Search

Alkaptonuria is a rare genetic disorder resulting in abnormality of tyrosine metabolism. It is one of the Garrod’s tetrad of ‘inborn errors of metabolism’ proposed to have Mendelian recessive inheritance. The disorder is characterised by deposition of homogentisic acid leading to ochronosis and ochronotic osteoarthropathy; however, blackish discoloration of urine is the only childhood manifestation. Other manifestations present only after third decade. A 13-year-old boy presented to paediatric nephrology clinic with blackish discolouration of urine since infancy. Examination revealed bluish black discolouration of bilateral sclera and ear cartilage; however, he had no symptoms of ochronotic osteoarthropathy. Genetic test pointed towards alkaptonuria. Currently, he is on regular follow-up and is being treated with vitamin C to delay the progression of the disease. Early diagnosis with appropriate intervention delays the onset of complications and preserves the quality of life of the patient.

Alkaptonuria-related rapidly destructive arthropathy of the hip joint has not been reported in detail with both imaging and histopathological findings in the literature. We, herein, presented the case of a 79-year-old male patient who suddenly started experiencing marked right hip pain. Radiography showed that the femoral head was spherical; however, after 3 months, approximately half of the femoral head was destroyed despite there being almost no change in the acetabulum. Radiographs of the spine also showed fusion between multiple vertebrae. Significant osteoporosis was observed on roentgenography, together with decreased bone density. Urinary gas chromatography-mass spectrometry analysis revealed that a large amount of homogentisic acid was excreted. During total hip arthroplasty, gray and muddy contents were observed in the joint capsule, and the surface of the destroyed femoral head was black. Histopathologically, granulomatous foci containing fragmented bone and cartilage debris were found in the bone marrow space of the joint surface, and the cartilage tissue was pigmented brownish black. The patient was subsequently diagnosed with ochronotic hip joint destruction. The present case report is the first to demonstrate rapidly destructive coxopathy associated with alkaptonuria using both imaging and histopathological findings. These findings clearly show that severe hip joint destruction defined as rapidly destructive hip arthropathy can occur in a very short time period for patients with alkaptonuria.

A large alkaptonuria (AKU) cohort was studied to better characterise the poorly understood phenotype of aortic stenosis of rare disease AKU.Eighty-one patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Nine only attended once. Fifty-one attended more than once and received nitisinone 2 mg daily. Twenty-one attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, standard transthoracic echocardiography, as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of aortic stenosis and aortic valve replacement were 22.2 and 6.2% in the current group. Aortic maximum velocity (Vmax) was directly related to varying degrees to age (R = 0.58, p 0.001), systolic blood pressure (R = 0.32, p 0.05), serum homogentisic acid (sHGA) (R = 0.28, p 0.05), ochronosis scores (R = 0.72, p 0.001), and alkaptonuria severity score index (AKUSSI) (R = 0.58, p 0.001) on linear regression analysis. Age and ochronosis scores were significantly related to Vmax on multiple regression analysis (p 0.005). Nitisinone decreased sHGA, 24-h urine HGA (uHGAAortic valve disease is highly prevalent in this NAC cohort, and strongly associated with ochronosis and disease severity. Nitisinone decreases ochronosis and had a similar significant effect on Vmax.

Background We present this report of a new ophthalmic finding in a patient with ochronosis. Case presentation An 85-year-old Caucasian male patient with bilateral dark temporal and nasal pigmentation of conjunctiva and sclera was referred to our hospital owing to low visual acuity. On biomicroscopic examination, bilateral horizontal Descemet’s membrane folds were observed. Corneal tomography revealed irregular and asymmetric “against-the-rule” astigmatism in both eyes. Anterior segment optical coherence tomography demonstrated numerous central Descemet’s without edema or other corneal structure alterations. Conclusion This is the first report of Descemet’s membrane folds in ochronosis. These corneal findings suggest that the accumulation of homogentisic acid in the sclera leads to thickening and stiffness of this region. These alterations could remarkably decrease visual acuity owing to topographic corneal curvature alterations, especially in elderly patients.

