Abnormalities of tetrahydrobiopterin metabolism …

Neurogenetic Disorders

Updated 04.07.2024
Released 03.30.1995
Expires For CME 04.07.2027

Abnormalities of tetrahydrobiopterin metabolism

Authors: Georg F Hoffmann MD, Oya Kuseyri Hübschmann MD

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Editor: Barry Wolf MD PhD

Abnormalities of tetrahydrobiopterin metabolism

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Introduction

Overview

Tetrahydrobiopterin (BH₄) deficiencies, a group of rare inherited neurologic diseases with monoamine neurotransmitter deficiency, result in insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin. They may present with or without hyperphenylalaninemia (HPA). Tetrahydrobiopterin (BH₄) is an essential cofactor not only for phenylalanine hydroxylase but also for tyrosine and two tryptophan hydroxylases, three 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 degradation as well as compromised catecholamine and serotonin biosynthesis. This heterogeneous group of monogenic disorders is caused by a deficiency of either 6-pyruvoyl-tetrahydropterin synthase (PTPS), GTP cyclohydrolase (GTPCH), pterin-4 alpha-carbinolamine dehydratase (PCD), sepiapterin reductase (SR), or dihydropteridine reductase (DHPR). The same biochemical consequences are also caused by a sixth disorder, DNAJC12 deficiency. 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, including DNAJC12 deficiency. Two forms of cerebral BH₄ deficiency occur without hyperphenylalaninemia: the autosomal dominantly inherited form of GTPCH deficiency (dopa-responsive dystonia, initially described as Segawa disease, see also MedLink article, Dopa-responsive dystonia) and sepiapterin reductase deficiency. Autosomal recessive GTPCH deficiency may present with or without hyperphenylalaninemia. 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.

Since 2014, an international network of physicians and scientists, the International Working Group on Neurotransmitter Related Disorders (iNTD, www.intd-online.org), aims to more completely describe the initial and evolving clinical phenotypes of BH4 deficiency, including the development of guidelines for diagnostic and therapeutic interventions. Biochemical, clinical, and DNA data of patients with BH4 deficiencies are tabulated in the BIODEF and BIOMDB databases and are available on the internet (www.biopku.org).

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, and GTPCH deficiency is also inherited in an autosomal dominant manner.
	• DNAJC12 deficiency can have identical pathobiochemical consequences.
	• Without early diagnosis and treatment, BH₄ deficiencies result in progressive developmental impairment and severe neurologic dysfunction.
	• Babies presenting with any degree of hyperphenylalaninemia in the newborn screening program must be evaluated promptly to exclude or diagnose one of the BH₄ deficiencies, including DNAJC12 deficiency.

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, two independent reports of children with a form of phenylketonuria were accompanied by a complex, severe progressive neurologic illness unresponsive to dietary treatment (02; 43). 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 (49).

Tetrahydropterin formation and recycling

The diagram illustrates how tetrahydropterin is formed from guanosine triphosphate (GTP) utilized in the hydroxylation reactions and recycled. Metabolism of tetrahydrobiopterin (BH4), cofactor of tyrosine hydroxylase (TYH), of try...

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 dopamine 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 (49). The continuing deficiency of all monoamine 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 (24). In 1976, evidence appeared for a defect affecting tetrahydrobiopterin biosynthesis (29). In this case, low concentrations of biopterins were found, and an unusual pterin was detected (later identified as neopterin). Identification of low concentrations of biopterin in association with high concentrations of neopterin indicated a block after the formation of dihydroneopterin triphosphate. Additional reports soon confirmed that this new entity was due to a defect in tetrahydrobiopterin synthesis. 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).

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 (35).

In 1984 a defect affecting GTP cyclohydrolase 1, the first enzyme in the biosynthetic pathway for tetrahydrobiopterin synthesis, was described (31). Since then, several other cases have been reported (35; 27). Not all cases of autosomal recessively inherited GTP cyclohydrolase deficiency have hyperphenylalaninemia; however, severe neurotransmitter deficiencies are detectable by CSF analyses. In several reported cases with well-defined, confirmed pathogenic mutations, progressive severe neurologic symptoms developed that responded well to L-dopa supplementation. These included neonatal-onset of rigidity, tremor, spasticity, oculogyric crises, and dystonia (04; 11; 18; 37). Abnormal phenylalanine metabolism could sometimes only be demonstrated after stressing the phenylalanine to tyrosine hydroxylation system by administering a phenylalanine loading challenge (36). 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 (36).

In 1988, a new type of defect affecting tetrahydrobiopterin metabolism was found (09). 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 4-alpha-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 (20). This disorder was first described by Segawa, who named the disorder "hereditary progressive dystonia with marked diurnal fluctuation" (41). 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 (19; 38; 37).

In 1999, another defect in tetrahydrobiopterin metabolism was described that did not lead to hyperphenylalaninemia but elevated phenylalanine in CSF. It was first presumed to be a variant of dihydropteridine reductase deficiency (06) but was later shown to be due to sepiapterin reductase deficiency (07). 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 "atypical phenylketonuria" and then malignant hyperphenylalaninemia because they were unresponsive to classic dietary treatment. The term "tetrahydrobiopterin deficiencies" now encompasses all of the disorders (37).

