Tetrahydrobiopterin (BH4) deficiencies are disorders affecting
phenylalanine metabolism in the liver and
neurotransmitter biosynthesis in the brain. BH4 is the essential cofactor in the enzymatic hydroxylation of 3
aromatic amino acids (
phenylalanine,
tyrosine, and
tryptophan). BH4 is synthesized from
guanosine triphosphate (
GTP), catalyzed by
GTP cyclohydrolase I (GTPCH),
6-pyruvoyl-tetrahydropterin synthase, and
sepiapterin reductase (SR), and in
aromatic amino acids, the hydoxylating system is regenerated by pterin-4a-carbinolamine dehydrolase and
dihydropteridine reductase (DHPR).
BH4 deficiency has been diagnosed in patients with hyperphenylalaninemia (HPA) by neonatal mass-screening based on BH4 oral-loading tests, analysis of urinary or serum
pteridines, and measurement of DHPR activity in blood using a Guthrie card.
BH4 deficiency without treatment causes combined symptoms of HPA and
neurotransmitter (
dopamine,
norepinephrine,
epinephrine, and
serotonin) deficiency, such as red hair, psychomotor retardation, and progressive neurological deterioration. However, autosomal dominant
GTPCH deficiency and autosomal recessive SR deficiency leads to BH4 and
neurotransmitter deficiency without HPA and may not be detected by neonatal screening for
phenylketonuria. The former is Segawa's disease, which is characterized by
dopa-responsive dystonia with marked diurnal fluctuation and is caused by a defect of GTPCH, and the latter is SR deficiency, which is characterized by progressive psychomotor retardation,
dystonia, and severe
dopamine and
serotonin deficiencies. Biochemical diagnosis is performed by the measurement of
neopterin and
biopterin levels, since both are low in Segawa disease, and the
biopterin level is high in SR deficiency in cerebrospinal fluid. We must consider metabolic disorders of
biopterin in child neurologic diseases with
dystonia.