6-pyruvoyl-tetrahydropterin synthase deficiency (ORPHA:13)
A rare form of hyperphenylalaninemia due to tetrahydropterin (BH4) biosynthesis deficiency, leading to central dopamine and serotonin deficiency, and characterized by infantile-onset neurological disease of variable severity ranging from mild forms with normal 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. 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPSD) is the most frequent of all HPA-associated BH4 deficiencies, representing approximately half of cases.
Clinical description
When left untreated, the deficiency leads to neurological symptoms starting at 4-5 months of age. Very frequent symptoms (>50% of patients) are developmental delay and (axial) hypotonia. Frequent symptoms (25-50% of patients) are hypertonia of the extremities, impaired speech development and being small for gestational age. There are no consistent reports on genotype-phenotype correlation.
Etiology
PTPSD is caused by variants in the PTS gene, which encodes 6-pyruvoyl-tetrahydropterin synthase. BH4 is an essential cofactor for phenylalanine hydroxylase (PAH), tyrosine (TH) and tryptophan hydroxylase (TPH). Therefore, the tetrahydrobiopterin deficiency causes not only HPA, but also a central dopamine and serotonin deficiency.
Diagnostic methods
PTPSD should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when HPA is moderate. 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. The suspected diagnosis can be further confirmed by genetic evaluation of the PTS gene and/or the measuring of the neurotransmitters 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and pterins in cerebrospinal fluid. Clinical consensus guidelines on the different diagnostic options are available with open access.
Differential diagnosis
The differential diagnosis includes classic phenylketonuria and hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I, pterin-4-alpha-carbinolamine dehydratase, dihydropteridine reductase, and DNAJC12 deficiencies.
Antenatal diagnosis
Prenatal diagnosis is possible by molecular analysis where the pathogenic variant has previously been identified in a family member.
Genetic counseling
PTPS deficiency is an autosomal recessive genetic disorder. 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) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophan). 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.
Prognosis
Levodopa/carbidopa supplementation drastically improves, often even reconstitutes motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation.

                            Last update: 
                            April 2024


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


                                * European Reference Network