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 (05; 35).

Several 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 (33), which includes autosomal dominant dopa-responsive dystonia caused by mutations in the GTP cyclohydrolase 1 gene (20) (see also the MedLink article Dopa-responsive dystonia).

Since 2017, an additional disease has been included in the differential diagnosis of hyperphenylalaninemia with deficiency of monoamine neurotransmitters. It is caused by biallelic mutations in the DNAJC12 gene and associated with a variable neurologic phenotype (01).

Clinical manifestations

Presentation and course

More than 700 individuals with recessively inherited defects affecting tetrahydrobiopterin metabolism have been reported (35; 27). The most common diagnosis was PTPS deficiency, followed by DHPR deficiency. Autosomal recessive GTP cyclohydrolase, sepiapterin reductase, and pterin-4 alpha-carbinolamine dehydratase deficiencies are detected less frequently. The number of described cases of the autosomal dominantly inherited GTP cyclohydrolase 1 deficiency has increased rapidly since the molecular lesion was described (20). It is, therefore, difficult to provide a realistic prevalence because there remain many undiagnosed cases. A website listing all the details regarding the defects of tetrahydrobiopterin metabolism is updated regularly and can be accessed at the Database of Patients and Genotypes Causing HPA/PKU including BH4-Responsive Phenotype.

The presenting clinical signs of untreated autosomal recessively inherited GTP cyclohydrolase deficiency, of severe forms of 6-pyruvoyltetrahydropterin synthase deficiency, and of dihydropteridine reductase deficiency are similar and mostly due to the reduced synthesis of the biogenic amine neurotransmitters. Prematurity is common; at birth, there may be poor sucking, decreased spontaneous movements, floppiness, and microcephaly (04; 35). The increased incidence of decreased birth weight in 6-pyruvoyltetrahydropterin synthase deficiency and the appearance of neurologic signs at an earlier age in this disease as compared to dihydropteridine reductase deficiency have been attributed to effects in utero (04). Being small-for-gestational age frequently occurs in 6-pyruvoyl-tetrahydropterin synthase, dihydropteridine reductase, sepiapterin reductase, and autosomal recessive GTP cyclohydrolase deficiency (27). In addition, symmetrical intrauterine growth retardation and congenital microcephaly frequently occur in 6-pyruvoyl-tetrahydropterin synthase deficiency.

Obvious neurologic signs starting in the neonatal period/early infancy include truncal hypotonia, pinpoint pupils, and brisk tendon reflexes, as well as movement disorders such as dystonia, hypokinesia, distal chorea, myoclonus, and oculogyric crises. Developmental delay is commonly observed. Less frequent symptoms comprise muscular hypertonia and convulsions (grand mal or myoclonic), the latter being more frequent in dihydropteridine reductase and 6-pyruvoyl-tetrahydropterin synthase deficiency. Autonomic symptoms, hypersalivation, temperature disturbance (in the absence of infection), sweating, swallowing difficulties, drowsiness, and irritability can be very troublesome (04; 35). Diurnal fluctuation of symptoms is frequently observed, most likely due to the effects of the concurrent fluctuation of monoamines. Progressive neurologic deterioration and microcephaly may occur if not diagnosed and correctly treated.

EEG findings are abnormal in approximately 90% of dihydropteridine reductase-deficient patients and 80% of 6-pyruvoyl-tetrahydropterin synthase-deficient patients (n=24). EEG patterns were nonspecific and did not allow differentiation between the individual BH₄ deficiencies (35).

Endocrine dysfunction, such as growth-hormone deficiency or central hypothyroidism, has been described in several patients. Hyperprolactinemia with or without pituitary adenoma has been observed in individuals with BH4 deficiencies (48; 51). Close clinical monitoring of onset and course of puberty and prolactin measurements on demand are recommended.

An insidious folate deficiency may occur in dihydropteridine reductase deficiency (24; 44). This is usually not associated with megaloblastic changes and can lead to devastating changes within the central nervous system if not recognized. Brain lesions consist of multifocal, perivascular demyelination in the subcortical white matter accompanied by perivascular microcalcification, which is also present in the basal ganglia (44).

Variant forms of 6-pyruvoyltetrahydropterin synthase and dihydropteridine reductase deficiency have been described in which the neurologic signs are either minor or absent. A late-onset case of 6-pyruvoyltetrahydropterin synthase deficiency was described where dystonia was the major symptom at the age of 44 years (14). Two unusual cases with dihydropteridine reductase deficiency have been studied in detail (05). In these there was some residual activity of the enzyme in fibroblasts. In one untreated child, plasma phenylalanine ranged from 73 to 399 mmol/L, and there were no neurologic signs at 18 months. In the second case, treatment with 10 mg/kg of tetrahydrobiopterin per day was commenced after 3 months because of a reduced concentration of 5-hydroxyindoleacetic acid in CSF. Psychomotor development was normal until 30 months, at which time a deceleration of head growth was observed. In both of these cases, concentrations of homovanillic acid in CSF were always normal, whereas concentrations of 5-hydroxyindoleacetic acid were greatly reduced.

