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For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence suggesting its efficacy as a disease modifying agent. NTBC-induced hypertyrosinaemia has been associated with cognitive impairment and potentially sight-threatening keratopathy. In the context of a non-lethal condition (ie, AKU), these serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. We hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. In AKU mice tyrosine concentrations of tissue homogenates were measured before and after treatment with NTBC. In humans, pulse injection with l-[13 C9 ]tyrosine and l-[d8 ]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC. We found that NTBC increased tyrosine concentrations in murine tissues by five to nine folds. It also significantly increased the tyrosine pool size in humans (P

BACKGROUND: Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. METHODS: Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. RESULTS: Elevated tyrosine (813μmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3μmol/L, 274.8μmol/L and 144.3μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3μmol/L, 530.2μmol/L and 656.2μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (p=0.002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine

Introduction In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. Methods All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. Results NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p

Tyrosinemia type I is a recessive inborn error of metabolism caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme in the metabolism of tyrosine. This renders FAH nonfunctional and without treatment, toxic metabolites accumulate causing liver and kidney damage. Introduction of the drug NTBC in 2002 offered a treatment which inhibits an upstream enzyme, preventing the production of the toxic metabolites. There is now a long-term survival rate of greater than 90 % in children, but there are reports of lower cognitive function and IQ as well as schooling and behavioral problems in these children. We studied a mouse model of tyrosinemia type I to gain insight into the effects of tyrosinemia type I and treatment with NTBC on mouse learning, memory, and behavior. In the Barnes maze, visual and spatial cues can be used by mice to remember the location of a dark escape box. The primary time, distance, and strategy taken by the mice to locate the escape box is a measure of learning and memory. Our findings show that mice with tyrosinemia type I were slower to learn than wild-type mice treated with NTBC and made more mistakes, but were capable of learning and storing long-term memory. After learning the location of the target hole, mice with tyrosinemia type I respond differently to a change in location and were less flexible in learning the new target hole location. Our findings suggest that this slower learning and cognitive difference is caused by tyrosinemia type I and not by the treatment with NTBC.

Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU.

Alkaptonuria (AKU) is due to excessive homogentisic acid accumulation in body fluids due to lack of enzyme homogentisate dioxygenase leading in turn to varied clinical manifestations mainly by a process of conversion of HGA to a polymeric melanin-like pigment known as ochronosis. A potential treatment, a drug called nitisinone, to decrease formation of HGA is available. However, successful demonstration of its efficacy in modifying the natural history of AKU requires an effective quantitative assessment tool. We have described two potential tools that could be used to quantitate disease burden in AKU. One tool describes scoring the clinical features that includes clinical assessments, investigations and questionnaires in 15 patients with AKU. The second tool describes a scoring system that only includes items obtained from questionnaires used in 44 people with AKU. Statistical analyses were carried out on the two patient datasets to assess the AKU tools; these included the calculation of Chronbach's alpha, multidimensional scaling and simple linear regression analysis. The conclusion was that there was good evidence that the tools could be adopted as AKU assessment tools, but perhaps with further refinement before being used in the practical setting of a clinical trial.

A 22 year-old woman with tyrosinemia type I (HT1) married her first cousin who is heterozygous for the same FAH mutation for which the patient is homozygous. During her pregnancy she was treated with diet (prescribed tyrosine intake 300 mg/day), and nitisinone (60 mg/day). Median plasma tyrosine levels were 560 μmol/L (range: 375-838, n = 21) and nitisinone 51 μmol/L (range: 41-57, n = 3) during pregnancy. She gave birth to a clinically healthy girl affected with tyrosinemia type 1. Birth was normal (birth weight 2615 g) and the baby had normal liver function, normal plasma alpha-fetoprotein concentrations, low urinary excretion of phenolic acids and no detectable succinylacetone. At birth, the baby had hypertyrosinemia (860 μmol/L in blood cord) and nitisinone levels of 14 μmol/L. Following molecular confirmation of the diagnosis of HT1 specific treatment began on day 15 by which time she had detectable urinary succinylacetone.

