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Subclinical Ochronosis Features in Alkaptonuria: a Cross-Sectional Study

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Subclinical Ochronosis Features in Alkaptonuria: a Cross-Sectional Study BMJ Innov: first published as 10.1136/bmjinnov-2018-000324 on 28 September 2019. Downloaded from DIAGNOSTICS ORIGINAL RESEARCH Subclinical ochronosis features in alkaptonuria: a cross-sectional study Trevor Cox,1 Eftychia Eirini Psarelli,2 Sophie Taylor,3 Hannah Rose Shepherd ,4 Mark Robinson,5 Gabor Barton ,5 Alpesh Mistry,6 Federica Genovese ,7 Daniela Braconi ,8 Daniela Giustarini,9 Ranieri Rossi,9 Annalisa Santucci ,8 Milad Khedr ,10 Andrew Hughes,11 Anna Milan,11 Leah Frances Taylor ,12 Elizabeth West,13 Nicolas Sireau,14 Jane Patricia Dillon ,15 Nicholas Rhodes ,16 James Anthony Gallagher,15 Lakshminarayan Ranganath17 ► Additional material is ABSTRACT characterised by high circulating homo- published online only. To view Background Alkaptonuria (AKU) is present gentisic acid (HGA).1 The frequency please visit the journal online (http:// dx. doi. org/ 10. 1136/ from birth, yet clinical effects are considered to of AKU is around 1 in 250 000 to 1 in bmjinnov- 2018- 000324). appear later in life. Morbidity of AKU, considered 1 000 000 in most populations worldwide. irreversible, is secondary to ochronosis. Age of Deposition of HGA in connective tissue For numbered affiliations see 2 end of article. ochronosis onset is not clearly known. Nitisinone as pigment in AKU is termed ochronosis. profoundly lowers homogentisic acid (HGA), Debilitating manifestations of AKU are Correspondence to the metabolic defect in AKU. Nitisinone also due to ochronosis including premature Dr Lakshminarayan Ranganath, arrests ochronosis and slows progression of AKU. arthritis, cardiac valve disease, fractures, Clinical Biochemistry and 3 Metabolic Medicine, Royal However, tyrosinaemia post-nitisinone has been and muscle and tendon ruptures. Despite Liverpool University Hospital, associated with corneal keratopathy, rash and the presence of the defect from birth, Liverpool L7 8XP, UK; lr ang@ cognitive impairment in HT 1. The optimal time apart from dark urine, and sometimes liv. ac. uk to start nitisinone in AKU is unknown. renal stones, there are few osteoarticular 4 http://innovations.bmj.com/ Received 10 October 2018 Methods In an open, cross-sectional, single- symptoms until around age 25 years. Revised 4 April 2019 site study, 32 patients with AKU were to be A recent study has shown that nitisinone, Accepted 11 August 2019 recruited. The primary outcome was presence of an inhibitor of p-hydroxyphenylpyruvate ochronosis in an ear biopsy. Secondary outcomes dioxygenase (EC:1.13.11.27), is effective included analysis of photographs of eyes/ears, in AKU.5–8 Nitisinone decreases circu- serum/urine HGA, markers of tissue damage/ lating HGA, and inhibits ochronosis in inflammation/oxidation, MRI imaging, gait, AKU mice and humans, slowing progres- quality of life and Alkaptonuria Severity Score sion of human AKU, but is expensive.9 10 Index (qAKUSSI). It is an imperfect treatment producing Results Thirty patients, with mean age (SD) a different metabolic block, character- on September 29, 2019 by guest. Protected copyright. 38 (14) years, were recruited. Percentage ised by tyrosinaemia; toxic consequences pigmentation within ear biopsies increased such as corneal keratopathy, eczema-like with age. Ear pigmentation was detected in a skin rash and cognitive impairment can 20-year-old woman implying ochronosis can ensue.11 start in patients before the age of 20. Gait and AKU is not fully reversible and would qAKUSSI were outside the normal range in all benefit from early treatment. Mouse © Author(s) (or their the patients with AKU. studies show that nitisinone can prevent employer(s)) 2019. No Conclusions Ochronosis can be present before onset of ochronosis when started soon commercial re-use. See rights age 20 years. after birth and arrest ochronosis when and permissions. Published by 9 10 BMJ. started later. Mouse studies revealed ochronotic pigment laid down in knee To cite: Cox T, Psarelli EE, 9 Taylor S, et al. BMJ Innov joints as early as 15 weeks. These find- Epub ahead of print: BACKGROUND ings highlight the concern that subclinical [please include Day Month Alkaptonuria (AKU) (OMIM #203500) ochronosis could be damaging connec- Year]. doi:10.1136/ is a rare genetic deficiency of homo- tive tissues early in life. Starting nitis- bmjinnov-2018-000324 gentisate dioxygenase (EC:1.13.11.5), inone later in AKU is expected to result Cox T, et al. BMJ Innov 2019;0:1–10. doi:10.1136/bmjinnov-2018-000324 1 BMJ Innov: first published as 10.1136/bmjinnov-2018-000324 on 28 September 2019. Downloaded from DIAGNOSTICS in residual disease as AKU is irreversible.4 Identifying Disease questionnaires were used to calculate when ochronosis takes hold in