Some children with recessively inherited GTP cyclohydrolase deficiency also did not have hyperphenylalaninemia (11; 18; 34). The severity of clinical presentations was different. Female twins presented with neonatal onset of rigidity, tremor, and dystonia suggestive of a diffuse CNS involvement; a female presented with typical features of tetrahydrobiopterin deficiency at around 6 months of age, whereas a male presented with a clinical picture more like that seen in the autosomal dominantly inherited GTP cyclohydrolase deficiency. Between the ages of 4 and 6 years, he lost motor and speech function and developed generalized dystonia and symmetrical hyperreflexia with bilateral extensor plantar responses. Oral phenylalanine loading in these patients uncovered a decreased ability to convert phenylalanine to tyrosine, demonstrating a compromised phenylalanine hydroxylation system in the liver (11; 18; 34).

Hyperphenylalaninemia is absent in sepiapterin reductase deficiency because 3-alpha-hydroxysteroid dehydrogenase and aldose reductase replace the activity of sepiapterin reductase in the liver (15). These enzymes are not present in the brain. High concentrations of phenylalanine are detected in cerebrospinal fluid. More than 50 cases have been described (10). Almost all patients exhibited hypotonia in the first 6 months of life. Subsequent symptoms included progressive dystonia, chorea, oculogyric crises, tremor, spasticity, microcephaly, growth retardation, depressive and aggressive behavior, and psychomotor retardation. Diurnal variation is usually present. Signs of autonomic dysfunction have included hypersalivation, temperature instability, lethargy, hypersomnolence, and episodes of sweating and pallor. Initially, patients are often misdiagnosed as having cerebral palsy, and delay in determining the correct diagnosis can be many years or even decades (27). Although most patients present with a typical dopa-responsive dystonia, dystonia may be absent.

None of the prominent signs of abnormal serotonin and catecholamine metabolism are typically found in either pterin-4 alpha-carbinolamine dehydratase deficiency or the atypical forms of 6-pyruvoyltetrahydropterin synthase deficiency, and the concentrations of homovanillic acid and 5-hydroxyindoleacetic acid in CSF are essentially normal. More than 75% of neonates with the mild phenotype of 6-pyruvoyl-tetrahydropterin synthase deficiency (ie, initially normal neurotransmitters in the CSF, treated with BH₄ monotherapy, approximately 20% of all patients) remained asymptomatic throughout life. However, 15% of those develop retardation, dystonia, movement disorders, or autonomic symptoms. Some will also develop very low concentrations of neurotransmitter metabolites after several months.

Minor neurologic signs of slight tremors of upper limbs and hypertonia or hypotonia have been reported in the neonatal period in pterin-4 alpha-carbinolamine dehydratase deficiency. Only 1 of 23 patients listed in the BIODEF database needed a substitution with BH₄ and neurotransmitter precursors. Several patients later developed neurologic abnormalities and are at risk of developing both hypomagnesemia and maturity-onset diabetes of the young (MODY) type 3 and insulin resistance in adolescence (42). In summary, all patients with disorders of biopterin metabolism, except with pterin-4 alpha-carbinolamine dehydratase deficiency, should be regularly evaluated in terms of their central amine status and continued to be followed in a specialized center.

The autosomal dominantly inherited form of GTP cyclohydrolase deficiency (dopa-responsive dystonia) classically presents as a dystonic gait disorder with diurnal variation of symptoms. The mean age of onset of symptoms is 5 years to 6 years. The first symptom is usually postural dystonia of one leg, with progression to all limbs, followed by action dystonia and hand tremor within the next 10 to 15 years, during which time cognition remains intact. Fluctuation of symptoms later in life fade away, and parkinsonism with or without dystonia becomes the major manifestation. Penetrance is reduced, with the frequency of symptoms being 3- to 4-fold higher in females than males (32). In older children, the first signs may start in the arms or be torticollis or writer's cramp (focal dystonia). The spectrum of clinical manifestations is broad and may include minor muscle cramps, an early nonprogressive course, delayed attainment of motor milestones, and spastic diplegia. Parkinsonism usually occurs in adult-onset disease (32). A patient has been described in whom the first symptom was an adult-onset oromandibular dystonia (45); in others, presentation was an apparent primary torsion dystonia that was responsive to anticholinergic agents (21) or with a myoclonus-dystonia syndrome (30).

Of those patients who present in childhood with the typical dystonic gait disorder, 20% also have hyperreflexia, apparent extensor plantar responses, and other clinical features suggesting spasticity. These, together with the prominent upper motor neuron findings, including spastic diplegia, have led to a diagnosis of cerebral palsy in many cases.

The GTP cyclohydrolase gene has also been suggested as a susceptibility gene in bipolar disorder (25), and some patients with dopa-responsive dystonia developed psychiatric disorders. A tetrahydrobiopterin deficit has been demonstrated in schizophrenia, although the cause of the deficit is unclear (40).