Objectives Alkaptonuria is a rare autosomal recessive genetic disorder resulting from the deficiency of homogentisate 1,2 dioxygenase (HGD), the third enzyme in the tyrosine degradation pathway. Homogentisic acid produced in excess oxidizes into ochronotic pigment polymer. Accumulation of this pigment in various tissues leads to systemic disease. Methods Clinical, laboratory, molecular findings and treatment characteristics of 35 patients followed up in Ege University Pediatric Nutrition, and Metabolism Department with the diagnosis of alkaptonuria were evaluated retrospectively. Results Twenty-four males (68.57%) and 11 females (31.42%) with a confirmed diagnosis of alkaptonuria from 32 different families were included in the study. We identified 11 different genetic variants; six of these were novel. c.1033C>T, c.676G>A, c.664G>A, c.731_734del, c.1009G>T, c.859_862delins ATAC were not previously reported in the literature. 24 (68.57%) patients only adhered to a low-protein diet in our study group. Seven (20%) patients initiated a low protein diet and NTBC therapy. Mean urinary HGA decreased by 88.7% with nitisinone. No statistical changes were detected in urinary HGA excretion with the low protein diet group. Conclusions In our study, alkaptonuria patients were diagnosed at different ages, from infancy to adulthood, and progressed with other systemic involvement in the follow-up. Since the initial period is asymptomatic, giving potentially effective treatment from an early age is under discussion. Raising disease awareness is very important in reducing disease mortality and morbidity rates.

This study aimed to determine the patient characteristics and clinical presentation of Alkaptonuria cases reported by the Biochemical Genetics Lab. An observational study was conducted at the Biochemical Genetics Lab. Alkaptonuria patients were diagnosed based on the homogentisic acid peak in urine and their demographics and clinical data collected from to 2013 to 2019. Clinical history related to joint diseases, ochronotic presentation, and urine darkening on standing was collected. During 7 years, 21 Alkaptonuria cases were reported from BGL; mean age 19.4 ± 24.5 years (range 0.2–66 years) and male to female ratio of 2:1. Of the total, only 9 were adults (mean age, 44 ± 12 years). Most adult patients had musculoskeletal involvement, with joint pain (n = 9) and ochronotic pigmentation (n = 6), whereas all patients presented with a history of urine darkening on standing (21/21 cases). The high prevalence of musculoskeletal involvement observed in patients with albuminuria is likely to be missed by physicians unless specifically tested for in such cases.

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs due to a deficiency in functional levels of the enzyme homogentisate 1,2-dioxygenase (HGD), required for the breakdown of HGA, because of mutations in the HGD gene. Over time, HGA accumulation causes the formation of the ochronotic pigment, a dark deposit that leads to tissue degeneration and organ malfunction. Such behaviour can be observed also in vitro for HGA solutions or HGA-containing biofluids (e.g. urine from AKU patients) upon alkalinisation, although a comparison at the molecular level between the laboratory and the physiological conditions is lacking. Indeed, independently from the conditions, such process is usually explained with the formation of 1,4-benzoquinone acetic acid (BQA) as the product of HGA chemical oxidation, mostly based on structural similarity between HGA and hydroquinone that is known to be oxidized to the corresponding para-benzoquinone. To test such correlation, a comprehensive, comparative investigation on HGA and BQA chemical behaviours was carried out by a combined approach of spectroscopic techniques (UV spectrometry, Nuclear Magnetic Resonance, Electron Paramagnetic Resonance, Dynamic Light Scattering) under acid/base titration both in solution and in biofluids. New insights on the process leading from HGA to ochronotic pigment have been obtained, spotting out the central role of radical species as intermediates not reported so far. Such evidence opens the way for molecular investigation of HGA fate in cells and tissue aiming to find new targets for Alkaptonuria therapy.

A 52-year-old men suffered from osteoarthritis of the knee. During knee replacement surgery, the remaining cartilage appeared black. This discoloration and early degeneration of the cartilage is characteristic for the metabolic disorder alkaptonuria in which homogentisic acid accumulates in the body.

A large alkaptonuria (AKU) cohort was studied to better characterize the poorly understood spondyloarthropathy of rare disease AKU. Eighty-seven patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, 18F Positron emission tomography computerised tomography (PETCT), as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of ochronosis, as well as pain, PETCT and combined pain and PETCT scores, was greatly increased at 90.5%, 85.7%, 100%, and 100%, respectively. Joint pain scores were greatest in proximal joints in upper and lower limbs. PETCT joint scores were higher in proximal joints in upper limb but higher in distal joints in the lower limb. Spine pain scores were highest in lumbar, followed by cervical, thoracic, and cervical regions at 77.4%, 59.5%, 46.4%, and 25%, respectively. PETCT spine scores were highest in thoracic followed by lumbar, cervical, and sacroiliac regions at 74.4%, 70.7%, 64.6%, and 47.8% respectively; ochronosis associated closely with spondyloarthropathy scores (R = .65; P