Tyrosinaemia type I (TTI) is an inherited deficiency in the enzyme fumarylacetoacetate hydrolase and is frequently complicated by renal tubular dysfunction which may persist in some patients after hepatic transplantation. Nitisinone has revolutionized the management of TTI but its effect on renal tubular dysfunction has not been described in a large cohort of patients.To document the incidence and progression of renal tubular dysfunction in children with TTI treated with nitisinone at a single centre.Twenty-one patients with TTI from a single centre were treated with nitisinone for at least 12 months. Median age at first treatment was 17 weeks (range 1 week to 27 months). Nine patients (43%) presented in acute liver failure, seven (33%) had a chronic presentation and five (24%) were detected pre-clinically.A retrospective case analysis of plasma phosphate, urinary protein/creatinine ratio and tubular reabsorption of phosphate was performed for all patients as markers of tubular function. Renal ultrasounds were examined for evidence of nephrocalcinosis and where available, skeletal radiographs for rickets.All patients had biochemical evidence of renal tubular dysfunction at presentation. After nitisinone and dietary treatment were started, all three markers normalized within one year. Four children had clinical rickets at presentation (which improved), of whom one had nephrocalcinosis, which did not reverse on nitisinone. No child redeveloped tubular dysfunction after commencing nitisinone. All patients with TTI had evidence of tubular dysfunction at presentation and in all cases this resolved with nitisinone and dietary control.The tubulopathy associated with TTI is reversible.

Alkaptonuria (AKU, MIM#203500), an iconic disease, has the distinction of being the disorder leading to the creation and evolution of the inherited metabolic disease branch of medicine (Garrod 1908). Despite its distinctive status, and early recognition, progress in AKU has been gradual; there are still important gaps in our knowledge and understanding of the disease. Following the cloning of the AKU gene in 1996 (Fernandez-Canon et al 1996), La Du posed the question BAre we ready to try to cure alkaptonuria?^ (La Du 1998). That era in which many of the genes mutated in Mendelian diseases were first identified and cloned, was a time of hope that there would be rapid progress in curing genetic disorders. In fact La Du went on to say BAttempts to treat alkaptonuria by use of genetic engineering to replace the missing enzyme no doubt will be made soon^. This optimism has been tempered by the many obstacles still to be overcome in developing safe and effective gene therapies, however progress is ongoing and with the further development of seamless gene correction technologies La Du’s forecast will eventually come to pass. However, whilst we are awaiting a cure, research on AKU continues. Recent progress has brought us to the stage of posing another question BAre we near to an effective therapy for Alkaptonuria? A series of publications reported in this issue of the JIMD addresses some of these gaps in our knowledge of AKU. It is notable that three of these papers are focussed on the potential of nitisinone in treating the disease. Nitisinone, a phyodroxyphenyl pyruvate dioxygenase inhibitor, is not approved for AKU, although it has been used in a lifethreatening disease hereditary tyrosinaemia type 1 for more than 20 years with great success. Despite the inconclusive results of the first trials of nitisinone in AKU (Introne et al 2011), the drug has been shown to be completely effective in inhibiting ochronosis in AKUmice (Preston et al 2014) and at lowering circulating HGA in AKU patients (Ranganath et al 2014). The opportunity to modulate the tyrosine pathway by employing nitisinone brings with it considerations of the most appropriate time of life to begin treatment, both to minimise cost and to prevent unnecessary exposure to risk of toxicity. Keenan et al (2015) in this volume describe the experience of using nitisinone in a mouse analogue of the human disease, a much easier proposition to determine lifetime exposure to nitisinone, and show that nitisinone arrests but does not reverse ochronosis. This will be critical to help determine the most desirable time of life to begin taking nitisinone. Olsson et al (2015) describe the changes in tyrosine metabolism following nitisinone in a short-term study in AKU patients; clear efficacy has been demonstrated and in this short study no safety concerns were noted. However, safety concerns are paramount because nitisinone introduces a metabolic block proximal to the defect in AKU. Understanding the metabolic picture post-nitisinone is therefore necessary as this can allow the most appropriate dose of the drug to be used in AKU. The dose of nitisinone in AKU, needed to decrease This editorial is dedicated to Mr Robert Gregory, co-founder of the AKU Society. Born in Liverpool on 14th February 1949, died in Liverpool on 15th October 2014.