Prognosis and complications

The response to treatment and the prognosis following treatment strongly depends on the age at which treatment begins and the degree of damage that has already occurred before initiating therapy (35; 37). The prognosis for untreated patients with the typical recessively inherited forms (those requiring treatment of a central serotonin and catecholamine deficiency) of tetrahydrobiopterin deficiency is poor, with many patients dying within the first few years of life. When treatment begins in the neonatal period, patients are frequently asymptomatic or show less retardation, movement disorders, and convulsions. Some degree of neurologic improvement is generally seen in children if treatment is started late. However, in individual cases, the overall outcome is quite variable. In some cases, outcome is poor, despite normalization of plasma phenylalanine and correction of the central amine deficiency within a few weeks of birth. In other cases, normal or near-normal development is achieved. Patients with dihydropteridine reductase deficiency may initially make good progress following correction of plasma phenylalanine and the central neurotransmitter deficiency, only to succumb to a devastating neurologic degeneration as a result of the central folate deficiency that can arise as a secondary manifestation of this disease (44).

In addition, early and well-treated patients may have increased incidences of various psychiatric and behavioral problems as well as sleep disturbance (10; 37).

Prognosis for patients with the autosomal dominantly inherited GTP cyclohydrolase deficiency (dopa-responsive dystonia) is good once the diagnosis has been made and treatment with levodopa has commenced. In most cases complete recovery is achieved, cognitive function does not seem to be impaired, and no adverse effects of levodopa therapy have been reported once the correct dosage has been ascertained.

Clinical vignette

The male patient from first-cousin parents of Turkish ancestry was born after transitory neonatal distress secondary to maternal infection. Postpartum recurrent hypoglycemia (on admission 22 mg/dL), dyspnea, and metabolic acidosis quickly resolved. The development was considered normal until a first prolonged afebrile seizure occurred when he was 6 months old. EEG showed generalized hypersynchronous activity. In the next month he developed recurrent generalized clonus with dystonic movements of the left hand and arm, episodic recurrent deviation of the eyes to the left and the right upper sides, and varying opisthotonic posturing. This combination of symptoms was interpreted as seizures, and antiepileptic therapy was started with phenobarbital. This led to an amelioration of symptoms, but the eye deviations persisted. In retrospect, these typical oculogyric crises were interpreted as atypical absences (EEGs and cranial MRI at the age of 12 months were normal). The neurologic status slowly worsened, and the boy developed generalized spasticity and pyramidal signs. Progressive global developmental delay became more and more obvious. At the age of 18 months, phenobarbital was stopped, and he was recognized as having dystonia and ataxic posturing for the first time, in addition to tetraspasticity.

At the age of 7 years, he was reevaluated. It was recognized that his motor functions worsened during the day as well as from day to day. He could walk in the morning, although with a dystonic gait and spasticity. Later in the day, he had to use a wheelchair. He had a cogwheel muscular resistance, and for the first time, the eye deviations were correctly interpreted as oculogyric crises. A lumbar puncture for to analyze neurotransmitter metabolites was performed and confirmed neurotransmitter disease, specifically dopamine and serotonin deficiency, which was finally delineated to be due to sepiapterin reductase deficiency. Therapy with L-dopa without carbidopa was started with 4 mg/kg bw/d and slowly increased up to 16 mg/kg bw/d. The child learned to walk and run, to go up and downstairs without holding on to a banister, and, eventually to play soccer and dance. He is now 29 years old and almost walking normally. His handwriting is nearly normal (initially, he could not write at all). He could speak normal sentences in German and Turkish, which became more clearly and distinctly pronounced from year to year. He has become more self-confident, finished schooling for physically handicapped people, and started working. Intellectual function remained below average.

Biological basis

Etiology and pathogenesis

Generalized BH₄ deficiency results in impaired degradation of phenylalanine with the pathophysiological consequences known to develop in untreated hyperphenylalaninemia and, in addition, in depletion of the monoamine neurotransmitters in the central nervous system. Tetrahydrobiopterin (BH₄) is an essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases (the last two being the rate-limiting enzymes in catecholamine and serotonin biosynthesis, respectively). In addition, BH₄ is an essential cofactor for the three isoforms of nitric oxide synthase. It is also involved in cardiovascular and endothelial dysfunction, and pain modulation. The de novo pathway for the biosynthesis of BH₄ from GTP requires three enzymes, GTP cyclohydrolase (committing and rate-limiting step), 6-pyruvoyltetrahydropterin synthase, and sepiapterin reductase.

Tetrahydropterin formation and recycling

Regeneration of BH₄ is an essential part of the system. BH₄ is hydroxylated and oxidized to form tetrahydrobiopterin-4 alpha-carbinolamine, which produces q-dihydrobiopterin after the removal of a water molecule by pterin-4 alpha-carbinolamine dehydratase. In the final step, dihydropteridine reductase regenerates BH₄ from q-dihydrobiopterin.