Background. Metabolic disorder alkaptonuria is an autosomal recessive disorder caused by mutations in the HGD gene, and a deficiency HGD enzyme activity results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. Methods. We clinically evaluated 18 alkaptonuria patients (age range, 3 to 60 years) from four unrelated families. Furthermore, 11 out of 18 alkaptonuria patients and 7 unaffected members were enrolled for molecular investigations by utilizing Sanger sequencing to identify variants of the 14 exons of HGD gene. Results. We found that the seven patients from the 4 unrelated families carried a recurrent pathogenic missense variant (c.365C>T, p. Ala122Val) in exon 6 of HGD gene. The variant was fully segregated with the disease in affected family members while the other unaffected family members were heterozygous carriers for this variant. Additionally, the clinical features were fully predicted with alkaptonuria disorder. Conclusion. In this study, we confirmed that the most common variants in Jordanian AKU patients was c.365C>T, p. Ala122Val in exon 6 of HGD gene. Additionally, we correlated the clinical and genetic features of AKU patients at various ages (3-60 years).

Arthroplasty in the spondyloarthropathy (SPOND) of alkaptonuria (AKU) in incompletely characterised. The aim was to improve the understanding of arthroplasty in AKU through a study of patients attending the National Alkaptonuria Centre (NAC). Eighty-seven patients attended the NAC between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments including questionnaire analysis eliciting details of arthroplasty and other surgical treatments for SPOND, 18 FPETCT and CT densitometry at the neck of hip and lumbar spine, as well as photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Photographs were scored to derive ochronosis scores. Blood and urine samples were collected for chemical analyses. The prevalence of arthroplasty was 36.8%, similar in males and females, occurring especially in the knees, hips and shoulders. Multiple arthroplasties were found in 29 patients (33.3%) in this cohort. Incident arthroplasty was 6.5% in the nitisinone group and 7.1% in the no-nitisinone group. Incident arthroplasty was 11.3% in the group with baseline arthroplasty and 3.51% in the group without. A strong association of arthroplasty with SPOND (R = 0.5; P <

Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis), stiffening the tissue. This process over many years leads to a painful and severe osteoarthropathy, particularly affecting the cartilage of the spine and large weight bearing joints. Evidence in human AKU tissue suggests that pigment binds to collagen. The exposed collagen hypothesis suggests that collagen is initially protected from ochronosis, and that ageing and mechanical loading causes loss of protective molecules, allowing pigment binding. Schmorl’s staining has previously demonstrated knee joint ochronosis in AKU mice. This study documents more comprehensively the anatomical distribution of ochronosis in two AKU mouse models (BALB/c Hgd−/−, Hgd tm1a−/−), using Schmorl’s staining. Progression of knee joint pigmentation with age in the two AKU mouse models was comparable. Within the knee, hip, shoulder, elbow and wrist joints, pigmentation was associated with chondrons of calcified cartilage. Pigmented chondrons were identified in calcified endplates of intervertebral discs and the calcified knee joint meniscus, suggesting that calcified tissues are more susceptible to pigmentation. There were significantly more pigmented chondrons in lumbar versus tail intervertebral disc endplates (p = 0.002) and clusters of pigmented chondrons were observed at the insertions of ligaments and tendons. These observations suggest that loading/strain may be associated with increased pigmentation but needs further experimental investigation. The calcified cartilage may be the first joint tissue to acquire matrix damage, most likely to collagen, through normal ageing and physiological loading, as it is the first to become susceptible to pigmentation.

Alkaptonuria is an inherited metabolic disease caused by a genetic deficiency of homogentisate 1,2-dioxygenase and characterized by dark-brown connective tissue related to the deposition of oxidized homogentisic acid. Pigment deposition is also observed in the cardiovascular system, such as in the coronary arteries, cardiac valves, and aorta. Because aortic stenosis may develop secondary to pigment deposition-related calcification at the aortic valve, aortic valve replacement may be necessary for severe aortic valve disease. We report the case of a 75 year-old man with alkaptonuria-associated severe aortic stenosis who was successfully treated with minimally invasive endoscopic aortic valve replacement via right anterior minithoracotomy. The tricuspid aortic valve was severely calcified and both the valve and the aortic intima were ochronotic. No perioperative complications were observed and the postoperative course was uneventful.

Background Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. Methods SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). Findings Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p

Alkaptonuria is a rare autosomal-recessive disorder that produces accumulation of homogentisic acid in body fluids. The accumulation in collagen tissues, mainly in the joint cartilage, produces ochronotic arthropathy. We report two clinical cases of one brother and sister with alkaptonuria and ochronotic arthropathy diagnosed in old age. In the first case, the patient is diagnosed by musculoskeletal involvement with long-term low back pain with other associated manifestations that made this pathology suspected. In the second case, the patient comes due to osteoporosis and other associated fractures and with the family history and the rest of the clinic, the appropriate complementary tests were performed and the diagnosis is established. It is unknown if there is consanguinity in these patients between parents or ancestors. It is an infrequent pathology that is often diagnosed intraoperatively. Despite the poor efficacy of medical treatment, it would be advisable to make an early diagnosis to avoid accumulation of the pigment and accelerated joint destruction and deposition in other locations. Owing to its prevalence, it is difficult to find a significant number of patients to search for new treatments that are intended to correct the enzyme deficit and not only to modify the elimination.

