BH4

**Synthesis and recycling** - Synthesis: GTP → (GTP cyclohydrolase I, GCH1) → dihydroneopterin triphosphate → (6-pyruvoyl-tetrahydropterin synthase, PTPS) → BH4 (sepiapterin reductase completes the final steps). - Recycling: during hydroxylation, BH4 is oxidized to quinonoid dihydrobiopterin (qBH2). Dihydropteridine reductase (DHPR) regenerates BH4 using NADH. DHPR is distinct from dihydrofolate reductase (DHFR).

**Enzymes that require BH4** 1. Phenylalanine hydroxylase: Phe → Tyr 2. Tyrosine hydroxylase: Tyr → L-DOPA, the rate-limiting step of catecholamine synthesis (dopamine, norepinephrine, epinephrine) 3. Tryptophan hydroxylase: Trp → 5-HTP, which leads to serotonin and melatonin 4. Nitric oxide synthase (all isoforms): Arg → NO + citrulline. BH4 deficiency "uncouples" eNOS, which produces superoxide and endothelial dysfunction. 5. Alkylglycerol monooxygenase (ether lipid metabolism)

**BH4 deficiency (about 2% of hyperphenylalaninemia cases)** - Causes: autosomal recessive defects in GCH1, PTPS (the most common), DHPR, or sepiapterin reductase. - Biochemistry: elevated Phe, plus low dopamine and serotonin because tyrosine and tryptophan hydroxylation are impaired. - Clinical features: despite a low-Phe diet, patients develop progressive neurologic deterioration. Findings include intellectual disability, seizures, hypotonia, microcephaly, developmental delay, and movement disorders. They may also show a musty or mousy odor, hypopigmentation, and eczema, as in classic PKU. - Diagnosis: newborn screening finds hyperphenylalaninemia. Then check urinary or blood pterins, DHPR activity, and a BH4 loading test. Cerebrospinal fluid neurotransmitter metabolites (low HVA and 5-HIAA) support the diagnosis. - Treatment: BH4 (sapropterin), a low-Phe diet, and neurotransmitter precursors (L-DOPA/carbidopa and 5-hydroxytryptophan). Some patients also need folinic acid, especially in DHPR deficiency, because of secondary cerebral folate deficiency. - Dopa-responsive dystonia (Segawa disease): autosomal dominant GCH1 mutation. Phe is normal. Dystonia shows diurnal variation and responds dramatically to L-DOPA.

**Classic PKU vs. BH4 deficiency (high-yield comparison)** - Classic PKU: phenylalanine hydroxylase deficiency. Tyrosine becomes essential. Treatment is a low-Phe, high-Tyr diet. - BH4 deficiency: Phe is elevated as in PKU, but patients also have neurotransmitter deficiency and a poor response to diet alone. - Sapropterin (a synthetic BH4) is approved for BH4-responsive PKU, mainly patients with residual PAH activity. It acts as a cofactor and a chaperone that stabilizes PAH.

**Other clinical points** - Maternal PKU: poorly controlled maternal Phe causes microcephaly, congenital heart defects, intellectual disability, and growth restriction in the fetus. - Pharmacology: sapropterin is a Phe-lowering agent. Pegvaliase (a PEG-modified phenylalanine ammonia lyase) is used in adults with uncontrolled PKU. It can cause anaphylaxis. - Cardiovascular: BH4 depletion and eNOS uncoupling contribute to oxidative stress and endothelial dysfunction in hypertension, diabetes, and atherosclerosis.

**Boards pearl:** PKU-like presentation + neurologic deterioration despite diet → think BH4 deficiency. Treatment adds neurotransmitter precursors (L-DOPA/carbidopa and 5-HTP).