Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Abstract

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.

Long-term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein-restricted diet

“…Association between low phenylalanine concentrations and delayed psychomotor development and skin problems, and responsiveness to Phe supplementation at early stages of development, have been reported [17]. Thus, both high tyrosine and low phenylalanine concentrations may be important in the cascade ultimately leading to brain dysfunction in HT1.…”

Development of Risk Prediction Equations for Incident Chronic Kidney Disease

“…High phenylalanine and tyrosine levels may have toxic effects on the brain, as shown in disorders such as phenylketonuria and tyrosinemia type 2 [18,[21][22][23]. There is also evidence that low plasma phenylalanine concentrations adversely affect the outcomes in PKU [24] and TT1 [5,12,13]. It is important to note that low plasma phenylalanine concentrations in TT1 are likely to cause even lower phenylalanine concentrations in the brain because of competition with tyrosine for influx across the blood-brain barrier.…”

“…These neurocognitive defects may underlie problems in TT1 patients' daily lives, such as school problems and attention deficits. At present, knowledge of the cognitivebehavioral phenotype associated with TT1 and its cause is limited, although high tyrosine and low phenylalanine concentrations may both be associated with brain dysfunction [5,8,[12][13][14].…”

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

“…With respect to the second issue, phenylalanine concentrations were both statistically and clinically significantly lower at T2 and T3 compared to T1, showing levels <30 mmol/L. This indeed is of clinical importance since too low phenylalanine concentrations in PKU are related to impaired growth and development (Rouse 1966;Smith et al 1990;Teissier et al 2012), and possibly also to physical and mental development in HT1 (de Laet et al 2011;van Vliet et al 2014). …”

“…Neurocognitive delay is reported in HT1 (Masurel-Paulet et al 2008;de Laet et al 2011;Bendadi et al 2014;van Vliet et al 2014), suggesting a relation with both low phenylalanine and high tyrosine concentrations (de Laet et al 2011;van Vliet et al 2014) and/or Phe:Tyr ratios (de Laet et al 2011). Therefore, regular and reliable measurement of both phenylalanine and tyrosine concentrations could be important.…”