The major neurologic features seen in the typical forms of BH4 deficiency are due to decreased synthesis of the catecholamines and serotonin. They are all implicated in the modulation of motor control, pain perception, mood, attention, and other higher cognitive and executive functions (08). Hyperphenylalaninemia is not a feature in patients with the autosomal dominantly inherited GTP cyclohydrolase deficiency, sepiapterin reductase deficiency, or some compound heterozygotes with GTP cyclohydrolase deficiency. An abnormality in phenylalanine metabolism can be exposed if the phenylalanine hydroxylation system is stressed by administration of an oral phenylalanine load (19; 07).

Tetrahydrobiopterin is also required for nitric oxide synthase activity (49). Nitrite and nitrate concentrations (indicators of nitric oxide concentrations) are low in the spinal fluid of patients with tetrahydrobiopterin deficiencies, but it is unclear if the disturbed nitric oxide metabolism contributes to the neurologic or other symptoms.

Cerebral folate deficiency may occur in BH4 deficiencies, most prominently in dihydropteridine reductase deficiency because dihydropteridine reductase enzyme supports dihydrofolate reductase (DHFR) to maintain folate in its active "tetrahydro" form, where it serves as a precursor for the universal methyl donor substance S-adenosyl-methionine (50). However, there is a risk of development of cerebral folate depletion in the other BH4 deficiencies as well because long-term administration of L-Dopa in high doses can result in reduced availability of these methyl groups due to the methylation of L-Dopa to 3-O-methydopa.

It is likely that tetrahydrobiopterin deficiency leads to in-utero pathology because low birth weight, being small-for-gestational age, intrauterine growth retardation, or congenital microcephaly are observed in different BH4 deficiencies and corresponding knock-out murine models (27). The latter demonstrates that BH4 regulates catecholamine synthesis through altering TH protein concentrations, and its deficiency leads to disruption of the postnatally expected increase of dopamine and TH protein concentrations in the brain.

The deficiencies of GTP cyclohydrolase, 6-pyruvoyltetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase, and pterin-4 alpha-carbinolamine dehydratase are autosomal recessive disorders, the exception being the autosomal dominantly inherited form of GTP cyclohydrolase deficiency (dopa-responsive dystonia). All defects have been molecularly characterized (47). Mutations in dihydropteridine reductase deficiency are a variety of mutations throughout the coding region, with a corresponding variation of effects on the structure and function of the protein. In addition, mutations leading to two cases of a mild atypical form of dihydropteridine reductase deficiency have been located (05). So far, the study of these mutations has not revealed the tetrahydrobiopterin binding domain (17; 22).

A study of the mutations in 6-pyruvoyltetrahydropterin synthase deficiency demonstrated that a typical form of the disease is due to a homozygous G-to-A transition at codon 25, causing a replacement of arginine by glutamine. A peripheral defect was caused by compound heterozygosity, one allele having a C-to-T transition resulting in substitution of arginine 16 for cysteine. On the second allele, there was a 14-bp deletion leading to a frameshift at lysine 120 and a premature stop codon. Forty-two percent of Chinese patients with 6-pyruvoyltetrahydropterin synthase deficiency have a C259T missense mutation, which results in an amino acid change from proline to serine at codon 87. Many more mutations have been described. Of particular interest is that found in a patient with a homozygous missense mutation (K129E) who had transient hyperphenylalaninemia, but did not require tetrahydrobiopterin or neurotransmitter precursor therapy. No 6-pyruvoyltetrahydropterin synthase activity was detectable in fibroblasts or red blood cells. However, the mutant enzyme was 2-fold to 3-fold more active than the wild type when transfected into COS-1 cells and a human hepatoma cell line implying that there are cell-specific expression regulators for this protein (39).

Mutations have been reported in the GTP cyclohydrolase 1 gene, causing the autosomal recessively inherited form of hyperphenylalaninemia. Two compound heterozygotes have also been described who did not have hyperphenylalaninemia in infancy, yet had severe central nervous system signs (11). Most of the other mutations, which are scattered over the entire coding region, are observed in the heterozygous state with the wild-type allele and are associated with the dominant dopa-responsive dystonia (47). It is suggested that a difference in the ratio of mutant to wild-type GTP cyclohydrolase mRNA that depends on the locus of a mutation might explain the intrafamilial and interfamilial variation of phenotype seen in dominantly inherited GTP cyclohydrolase deficiency. However, the finding of phenotypic heterogeneity in monozygotic twins demonstrates that other factors are also likely involved (13).

In dihydropteridine reductase deficiency, more than 50 mutations have been identified and are spread throughout QDPR (the gene). Insertion of an extra codon for threonine between alanine at position 122 and the threonine at residue 123 was one of the first variants reported but accounts for most of the mutations reported (47).

In a cohort of patients with sepiapterin reductase deficiency, 16 different mutations were described (seven missense, four nonsense, three frameshift, one splice-site, and one in promoter region), the intronic homozygous variant c.596-2A>G being the most common (10). There was no correlation between neurologic presentation and course or cognitive function with either specific mutations or CSF metabolite concentrations.

