Increase of CSF tyrosine and impaired serotonin turnover in tyrosinemia type I

Thimm, Eva; Herebian, Diran; Assmann, Birgit; Klee, Dirk; Mayatepek, Ertan; Spiekerkoetter, Ute

doi:10.1016/j.ymgme.2010.11.003

Cited by 53 publications

(63 citation statements)

References 29 publications

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“…High blood tyrosine is often regarded as the cause of neurocognitive problems in HT1 (Thimm et al 2011(Thimm et al , 2012. 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).…”

Section: Discussionmentioning

confidence: 84%

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: 84%

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

et al. 2014

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“…At the same time, high blood tyrosine concentrations may cause a high influx of tyrosine into the brain causing higher-than-normal CSF dopamine levels [13].…”

Section: Discussionmentioning

confidence: 99%

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

García

Parra

Arias

et al. 2017

Molecular Genetics and Metabolism Reports

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IntroductionTyrosinemia Type 1 (HT1) is an autosomal recessive disorder caused by a defect in the enzyme fumarylacetoacetate hydroxylase in the tyrosine pathway. Implementation of nitisinone (NTBC) treatment has dramatically improved survival rate of individuals with HT1, yet recent reports on cognitive impairment in treated patients exist.AimsDescribe long-term neurocognitive outcome individuals with HT1 treated with nitisinone and protein restricted diet.MethodologyTwelve individuals with HT1 were analyzed with respect to psychomotor development and cognitive functioning using standardized psychometric tests. Plasma tyrosine and phenylalanine concentrations were also collected and analyzed, as part of the regular HT1 follow up program in our clinic.ResultsDelayed performance in Bayley scale mental developmental index (MDI) was identified in 29% to 38% of the patients assessed at different ages. At preschool age, mean full scale IQ (FSIQ) was 88 ± 16; six out of nine assessed children preformed within normal range, and one child presented with intellectual disability. At school age mean FSIQ was 79 ± 18, three out of nine children preformed within normal range and two showed intellectual disability. Repeated measures showed IQ decline over time in four out of eight patients, all of whom presented with symptoms in their first months of life. Patients that showed no progressive IQ decline were 8 months or older at diagnosis, with a mean age of 17 months. Significant correlation between Phe/Tyr ratio and FSIQ at school age was identified (r = − 0.689; p < 0.044).ConclusionSome patients with HT1 treated with nitisinone and protein restricted diet are at risk of presenting developmental delay and impaired cognitive functioning. Patients with early onset of symptoms could be at risk for progressive cognitive functioning decline over time.

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“…The target plasma concentrations of tyrosine and phenylalanine are unclear and long term follow-up studies are urgently needed. The increase in plasma concentrations are associated with increased CSF concentrations of tyrosine [32]. The effects on the tryptophan-derived neurotransmitters [29] is unknown.…”

Section: Long Term Managementmentioning

confidence: 99%

“…However a stricter diet is not easy and the evidence that stricter control of plasma tyrosine concentrations improves the outcome is not conclusive [36,37]. The relevance of the concentrations of other large neutral aminoacids, notably tryptophan, is uncertain [32]. …”

Section: Long Term Managementmentioning

confidence: 99%

Recommendations for the management of tyrosinaemia type 1

Laet

Dionisi‐Vici

Leonard³

et al. 2013

Orphanet J Rare Dis

196

231

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The management of tyrosinaemia type 1 (HT1, fumarylacetoacetase deficiency) has been revolutionised by the introduction of nitisinone but dietary treatment remains essential and the management is not easy. In this review detailed recommendations for the management are made based on expert opinion, published case reports and investigational studies as the evidence base is limited and there are no prospective controlled studies.The added value of this paper is that it summarises in detail current clinical knowledge about HT1 and makes recommendations for the management.

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Increase of CSF tyrosine and impaired serotonin turnover in tyrosinemia type I

Cited by 53 publications

References 29 publications

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

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

Recommendations for the management of tyrosinaemia type 1

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