Nitisinone treatment during two pregnancies and breastfeeding in a woman with tyrosinemia type 1 - a case report.

OBJECTIVES: Tyrosinaemia type 1, an inherited disorder of tyrosine metabolism, is usually treated with a tyrosine-defined diet and since 2000 with nitisinone. So far, data about effects of nitisone during pregnancy and breastfeeding are rare. This is the first report of two pregnancies in a patient with tyrosinaemia type 1 while under treatment with nitisinone. CASE PRESENTATION: We here present a 20-year-old female patient with tyrisonemia type 1 receiving treatment with nitisinone and a tyrosine-defined diet since she was diagnosed with tyrosinaemia type 1 at the age of 18 months. During two pregnancies blood concentrations of tyrosine, succinylacetone and nitisinone were measured regularly. Neither infant has tyrosinaemia type 1 and both showed an initial increase in concentrations of tyrosine, succinylacetone and nitisinone. All three metabolites dropped within two weeks after birth. Both were exclusively breastfed for about two weeks. Both children show age-appropriate physical and mental development. CONCLUSIONS: Nitisinone therapy during pregnancy and the short breastfeeding period did not result in adverse events in our patient or her children. Regular assessments of tyrosine, succinylacetone and nitisinone should be made during pregnancy and the breastfeeding period in both the mother and the infant. For better understanding, in principle, all cases of pregnancy and breastfeeding with tyrosinemia type 1 should be assessed and followed to further evaluate the implications of tyrosinaemia type 1 and its treatment during pregnancy. Additionally, even though experience with breastfeeding is limited, medication with nitisinone is safe and there is no reason to consider breastfeeding unsafe or to not recommend it.

Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study.

BACKGROUND: Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1. METHODS: We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only). FINDINGS: 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment. INTERPRETATION: Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy. FUNDING: Swedish Orphan Biovitrum (Sobi).

R (-)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine.

The newfound antidepressant efficacy of ketamine has provided opportunities for the development of new-generation, rapid-acting, glutamate-based antidepressants. We previously identified that methoxetamine (MXE), a ketamine analog, and an N-Methyl-d-aspartate (NMDA) receptor antagonist, produced rapid and sustained antidepressant effects in mice. MXE (R, S (±)-MXE) is a racemic mixture containing equal parts of S (+)-MXE and R (-)-MXE. However, studies have yet to investigate the antidepressant effects of its enantiomers. Here, we examined the potential antidepressant properties and behavioral side effects of S- and R-MXE in mice. Both S- and R-MXE showed significant NMDA receptor affinity and appreciable inhibitory activity on serotonin transporter. Also, S- and R-MXE (10 mg kg-1) exerted antidepressant effects and increased gamma waves (electroencephalography) but were inhibited by NBQX (an AMPA receptor antagonist). Subsequently, they increased mammalian target of rapamycin phosphorylation and AMPA receptor subunits GluA1 and GluA2 protein levels in the hippocampus or prefrontal cortex. Furthermore, they increased 5HT2a and 5HT2c receptor mRNA levels in the prefrontal cortex, with their antidepressant effects inhibited by ketanserin (a 5HT2a/c receptor antagonist). Taken together, S-MXE and R-MXE elicit antidepressant effects that are probably mediated via glutamatergic and serotonergic mechanisms. Unlike S-MXE, R-MXE did not induce prepulse inhibition deficits, hyperlocomotion, conditioned place preference, and locomotor sensitization, although it acutely altered motor coordination. This suggests that R-MXE induces fewer behavioral side effects and is a safer antidepressant than S-MXE. Overall, this study provides significant implications for future research on the next generation of rapid-acting, glutamate-based antidepressant drugs.

Possible Protective Effects of TA on the Cancerous Effect of Mesotrione.

