eP016: Biochemical diagnosis of pterin defect after negative broad genetic evaluation


      Tetrahydrobiopterin (BH4) deficiencies comprise a group of several rare neurometabolic disorders characterized by insufficient synthesis of neurotransmitters due to a disturbance of BH4 biosynthesis. Patients may exhibit a wide spectrum of clinical severity. Common features of BH4 deficiencies are non-specific and may include hypotonia, impaired motor and cognitive development, and movement disorders. Pterin defects associated with hyperphenylalaninemia (HPA) may be identified on newborn screening, but do not identify every individual with a pterin defect.

      Case presentation

      We present a 14-month-old male with a complex medical history notable for developmental delay, epilepsy, infantile spasms, ocular anomalies, and concern for chorea-like movements; now diagnosed biochemically with a defect in the tetrahydrobiopterin pathway. He initially presented to genetics at 2 months of age with severe hypotonia. He developed significant developmental delay over the next several months, which prompted genetic testing including microarray and whole exome sequencing, both of which were non-diagnostic. Broad metabolic testing, including plasma aminos, was also sent and resulted within the normal reference range. At 11 months of age he underwent further evaluation with neurology. CSF studies at this time showed abnormal neurotransmitters: 5-hydroxyindoleacetic acid - 88nmol/L (129-520), homovanillic acid - 37nmol/L (294-1115), 3-O-methyldopa - 6nmol/L (<300). This prompted further evaluation for an underlying pterin defect. Urine pterins showed biopterin of 3.31mmol/mole Cr (0.78-2.68), neopterin total of 1.85 mmol/mole Cr (0.4-1.33) and biopterin as 64% of the sum of biopterin and neopterin. CSF dihydrobiopterin resulted at 1.8nmol/L (3-18), sepiapterin at <1nmol/L (<2), neopterin at 9nmol/L (7-65) and tetrahydrobiopterin at 5nmol/L (18-58). Dihydropteridine reductase activity in dried blood spots was found to be deficient. We believe this fits with a biochemical diagnosis of dihydropteridine reductase deficiency, however, repeat genetic testing has not identified underlying disease causing variants.


      This case illustrates the need for further biochemical studies in patients with high clinical suspicion for disease and non-diagnostic comprehensive genetic testing. Establishment of diagnosis has been life altering for our patient and his family, as they have appreciated developmental gains within days of initiating appropriate neurotransmitter replacement and tyrosine supplementation. Without this biochemical evaluation, our patient would have suffered natural disease progression. Our experience shows one should consider further biochemical evaluation in a child with severe hypotonia with negative molecular sequencing.