Dihydropteridine reductase deficiency (ORPHA:226)
A rare form of hyperphenylalaninemia due to tetrahydropterin (BH4) recycling deficiency, leading to central dopamine and serotonin deficiency, clinically 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. Some patients may present refractory neurological symptoms like a degree of developmental delay, epilepsy and brain abnormalities.
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 dihydropteridine reductase deficiency (DHPRD) is the second most frequent of all HPA-associated BH4 deficiencies, representing approximately one third of cases. It is more frequent in regions around the Mediterranean Sea.
Clinical description
When left untreated, the deficiency leads to neurological symptoms typically starting at 4-5 months of age. Neonatal onset has been described in single cases characterized by hypotonia, poor sucking and decreased spontaneous movements. Very frequent symptoms (occurring in >50% of patients) are developmental delay and axial hypotonia. Frequent symptoms (occurring in 25-50% of patients) are, hypertonia of the extremities, epilepsy, impaired speech development and microcephaly. Brain imaging might show progressive calcifications in basal ganglia, white or grey matter, and a pattern of bilateral parietooccipital, and to a lesser extent, frontal and/or cerebellar changes in arterial watershed areas. There are no consistent reports on genotype-phenotype correlation.
Etiology
DHPR deficiency is caused by variants in the QDPR gene, which encodes quinoid dihydropteridine reductase involved in the second step of BH4 regeneration. 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
DHPRD 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 QDPR gene and/or the measuring of 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 classical phenylketonuria and hyperphenylalaninemia due to autosomal recessive GTP cyclohydrolase I, pterin-4-alpha-carbinolamine dehydratase, 6-pyruvoyl-tetrahydropterin synthase, 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
DHPR 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). Administration of methylfolate or folinic acid can restore cerebral folate levels. 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 motor function. However, long-term prognosis correlates with early diagnosis and treatment initiation. In DHPRD, even with treatment, some patients have a degree of developmental delay, epilepsy and, in some cases, brain abnormalities.

                            Last update: 
                            April 2024


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


                                * European Reference Network