The interaction of different food ingredients is now a very important and often emerging topic of research. Pesticides and their breakdown products, which may be carcinogenic, are one of the frequently occurring food contaminants. Compounds like traumatic acid (TA), which originates from plants, are beneficial, antioxidant, and anticancer food ingredients. Previously obtained results from our research group indicated antioxidative in normal human fibroblasts and prooxidative in cancer cells activity of TA. Since the literature data show an undoubted connection between the presence of pesticides in food and the increased incidence of different types of cancers, we attempted to clarify whether TA can abolish the effect of mesotrione stimulating the growth of cancer cells. In order to study the influence of mesotrione on breast cancer cells, we decided to carry out cytotoxicity studies of environmentally significant herbicide concentrations. We also analyzed the cytotoxicity of TA and mixtures of these two compounds. After selecting the most effective concentrations of both components tested, we conducted analyses of oxidative stress parameters and apoptosis in ZR-75-1 cells. The obtained results allow us to conclude that traumatic acid by stimulating oxidative stress and apoptosis contributes to inhibiting the growth and development of cells of the ZR-75-1 line strengthened by mesotrione. This may mean that TA is a compound with pro-oxidative and proapoptotic effects in cancer cells whose development and proliferation are stimulated by the presence of mesotrione. The presented results may be helpful in answering the question of whether herbicides and their residues in edibles may constitute potential threat for people diagnosed with cancer and whether compounds with proven pro-oxidative effects on cancer cells can have potential cytoprotective functions.

Pediatric liver diseases and ocular changes: What hepatologists and ophthalmologists should know and share with each other.

Several rare pediatric liver disorders are accompanied by ophthalmic signs whose awareness and early identification may be of value in confirming/accelerating their diagnosis. Many of these signs are asymptomatic and can only be detected with an ophthalmological examination. Corneal signs are described in patients with Wilson's disease, Alagille's syndrome and some liver storage diseases. Cataract plays an important role to diagnose galactosemia. Retinal involvement is seen in some peroxisomal disorders (e.g. Zellweger's syndrome), in mucopolysaccharidoses (pigmentary retinopathy), and in Niemann-Pick disease (macular cherry red spot). In mucopolysaccharidoses optic nerve can be involved as optic atrophy secondary to pigmentary retinopathy or to chronic papilledema. Children with neonatal cholestasis due to hypopituitarism may present septo-optic dysplasia. Several infectious agents have an ophthalmological/hepatic involvement in the fetal life and/or thereafter. Some mitochondrial liver diseases, such as Pearson's syndrome, present pigmentary retinopathy and a chronic progressive external ophthalmoplegia. Finally, some drugs while protecting the liver may damage the ocular system as seen with long-term glucocorticoids and Nitisinone administration. This review provides a synopsis of those conditions that hepatologists and ophthalmologists should share among themselves to better take care of patients. Synoptic tables are presented to facilitate the mutual understanding of the issues.

Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1.

Tyrosinemia type 1 (TT1) is a rare metabolic disease caused by a defect in tyrosine catabolism. TT1 is clinically characterized by acute liver failure, development of hepatocellular carcinoma, renal and neurological problems, and consequently an extremely poor outcome. This review showed that the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in 1992 has revolutionized the outcome of TT1 patients, especially when started pre-clinically. If started early, NTBC can prevent liver failure, renal problems, and neurological attacks and decrease the risk for hepatocellular carcinoma. NTBC has been shown to be safe and well tolerated, although the long-term effectiveness of treatment with NTBC needs to be awaited. The high tyrosine concentrations caused by treatment with NTBC could result in ophthalmological and skin problems and requires life-long dietary restriction of tyrosine and its precursor phenylalanine, which could be strenuous to adhere to. In addition, neurocognitive problems have been reported since the introduction of NTBC, with hypothesized but as yet unproven pathophysiological mechanisms. Further research should be done to investigate the possible relationship between important clinical outcomes and blood concentrations of biochemical parameters such as phenylalanine, tyrosine, succinylacetone, and NTBC, and to develop clear guidelines for treatment and follow-up with reliable measurements. This all in order to ultimately improve the combined NTBC and dietary treatment and limit possible complications such as hepatocellular carcinoma development, neurocognitive problems, and impaired quality of life.

Safety and pharmacokinetics of the oral iron chelator SP-420 in ß-thalassemia.

Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent ß-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for Cmax and AUC0-τ over the dose range evaluated. The median tmax ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug.

Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats.

