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Pregnancy during nitisinone treatment for tyrosinaemia type I: first human experience.

ABSTRACT: A 19 year old woman with tyrosinaemia type 1 gave birth to a healthy girl after 41 weeks of gestation. Nitisinone was continued throughout the pregnancy (maternal levels 68-96 μmol/l, target level 30-60 μmol/l). Tyrosine levels during pregnancy were between 500 and 693 μmol/l (normal values 20-120 μmol/l) and phenylalanine levels between 8 and 39 μmol/l (normal values 30-100 μmol/l). Nitisinone was measurable in neonatal blood immediately after birth, at a level comparable to the simultaneous level in the mother. Nitisinone half-life in the neonate was estimated to be 90 h. Tyrosine levels in the neonate decreased from 1,157 μmol/l at birth (cord blood) to normal levels within 4 weeks. Phenylalanine levels in the neonate were normal from birth on. The child had a normal psychomotor development as assessed throughout the first year of life.This is the first report worldwide of a pregnancy during treatment with nitisinone.In this case, no adverse effects of nitisinone, maternal high tyrosine or low phenylalanine were detected in the child, so far. Long-term results in a larger cohort of pregnancies and births are needed to determine whether nitisinone can be administered safely during pregnancy.

SUBMITTER: Vanclooster A

PROVIDER: S-EPMC3509920 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Pregnancy during nitisinone treatment for tyrosinaemia type I: first human experience.

Vanclooster A A Devlieger R R Meersseman W W Spraul A A Kerckhove K Vande KV Vermeersch P P Meulemans A A Allegaert K K Cassiman D D

JIMD reports 20111216

A 19 year old woman with tyrosinaemia type 1 gave birth to a healthy girl after 41 weeks of gestation. Nitisinone was continued throughout the pregnancy (maternal levels 68-96 μmol/l, target level 30-60 μmol/l). Tyrosine levels during pregnancy were between 500 and 693 μmol/l (normal values 20-120 μmol/l) and phenylalanine levels between 8 and 39 μmol/l (normal values 30-100 μmol/l). Nitisinone was measurable in neonatal blood immediately after birth, at a level comparable to the simultaneous le ...[more]

PMID: 23430914

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Project description:Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.

Project description:Acute aortic dissection (AAD) is among the most challenging cases for surgical treatment and requires procedural expertise for its safe conduct. Aortic surgery has undergone several changes over the last years, especially concerning cerebral protection. The brilliant results obtained with the aid of selective anterograde cerebral perfusion led to a progressive increase of circulatory arrest temperature, with the rise of safe time along with a reduction of the extracorporeal circulation time and hypothermia-related side effects. However, there is still no definitive consensus concerning the optimal range of temperature to be used during circulatory arrest. Objectives. This is a retrospective observational study, and we examined 16-year trends in the presentation, diagnosis, hospital outcome and treatment of A AAD type. In our Cardiac Surgery Unit in Policlinico Umberto I of Rome, our analysis focused on patients, who received ACP during aortic surgery and we analyzed the differences between two distinct groups based on the lowest temperature reached during CPB conduction: Lower Temperature Group (LT) (T < 24°C) versus Higher Temperature Group (HT) (T ≥ 24°C) arrest circulation temperature. Methods. Data from 241 patients enrolled between August 2002 and March 2018 were analyzed. Patients were divided according to the lowest temperature reached into 2 groups: Lower Temperature group (LT) (94 patients) and Higher Temperature Group (HT) (147 patients). Results. Our results showed a significant reduction of in-hospital mortality and in-hospital results in patients with higher CPB temperature. The global incidence of complications was statistically reduced in HT group: we found a statistical significant reduction of intestinal ischemia, and a similar trend also for other complications analyzed, such as infections. Since the two groups were similar for type of surgical procedures, we considered these differences depending on the lower temperature value reached, according to the current literature. Conclusions. We found a significantly higher mortality in patients with lower temperature during CPB and a global reduction of complications and in particular a significant reduction of intestinal ischemia in patients with higher temperature during CPB. We found a similar trend in other fields of investigations, so we can conclude that circulatory arrest performed at temperature ≥24°C nasopharyngeal temperature associated with ACP is a safe strategy for aortic surgery for AAD.

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Pregnancy during nitisinone treatment for tyrosinaemia type I: first human experience.

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Pregnancy during nitisinone treatment for tyrosinaemia type I: first human experience.

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