For an updated list of reported disease-causing variants, please visit the following website: www.ncbi.nlm.nih.gov.

Differential diagnosis

The detection of hyperphenylalaninemia (in the absence of changes in other large neutral amino acids) by newborn screening in most cases of autosomal recessively inherited tetrahydrobiopterin deficiency allows rapid detection that must be followed by timely differentiation of this group of diseases from other metabolic conditions affecting phenylalanine hydroxylase activity. It is important to distinguish between the tetrahydrobiopterin deficiencies and deficiency of phenylalanine hydroxylase and also to identify the exact site of the lesion leading to tetrahydrobiopterin deficiency because the treatment is different. This is accomplished by examination of the pattern of biopterins and neopterins in urine or dried blood spots and by mutation analysis or direct measurement of enzyme activities (37). Under resting conditions, patients with the autosomal dominantly inherited GTP cyclohydrolase deficiency (dopa-responsive dystonia) or sepiapterin reductase deficiency do not have hyperphenylalaninemia; neither do some patients who are compound heterozygotes for GTP cyclohydrolase deficiency. However, a defect in the phenylalanine hydroxylation system can be exposed by administration of an oral phenylalanine load (19; 07; 38).

The neurologic symptoms found in typical autosomal recessively inherited cases of tetrahydrobiopterin deficiency in the neonatal period are nonspecific (they include poor sucking, decreased spontaneous movement, floppiness, and microcephaly) (35; 37), and do not allow clinical diagnosis in a situation where newborn screening for hyperphenylalaninemia is not performed. More obvious neurologic signs appear in early infancy and include hypersalivation and temperature disturbance (in the absence of infection), sweating, pinpoint pupils, oculogyric crises, hypokinesis, dystonia, distal chorea, truncal hypotonia, swallowing difficulties, drowsiness, irritability, myoclonus, brisk tendon jerks, and development delay. In addition, there may be microcephaly, progressive neurologic deterioration, and convulsions (grand mal or myoclonic), the latter being more frequent in dihydropteridine reductase deficiency and PTPS deficiency (35; 27). Many of these symptoms are also seen in aromatic-L-amino-acid decarboxylase deficiency, tyrosine hydroxylase deficiency, and 6-pyruvoyl-tetrahydropterin synthase deficiency (16; 27), which are conditions that also lead to gross deficiencies of the catecholamine neurotransmitters. In these diseases, plasma phenylalanine concentrations and biopterin and neopterin profiles are mostly normal in CSF and plasma.

The autosomal dominantly inherited form of GTP cyclohydrolase deficiency (dopa-responsive dystonia) classically manifests with difficulty walking due to postural dystonia, with an average age of onset symptoms of 5 years to 6 years. The spectrum of clinical manifestations may include minor muscle cramps, infantile or adult-onset, an early nonprogressive course, delayed attainment of motor milestones, spastic diplegia, and the occurrence of parkinsonian-like features in later life (32). Fortunately, the mean time span between appearance of clinical symptoms and diagnosis has decreased last year from 13 years to 5 years (46; 27).

A diagnosis of dopa-responsive dystonia is generally considered because of a prior family history or the presence of a dystonic gait disorder, together with diurnal variation of symptoms. A response to levodopa obviously adds more weight to the diagnosis, but it is widely recognized that many dystonic and other movement disorders may respond to levodopa. In these cases, the effect of levodopa eventually wears off. This is not the case in dopa-responsive dystonia, where there have not been any reports of a decrease in the drug’s effectiveness.

Diagnostic workup

The possibility of a defect in tetrahydrobiopterin metabolism should be considered in all cases where hyperphenylalaninemia has been found on newborn screening. The analysis of pterins and neurotransmitter amine metabolites in CSF should also be considered in any child or adolescent who does not have hyperphenylalaninemia if characteristic neurologic symptoms develop. Depending on the availability of tests, multigene panel testing or next-generation sequencing can be used before metabolic testing, but pathophysiological consequences of detected findings must then always be verified by CSF analysis.

In addition to genetic analysis, 43 separate procedures are used to identify the location of the defect in patients with hyperphenylalaninemia and to separate the tetrahydrobiopterin deficiencies from defects of phenylalanine hydroxylase: (1) analysis of pterins in urine, blood, CSF, or dried blood spots; (2) measurement of dihydropteridine reductase activity in fresh blood or from blood on filter-paper screening cards; (3) analysis of pterins and neurotransmitter metabolites in CSF (37).