Nitisinone or 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione is a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme important in tyrosine catabolism. Today, nitisinone is successfully used to treat Hereditary Tyrosinaemia type 1, although its original expected role was as a herbicide. In laboratory animals, treatment with nitisinone leads to the elevation of plasma tyrosine (tyrosinaemia). In rats and Beagle dogs, repeat low-dose exposure to nitisinone leads to corneal opacities whilst similar studies in the mouse and Rhesus monkey showed no comparable toxicities or other treatment related findings. The differences in toxicological sensitivities have been related to the upper limit of the concentration of tyrosine that accumulates in plasma, which is driven by the amount/activity of tyrosine aminotransferase. A physiologically based, pharmacodynamics ordinary differential equation model of HPPD inhibition to bolus exposure of nitisinone in vivo is presented. Going beyond traditional approaches, asymptotic analysis is used to separate the different timescales of events involved in HPPD inhibition and tyrosinaemia. This analysis elucidates, in terms of the model parameters, a critical inhibitor concentration (at which tyrosine concentration starts to rise) and highlights the contribution of in vitro measured parameters to events in an in vivo system. Furthermore, using parameter-fitting methods, a systematically derived reduced model is shown to fit well to rat data, making explicit how the parameters are informed by such data. This model in combination with in vitro descriptors has potential as a surrogate for animal experimentation to predict tyrosinaemia, and further development can extend its application to other related medical scenarios.

Natural Killer Cells-Produced IFN-γ Improves Bone Marrow-Derived Hepatocytes Regeneration in Murine Liver Failure Model.

Bone-marrow transplantation (BMT) can repopulate the liver through BM-derived hepatocyte (BMDH) generation, although the underlying mechanism remains unclear. Using fumarylacetoacetate hydrolase-deficient (Fah(-/-)) mice as a liver-failure model, we confirmed that BMDHs were generated by fusion of BM-derived CD11b(+)F4/80(+)myelomonocytes with resident Fah(-/-) hepatocytes. Hepatic NK cells became activated during BMDH generation and were the major IFN-γ producers. Indeed, both NK cells and IFN-γ were required for BMDH generation since WT, but not NK-, IFN-γ-, or IFN-γR1-deficient BM transplantation successfully generated BMDHs and rescued survival in Fah(-/-) hosts. BM-derived myelomonocytes were determined to be the IFN-γ-responding cells. The IFN-γ-IFN-γR interaction contributed to the myelomonocyte-hepatocyte fusion process, as most of the CD11b(+) BMDHs in mixed BM chimeric Fah(-/-) hosts transplanted with a 1:1 ratio of CD45.1(+) WT and CD45.2(+) Ifngr1(-/-) BM cells were of CD45.1(+) WT origin. Confirming these findings in vitro, IFN-γ dose-dependently promoted the fusion of GFP(+) myelomonocytes with Fah(-/-) hepatocytes due to a direct effect on myelomonocytes; similar results were observed using activated NK cells. In conclusion, BMDH generation requires NK cells to facilitate myelomonocyte-hepatocyte fusion in an IFN-γ-dependent manner, providing new insights for treating severe liver failure.

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice.

BACKGROUND: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. METHODS: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. RESULTS: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 µM) and NTBC-levels in the therapeutic range (20-40 µM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). CONCLUSION: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

Corneal depositions in tyrosinaemia type I during treatment with Nitisinone.

We present a 17-year-old boy, diagnosed with tyrosinaemia type I at an age of 7 months, with new complaints of severe intermittent photophobia and burning eyes. His tyrosinaemia type I is treated with nitisinone and a protein-restricted diet. Dietary compliance is low since he entered puberty. His ocular complaints are attributable to subepithelial corneal deposits, resembling the common corneal phenotype of tyrosinaemia type II. Serum tyrosine levels were markedly elevated. Tyrosinaemia is a metabolic disease of tyrosine metabolism, subdivided into two types. Corneal deposits and photophobia are cardinal features of untreated tyrosinaemia type II, but not of type I. Novel treatment strategies (with nitisinone) for type I tyrosinaemia lead to a phenotype comparable with type II, including these corneal deposits. At follow-up visits his ocular complaints unfortunately remained unchanged, though he states his dietary compliance improved through the years.

Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec.

