Bit · Biochem
PKU vs MSUD vs Homocystinuria vs Alkaptonuria
Four inherited amino-acid disorders that all show up in newborn screening or early childhood. Each has a different broken enzyme and a different odour, urine colour, or physical sign that NBME loves.
Mechanism
Each is an autosomal recessive enzyme deficiency in amino acid catabolism. The pivot is which enzyme and what accumulates:
- PKU — phenylalanine hydroxylase deficiency (or tetrahydrobiopterin cofactor deficiency). Phenylalanine accumulates; tyrosine becomes essential. Phenylketones in urine give a musty/mousy odour.
- MSUD — branched-chain α-ketoacid dehydrogenase (BCKD) complex deficiency. Leucine, isoleucine, and valine accumulate. Urine smells like maple syrup.
- Homocystinuria — most commonly cystathionine β-synthase deficiency (B6-dependent). Homocysteine and methionine accumulate.
- Alkaptonuria — homogentisate oxidase deficiency. Homogentisic acid accumulates. Urine turns black on standing; cartilage/sclera darken later in life (ochronosis).
Differentiator Table
| PKU | MSUD | Homocystinuria | Alkaptonuria | |
| Enzyme deficient | Phenylalanine hydroxylase (or BH₄) | BCKD complex | Cystathionine β-synthase (most common) | Homogentisate oxidase |
| What accumulates | Phenylalanine, phenylketones | Leucine, isoleucine, valine + α-ketoacids | Homocysteine, methionine | Homogentisic acid |
| Classic clue | Musty/mousy odour, fair skin/hair/eyes, eczema | Maple syrup–smelling urine, vomiting, coma in neonate | Marfanoid habitus, lens dislocation DOWNWARD, thrombosis, intellectual disability | Urine darkens on standing, ochronosis (blue-black sclera/cartilage), arthritis |
| Onset | Untreated: intellectual disability over months | Days of life — encephalopathy | Childhood to adulthood | Childhood urine finding; arthritis in adulthood |
| Treatment | Phe-restricted diet (avoid aspartame); tyrosine supplementation | Restrict branched-chain AAs; thiamine in some forms | Restrict methionine, supplement B6, B9, B12, cysteine | Vitamin C may slow ochronosis; no curative treatment |
The Pivot
NBME hands you the smell, the colour, or the body habitus and asks the enzyme:
- Musty/mousy + fair skin? PKU.
- Maple syrup urine + neonatal encephalopathy? MSUD.
- Tall, lens dislocation downward, thrombotic event? Homocystinuria. (Marfan dislocates lens upward.)
- Urine that darkens on standing, blue-black cartilage? Alkaptonuria.
NBME-Style Stem
A 6-month-old infant has fair skin, blue eyes, and eczema. The mother notes a musty smell to his urine. Developmental milestones are delayed. Newborn screening was not performed. Which of the following dietary modifications is most appropriate?
Concept Anchor
Each amino-acid disorder is a different broken step on the catabolic pathway — the substrate piles up, gives the patient a signature odour, urine colour, or body sign, and the treatment is to restrict the substrate (or replace what's now essential).