The methods for urinary pterin analysis rely on the appearance of characteristic pterin profiles from children affected with different defects (23). These tests should always be performed at elevated plasma phenylalanine concentrations greater than 120 µmol/L (not with a low-phenylalanine diet). Liquid urine or urine on dried filter paper may be used. Urine is oxidized to convert all the reduced biopterin species (tetrahydrobiopterin; dihydrobiopterin; and quinonoid) to biopterin and reduced neopterin (dihydroneopterin) to neopterin, and then the concentration of the total biopterin and neopterin is determined by fluorescence detection after HPLC separation. The use of dried blood spots on filter paper is slightly less sensitive but more practical; it allows for measurements of pterins, dihydropteridine reductase activity, and amino acids from a single specimen (34). Concentrations of neopterin and biopterin are greatly reduced in GTP cyclohydrolase deficiency. Patients with 6-pyruvoyltetrahydropterin synthase deficiency have decreased biopterins with elevated neopterins, and those with dihydropteridine reductase deficiency have elevated biopterins with normal or slightly elevated neopterins. The pattern seen in dihydropteridine reductase deficiency is sometimes normal and sometimes similar to that seen in patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency; therefore, definitive differential diagnosis can only be made by and must include direct measurement of dihydropteridine reductase activity in blood or from blood on filter-paper cards. In pterin-4 alpha-carbinolamine dehydratase deficiency, an additional peak of 7-biopterin, as opposed to the normal 6-biopterin, is detected.

The tetrahydrobiopterin loading test can be considered in patients with hyperphenylalaninemia for BH4-responsiveness assessment, but it does not present a key diagnostic modality (37). It neither completely distinguishes between hyperphenylalaninemia due to a phenylalanine hydroxylase deficiency and a BH4 deficiency nor between different BH4 deficiencies. It should be noted that a decrease in plasma phenylalanine may also occur in some patients with mutations in the phenylalanine hydroxylase gene (03).

Urine analysis of pterins and the tetrahydrobiopterin loading test cannot distinguish between typical and atypical 6-pyruvoyltetrahydropterin synthase deficiency. The atypical forms still have phenylketonuria, demonstrating that tetrahydrobiopterin metabolism is abnormal peripherally; however, the concentrations of neurotransmitter metabolites (homovanillic acid and 5-hydroxyindoleacetic acid) are normal within CSF, and neurologic symptoms remain absent in the majority of cases following correction of the hyperphenylalaninemia. Therefore, measurement of CSF neurotransmitter metabolites is essential for differentiation between the two forms. In the cases where it has been measured, the concentrations of total biopterin in CSF are within the normal range, whereas total neopterin is elevated.

The autosomal dominantly inherited form of GTP cyclohydrolase deficiency (dopa-responsive dystonia), some compound heterozygotes with GTP cyclohydrolase deficiency (11), and sepiapterin reductase deficiency (07) are not detected by newborn screening because of lack of overt hyperphenylalaninemia. Evidence for these three conditions can be obtained by the analysis of CSF because all cases investigated have had low concentrations of neurotransmitter metabolites and an abnormal pterin profile. An oral phenylalanine-loading test (100 mg/kg) can be used to identify symptomatic and asymptomatic individuals with dopa responsive dystonia, sepiapterin reductase deficiency, and compound heterozygotes for GTP cyclohydrolase deficiency when first-line diagnostic tests (biogenic amines and pterins in CSF or genetic studies) are not available (19; 07; 36; 37).

Neuroradiological findings among different BH4 deficiencies include brain atrophy, basal ganglia calcifications, white matter changes, ventricular dilatation, areas of hypodensity, and global demyelinating signs. Due to nonspecific pattern of MRI abnormalities, brain imaging is not required to diagnose BH4 deficiencies, but it is required to exclude other differential diagnoses and to further investigate in case of an unexpected deviation of the clinical course (37). Changes consistent with varying degrees of cerebral and cerebellar watershed injury were predominantly found in patients with dihydropteridine reductase deficiency (28).

Management

The management of the autosomal recessively inherited abnormalities of tetrahydrobiopterin metabolism requires the correction of hyperphenylalaninemia when present, correction of the serotonin and catecholamine deficiency in the typical forms of the disease, and prevention of the onset of folate deficiency within the central nervous system in dihydropteridine reductase deficiency (16; 37).

Strict control of plasma phenylalanine concentration is particularly important because phenylalanine also interferes with the passage of L-dopa and 5-hydroxytryptophan across the blood-brain barrier, and fluctuation in plasma phenylalanine may, therefore, make control of the central neurotransmitter deficiency more difficult. Normal plasma phenylalanine concentrations in GTP cyclohydrolase deficiency, 6-pyruvoyltetrahydropterin synthase deficiency, and pterin-4 alpha-carbinolamine dehydratase deficiency can be maintained by administration of small doses of tetrahydrobiopterin (2 to 45 mg/kg per day). This therapy is preferable to the low-phenylalanine diet. It has been postulated that tetrahydrobiopterin supplementation had caused an increased 7,8-dihydrobiopterin (BH2) production and a decreased BH4/BH2 ratio leading to uncoupling of endothelial NOS, resulting in the generation of oxygen radicals. Following the evaluation of the evidence in the medical literature, no reliable justification for withholding tetrahydrobiopterin supplementation from patients with DHPR deficiency could be concluded (37). The use of tetrahydrobiopterin supplementation can be considered in dihydropteridine reductase deficiency.