Alkaptonuria is a rare metabolic disorder, and only a few case reports of total joint arthroplasty (TJA) for ochronotic arthropathy are described in the literature. We aim to analyse the functional and radiological outcomes of TJA in patients with ochronotic arthropathy. We retrospectively collected the data of twenty-seven TJA in sixteen patients with ochronotic arthropathy from April 2007 to December 2017. We assessed the functional outcome through pre- and post-operative modified Harris hip score (HHS) and knee society score (KSS). The hip radiographs were analysed for migration and radiolucent zones, and the knee radiographs were assessed using knee society roentgenographic evaluation and scoring system. The mean follow-up was 39.4 months (12–132 months). Two patients died before the final follow-up. There was a statistically significant improvement in mean HHS from 17.8 preoperatively to 78 at the final follow-up (p

Alkaptonuria is an autosomal recessive disease caused by the accumulation of homogentisic acid (HGA) products in the ligament, cartilage, skin and various organs due to the lack of HGA oxidase enzyme. In this article, we present a 61-year-old male patient operated on due to a diagnosis of spontaneous Achilles tendon rupture and diagnosed as alkaptonuria due to the intraoperative color of the tissues and the subsequent examinations. We also reviewed alkaptonuria and its accompanying pathologies in light of the literature.

Alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase (HGD) deficiency. Circulating homogentisic acid (HGA) is elevated and deposits in connective tissues as ochronotic pigment. In this study, we aimed to define developmental and adult HGD tissue expression and determine the location and amount of gene activity required to lower circulating HGA and rescue the alkaptonuria phenotype.We generated an alkaptonuria mouse model using a knockout-first design for the disruption of the HGD gene. Hgd tm1a −/− mice showed elevated HGA and ochronosis in adulthood. LacZ staining driven by the endogenous HGD promoter was localised to only liver parenchymal cells and kidney proximal tubules in adulthood, commencing at E12.5 and E15.5 respectively. Following removal of the gene trap cassette to obtain a normal mouse with a floxed 6th HGD exon, a double transgenic was then created with Mx1-Cre which conditionally deleted HGD in liver in a dose dependent manner. 20% of HGD mRNA remaining in liver did not rescue the disease, suggesting that we need more than 20% of liver HGD to correct the disease in gene therapy.Kidney HGD activity which remained intact reduced urinary HGA, most likely by increased absorption, but did not reduce plasma HGA nor did it prevent ochronosis. In addition, downstream metabolites of exogenous 13C6-HGA, were detected in heterozygous plasma, revealing that hepatocytes take up and metabolise HGA.This novel alkaptonuria mouse model demonstrated the importance of targeting liver for therapeutic intervention, supported by our observation that hepatocytes take up and metabolise HGA.

A 39-year-old man presented with progressive gait disturbance and urinary incontinence. Medical history disclosed nephrolithiasis, dark urine, osteopenia and osteoarthrosis for 15 years. Examination disclosed crural spastic paraparesis with sensory level at T1 and hyperpigmentation of the sclerae (figure). Neuroimaging studies disclosed cervical spondylotic myelopathy and several discs prolapses. Homogentisic acid levels by HPLC were high in 24-hour urine.

Alkaptonuria (AKU) is an inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase (HGD) as a result of a defect in the HGD gene. HGD enzyme deficiency results in accumulation of homogentisic acid (HGA) in the body, which in turn leads to multisystemic clinical symptoms. The present study aimed to investigate the presenting symptoms, age at diagnosis, and clinical and genetic characteristics of AKU patients followed-up in different centers in Turkey. In this cross-sectional, multicenter, descriptive study, medical records of 66 AKU patients were retrospectively evaluated. Patients’ data regarding demographic, clinical and genetic characteristics were recorded. HGD database ( http://hgddatabase.cvtisr.sk/ ) was used to identify HGD gene variants. Of the patients, 37 (56.1%) presented with isolated dark urine and 29 (43.9%) were diagnosed based on the clinical symptoms or family screening. One of these patients was on follow-up for 2 years due to Parkinsonism and was diagnosed with AKU on further analyses. Signs of ochronosis such as joint pain, low back pain and renal stones developed in childhood in 7 patients. Eight patients were diagnosed with depression via psychiatric evaluation. There were 14 (21.2%) patients operated on for ochronosis. The most frequent mutation observed in the patients was c.175delA, which was followed by c.674G > A and c.1007-2A > T mutations. Four novel mutations (c.189G > A, c.549+1G > T, c.1188+1G > A, and c.334 T > G) were identified in the patients included in the study. In addition to the known signs such as dark urine and skin pigmentation, symptoms involving different systems such as neurological findings and depression can also be encountered in AKU patients. The presence of a change in urine color needs to be questioned in patients presenting with different symptoms such as arthralgia/arthritis, renal stones or low-back pain, particularly in childhood, when skin ochronosis is not pronounced, and further examination should be performed.

