Tyrosinemia type 1 (HT1) is an inborn error of
tyrosine catabolism caused by
fumarylacetoacetase deficiency. Biochemically, this results in accumulation of toxic metabolites including
succinylacetone. Clinically, HT1 is characterized by severe liver, kidney, and neurological problems. Treatment with NTBC and
dietary restriction of
tyrosine and
phenylalanine have strongly improved outcome, but impaired neurocognitive development has been reported. Whether impaired neurocognitive outcome results from high blood
tyrosine or low blood
phenylalanine concentrations is currently unknown. In this report, two HT1 newborns, diagnosed by neonatal screening, are presented. The first patient showed low
phenylalanine concentrations, growth retardation, neurological impairments, and skin problems, clearly improving after institution of
phenylalanine supplementation (~30 mg/kg/day) at age 6 months, while both blood
phenylalanine and
tyrosine concentrations increased. In the second patient,
phenylalanine supplementation (~20 mg/kg/day) was initiated as soon as low
phenylalanine concentrations were observed at age 19 days. On this regimen, blood
phenylalanine concentrations increased, and hypophenylalaninemia was less frequently observed than in the first patient, whereas blood
tyrosine concentrations tended to increase. Clinically, no growth, neurological, or skin problems have been observed. The combination of knowledge obtained from these cases suggests that hypophenylalaninemia rather than
hypertyrosinemia during the first months of life may impair neurocognitive development in young HT1 infants.
Phenylalanine supplementation should really be considered in HT1 patients with consistently low blood
phenylalanine concentrations during the first months of life. However, the minimal
phenylalanine concentrations acceptable and the optimal
phenylalanine supplementation regimen require further investigation.