Introduction Dihydropteridine reductase (DHPR) deficiency is an autosomal recessive genetic disorder where the synthesis of tetrahydrobiopterin (BH4) is affected. BH4 is an essential co-factor for the hydroxylation of the aromatic amino acids; phenylalanine, tyrosine and tryptophan. A deficiency of BH4 results in hyperphenylalaninaemia, and a lowered synthesis of dopamine and serotonin and therefore low levels of cerebrospinal fluid (CSF) neurotransmitters cause the clinical symptoms. Patients with DHPR deficiency may present with hypotonia, abnormal movements, poor temperature control, irritability, seizures, progressive developmental delay and microcephaly. Long term amine replacement with 5-hydroxytryptophan and levodopa, the respective precursors to serotonin and dopamine, is the main treatment to supplement CSF neurotransmitters, and diet restriction of phenylalanine. Folinic acid is also given to prevent CNS folate deficiency.
Case report This patient was born by caesarean section at 39 weeks and detected through newborn screening with an elevated phenylalanine level of 634 micromol/l and later a confirmatory repeat level was 850 micromol at the age of 12 days. Subsequent tests confirmed a defect in biopterin recycling due to DHPR deficiency. The patient did not show any symptoms and looked well but the guidelines are to commence treatment and regular monitoring of the treatment. The doses started were levodopa as co-beneldopa dispersible tablets (benserazide 12.5 mg and levodopa 50 mg) initially 1 mg/kg in 4 divided doses, 5-hydroxytrptophan 1–2 mg/kg in 4 divided doses, calcium folinate 15 mg OD and a low phenylalanine diet. Doses were adjusted in response to the lumber puncture CSF results. During this time the patient was developing but was a little behind on some milestones especially speech development, some challenging behaviour and during this period of time the parents reported that the child was unsteady on his feet, and kept falling over.
Results The measurement of the CSF neurotransmitter metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) are essential to the diagnosis of these patients and also to monitor amine replacement with 5-hydroxytryptophan and levodopa. When the levels were checked in this patient at the time of the symptoms being reported it was found that both the HVA and 5-HIAA CSF concentrations, and were well below the reference ranges. They were the lowest seen in this patient HVA 86 nmol/L (154–867) and 5-HIAA 34 nmol/L (89–367). The methyltetrahydrofolate level was in range 97 nmol/L (52–178) and the phenylalanine levels were in the desired range.
Conclusion Doses had always been adjusted according to the patient’s weight and the CSF results, so the compliance of the medication could have been an issue. The pharmacist checked with the parents how they were administering the drug. The capsules for the 5-hydroxytrptophan were being opened dispersed in water and the volume for the dose to be given taken, a similar method was used for the co-beneldopa tablets. The 5-hydroxytrptophan capsules were an imported food supplement formulation and the contents did not disperse well and uniformly in water. A new pharmaceutical grade formulation was ordered in and the subsequent CSF levels showed a steady increase back into the ranges for HVA and 5-HIAA.
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