BACKGROUND: Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994. METHODS: We recorded the clinical course of 78 Québec HT1 patients born between 1984 and 2004. There were three groups: those who never received nitisinone (28 patients), those who were first treated after 1 month of age (26 patients) and those treated before 1 month (24 patients). Retrospective chart review was performed for events before 1994, when nitisinone treatment began, and prospective data collection thereafter. FINDINGS: No hospitalizations for acute complications of HT1 occurred during 5731 months of nitisinone treatment, versus 184 during 1312 months without treatment (p<0.001). Liver transplantation was performed in 20 non-nitisinone-treated patients (71%) at a median age of 26 months, versus 7 late-treated patients (26%, p<0.001), and no early-treated patient (p<0.001). No early-treated patient has developed detectable liver disease after more than 5 years. Ten deaths occurred in non-nitisinone treated patients versus two in treated patients (p<0.01). Both of the latter deaths were from complications of transplantation unrelated to HT1. One probable nitisinone-related event occurred, transient corneal crystals with photophobia. INTERPRETATION: Nitisinone treatment abolishes the acute complications of HT1. Some patients with established liver disease before nitisinone treatment eventually require hepatic transplantation. Patients who receive nitisinone treatment before 1 month had no detectable liver disease after more than 5 years.

Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC.

OBJECTIVE: The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations. METHODS: We here assess the neurocognitive development using standardized psychometric test batteries with respect to cognition, motor abilities and speech in nine early-treated patients with HT I under long-term NTBC treatment. RESULTS: High plasma tyrosine concentrations were frequently documented resulting in elevated 12-month median plasma tyrosine concentrations in seven out of nine patients. Plasma NTBC concentrations were generally in the lower therapeutic range. Five out of seven patients (71%) above 3 years of age had a total IQ score below the average. In addition, five out of seven patients above 3 years showed an inhomogenous test profile with significant differences between the different testing scales. Motor abilities were subnormal in four out of seven patients(57%). Cerebral MRI revealed no abnormalities. Logopedic evaluation in children at school age documented dysfunction or retardation in language development in all but one of the tested patients (80%), however, all but one patients had a migration background. CONCLUSIONS: A high number of patients performed below normal in the assessment of development, motor function and speech. We propose intellectual impairment as long-term complication in HT type I with elevated plasma tyrosine under NTBC treatment as observed in other hypertyrosinemias. These findings remain to be reproduced in greater patient numbers.

Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1.

BACKGROUND: Hereditary tyrosinaemia type 1 is a rare inherited metabolic condition, which leads to a fatal multisystemic disease in childhood. Since 1992, nitisinone - a compound developed from work on triketone herbicides - has become an effective pharmacological treatment by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase. OBJECTIVES: This review examines recent pharmacological and clinical literature on nitisinone, and assesses its impact as a pharmacological treatment for hereditary tyrosinaemia type 1. METHODS: English language literature from MedLine and EmBase for nitisinone was searched from 1990 to 2008 for all papers relevant to the use of nitisinone in hereditary tyrosinaemia type 1. CONCLUSIONS: Nitisinone can prevent the development of liver disease and significantly reduce the risk of developing hepatocellular carcinoma; however, vigorous surveillance for the development of HCC needs to be continued lifelong.

NTBC treatment in tyrosinaemia type I: long-term outcome in French patients.

We describe a retrospective study of long-term outcome of 46 patients treated and regularly followed in France with 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) for tyrosinaemia type I. Most had initial good response with normalization of liver function and metabolic parameters. Only one infant had no response to treatment and required liver transplantation. Among the 45 long-term treated patients, three underwent secondary liver transplantation: one for cirrhosis and two because of hepatocellular carcinoma. One of the latter died of transplantation complications, so that the overall survival rate was 97.5%. However, 17 of 45 showed persistent abnormal liver imaging (heterogeneous liver) and 6 had cirrhosis. Furthermore, 15 had persistently elevated levels of alpha-fetoprotein, highlighting the question of the persistent risk of carcinoma. Quality of life was usually good but compliance problems were frequent, mainly regarding the low phenylalanine-tyrosine diet. Few adverse effects were observed. A main concern was the high frequency of cognitive impairment causing schooling problems, which may be related to persistent chronic hypertyrosinaemia. In conclusion, this series confirms that NTBC treatment has clearly improved the vital prognosis and quality of life of tyrosinaemia type I patients but that many late complications persist. Long-term studies are necessary to determine whether this drug may prevent or only delay liver complications, andto survey the possible risks of the drug. A more restricted diet could be necessary to prevent the neurological impact of the disease.

