PNDs with Elevated Phenylalanine Levels
The neurotransmitter deficiency in infants in this group arises as a result of defects in BH4 metabolism (figure 1). Patients are usually identified by elevated phenylalanine levels on newborn screening, as BH4 is required for phenylalanine hydroxylation in the liver. The accompanying neurotransmitter deficiency results from the lack of BH4, an obligatory cofactor required for the synthesis of catecholamines and serotonin.
Although most academic biochemical genetics clinics that follow children with phenylketonuria (PKU) systematically perform the additional studies required to diagnose this group of disorders, occasionally children are not identified until they have progressive neurologic symptoms or clear evidence of developmental delay despite a phenylalanine-restricted diet. In the past, these patients were referred to as “atypical phenylketonurics”. In some cases such infants are missed because screening was performed before an adequate interval of protein intake, resulting in a falsely negative result on newborn testing.
Approximately 1–3% of patients with elevated blood phenylalanine levels have an associated BH4 deficiency state. Thus, it is critical to identify such children so that BH4 and neurotransmitter precursors can be supplemented as early as possible. The two most commonly identified disorders in children presenting with elevated blood phenylalanine levels in the newborn period are:
- 6-pyruvoyltetrahydropterin synthase (PTS) deficiency and
- dihydropteridine reductase (DHPR) deficiency.
PTS deficiency results in inadequate BH4 synthesis, while DHPR deficiency results in decreased regeneration of BH4 from dihydrobiopterin (figure 1). Both are autosomal recessive disorders in which hyperphenylalaninemia results from a deficiency of BH4. Because of the involvement of BH4 in catecholamine and serotonin synthesis, such infants also have a manifest deficiency of neurotransmitter metabolites in addition to hyperphenylalaninemia. Other conditions in this category include autosomal recessive GTP cyclohydrolase deficiency and primapterinuria.