Alkaptonuria (AKU) is a hereditary disorder that results from altered structure and function of homogentisate 1,2 dioxygenase (HGD). This enzyme, predominantly produced by liver and kidney, is responsible for the breakdown of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway. A deficient HGD activity causes HGA levels to rise systemically. The disease is clinically characterized by homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and joint arthropathy. Additional manifestations are cardiovascular abnormalities, renal, urethral and prostate calculi and scleral and ear involvement. While the radiological aspect of ochronotic spondyloarthropathy is known, there are only few data regarding an exhaustive ultrastructural and histologic study of different tissues in AKU. Moreover, an in-depth analysis of tissues from patients of different ages, having varied symptoms, is currently lacking. A complete microscopic and ultrastructural analysis of different AKU tissues, coming from six differently aged patients, is here presented thus significantly contributing to a more comprehensive knowledge of this ultra-rare pathology.

In this study the authors report the first example of spinal pseudarthrosis in a patient with ochronosis, and they describe the application of posterior-only 360° surgery as an alternative approach to combined anterior-posterior surgery in the management of pseudarthrosis of an ankylosed spine, regardless of its etiology. Spinal involvement in ochronosis produces loss of flexibility and ankylosis of thoracic and lumbar segments. Pseudarthrosis is a serious complication of the diseases that present with ankylosis of the spine. However, its occurrence in ochronotic spine has not been reported previously. Evaluation of progressive paraparesis in a 68-year-old man with ochronosis revealed pseudarthrosis at the T11–12 level. Circumferential dural sac decompression, debridement of the disc space, interbody fusion, and screw-rod fixation were all done via a posterior-only approach. Postoperatively the patient exhibited a marked recovery in terms of pain and neurological status. At the 3-month follow-up, he was able to walk independently. Ochronosis should be included in the etiology of pseudarthrosis. With aggravation of back pain and the appearance of neurological deficits in an already stable patient with any ankylosing disease, pseudarthrosis should be suspected. Furthermore, single-stage, 360°, posterior-only surgery may obviate the need for single-stage or staged anterior-posterior surgical intervention in patients with pseudarthrosis of the thoracic and lumbar spine.

Background The practice of skin lightening has been reported from North America, Europe, Asia, and Africa. In literature, some prevalence rates exceed 50%, and both sexes are involved. Common agents used include hydroquinone, mercury, corticosteroids, and caustic agents. The agents are easily accessible and affordable with very little regulation. Cutaneous and systemic side effects occur but do not appear to be a deterrent, as the notion of light skin as a surrogate for beauty is strong. In Ghana, anecdotal reports of high bleaching rates among certain urban communities resulted in a study supported by the Food and Drugs Authority to determine various facets of this practice. Methods A cross-sectional study among adults in selected urban fishing communities of Accra was undertaken. Consecutive cases were enrolled after written informed consent. A questionnaire was administered, followed by physical examination and clinical photographs. Descriptive statistics were used to analyze the data. Results Of the 555 participants from the three communities, prevalence was 279 (50.3%). Duration of use ranged from 2 months to 17 years. Approximately 212 (76%) used more than one product, and 231 (82%) used agents on their face and body. Dermatological features were hypopigmentation 270 (96.8%), other color changes including ochronosis 241 (86.4%), changes in consistency 141 (50.3%), striae 157 (56.3%), and infections 42 (15.1%). Conclusions The prevalence of skin bleaching was 50.3% in these communities, which is high considering the adverse effects from the practice. We recommend regulation of products by enforcing the law, more education, and a population prevalence study.

