Impaired Cognitive Functioning in Patients with Tyrosinemia Type I Receiving Nitisinone

Bendadi, Fatiha; Koning, Tom J. de; Visser, Gepke; Prinsen, Hubertus C.M.T.; Sain, Monique G.M. de; Verhoeven‐Duif, Nanda M.; Sinnema, Gerben; Spronsen, Francjan J. van; Hasselt, Peter M. van

doi:10.1016/j.jpeds.2013.10.001

Cited by 74 publications

(74 citation statements)

References 16 publications

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“…However, these two cases support the hypothesis that hypophenylalaninemia rather than hypertyrosinemia could be the most important (De Laet et al 2011;Bendadi et al 2014). Patient 1 with the lowest incidence of hypertyrosinemia but highest incidence of hypophenylalaninemia showed skin problems, poor growth, and impairment in motor and cognitive development.…”

Section: Discussionmentioning

confidence: 54%

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Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 54%

“…Unfortunately, however, neurocognitive deficits are observed, which may be related to HT1 itself, NTBC treatment, increased tyrosine concentrations, or low phenylalanine concentrations (De Laet et al 2011;Masurel-Paulet et al 2008;Thimm et al 2012;Bendadi et al 2014). NTBC increases tyrosine concentrations.…”

Section: Introductionmentioning

confidence: 99%

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

et al. 2014

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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Background: Treatment of hereditary tyrosinemia type 1 with nitisinone and phenylalanine and tyrosine restricted diet has largely improved outcome, but the best blood sampling time for assessment of metabolic control is not known. Aim: To study diurnal and day-to-day variation of phenylalanine and tyrosine concentrations in tyrosinemia type 1 patients. Methods: Eighteen tyrosinemia type 1 patients aged >1 year (median age 7.9 years; range 1.6-20.7) were studied. Capillary blood samples were collected 4 times a day (T1: pre-breakfast, T2: pre-midday meal, T3: before evening meal, and T4: bedtime) for 3 days. Linear mixed-effect models were used to investigate diurnal and day-to-day variation of both phenylalanine and tyrosine. Results: The coefficients of variation of phenylalanine and tyrosine concentrations were the lowest on T1 (13.8% and 14.1%, respectively). Tyrosine concentrations did not significantly differ between the different time points, but phenylalanine concentrations were significantly lower at T2 and T3 compared to T1 (50.1 mmol/L, 29.8 mmol/L, and 37.3 mmol/L, respectively). Conclusion: Our results indicated that for prevention of too low phenylalanine and too high tyrosine concentrations, measurement of phenylalanine and tyrosine pre-midday meal would be best, since phenylalanine concentrations are the lowest on that time point. Our results also indicated that whilst blood tyrosine concentrations were stable over 24 h, phenylalanine fluctuated. Day-to-day variation was most stable after an overnight fast for both phenylalanine and tyrosine. Therefore, in tyrosinemia type 1 patients the most reliable time point for measuring phenylalanine and tyrosine concentrations to enable interpretation of metabolic control is pre-breakfast.

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“…HT1 patients treated with nitisinone are found to be at risk of developing impaired cognitive function and a total intelligence quotient (IQ) score below the average despite a protein-restricted diet. 114,115 They were found to have 20 IQ points lower when compared to their unaffected siblings. 114 The lower IQ may be an unwanted side effect of treatment.…”

Section: Adverse Effects Of Nitisinonementioning

confidence: 99%

Nitisinone: a review

Aktuglu-Zeybek¹,

Zübarioğlu²

2017

ODRR

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Nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]cyclohexane-1,3-dione), an effective triketone herbicide, is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the tyrosine catabolic pathway. Since 1992, the drug has become an effective pharmacological treatment for hereditary tyrosinemia type 1 (HT1). Nitisinone can prevent the development of liver disease, reverse and prevent the renal tubular dysfunction, severe neurological crisis and cardiomyopathy and significantly reduce the risk of developing hepatocellular carcinoma in HT1 patients. Its mode of action, with few side effects reported, make the drug a potential candidate for the treatment of other disorders of tyrosine metabolism, including alkaptonuria, with successful reduction in homogentisic acid production to prevent long-term complications. Nitisinone could also be a promising agent in the treatment of tumors with active tyrosine metabolic pathways. In this review, we discuss the effects of nitisinone for various tyrosine pathway disorders.

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Impaired Cognitive Functioning in Patients with Tyrosinemia Type I Receiving Nitisinone

Abstract: Patients with tyrosinemia type I treated with nitisinone are at risk for impaired cognitive function despite a protein-restricted diet.

Cited by 74 publications

References 16 publications

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

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

Nitisinone: a review

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