinuria
AR
Renal PCT and intestinal transporter for Cystine, Ornithine, Lysine, Arginine
Recurrent hexagonal cystine stones, staghorn possible
+ Cyanide-nitroprusside test · hydration, urinary alkalinization, chelators (penicillamine, tiopronin)
Hartnup disease
AR
Neutral amino acid transporter (SLC6A19) in PCT and gut → ↓ tryptophan absorption
Pellagra-like rash, cerebellar ataxia; neutral aminoaciduria
High-protein diet, nicotinic acid
Cystinosis (contrast)
Lysosomal cystine transporter (cystinosin) ↓
Renal Fanconi syndrome, corneal crystals, growth failure
Cysteamine
Organic acidemia pattern
Toxic CoA esters inhibit gluconeogenesis and NAG synthesis
Anion gap acidosis + ketosis + ↑ ammonia + hypoglycemia
Separates them from urea cycle defects (alkalosis)

Mechanism — homocysteine at the crossroads

Methionine
→
SAM → homocysteine
→
Cystathionine β-synthase (B6)→ cystathionine → cysteine
Homocysteine
→
Methionine synthase (B12, folate)→ back to methionine

Block either exit and homocysteine rises; CBS block also raises methionine, remethylation block lowers it.

Odd-chain catabolism path

STEP
ENZYME · COFACTOR
DEFICIENCY
Propionyl-CoA → methylmalonyl-CoA
Propionyl-CoA carboxylase · biotin
Propionic acidemia
Methylmalonyl-CoA → succinyl-CoA
Mutase · B12
Methylmalonic acidemia
Succinyl-CoA → TCA
—
—

How it's tested

COMMON CONFUSIONCystinuria is a transporter defect (stones); cystinosis is a lysosomal defect (Fanconi, corneal crystals); homocystinuria is an enzyme defect (thrombosis, lens).
THE TRAPA neonate with vomiting, anion gap acidosis and ↑ ammonia → organic acidemia, not a urea cycle defect.
YOUR APPROACHSmell (maple syrup), stones (hexagonal), lens (down), rash (pellagra), acid-base status (acidosis vs alkalosis) → disorder.

If you see… think…

Marfanoid + lens down and in + stroke in a teen → homocystinuria (CBS)
Sweet-smelling urine and seizures in a newborn → MSUD
Amino acids elevated in MSUD → leucine, isoleucine, valine
Newborn with anion gap acidosis + hyperammonemia + hypoglycemia → propionic or methylmalonic acidemia
Hexagonal crystals in urine → cystinuria
Positive cyanide-nitroprusside urine test → cystinuria
Pellagra-like rash + neutral aminoaciduria → Hartnup
Corneal crystals + Fanconi syndrome in a child → cystinosis
Cofactor that helps some CBS deficiency → B6
Dibasic amino acids in urine → COLA (cystinuria)