Summary Objective Alkaptonuria (AKU) is a rare, inherited disorder of tyrosine metabolism, where patients are unable to breakdown homogentisic acid (HGA), which increases systemically over time. It presents with a clinical triad of features; HGA in urine, ochronosis of collagenous tissues, and the subsequent ochronotic arthritis of these tissues. In recent years the advance in the understanding of the disease and the potential treatment of the disorder looks promising with the data on the efficacy of nitisinone. However, there are limited methods for the detection and monitoring of ochronosis in vivo, or for treatment monitoring. The study aim was to test the hypothesis that Raman spectra would identify a distinct chemical fingerprint for the non-ochronotic, compared to ochronotic cartilage. Design Ochronotic and non-ochronotic cartilage from human hips and ears were analysed using Raman spectroscopy. Results Non-ochronotic cartilage spectra were similar and reproducible and typical of normal articular cartilage. Conversely, the ochronotic cartilage samples were highly fluorescent and displayed limited or no discernible Raman peaks in the spectra, in stark contrast to their non-ochronotic pairs. Interestingly, a novel peak was observed associated with the polymer of HGA in the ochronotic cartilage that was confirmed by analysis of pigment derived from synthetic HGA. Conclusion This technique reveals novel data on the chemical differences in ochronotic compared with non-ochronotic cartilage, these differences are detectable by a technique that is already generating in vivo data and demonstrates the first possible procedure to monitor the progression of ochronosis in tissues of patients with AKU.

This article presents the case of a 53-year-old male patient born in Sri Lanka, who presented to the outpatient unit with the suspicion of empyema of the knee joint. Within the framework of knee arthroscopy, the diagnosis of ochronosis was made and later confirmed by histopathological biopsy. The alkaptonuria is caused by a homogentisate 1,2-dioxygenase deficiency and leads to an accumulation of homogentisic acid, a degradation product of tyrosine. This leads to the characteristic appearance of ochronosis with bluish-black deposits in the tissue (e.g. in connective tissue, sclera and ear cartilage) and a black coloration of the urine.

The clinical effects of alkaptonuria (AKU) are delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. Data from AKU patients from four studies were merged to form a single AKU group. A control group of non-AKU subjects was generated by merging data from two non-AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. There were 225 AKU patients in the AKU group and 52 in the non-AKU control group. Circulating HGA increased with age (P

Purpose To report a case of alkaptonuria (AKU) in a patient with bilateral conjunctival and scleral black colorization who was diagnosed with glaucoma thereafter. Methods This is a single case report. Results A 67-year-old male patient with bilateral black colorization of conjunctiva and sclera was referred to our hospital. In the biomicroscopic examination, globular dark pigmentation was observed in the conjunctiva, sclera, and limbal cornea. The patient was diagnosed with a nuclear cataract in both eyes. He also had gray skin pigmentation at his nose and paranasal area. Corneal topography examination revealed irregular astigmatism. Intraocular pressure values were 29 and 31 mm Hg, in the right and left eye, respectively, with Goldmann applanation tonometry. The diagnosis of AKU was made after pathologic assessment of conjunctival biopsy by the internal medicine department. Conclusions AKU is characterized by the accumulation of homogentisic acid in the connective tissues of many organs including the eye. Patients should be carefully examined in ophthalmology clinics in order to not miss systemic diagnoses. It should be kept in mind that AKU may cause iridocorneal angle pigmentation, which leads to glaucoma, and patients should be treated with proper medication when presenting with elevated intraocular pressure values.

Purpose To present a case series of patients with corneal and scleral changes associated with the use of skin-lightening creams. This is the first report of corneal changes with these widely available creams. Methods Three patients of West African origin presented with strikingly similar skin, corneal, and scleral changes and were found to have all been using skin-lightening creams containing hydroquinone. Histopathology was obtained for 1 patient. Results Three patients were referred to the corneal clinics of 2 hospitals with corneal changes and a history of blurred vision for 1 to 3 years. There was a 60-year-old woman from Nigeria and a 68-year-old woman and a 73-year-old man both from Ghana. All 3 had been using skin-lightening lotions containing hydroquinone on their faces for between 3 and 15 years and had black-blue facial pigmentation of exogenous ochronosis, a recognized complication of these creams. Their corneas all had horizontal striae radiating across the posterior corneas with scleral thinning and plaques. Linear brown epithelial pigmentation was observed within the lower third of the corneas. Biopsy of the sclera in 1 patient showed ochronosis. Conclusions We present previously unreported eye changes associated with the use of skin-lightening creams containing hydroquinone, with a triad of signs: posterior corneal striae radiating from 3 o'clock to 9 o'clock, thinning and plaques in the sclera, and a normal endothelial cell count. Similar pathological changes are seen in exogenous ochronosis, a recognized skin complication of hydroquinone, are seen in the sclera.

