Nutritional interventions for patients with alkaptonuria: A minireview (original) (raw)
Related papers
Annals of clinical biochemistry, 2017
Background Alkaptonuria (AKU) is a rare, debilitating autosomal recessive disorder affecting tyrosine metabolism. Deficiency of homogentisate 1,2-dioxygenase leads to increased homogentisic acid (HGA) which is deposited as ochronotic pigment. Clinical sequelae include severe early onset osteoarthritis, increased renal and prostate stone formation and cardiac complications. Treatment has been largely based on analgaesia and arthroplasty. The National AKU Centre in Liverpool has been using 2mg nitisinone (NTBC) off-license for all patients in the United Kingdom with AKU and monitoring the tyrosine metabolite profiles. Methods Patients with confirmed AKU are commenced on 2mg dose (alternative days) of NTBC for three months with daily dose thereafter. Metabolite measurement by LC-MS/MS is performed at baseline, day 4, three-months, six-months and one-year post-commencing nitisinone. Thereafter, monitoring and clinical assessments are performed annually. Results Urine HGA concentration d...
Annals of the rheumatic diseases, 2014
Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mm...
Journal of inherited metabolic disease, 2015
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 cl...
JIMD reports, 2015
Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported. To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients. Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment. Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/h·kg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a ...
Metabolites
Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic pathway during KP is not understood. The objective of this study is to assess potential differences in the PHE/TYR pathway during KP and the influence of gender in NIT-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24 h urine collected from patients treated with NIT during a 4-year randomized study in NIT vs. no-treatment controls (SONIA 2; Suitability Of Nitisinone In Alkaptonuria 2; EudraCT no. 2013-001633-41) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), TYR, PHE, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine in the NIT-group. All statistical analyses were post hoc. Keratopathy occurred in 10 out of 69 AKU patients, eight of them male. Thirty-five sampling poin...
Osteoarticular cells tolerate short-term exposure to nitisinone-implications in alkaptonuria
Clinical rheumatology, 2015
Alkaptonuria (AKU) is a rare genetic disease resulting in severe, rapidly progressing, early onset multi-joint osteoarthropathy. A potential therapy, nitisinone, is being trialled that reduces the causative agent; homogentisic acid (HGA) and in a murine model has shown to prevent ochronosis. Little is currently known about the effect nitisinone has on osteoarticular cells; these cells suffer most from the presence of HGA and its polymeric derivatives. This led us to investigate nitisinone's effect on chondrocytes and osteoblast-like cells in an in vitro model. Human C20/A4 immortalized chondrocytes, and osteosarcoma cells MG63 cultured in DMEM, as previously described. Confluent cells were then plated into 24-well plates at 4 × 10(4) cells per well in varying concentrations of nitisinone. Cells were cultured for 7 days with medium changes every third day. Trypan blue assay was used to determine viability and the effect of nitisinone concentration on cells. Statistical analysis w...
2015
Lakshminarayan R Ranganath, FRCP(Edin), FRCPath1, Anna M Milan PhD, FRCPath1, Andrew T Hughes MPhil1, John J Dutton FIBMS1, Richard Fitzgerald MRCP2, Michael C Briggs FRCS3, Helen Bygott BSc1, Eftychia E Psarelli MSc4, Trevor F Cox PhD4, James A Gallagher PhD5, Jonathan C Jarvis PhD6, Christa van Kan7, Anthony K Hall MBBS, BSc, AKC8, Dinny Laan MSc7, Birgitta Olsson MSc9, Johan Szamosi MSc9, Mattias Rudebeck MSc, BMedSc9, Torbjörn Kullenberg MD9, Arvid Cronlund MSc9, Lennart Svensson PhD9, Carin Junestrand DDS9, Hana Ayoob BA10, Oliver G Timmis BA10, Nicolas Sireau PhD10, Kim-Hanh Le Quan Sang11, Federica Genovese PhD12, Daniela Braconi PhD13, Annalisa Santucci PhD13, Martina Nemethova MSc14, Andrea Zatkova PhD14, Judith McCaffrey MSc, Peter Christensen PhD, Gordon Ross PhD, Richard Imrich MD, PhD17, Jozef Rovensky17.