Precursor therapy with L-dopa and 5-hydroxytryptophan, in conjunction with carbidopa (25% of L-dopa daily dosage, if the total daily dose is below 400 mg/day, 10% of L-dopa daily dosage if above 400 mg/day), a peripheral decarboxylase inhibitor is the main treatment for the central deficiency of serotonin and the catecholamines (16; 37). The doses required in each patient vary substantially, ranging from 1.7 to 20 for L-dopa, 0.8 to 12 for 5-hydroxytryptophan, and 0.2 to 2.5 for carbidopa. The initial dose should be low and gradually increased over a few weeks to the optimum. This optimum dose is established by measurement of neurotransmitter metabolites (homovanillic acid and 5-hydroxyindoleacetic acid) in CSF, by assessment of improvement or disappearance of neurologic symptoms when they exist, and by balancing these criteria with any side effects that may arise due to the therapy. Repeated lumbar puncture for neurotransmitter assessment can help adjust drug dosage or for clarification in clinical deterioration. This test must be performed in a laboratory that has good age-related reference ranges for these metabolites, as metabolite concentration is rapidly decreased, especially in the period up to 1 year of age. Treatment is further complicated as 5-hydroxytryptophan can lead to anorexia, diarrhea, and tachycardia, and 5-hydroxytryptophan and L-dopa compete for the same transporter site for their passage across the blood-brain barrier. Therefore, each antagonizes the passage of the other for entry into the brain.

Improved outcome has been described with a combination of monoamine oxidase inhibitors and neurotransmitter precursor therapy. Measurement of neurotransmitter metabolites to monitor therapy is less meaningful in this case; however, plasma prolactin concentrations provide a simple tool for treatment monitoring as dopamine is the essential inhibitory factor of prolactin secretion (16). Furthermore, reasons for increased prolactin concentrations in blood (eg, physiological or pathological endocrine conditions, hypothalamus and pituitary disorders, infections, drug-related changes, and postictal status) should be taken into consideration when interpreting prolactin concentrations (37).

Combination of L-dopa substitution with anticholinergic treatment (trihexiphenidyl) or adjunctive treatment of L-dopa substitution with inhibitors of monoamine oxidase B, such as Selegelin, and dopamine agonists, such as bromocriptine, may be helpful therapeutic combinations in some patients, but experience is limited (16). Non-ergot-derived dopamine agonists (pramipexole, ropinirole, and rotigotine) can be introduced in addition to precursor therapy in patients with residual symptoms and side effects.

The central folate deficiency that arises in most patients with dihydropteridine reductase deficiency can lead to rapid neurologic deterioration despite good control of plasma phenylalanine and treatment of the neurotransmitter deficiency with precursor therapy (44). Therefore, treatment with folinic acid is recommended; 10 to 20 mg/day together with the above therapy may reverse or at least halt both the demyelinating processes and the calcification of the basal ganglia (16).

Treatment of the autosomal dominantly inherited GTP cyclohydrolase deficiency (dopa-responsive dystonia) requires correction of the nigrostriatal dopamine deficiency. Levodopa, in conjunction with carbidopa, is commenced at a low dosage and titrated to achieve optimum levels (20) (see also the MedLink article Dopa-responsive dystonia). It is still unclear whether patients should also be treated with supplementation of 5-hydroxytryptophan.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Georg F Hoffmann MD

Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.
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Oya Kuseyri Hübschmann MD

Dr. Hübschmann of University Children's Hospital in Heidelberg, Germany has no relevant financial relationships to disclose.
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Editor

Barry Wolf MD PhD

Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.
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Former Authors

Keith Hyland PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: female=male, 3-4:1 (dominant GTP cyclohydrolase 1 deficiency, Segawa disease, Dopa-responsive dystonia)

female=male, 1:1 (all other defects)
Heredity: heredity typical

autosomal recessive

autosomal dominant
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Phenylketonuria: 270.1

Hyperphenylalaninemia: 270.1
ICD-10: Classical phenylketonuria: E70.0

Other hyperphenylalaninemias: E70.1
OMIM: Phenylketonuria: #261600

GTP cyclohydrolase I deficiency: #233910

Dihydropteridine reductase deficiency: #261630

6-pyruvoyl-tetrahydropterin synthase deficiency: #261640

Pterin-4α-carbinolamine dehydratase deficiency: #264070

Sepiapterin reductase deficiency: #182125

Dopa-responsive dystonia: #128230

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Abnormalities of tetrahydrobiopterin metabolism

Associated Disorders

Chorea
Developmental delay
Dystonia
Epilepsy
Hypotonia
- Intellectual disability
- Phenylketonuria
- Seizures

Abnormalities of tetrahydrobiopterin metabolism …

Abnormalities of tetrahydrobiopterin metabolism

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Drugs to avoid

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
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to access the full version.

Questions or Comment?

Also in This Category

Carnitine palmitoyltransferase II deficiency

Pyruvate carboxylase deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

Abnormalities of tetrahydrobiopterin metabolism

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Drugs to avoid

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Carnitine palmitoyltransferase II deficiency

Pyruvate carboxylase deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

This is an article preview.
Start a Free Account
to access the full version.