Alkaptonuria (AKU) is a rare inherited metabolic disorder of tyrosine metabolism that results from a defect in an enzyme called homogentisate 1,2-dioxygenase. The result of this is that homogentisic acid (HGA) accumulates in the body. HGA is central to the pathophysiology of this disease and the consequences observed; these include spondyloarthropathy, rupture of ligaments/muscle/tendons, valvular heart disease including aortic stenosis and renal stones. While AKU is considered to be a chronic progressive disorder, it is clear from published case reports that fatal acute metabolic complications can also occur. These include oxidative haemolysis and methaemoglobinaemia. The exact mechanisms underlying the latter are not clear, but it is proposed that disordered metabolism within the red blood cell is responsible for favouring a pro-oxidant environment that leads to the life threatening complications observed. Herein the role of red blood cell in maintaining the redox state of the body is reviewed in the context of AKU. In addition previously reported therapeutic strategies are discussed, specifically with respect to why reported treatments had little therapeutic effect. The potential use of nitisinone for the management of patients suffering from the acute metabolic decompensation in AKU is proposed as an alternative strategy.

NTBC has revolutionized the management of tyrosinaemia type I, although animal experiments have shown that long-term administration may produce corneal opacities analogous to those in tyrosinaemia type II. We have assessed the prevalence of ocular side-effects in 11 tyrosinaemia type I patients on NTBC attending the Birmingham Children's Hospital. Despite high plasma tyrosine concentrations in some patients, they did not experience symptoms or signs of ocular toxicity.

Alkaptonuria (AKU) is caused by deficiency of the enzyme homogentisate 1,2 dioxygenase. It results in an accumulation of homogentisate which oxidizes spontaneously to benzoquinone acetate, a highly oxidant compound, which polymerises to a melanin-like structure, in a process called ochronosis. Asymptomatic during childhood, this accumulation will lead from the second decade of life to a progressive and severe spondylo-arthopathy, associated with multisystem involvement: osteoporosis/fractures, stones (renal, prostatic, gall bladder, salivary glands), ruptures of tendons/muscle/ligaments, renal failure and aortic valve disease. The pathophysiological mechanisms of AKU remain poorly understood, but recent advances lead us to reconsider the treatment strategy in AKU patients. Besides the supporting therapies (pain killers, anti-inflammatory drugs, physiotherapy, joints replacements and others), specific therapies have been considered (anti-oxidant, low protein diet, nitisinone), but clinical studies have failed to prove efficiency on the rheumatological lesions of the disease. Here we propose a treatment strategy for children and adults with AKU, based on a review of the latest findings on AKU and lessons from other aminoacipathies, especially tyrosinemias.

Hereditary tyrosinaemia type I (HTT-I ; McKusick 27670) is an autosomal recessive disorder caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (EC 3.7.1.2). The main symptoms include hepatic and renal dysfunction and sometimes neurological crisis. It is characterized by increased plasma levels of tyrosine and methionine, and excessive urinary excretion of p-hydroxyphenylacids, tyrosine, succinylacetone and δ-aminolevulinic acid. The presence of succinylacetone in biological samples is diagnostic for this condition (Mitchell et al 1995). Most patients show a partial response to dietary restriction of phenylalanine and tyrosine. Further improvement might be obtained by liver transplantation, although production of toxic metabolites may persist (Laine et al 1995). Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione (NTBC) prevents the formation of the potentially toxic products. Treatment with NTBC has been shown to be superior to dietary treatment and liver transplantation (Lindstedt et al 1992). The disturbance of porphyrin metabolism in HTT-I is ascribed to the role of succinylacetone as an inhibitor of the δ-aminolevulinic acid dehydratase, the activity of which is greatly reduced in liver and erythrocytes. Coproporphyrin (CP) is by far the most common porphyrin excreted in secondary alteration in the haem biosynthetic pathway. CP has four isomers, but only CP I and CP III isomers are detected in urine. The aim of the present study was to determine whether other places along the haem pathway than δ-aminolevulinic acid dehydratase might be affected in HTT-I and to assess the influence of treatment with NTBC on porphyrin synthesis. We studied the coproporphyrinuria of a female patient who is undergoing NTBC treatment.

