Background Alkaptonuria (AKU) is present from birth, yet clinical effects are considered to appear later in life. Morbidity of AKU, considered irreversible, is secondary to ochronosis. Age of ochronosis onset is not clearly known. Nitisinone profoundly lowers homogentisic acid (HGA), the metabolic defect in AKU. Nitisinone also arrests ochronosis and slows progression of AKU. However, tyrosinaemia post-nitisinone has been associated with corneal keratopathy, rash and cognitive impairment in HT 1. The optimal time to start nitisinone in AKU is unknown.
Methods In an open, cross-sectional, single-site study, 32 patients with AKU were to be recruited. The primary outcome was presence of ochronosis in an ear biopsy. Secondary outcomes included analysis of photographs of eyes/ears, serum/urine HGA, markers of tissue damage/inflammation/oxidation, MRI imaging, gait, quality of life and Alkaptonuria Severity Score Index (qAKUSSI).
Results Thirty patients, with mean age (SD) 38 (14) years, were recruited. Percentage pigmentation within ear biopsies increased with age. Ear pigmentation was detected in a 20-year-old woman implying ochronosis can start in patients before the age of 20. Gait and qAKUSSI were outside the normal range in all the patients with AKU.
Conclusions Ochronosis can be present before age 20 years.
- natural history
- ear cartilage biopsy
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Contributors TC, JAG and LR: design of the study and manuscript writing. NS and NR: grant writing and conduct of the study. JAG and JPD: analysis of ear biopsy and qualitative scoring of eye ochronosis. JAG and LFT: quantitative analysis of eye ochronosis. EW: ear biopsies. AnM and AH: assay of HGA. AlM: scoring of MRI. GB, HRS and MR: gait analysis. FG: bone and cartilage biomarkers. DB, DG, RR, AS: inflammatory markers. MK: quality of life assessments. ST: analysis of questionnaires. AH: HGA assays. TC and EEP: statistical analysis. TC: first drafting and revision of the manuscript. NR was involved in obtaining grant funding and writing of the manuscript. All authors contributed to analysis of the data, edited the manuscript and approved the final version.
Funding This work was supported by European Commission Seventh Framework Programme funding granted in 2012 (DevelopAKUre, project no. 304985). Additional support was received from the UK National AKU Centre, funded by NHS England Highly Specialized Services.
Disclaimer The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. The funding source was not involved in the study design, collection, analysis and interpretation of data, the writing of the manuscript or in the decision to submit the manuscript for publication.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval UK Research Ethics Committee (REC) no. 15/NW/0749. Integrated Research Application System (IRAS) Project ID: 180968.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.
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