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Dihydropteridine reductase deficiency

Orpha number ORPHA226
Synonym(s) Hyperphenylalaninemia due to dihydropteridine reductase deficiency
PKU type 2
Phenylketonuria type 2
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • E70.1
ICD-O -
OMIM
UMLS
  • C0268465
  • C2936906
MeSH
  • C537896
MedDRA -
SNOMED CT
  • 58256000

Summary

Dihydropteridine reductase (DHPR) deficiency is a severe form of hyperphenylalaninemia (HPA) due to impaired regeneration of tetrahydrobiopterin (BH4) (see this term), leading to decreased levels of neurotransmitters (dopamine, serotonin) and folate in cerebrospinal fluid, and causing neurological symptoms such as psychomotor delay, hypotonia, seizures, abnormal movements, hypersalivation, and swallowing difficulties.

DHPR deficiency is extremely rare, but accounts for about one third of all forms of BH4 deficiencies. It is more frequent in regions around the Mediterranean Sea.

In the absence of treatment, the disease generally manifests at 4-5 months of age with psychomotor delay, tonus disorders, seizures, oculogiric crises, drowsiness (with diurnal fluctuation of alertness), irritability, hyperthermia, hypersalivation, swallowing difficulties and abnormal movements. Microcephaly is reported in one third of the patients. In severe cases, an increased risk of prematurity and low birth weight are observed, and clinical features such as hypotonia, poor sucking and decreased spontaneous movements are apparent from birth.

DHPR deficiency is caused by mutations in the QDPR gene, which encodes quinoid dihydropteridine reductase involved in the second step of BH4 regeneration. BH4 deficiency leads to hyperphenylalaninemia due to the secondary defect of phenylalanine hydroxylase, and depletion of dopamine and serotonin due to the deficiency of BH4 cofactor dependent enzymes involved in the synthesis of neurotransmitters. Two specific mutations (p.G151S and p.F212C) result in a mild form of DHPR deficiency in which only serotonin metabolism is affected.

The disease is generally suspected because of an elevated phenylalanine level upon newborn screening. It is diagnosed by measurement of decreased DHPR activity in blood cells and reduced serotonin and dopamine metabolites and folate in cerebrospinal fluid. Brain imaging might show progressive calcifications in basal ganglia, white or grey matter. In 50% of cases, EEG demonstrates paroxysmal activity. The diagnosis is confirmed by genetic testing.

Differential diagnosis includes classical phenylketonuria, other causes of BH4 deficiencies (e.g. 6-Pyruvoyl-tetrahydropterin synthase deficiency, GTP cyclohydrolase I deficiency; see these terms), prenatal infections, Aicardi-Goutieres syndrome, infantile parkinsonism (e.g. dopamine transporter or tyrosine hydroxylase deficiency), and disorders affecting the white matter (e.g. neuronal ceroid lipofucsinosis, gangliosidosis, Alexander disease) (see these terms).

Prenatal diagnosis can be accomplished by molecular analysis if the familial mutation is known.

Transmission is autosomal recessive with a 25% recurrence risk in subsequent pregnancies.

The goal of the therapy is to reduce the levels of phenylalanine in the blood through treatment with BH4 usually combined with a phenylalanine restricted diet, and restore the levels of neurotransmitters in the brain by treatment with neurotransmitter precursors (L-dopa/carbidopa and 5-hydroxytryptophan). Long-acting dopamine agonists (pramipexole, ropinorole) can be used to stabilize the clinical and biochemical picture. Monoamino oxidase inhibitors (selegiline) are also useful to prolong the action of neurotransmitter precursors. Administration of methylfolate or folinic acid can restore cerebral folate levels.

Without treatment, death generally occurs in infancy or childhood. With treatment, prognosis depends of the age at diagnosis and quality of treatment and compliance. Even with treatment, most patients have some degree of developmental delay and, in some cases, brain abnormalities.

Expert reviewer(s)

  • Dr Daniela CONCOLINO
  • Pr Nicola LONGO
  • Dr Pietro STRISCIUGLIO

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Detailed information

Review article
  • FR (2005,pdf)
  • EN (2005,pdf)
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