Neurological crises do not occur in patients with tyrosinaemia type I treated with NTBC. We report an 8 month-old boy with severe neurological crisis after interruption of NTBC treatment including progressive ascending polyneuropathy and diaphragmatic paralysis, arterial hypertension, respiratory distress requiring mechanical ventilation who later also developed impaired liver function and tubulopathy. After re-introduction of NTBC the patient slowly regained normal neurological functions and recovered completely.

In tyrosinaemia type I (McKusick 276700), fatal liver disease results either because of liver failure during infancy or early childhood or because of development of hepatocellular carcinoma during childhood or adolescence. This is caused by toxic metabolites which accumulate because of deficiency of fumarylacetoacetase, the last enzyme in the tyrosine catabolic pathway. NTBC is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase and has been shown to efficiently prevent tyrosine degradation, and production of succinylacetone, in patients with tyrosinaemia. Since the first trial of NTBC treatment for tyrosinaemia type I in 1991, over 220 patients have been treated by the drug using a protocol which includes regular follow-up with reports of clinical and laboratory investigations to the study centre in Gothenburg, where additional analysis of critical variables is done on regularly collected samples. The course of the disease in patients with acute tyrosinaemia has changed dramatically. Only 10% of the patients have not clinically responded to NTBC treatment. In half of these patients, successful liver transplantation has been performed which has further reduced the mortality rate during infancy to 5%. The international NTBC study has now been going for 5 years and data have emerged that indicate a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. There are now 101 patients aged 2-8 years who have started NTBC treatment before 2 years of age, and no cancer has developed after 2 years of age among these patients. However, there is no safe age with respect to occurrence of liver cancer, which has been recognized at diagnosis at 1 year of age in one patient and after a few months of treatment in an infant who was given NTBC at 5 months of age.

Tyrosinaemia type 1 (HT1) is a rare disorder of tyrosine metabolism leading to liver failure and hepatocellular carcinoma. Treatment previously consisted of dietary restriction and orthotopic liver transplantation (OLT) but was transformed by the introduction of nitisinone in 1992. We describe the impact of nitisinone on the outcome and need for OLT in a single centre.A retrospective analysis was performed of patients treated for HT1 at Birmingham Children's Hospital from 1989-2009.Thirty eight patients were treated during the study period. Prior to 1992 6/7 (85.7 %) underwent OLT compared to 7/31 (22.6 %) after 1992 (p = 0.004) when nitisinone treatment was available. Furthermore, nitisinone-treated patients proceeding to OLT started treatment at a median age of 428 (86-821) days compared to 52 (2-990) days in those who did not (p = 0.004). Pre-OLT calculated glomerular filtration rate (cGFR) was similar in both groups but nitisinone prevented early decline after OLT (pre-nitisinone median 99.8 to 45.8 ml/min/1.73 m2, p = 0.02 versus nitisinone-treated group median 104.3 to 89.9 ml/min/1.73 m2, p = 0.5). Urinary protein:creatinine ratio (PCR) fell post-OLT to within the normal range for those treated with nitisinone but remained elevated in those not treated with nitisinone. Tubular reabsorption of phosphate (TRP) was normal or near normal in both groups pre-OLT and post-OLT. Hypertension was commoner and more severe in those not treated with nitisinone.Nitisinone reduces the need for OLT particularly when started early. For those progressing to OLT the use of prior nitisinone therapy results in a preservation of their subsequent renal function.

Tyrosinaemia type 1 (HT1) is a rare disorder leading to accumulation of toxic metabolites such as succinylacetone (SA) and a high risk of hepatocellular carcinoma. Children with HT1 traditionally required liver transplantation (OLT) and while the need for this has been reduced by the introduction of nitisinone some still require OLT. SA inhibits the enzyme porphobilinogen (PBG) synthase and its activity can be used as a marker of active SA. Elevated urinary SA post OLT has been reported previously. This study describes a novel finding of elevated plasma SA following OLT for HT1. A retrospective analysis was performed of patients treated for HT1 at our institution from 1989-2010. Thirteen patients had an OLT for HT1. In patients who received nitisinone prior to OLT, mean urinary and plasma SA were elevated prior to treatment but normalised by the time of OLT (p ≤ 0.01). Mean PBG synthase activity increased from 0.032 to 0.99 nkat/gHb (ref range 0.58-1.25) at the time of OLT (p

NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione) is the mainstay of treatment in tyrosinemia type 1 (HT 1). The current recommendation is to divide the total daily dose of NTBC into two doses. We monitored the plasma NTBC concentrations in a series of seven patients who were changed from multiple divided doses to a single daily dose of NTBC. Two additional patients were started on a single daily dose of NTBC after the diagnosis of HT 1 was established. In three patients, NTBC kinetics were performed over 6 and 24 hours, respectively. The use of multiple divided doses or a single daily dose did not significantly affect plasma NTBC concentrations or the mean daily dose needed to attain therapeutic plasma NTBC concentrations. Moreover, kinetic studies demonstrated that plasma NTBC concentrations were completely stable over a period of 24 hours with a single dose regimen, as expected given the known NTBC plasma half life of 54 hours. Although these preliminary results need to be confirmed in more patients, our findings show that administration of NTBC in a single daily dose may be as effective as a multiple-dose regimen in reaching therapeutic plasma NTBC concentrations and suppressing succinylacetone formation in patients with HT 1. In fact, single dose treatment may increase patients' compliance with the drug treatment and improve metabolic control.

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.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.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.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.

Tyrosinaemia type I (TTI) is an inherited multisystemic disorder of tyrosine metabolism. In addition to hepatic and renal involvement, cardiomyopathy is an important clinical manifestation. Objective: To evaluate the incidence and outcome of cardiomyopathy in TTI. Subjects and methods: A retrospective study was performed of 20 consecutive children with TTI (12 male, 8 female) referred to a single centre between 1986 and 2002. All were initially treated with standard dietary therapy and, since 1992, with nitisinone. The indications for orthotopic liver transplantation (LT) changed during the study. Serial echocardiography was undertaken in all subjects. Results: 9/20 (45%) children had an acute hepatic presentation. Five (25%) received dietary treatment followed by LT, and 14 (70%) were treated with nitisinone at presentation. 6/20 (30%) had cardiomyopathy at initial assessment, with interventricular septal hypertrophy being the commonest finding (5/6). Cardiomyopathy was significantly less common in those treated initially with nitisinone. After a median follow-up of 3.6 (0.45–13.5) years, 5/6 (83%) had complete resolution of cardiomyopathy and 1/6 showed significant improvement. No child with a normal initial echocardiography subsequently developed cardiomyopathy. Conclusion: Cardiomyopathy is a common manifestation of TTI and it has a favourable long-term outcome. Children initially treated with nitisinone are less likely to develop this complication.

We report the case of a child who developed severe obstructive hypertrophic cardiomyopathy revealing hereditary tyrosinaemia type I, who was successfully treated with NTBC. The mechanisms underlying the association are discussed.

NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.

Hereditary tyrosinaemia type I (fumarylacetoacetase deficiency, McKusick 276700) is characterized by progressive liver and proximal renal tubular disease. Renal disease with development of disabling rickets may be the main clinical problem in some patients, and glomerular involvement leading to renal failure has been described (Kvittingen et al 1991). The parenchymal damage is believed to be due to accumulation of maleylacetoacetate and its metabolites, which may be formed in both liver and kidney, where 4-hydroxyphenyl-pyruvate dioxygenase is expressed (for a recent review see Mitchell et al 1995). The renal tubular dysfunction improves in most patients on treatment with a diet restricted in phenylalanine and tyrosine, but in some patients the response is poor and management of the kidney disease becomes the main clinical concern. Further improvement might be obtained by liver transplantation, although production of toxic metabolites and decreased renal function may persist (Tuchman et al 1987 ; Shoemaker et al 1992 ; Laine et al 1995). Formation of the potentially toxic products can be prevented by inhibition of 4-hydroxy-phenylpyruvate dioxygenase by NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (Lindstedt et al 1992). Treatment with NTBC has been shown to be superior to dietary treatment alone in short-standing renal tubular disease (Lindstedt et al 1992). We now present the effect of NTBC treatment on long-standing kidney tubular dysfunction in two cases with severe rickets as the dominating clinical feature. In these patients, treatment with NTBC resulted in normalized or almost normalized tubular function and in significant improvement of the rachitis over a period of 2 years.