Ochronotic degenerative arthropathy occurs in patients with alkaptonuria. Alkaptonuria disorder is an extremely rare disease characterized by black pigmentation of various tissues (e.g., cartilage and connective tissue). Ochronotic arthropathy is a disabling disease that primarily affects the large joints. Like other metabolic diseases that involve the musculoskeletal system, care must be taken with regard to the quality of the affected bones, tendons and ligaments, and therefore the stability and survival of joint prosthesis. The following is a report of a 66-year-old man affected by several musculoskeletal manifestations of alkaptonuria with severe joints disruption, who was successfully treated with total left hip and total right knee replacements. Surgical, anesthesiological and postoperative management of these patients may require more vigilance due to the associated comorbidities of this disorder.

Ochronosis (alkaptonuria) is an autosomal recessive inherited metabolic disease that causes pigmentation by accumulation of homogenous acid in the connective tissue. The most important causes of morbidity are ochronotic arthropathy and cardiovascular involvement seen in fourth and sixth decades, respectively. In this case report, we report the prevalence of F-18-FDG PET/BT findings in a 48-year-old man with ochronosis who underwent F-18-FDG PET/BT imaging for the evaluation of mediastinal lymphadenopathy.

Alkaptonuria is a rare metabolic disease caused by deficiency of homogentisic acid oxidase and characterized by bluish-black discoloration of cartilages and skin (ochronosis). Defective production of this enzyme results in the accumulation of homogentisic acid (HGA), a tyrosine degradation product, in the bloodstream. Accumulation of HGA and its metabolites in tissues causes ochronosis. The word ochronosis refers to the dark bluish-black discoloration of connective tissues including the sclera, cornea, auricular cartilage, heart valves, articular cartilage, tendons, and ligaments. Neurogenic claudication resulting from focal hypertrophy of the ligamentum flavum in the lumbar spine due to ochronotic deposits has only been previously reported once in the literature. In this article, we present a 71-year-old male patient with alkaptonuria-associated degenerative L3–L4–L5 stenosis, diagnosed after lumbar decompressive laminectomy.

Alkaptonuria is a rare disorder of amino acid metabolism that causes premature large joint spine arthropathy and cardiac disease. We describe a case of aortic stenosis and coronary artery disease associated with ochronosis in a 76-year-old man who underwent aortic valve replacement and coronary artery bypass grafting. Although the ochronosis was extensive, no ochronosis was seen in the internal thoracic artery which used for coronary artery bypass grafting. Ochronosis with alkaptonuria is considered to accelerate the atherosclerotic process, so the internal thoracic artery may ensure a better long-term outcome. Long-term follow-up may allow better understanding of this rare condition.

Background:Alkaptonuria is an inborn error of metabolism. It is a multisystem disease with characteristic ENT manifestations. This paper reports, for the first time, the ENT findings in a cohort of alkaptonuria patients.Method:Patients attending the National Centre for Alkaptonuria (Royal Liverpool and Broadgreen University Hospitals NHS Trust) underwent a full ENT assessment.Results:Eighteen of the 20 patients (90 per cent) had an ENT sign or symptom. These included discolouration of the pinna, cerumen, nasal septum and pharynx.Conclusion:Discolouration of cerumen may occur before 30 years of age and may therefore be an important early clinical sign. Further audiological assessment of patients is needed to clarify if an association exists between alkaptonuria and hearing loss. Alkaptonuria is a condition that could present to the otolaryngologist. Successful early diagnosis and referral to a specialist centre is essential so that patients can be offered disease-modifying therapy.

Study design Case report and literature review. Objective To characterize the rare presentation of myelopathy occurring secondary to alkaptonuria and to evaluate the available evidence regarding its treatment. Summary of background data Alkaptonuria is an autosomal recessive genetic condition with an estimated incidence of 1 in 250,000 to 1 in 1,000,000 people. Mutation of the enzyme homogentisate 1,2-dioxygenase leads to the production of high levels of homogentisic acid, with subsequent deposition in ligaments, cartilage, and menisci. Involvement of the spine is termed "ochronotic spondyloarthropathy," of which myelopathy is an uncommon presentation. Methods We present the case of a 57-year-old man with alkaptonuria-associated myelopathy, who underwent surgical decompression. Ten additional cases were identified in the literature by a systematic search of PubMed and Google Scholar. Results In a patient presenting with myelopathy, alkaptonuria may be suspected because of medical history, family history, symptoms (including darkened urine, pigmented ear cartilage, and sclera), or radiographic changes, such as multilevel disc collapse, progressive wafer-like disc calcification, extensive osteophyte formation, and spinal deformity. The diagnosis can be confirmed by urine homogentisic acid testing. Of the 11 patients presented here or identified in the literature, 2 were treated nonoperatively, 8 were treated with decompressive spinal surgery, and treatment of the myelopathy was not discussed for 1 patient. In all cases in which outcomes were reported, substantial improvement in the patient's condition was seen. Conclusion Alkaptonuria is a rare cause of myelopathy, but one that clinicians should understand. Although no disease-modifying treatment currently exists for alkaptonuria, the use of symptomatic treatments and, particularly, surgical decompression is recommended to address myelopathy if it develops. Level of evidence 4.