Nitisinone: new drug. Type 1 tyrosinemia: an effective drug.

(1) Type 1 hereditary tyrosinemia is a rare disease due to an enzyme deficiency. It is associated with life-threatening liver disorders, starting during the very first months of life. If left untreated (other than with a diet low in tyrosine and phenylalanine), most patients die during childhood. Liver transplantation is currently the only treatment to have an effect on survival. (2) Nitisinone is the first drug to be approved in Europe for the treatment of type 1 hereditary tyrosinemia. (3) An international non comparative trial included 207 patients treated with nitisinone in addition to a diet low in tyrosine and phenylalanine. Children treated before the age of 6 months had a far better four-year survival rate than patients treated previously with dietary measures alone (94% versus 60%). The difference was even greater in the subgroups treated before the age of two months (88% versus 29%). When disease onset occurred after the age of 6 months, the ten-year survival rate was about 85% with nitisinone, compared to 60% with dietary measures alone. Only one patient had a neurological crisis during nitisinone therapy. Early nitisinone treatment also reduced the incidence of liver transplantation (13%, compared to 25% with dietary measures alone). (4) Nitisinone seems to have few adverse effects, mainly consisting of thrombocytopenia, leukopenia, cutaneous disorders, and various visual disorders (most of which resolve spontaneously). There may also be a risk of seizures. (5) In practice, nitisinone seems to provide a major benefit for children with type 1 tyrosinemia, provided they are diagnosed and treated during the first 6 months of life. Adverse effects appear to be acceptable but need to be monitored.

Nitisinone in the treatment of hereditary tyrosinaemia type 1.

Hereditary tyrosinaemia type 1 (HT-1) is a rare genetic disease caused by mutations in the gene for the enzyme fumarylacetoacetase. It usually presents with liver failure but can be manifest as chronic liver disease. Rarely, it may present with nonhepatic manifestations such as renal dysfunction, porphyria-like illness or cardiomyopathy. There is a high lifetime risk of developing hepatocellular carcinoma (HCC). Prior to the development of liver transplantation, most patients died in childhood.The clinical manifestations stem from the cytotoxicity of tyrosine metabolites accumulating proximal to the metabolic defect. Nitisinone acts on tyrosine metabolism upstream of the defect to prevent the production of these metabolites. Nitisinone is used in combination with a tyrosine- and phenylalanine-restricted diet. Nitisinone has transformed the natural history of tyrosinaemia. Liver failure is controlled in 90% of patients, those with chronic liver disease improve and nonhepatic manifestations are abolished. Nitisinone is well tolerated and has few adverse effects other than a predictable rise in plasma tyrosine levels. Nitisinone provides protection against HCC if it is started in infancy, but if commenced after the age of 2 years, a significant risk of HCC remains. Furthermore, where nitisinone is used pre-emptively, liver disease appears to be prevented, suggesting the importance of neonatal screening for tyrosinaemia where possible. Nitisinone is indicated for all children with HT-1, and liver transplantation is only indicated where nitisinone fails, or where the development of HCC is likely or suspected.

Response of metastatic recurrent neuroblastoma to nitisinone: a modulator of tyrosine metabolism.

Nitisinone blocks the tyrosine pathway and may be effective in treating neuroblastoma. A 33-month-old male with heavily treated metastatic, recurrent, N-MYC amplified neuroblastoma received nitsinone (0.8 mg/kg/day escalated to 5.0 mg/kg/day). Dramatic tumor regression and resolution of pain without toxicity were observed. At 10 weeks, the tumor progressed. Nitisinone, low dose cyclophosphamide and doxorubicin subsequently produced a very good partial response. At 18 months the disease progressed. The child succumbed 21 months after starting nitisinone. Nitisinone produced an increase in tyrosine and catecholamine metabolite (HVA, VMA, and metanephrines) levels. Nitisinone may be a promising agent in metastatic neuroblastoma.