Abnormalities of tetrahydrobiopterin metabolism

Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated May 17, 2017; expires May 17, 2020

This article includes discussion of abnormalities of tetrahydrobiopterin metabolism, BH4 deficiency, dihydropteridine reductase deficiency, GTP cyclohydrolase deficiency, pterin-4 alpha-carbinolamine dehydratase deficiency, sepiapterin reductase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Tetrahydrobiopterin (BH4) deficiencies, a group of rare inherited neurologic diseases with monoamine neurotransmitter deficiency, may present with or without hyperphenylalaninemia (HPA). Tetrahydrobiopterin (BH4) is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and 2 tryptophan hydroxylases, 3 nitric oxide synthases, and glyceryl-ether monooxygenase. Defects of BH4 metabolism comprise a group of treatable pediatric neurotransmitter disorders. The major pathophysiology consists of disturbed phenylalanine homeostasis, as well as compromised catecholamine and serotonin biosynthesis. This heterogeneous group of disorders is caused by mutations in either 6-pyruvoly-tetrahydropterin synthase, GTP cyclohydrolase, pterin-4 alpha-carbinolamine dehydratase deficiency, sepiapterin reductase, or dihydropteridine reductase. Affected patients are usually clinically asymptomatic at birth and in early infancy. Without diagnosis and treatment they develop a progressive encephalopathy characterized by severe truncal hypotonia, decreased spontaneous movements, movement disorders, including chorea and dystonia, intellectual disability, and epileptic seizures. BH4 is also involved in cardiovascular and endothelial dysfunction and pain modulation.

Many patients present with hyperphenylalaninemia, which may be detected through newborn phenylketonuria screening programs. Two forms of cerebral BH4 deficiency may occur without hyperphenylalaninemia: the autosomal dominantly inherited form of GTPCH deficiency (dopa-responsive dystonia, initially described as Segawa disease, see also the chapter Dopa-responsive dystonia) and the recently delineated sepiapterin reductase deficiency. Treatment of tetrahydrobiopterin deficiencies relies on the use of a mixture of levodopa and carbidopa (ie, Sinemet®), 5-hydroxytryptophan, tetrahydrobiopterin and, if necessary, a low-phenylalanine diet and an additional supplementation of folinic acid in the treatment of dihydropteridine reductase deficiency. Treatment should be initiated as early as possible and continued for life.

Key points


• Tetrahydrobiopterin (BH4) deficiencies affect phenylalanine homeostasis, but most importantly impair catecholamine and serotonin biosynthesis.


• Five enzyme defects are all inherited in an autosomal recessive manner.


• Without early diagnosis and treatment, BH4 deficiencies result in progressive developmental impairment and severe neurologic dysfunction.


• Any baby presenting with any degree of hyperphenylalaninemia in the newborn screening program must be evaluated in a timely manner to exclude or diagnose 1 of the BH4 deficiencies.

Historical note and terminology

Phenylketonuria comprises a group of conditions that arise as a result of the inability to effectively convert phenylalanine to tyrosine. The first case was reported by Folling in 1934, and subsequent studies demonstrated that the majority of cases were due to defects of phenylalanine hydroxylase. Dietary control of the disease using a phenylalanine-restricted diet was introduced in 1953 by Horst Bickel and colleagues. In 1974, there were 2 independent reports of children with a form of phenylketonuria that was accompanied by a complex severe progressive neurologic illness unresponsive to dietary treatment (Bartholome 1974; Smith 1974). It was already hypothesized that these children lacked tetrahydrobiopterin, the cofactor required for the phenylalanine hydroxylase reaction. Tetrahydrobiopterin is formed from GTP in a multistep pathway involving dihydroneopterin and tetrahydropterin intermediates. During the hydroxylation of phenylalanine, tetrahydrobiopterin is oxidized to quinonoid dihydrobiopterin by pterin-4 alpha-carbinolamine dehydratase, and then reduced back to tetrahydrobiopterin by the action of dihydropteridine reductase (Werner et al 2011).

Diagram of tetrahydropterin formation and recycling Image: Tetrahydropterin formation and recycling

In addition to the phenylalanine hydroxylase reaction, tetrahydrobiopterin is also the cofactor for tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes required for the synthesis of the catecholamines and serotonin, the generation of nitric oxide from citrulline by nitric oxide synthases, and the production of an alkyl aldehyde and glycerol from a glycerol ether by glyceryl-ether monooxygenase (Werner et al 2011). The continuing deficiency of these neurotransmitters within the central nervous system explains why the neurologic symptoms in children with defects in tetrahydrobiopterin metabolism do not respond clinically to a low-phenylalanine diet alone.

Proof of a problem in cofactor metabolism came following demonstration of dihydropteridine reductase (DHPR) deficiency in the brain and liver of another child with phenylketonuria whose neurologic symptoms were unresponsive to diet (Kaufman et al 1975). In 1976 evidence appeared for a defect affecting the biosynthesis of tetrahydrobiopterin (Leeming et al 1976). In this case, low concentrations of biopterins were found and an unusual pterin was detected (later identified as neopterin). Identification of low concentrations of biopterins in association with high concentrations of neopterins indicated a block after the formation of dihydroneopterin triphosphate. Additional reports soon confirmed that this new entity was due to a defect in the synthesis of tetrahydrobiopterin. At that time, the biosynthetic pathway for tetrahydrobiopterin was thought to occur via a dihydrobiopterin intermediate, and the new defects were classified as "dihydrobiopterin synthetase deficiencies." It is now known that tetrahydrobiopterin is synthesized via tetrahydropterin intermediates and the enzyme deficiency leads to blockage at the level of 6-pyruvoyltetrahydropterin synthase (PTPS).

