Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (ORPHA:238583)
A disorder of pterin metabolism characterized by tetrahydropterin (BH4) biosynthesis or recycling deficiencies, leading to central dopamine and serotonin deficiency, characterized by infantile-onset neurological disease of variable severity ranging from mild forms with minor neurological development to severe forms with hypotonia, developmental delay, complex movement disorder dominated by dystonia or dystonia parkinsonism.
Epidemiology
The global prevalence of BH4 deficiencies remains unknown and great variance can be found among different countries. European newborn screening programs (NBS) reveal that the mean incidence of all hyperphenylalaninemias (HPA) is approximately 1/10,000, with BH4 deficiencies representing 1-2% of cases.
Clinical description
When left untreated, the deficiency leads to neurological symptoms starting shortly after birth. While the overall clinical phenotype of BH4Ds may overlap with numerous other disorders (e.g. cerebral palsy) certain clinical features may raise the clinical suspicion for a disorder of impaired neurotransmission (e.g. early onset parkinsonism, oculogyric crises, diurnal fluctuation of symptoms, or an unexplained cerebral palsy-like picture). It is important to note that patients may show a wide spectrum of clinical severity, ranging from asymptomatic individuals requiring no treatment to very severe disease courses.
Etiology
BH4Ds are caused by variants in the GCH1, PTS, SPR, QDPR and PCBD1 genes, which encode enzymes required for the BH4 biosynthesis or recycling. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). While variants in PTS, QDRP and PCBD1 cause a central dopamine and serotonin deficiency and HPA, patients with variants in GCH1 and SPR mostly have normal phenylalanine concentrations.
Diagnostic methods
BH4D should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. Since phe levels can be normal in GTP cyclohydrolase I and sepiapterin reductase deficiency, the occurrence of certain clinical features should raise the clinical suspicion for a disorder of impaired neurotransmission. The analysis of pterins in urine or dried blood spot (DBS) in patients and the analysis of dihydropteridine reductase (DHPR) enzyme activity in DBS has to follow in all patients with HPA on NBS. With suspicion clinical picture and missing HPA or the confirm the biochemical diagnosis by genetic evaluation of the respective gene is recommended. Depending on availability the measuring of the neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid can be helpful for the diagnosis or during follow-up of BH4Ds.
Differential diagnosis
BH4Ds should be differentiated from each other, namely hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I deficiency, pterin-4-alpha-carbinolamine dehydratase deficiency (PCDD) and 6-pyruvoyl-tetrahydropterin synthase deficiency. The differential diagnosis of BH4 deficiencies also includes classic phenylketonuria and hyperphenylalaninemia due to DNAJC12 deficiency.
Antenatal diagnosis
Prenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.
Genetic counseling
All BH4 deficiencies are autosomal recessive genetic disorders. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of sapropterin hydrochlorid) in disorders with HPA. In all disoders apart from PCDD, restoration of normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan) should be achieved. In case of insufficient clinical response or L-dopa-induced hyperkinesia long-acting dopamine agonists (e.g. pramipexole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors. PCDD patients receive sapropterin hydrdochlorid to control Phe levels.
Prognosis
Early treatment drastically improves, often even reconstitutes motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Dr Oya KUSEYRI HÜBSCHMANN | MetabERN* - Pr Thomas OPLADEN | MetabERN*


                                * European Reference Network