A newborn screening detects elevated phenylalanine. At 6 months, the infant has fair skin, blonde hair, musty body odor, and severe seizures refractory to anticonvulsants. Despite strict phenylalanine-restricted diet, neurological deterioration continues. Neurotransmitter supplementation with L-DOPA and 5-HTP is required. Which enzyme deficiency explains this MOST SEVERE variant of hyperphenylalaninemia?

A.	Phenylalanine hydroxylase (PAH)
B.	Dihydrobiopterin reductase (DHPR)
C.	Tyrosine aminotransferase
D.	Homogentisate oxidase

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Correct Answer � B Explanation

Malignant Hyperphenylalaninemia: Dihydrobiopterin Reductase (DHPR) Deficiency

The most severe form of hyperphenylalaninemia is caused by DHPR deficiency (or defects in BH4 biosynthesis). Unlike classical PKU, DHPR deficiency depletes tetrahydrobiopterin (BH4) — the cofactor not only for phenylalanine hydroxylase but also for tyrosine hydroxylase and tryptophan hydroxylase. This causes combined hyperphenylalaninemia AND catastrophic dopamine/serotonin deficiency, producing progressive neurological disease that does NOT respond to dietary phenylalanine restriction alone.

Core Concept

• Phenylalanine hydroxylase (PAH) reaction: Phenylalanine + O₂ → Tyrosine; requires BH4 (tetrahydrobiopterin) as cofactor
• BH4 regeneration: BH4 is oxidized to BH2 (dihydrobiopterin) during the PAH reaction → regenerated by DHPR (dihydrobiopterin reductase) using NADH
• BH4 is also the cofactor for:
• Tyrosine hydroxylase: Tyrosine → DOPA → Dopamine
• Tryptophan hydroxylase: Tryptophan → 5-HTP → Serotonin
• Nitric oxide synthase (NOS)
• DHPR deficiency → BH4 depletion:
• PAH cannot function → hyperphenylalaninemia (same as classical PKU)
• Tyrosine hydroxylase cannot function → ↓ DOPA → ↓ Dopamine, ↓ Norepinephrine
• Tryptophan hydroxylase cannot function → ↓ 5-HTP → ↓ Serotonin
• Result: Severe neurological disease (seizures, hypotonia, progressive intellectual disability)
• Why diet FAILS: Phenylalanine restriction addresses only the hyperphenylalaninemia but does NOT restore BH4 or neurotransmitter synthesis
• Treatment: BH4 supplementation + L-DOPA + carbidopa + 5-HTP (neurotransmitter precursors) + phenylalanine restriction
• Classical PKU (PAH deficiency): BH4 levels normal; only phenylalanine accumulates; dietary restriction ± BH4 supplementation (for BH4-responsive PAH mutations) is effective
• Screening alert: All infants with elevated phenylalanine MUST be tested for urine pterins and DHPR activity to exclude malignant PKU

Why B (“Dihydrobiopterin reductase (DHPR)”) is correct

• The combination of hyperphenylalaninemia + severe progressive neurological disease + failure of dietary restriction + requirement for neurotransmitter supplementation (L-DOPA + 5-HTP) is the clinical fingerprint of DHPR (or BH4 biosynthesis) deficiency
• DHPR deficiency depletes BH4 → impairs ALL three aromatic amino acid hydroxylases → combined neurotransmitter crisis

Why the Other Options Are Wrong

A. Phenylalanine hydroxylase (PAH) — Classical PKU (most common cause of hyperphenylalaninemia). BH4 levels are normal; dopamine and serotonin synthesis are INTACT. Dietary phenylalanine restriction is effective. Neurological outcomes are good if treated early. Discriminator: PAH deficiency = diet works; BH4 (DHPR) deficiency = diet FAILS, needs neurotransmitter replacement.

C. Tyrosine aminotransferase — Deficiency causes Tyrosinemia Type II (Richner-Hanhart syndrome): elevated tyrosine, NOT elevated phenylalanine. Clinical features are palmoplantar hyperkeratosis and corneal crystal deposits. Discriminator: Tyrosinemia Type II → elevated TYROSINE + corneal/skin lesions; DHPR deficiency → elevated PHENYLALANINE + neurological crisis.

D. Homogentisate oxidase — Deficiency causes alkaptonuria: homogentisic acid accumulates, urine darkens on standing (oxidation to alkapton), ochronosis (pigment deposits in connective tissue), and arthritis in adulthood. No hyperphenylalaninemia. Discriminator: Alkaptonuria = black urine + ochronosis; DHPR deficiency = neonatal hyperphenylalaninemia + neurotransmitter depletion.

High-yield Recap

Disorder	Enzyme	Elevated metabolite	Key features
Classical PKU	PAH	Phenylalanine	Musty odor, fair skin; diet works
Malignant PKU	DHPR (or GCH1)	Phenylalanine + ↓BH4	Seizures, neurodegeneration; diet fails
Tyrosinemia II	Tyrosine aminotransferase	Tyrosine	Corneal crystals, palmoplantar keratosis
Alkaptonuria	Homogentisate oxidase	Homogentisic acid	Black urine, ochronosis, arthritis
DOPA-responsive dystonia	GTP cyclohydrolase I	↓BH4 → ↓DOPA	Dystonia responding to low-dose L-DOPA