GTP cyclohydrolase I deficiency

GTP cyclohydrolase I (GTPCH I) deficiency is a rare inherited disorder of biopterin metabolism caused by mutations in the GCH1 gene, which encodes the enzyme GTP cyclohydrolase I — the first and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4). BH4 is an essential cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, meaning its deficiency disrupts both phenylalanine metabolism and neurotransmitter synthesis (dopamine and serotonin). This condition exists in two distinct forms: an autosomal dominant form known as Dopa-responsive dystonia (DRD) or Segawa disease, and an autosomal recessive form presenting as a severe BH4 deficiency with hyperphenylalaninemia. The autosomal dominant form (Segawa disease) typically presents in childhood with progressive dystonia, most often beginning in the lower limbs, with marked diurnal fluctuation — symptoms worsen throughout the day and improve after sleep. Parkinsonian features may develop later. This form shows a dramatic and sustained response to low-dose levodopa (L-dopa), which is a hallmark diagnostic and therapeutic feature. The autosomal recessive form is more severe, presenting in infancy with hyperphenylalaninemia, intellectual disability, seizures, truncal hypotonia, limb hypertonia, and progressive neurological deterioration due to profound neurotransmitter deficiency. Treatment differs by form. The dominant form is managed primarily with low-dose L-dopa/carbidopa, which typically produces excellent long-term results. The recessive form requires a more complex regimen including BH4 supplementation, dietary phenylalanine restriction, L-dopa, carbidopa, and 5-hydroxytryptophan to address both the metabolic and neurotransmitter deficits. Early diagnosis and treatment are critical, particularly in the recessive form, to prevent irreversible neurological damage.

Common questions about GTP cyclohydrolase I deficiency