AKU is important, as the modified questionnaire-based qAKUSSI (online this information would allow optimal use of nitisinone supplementary table S4).19 in terms of when to begin treatment. Fasting blood samples and 24-hour urine samples The SOFIA (Subclinical Ochronosis Features In were collected to measure metabolites and biomarkers Alkaptonuria) study was designed to identify the of inflammation, cartilage, bone and tissue. Serum and earliest age when ochronosis, microscopic and macro- urine HGA were quantitated by liquid chromatography– scopic, can be detected in patients and at what age it tandem mass spectrometry methods.20 21 Serum amyloid might be appropriate to begin nitisinone treatment. A (SAA) was analysed using a commercial assay. Quan- titative determination of serum protein thiols and S-thi- 22 METHODS olated proteins was carried out. Serum protein thiols Patients were measured by colorimetric reaction with 5,5′-dith- Patients with AKU, verified by elevated HGA levels, iobis-(2-nitrobenzoic acid).23 S-Thiolated proteins and at least 16 years old were eligible for inclusion. A were measured.24 Protein Thiolation Index (PTI) was non-AKU control group was also selected. None of the calculated as the molar ratio between total S-thiolated patients in this study received nitisinone at the time of proteins (RSSP, where RS is cysteine (CySSP), cysteinyl- participation. glycine (CyGlySSP), homocysteine (HcySSP), γ-glutam- ylcysteine (γGluCySSP) and glutathione (GSSP)) and the Study design concentration of protein thiols.25 SOFIA was an open, cross-sectional, single-site (Royal The rate of connective tissue remodelling was Liverpool University Hospital) study; 32 patients with analysed by the measurement in serum and urine of AKU were to be recruited (two males, two females biomarkers of collagen and other extracellular matrix in each age interval: 16–20, 21–25, 26–30, 31–35, protein formation and degradation using competitive 36–40, 41–45, 46–50, over 50) covering the age and sandwich ELISAs developed at Nordic Bioscience spread of non-ochronotic and ochronotic groups. (online supplementary table S5). The assays were run The primary outcome was the amount of ochronosis according to the standard procedure detailed in the measured in ear biopsies. The secondary outcomes references in online supplementary table S5. were visible ochronosis quantification in eyes and QoL was assessed using HAQ, SF-36 and Knee ears, MRI examination, deviation in gait, modified injury and Osteoarthritis Outcome Score (KOOS) qAKUSSI (questionnaire Alkaptonuria Severity Score questionnaires.26–28 Index), circulating and urine HGA, inflammation, cartilage damage, bone and other tissue biomarkers, Statistical analysis and quality of life (QoL). Multiple linear and LOESS regression were the main http://innovations.bmj.com/ analyses used. Outcome variables were plotted against Assessments age and regression analyses carried out. Comparisons Ear cartilage: a 4 mm diameter, 1–2 mm thick biopsy was with controls were made as appropriate. All analyses taken from the conchal bowl of the ear and stored using were conducted using SAS V.9.3 and R V.3.3.2. a standardised protocol. Ochronosis was measured by percentage of light absorbance in microscope photo- graphs (non-ochronotic tissue=0, completely ochro- RESULTS notic tissue=100) (see online supplementary material). Thirty patients with AKU (15 male, 15 female) were recruited. Mean age was 39 years for males and 37 Standardised photographs of eyes and ears were on September 29, 2019 by guest. Protected copyright. years for females; mean body mass index (BMI) was scored for ochronosis: for eyes using qualitative and 2 2 quantitative systems; for ears, a qualitative system 25 kg/m for males and 23 kg/m for females (online (online supplementary figure S1, tables S1, S2). supplementary tables S6–S8). Modified Pfirrmann Grading System and Spondy- loarthritis Research Consortium of Canada (SPARCC) Ear cartilage biopsy, eye and ear photographs scores of the spine and whole-organ MRI scores Ear biopsies from 28 samples were processed. Figure 1 (WORMS) of the knee were calculated (online supple- shows ear and eye ochronosis measured by biopsy and mentary figures S2–S5, table S3).12–14 Institutional photographs plotted against age, together with regres- MRI protocols were followed. sion lines. Figure 1A shows percentage of pigmenta- 3D gait analysis was performed for 36 patients with tion of whole-ear biopsy. Fitted regression lines were: AKU (29 from SOFIA, 7 from the UK National Alkap- % ear pigmentation=−23.5+1.43×age for males tonuria Centre) and for a control group of 10 volun- (age: p=0.001, gender: p=0.742, R2=0.39). teers free from gait problems.15 16 Mean deviation of % ear pigmentation=−26.9+1.43×age for females. AKU gait from normality (MDP ) was calculated Age was statistically significant
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