Use of nitisinone in patients with alkaptonuria
Introduction
Alkaptonuria, an autosomal recessive disorder with an incidence of approximately 1 in a million live births [1], [2], results from mutations in the gene HGD, which codes for an essential hepatic enzyme, homogentisate 1,2-dioxygenase [3], [4], [5]. This enzyme in the tyrosine degradation pathway converts homogentisic acid (HGA) to maleylacetoacetic acid; the enzyme deficiency results in massive urinary excretion of HGA and accumulation of this compound in the tissue of affected individuals. The urine turns dark upon standing due to oxidation of HGA to benzoquinones, which form melanin-like polymers. These compounds bind preferentially to connective tissue, causing ochronosis, with its darkening of ear cartilage, sclera, and bone, its arthritis and joint destruction, and its cardiac valve disease [1], [2]. Treatment with vitamin C to enhance HGA degradation has not proven helpful [6]. Dietary therapy restricting phenylalanine and tyrosine is difficult to maintain and has had no demonstrable efficacy in improving the symptoms of alkaptonuria, although long-term controlled clinical trials have not been performed [1].
Another possible approach to reducing HGA production involves the administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione, or nitisinone [7], a compound that inhibits 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), the enzyme that produces HGA (Fig. 1). Nitisinone is currently approved by the Food and Drug Administration for the treatment of tyrosinemia type I, a rare disease caused by deficiency of fumarylacetoacetate hydrolase and resulting in liver failure, hepatocellular carcinoma, and renal tubular dysfunction in infants and children [8]. Nitisinone decreases the formation of toxic, oxidizing metabolites in tyrosinemia type I children and constitutes the treatment of choice for this otherwise fatal disease [9], [10]. In 2 patients with alkaptonuria, low-dose nitisinone reduced the urinary excretion of HGA by 69% or more [2]. However, plasma tyrosine concentrations rose significantly, creating a risk of corneal crystal formation, corneal epithelial damage, and photophobia.
In the present study, we examined the safety of administering nitisinone at a dosage adequate to reduce urinary HGA excretion, typically 2 to 9 g/day in alkaptonuria patients [1], [2], to 0.5 g/day or less. We hypothesized that such a significant reduction, if maintained for years, might retard the progression of joint disease in alkaptonuria patients. We also incorporated a week of reduced dietary protein into our protocol, to determine whether restriction of tyrosine and phenylalanine would lower plasma tyrosine levels in nitisinone-treated patients. These investigations were performed to provide a basis for future clinical trials of nitisinone for the joint disease of alkaptonuria.
Section snippets
Patients
Nine patients (4 male and 5 female; aged 35-69 years) were enrolled in an open-label clinical protocol to investigate the safety and HGA-reducing efficacy of oral nitisinone in alkaptonuria patients. The protocol was approved by the Institutional Review Board of the National Human Genome Research Institute, and all patients gave written informed consent. All patients were previously enrolled in a clinical protocol to study the natural history of alkaptonuria. The diagnosis of alkaptonuria in
Patients
At baseline, the 9 patients under investigation had elevated urinary HGA excretion, normal plasma tyrosine concentrations, and variable joint and aortic valve involvement (Table 1). All patients continued to take medications prescribed for preexisting conditions in addition to nitisinone. Of the 9 patients, 4 exited the study before its conclusion, after 71, 5, 5, and 32 days, and 5 completed the entire study, including the final week of a low-protein diet (Fig. 2). All patients required the
Discussion
The devastating clinical repercussions of alkaptonuria include the destruction of vertebral disks, major joints, and cardiac valves, the formation of renal and prostatic stones, and calcification of the coronary arteries [1]. Progressive degenerative arthritis (ochronosis) of the spine and large appendicular joints often leads to progressive impairments, such as kyphosis, arthritis, and loss of motion often requiring joint replacement. The combination of aging and these impairments frequently
Acknowledgments
Nitisinone was kindly provided by Swedish Orphan International AB. The authors deeply appreciate the dedication and attention to this protocol offered by the study's medical monitor, Dr. Fred Gill. We also acknowledge the clinical staff on the 8West inpatient unit of the Warren G. Magnuson Clinical Center, National Institutes of Health, for the excellent care they provided our patients. We would like to thank Dr Rhona Jack of Children's Hospital, Seattle, Wash, for her kind assistance in
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Alkaptonuria – Past, present and future
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2022, Revue de Medecine InterneIdentification of key residues determining the binding specificity of human 4-hydroxyphenylpyruvate dioxygenase
2020, European Journal of Pharmaceutical SciencesEfficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial
2020, The Lancet Diabetes and EndocrinologyCitation Excerpt :Because activity of 4-hydroxyphenylpyruvate dioxygenase leads to formation of homogentisic acid (appendix p 10), nitisinone was hypothesised in the late 1990s to be a potential treatment for alkaptonuria.10 Following initial research of nitisinone for treatment of alkaptonuria,1,11 a 3-year clinical trial was done by the US National Institutes of Health (NIH),12 comparing a nitisinone-treated patient group receiving a 2-mg daily dose (n=20) with an untreated patient group (n=20). Although nitisinone showed excellent biochemical efficacy, the trial was inconclusive.12
Fatal acute haemolysis and methaemoglobinaemia in a man with renal failure and Alkaptonuria – Is nitisinone the solution?
2020, Molecular Genetics and Metabolism ReportsCitation Excerpt :Recently there has been a major focus on the use of nitisinone for the treatment of AKU. This competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is highly efficacious in reducing HGA [5–10] and has been shown to slow the progress of ochronosis and its consequences [11]. Less commonly observed in AKU are the life threatening acute complications – haemolysis and or methaemoglobinaemia (MetHb).
Alkaptonuria
2024, Nature Reviews Disease Primers