Diagram of tetrahydropterin formation and recycling Image: Tetrahydropterin formation and recycling
Previous names for this enzyme have included dihydrobiopterin synthetase, phosphate eliminating enzyme and sepiapterin synthesizing enzyme-1. More than half of the patients with BH4 deficiencies suffer from a deficiency of this enzyme (Opladen et al 2012).

In 1984 a defect affecting GTP cyclohydrolase 1, the first enzyme in the biosynthetic pathway for tetrahydrobiopterin synthesis, was described (Niederwieser et al 1984). Since then several other cases have been reported (Blau et al 2001; Opladen et al 2012). Not all cases of autosomal recessively inherited GTP cyclohydrolase deficiency have hyperphenylalaninemia; however, severe neurotransmitter deficiencies are detectable in CSF analyses. In several reported cases with well-defined, confirmed pathogenic mutations, progressive severe neurologic symptoms developed which responded well to L-Dopa supplementation. These included neonatal-onset of rigidity, tremor, spasticity, oculogyric crises, and dystonia (Furukawa et al 1998; Horvath et al 2008; Opladen et al 2011a). Abnormal phenylalanine metabolism could only be demonstrated after stressing the phenylalanine to tyrosine hydroxylation system by administering a phenylalanine loading challenge. The clinical spectrum of GTP cyclohydrolase 1 deficiency includes the classical dominant L-Dopa-responsive dystonia without hyperphenylalaninemia, type Segawa, at the mildest, to neonatal onset of progressive spasticity, rigidity, tremor, dystonia, and hyperphenylalaninemia in autosomal recessive dopa-responsive dystonia at the other end of the continuum. Intermediate phenotypes with graded clinical symptoms can be related to compound heterozygous mutations resulting in different residual activities, again sometimes without overt hyperphenylalaninemia.

In 1988, a new type of defect affecting tetrahydrobiopterin metabolism was found (Dhondt et al 1988). Dhondt and colleagues observed an unusual peak by HPLC used to screen for defects in tetrahydrobiopterin metabolism. This compound was later identified as 7-substituted biopterin (as opposed to the normal 6-substituted biopterin). It was shown to result from a deficiency of pterin-4 alpha-carbinolamine dehydratase, which functions as part of the phenylalanine hydroxylating system in the conversion of 4a-OH-tetrahydrobiopterin to quinonoid dihydrobiopterin.

In 1994, dopa-responsive dystonia was shown to be associated with dominant mutations in the gene for GTP cyclohydrolase 1 (Ichinose et al 1994). This disorder was first described by Segawa, who named the disorder “hereditary progressive dystonia with marked diurnal fluctuation” (Segawa 1976). Unlike the other defects in tetrahydrobiopterin metabolism, this condition is inherited in an autosomal dominant fashion, and affected and asymptomatic carriers of the mutation do not have hyperphenylalaninemia under resting conditions (Hyland et al 1997; Opladen et al 2010).

In 1998, another defect in tetrahydrobiopterin metabolism was described that did not lead to hyperphenylalaninemia. It was first presumed to be a variant of dihydropteridine reductase deficiency (Blau et al 1999) but was later shown to be due to sepiapterin reductase deficiency (Bonafe et al 2001b). Central nervous system catecholamine and serotonin metabolism were impaired leading to severe neurologic dysfunction.

Terminology for the group of defects that affect tetrahydrobiopterin metabolism has altered since the early descriptions. Initial cases were classified as forms of atypical phenylketonuria and then malignant hyperphenylalaninemia because they were unresponsive to classic dietary treatment. Currently, the term "tetrahydrobiopterin deficiencies" encompasses all of the disorders.

The BH4 deficiencies are clinically heterogeneous. There are variant forms of 6-pyruvoyltetrahydropterin synthase deficiency (transient cases, peripheral forms, and severe forms that affect both systemic and central systems) as well as several partial and mild cases of dihydropteridine reductase deficiency (Blau et al 1992; Opladen et al 2012).

Several different names have also been used to describe the autosomal dominantly inherited form of GTP cyclohydrolase 1. The condition was initially termed "hereditary progressive dystonia with marked diurnal fluctuation” or more commonly "Segawa syndrome." Since 1988, the term "dopa-responsive dystonia" has generally been applied to all dystonias responding to levodopa (Nygaard 1988), which includes autosomal dominant dopa-responsive dystonia caused by mutations in the GTP cyclohydrolase 1 gene (Ichinose et al 1994) (see also the article Dopa-responsive dystonia).

More than 600 individuals with recessively inherited defects affecting tetrahydrobiopterin metabolism have been reported (Opladen et al 2012). Of these, 355 patients, 56.7% had PTPS deficiency; 217 patients, 34.7%, had DHPR deficiency; 31 patients, 4.9%, had GTP cyclohydrolase deficiency; 23 patients, 3.7%, had pterin-4 alpha-carbinolamine dehydratase deficiency; and 43 patients, 6.8%, had sepiapterin reductase deficiency (Friedman et al 2012). The number of described cases of the autosomal dominantly inherited GTP cyclohydrolase 1 deficiency has increased rapidly since the molecular lesion was described (Ichinose et al 1994). A web site listing all details regarding the defects of tetrahydrobiopterin metabolism is updated regularly and can be accessed at the Tetrahydrobiopterin Home Page.

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