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

Phenylalanine & Tyrosine Disorders

Block phenylalanine → tyrosine and the brain suffers; block tyrosine's breakdown or melanin synthesis and the joints, urine, liver or skin show it.

FOCUS ON
PKU (AR): ↓ phenylalanine hydroxylase (or ↓ BH4) → ↑ Phe → ID, seizures, musty odor, fair skin, eczema; tyrosine becomes essential. Newborn screen; low-Phe diet, avoid aspartame. Maternal PKU → microcephaly, ID, heart defects in baby. Alkaptonuria: homogentisate oxidase ↓ → dark urine on standing, blue-black connective tissue (ochronosis), arthritis. Albinism: tyrosinase ↓ → no melanin, skin cancer risk.
DISORDER
ENZYME · INHERITANCE
FEATURES
CLUE · TREATMENT
Classic PKU
Phenylalanine hydroxylase · AR
Normal at birth → ID, seizures, growth delay, musty/mousy odor, eczema, fair hair/skin/eyes (↓ melanin)
↑ Phe, ↑ phenylketones (phenylpyruvate, phenyllactate) in urine · ↓ Phe diet, ↑ Tyr, avoid aspartame
BH4 deficiency
Dihydropteridine reductase or BH4 synthesis
PKU picture + ↓ dopamine, serotonin → movement disorder, worse neurologic outcome
Supplement BH4 (sapropterin), L-DOPA, 5-HTP
Maternal PKU
High maternal Phe crosses placenta
Microcephaly, ID, growth retardation, congenital heart defects
Restart low-Phe diet before conception
Alkaptonuria
Homogentisate oxidase · AR
Urine darkens on standing; dark ear cartilage and sclerae (ochronosis); arthralgia, back pain, valvular calcification
Usually benign early; nitisinone
Albinism (oculocutaneous)
Tyrosinase (OCA1) or tyrosine transporter · AR
Absent melanin in skin, hair, eyes; ↓ visual acuity, nystagmus
↑ Skin cancer (SCC) · melanocyte number normal
Ocular albinism
GPR143 · X-linked
Eyes only
—
Vitiligo (contrast)
Autoimmune loss of melanocytes
Patchy depigmentation
↓ Melanocytes (not ↓ melanin per cell)
Tyrosinemia type I
Fumarylacetoacetate hydrolase · AR
Liver failure, renal Fanconi syndrome, cabbage odor, ↑ HCC risk
Nitisinone + low Tyr/Phe diet
Tyrosine as essential
Only when PAH can't make it
Supplement in PKU diet
—

Mechanism — the phenylalanine pathway

Phenylalanine
→
PAH + BH4PKU
→
Tyrosine
→
TyrosinaseAlbinism → melanin
Tyrosine breakdown
→
Homogentisate
→
Homogentisate oxidaseAlkaptonuria
→
Fumarate + acetoacetate(FAH — tyrosinemia I)

Disorders compared

DISORDER
MAIN ORGAN
ODOR / COLOR
DIET
PKU
Brain
Musty, fair skin
↓ Phe, ↑ Tyr
Alkaptonuria
Joints, cartilage
Dark urine, blue-black tissue
—
Albinism
Skin, eyes
White skin, pale eyes
—
Tyrosinemia I
Liver, kidney
Cabbage odor
↓ Tyr, ↓ Phe

How it's tested

COMMON CONFUSIONAlbinism has normal melanocytes making no melanin; vitiligo has lost melanocytes.
THE TRAPA healthy-looking newborn with ID-causing PKU in a mother with poorly controlled PKU → the problem is maternal PKU, not the baby's genotype.
YOUR APPROACHWhere does the block sit on Phe → Tyr → melanin/catecholamines/breakdown? → what builds up (Phe, homogentisate) → organ sign.

If you see… think…

Musty odor, fair skin, eczema, developmental delay → PKU
PKU picture not improved by low-Phe diet → BH4 deficiency
Diet soda warning label → phenylalanine (aspartame) for PKU
Baby with microcephaly and heart defect, mother with PKU off diet → maternal PKU
Urine turns black when left standing → alkaptonuria
Dark ear cartilage and early arthritis → ochronosis (alkaptonuria)
White hair, pale skin, nystagmus from birth → oculocutaneous albinism (tyrosinase)
Cabbage-like odor, liver failure, Fanconi syndrome → tyrosinemia type I
Amino acid that becomes essential in PKU → tyrosine
Newborn screen for PKU timing → after protein feeding has started