QUESTION: Does Nitisinone prevent the clinical progression of the Alkaptonuria? FINDINGS: In this observational study on 39 patients, 2 mg of daily nitisinone inhibited ochronosis and significantly slowed the progression of AKU over a three-year period. MEANING: Nitisinone is a beneficial therapy in Alkaptonuria. BACKGROUND: Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU). METHODS: Thirty-nine AKU patients attended the National AKU Centre (NAC) in Liverpool for assessments and treatment. Nitisinone was commenced at V1 or baseline. Thirty nine, 34 and 22 AKU patients completed 1, 2 and 3 years of monitoring respectively (V2, V3 and V4) in the VAR group. Seventeen patients also attended a pre-baseline visit (V0) in the VAR group. Within the 39 patients, a subgroup of the same ten patients attended V0, V1, V2, V3 and V4 visits constituting the SAME Group. Severity of AKU was assessed by calculation of the AKU Severity Score Index (AKUSSI) allowing comparison between the pre-nitisinone and the nitisinone treatment phases. RESULTS: The ALL (sum of clinical, joint and spine AKUSSI features) AKUSSI rate of change of scores/patient/month, in the SAME group, was significantly lower at two (0.32 ± 0.19) and three (0.15 ± 0.13) years post-nitisinone when compared to pre-nitisinone (0.65 ± 0.15) (p

Anterior cervical osteophytes are commonly associated with degenerative spine in elderly people. The complications that arise due to the mechanical compression of cervical osteophytes are dysphagia, dysphonia and dyspnoea. The usual causes are osteoarthritis, ankylosing spondylitis and diffuse idiopathic spinal hyperostosis (DISH). Other causes are trauma, acromegaly, ochronosis, fluorosis and hypoparathyroidism.1 Surgical resection of osteophytes results in excellent relief of symptoms, but patients have a tendency for recurrence of osteophytes.2 We present here a case of dysphagia and dysphonia due to osteophyte recurrence in a postsurgical case of DISH. A 63-year-old man was admitted with progressive dysphagia, hoarseness of voice and neck pain for 3 months. His history began with neck and right arm pain 2 years back for which he consulted a spine surgeon, where he was diagnosed with C5 – C6 herniated cervical disc causing root …

Ochronosis is a late developing complication of alkaptonuria, a black brownish pigment in the fibrous and cartilaginous tissues. Although most previous studies reported alkaptonuria and back pain due to ochronosis, thoracic myelopathy is an extremely rare complication. In this report, a paraparetic patient who has ochronotic spondiloarthropathy with the presence of HLA B27 antigen is described. He had low back and leg pain and morning stiffness for 5 yrs. Last year, these were followed by tingling, numbness, and weakness the in lower extremities and he was operated on with preliminary diagnosis of prolapsed disc herniation and cord compression. Surgery is suggested for disc herniations related to ochronotic spondyloarthropathy if it is necessary or neurologic symptoms are present. However, his pain and weakness have partially recovered after the operation. After medical and physical treatment, he showed clinically significant improvements. This case report demonstrates that the management of ochronosis needs a multidisciplinary approach with physiologic, neurologic, and psychologic effects and proper treatment may significantly improve functional outcomes in these patients.

Not Available

Objective. Alkaptonuria (AKU) is a rare autosomal recessive disease resulting from a single enzyme deficiency in tyrosine metabolism. As a result, homogentisic acid cannot be metabolized, causing systemic increases. Over time, homogentisic acid polymerizes and deposits in collagenous tissues, leading to ochronosis. Typically, this occurs in joint cartilages, leading to an early onset, rapidly progressing osteoarthropathy. The aim of this study was to examine tissue turnover in cartilage affected by ochronosis and its role in disease initiation and progression. Methods. With informed patient consent, hip and knee cartilages were obtained at surgery for arthropathy due to AKU (n = 6; 2 knees/4 hips) and OA (n = 12; 5 knees/7 hips); healthy non-arthritic (non-OA n = 6; 1 knee/5 hips) cartilages were obtained as waste from trauma surgery. We measured cartilage concentrations (normalized to dry weight) of racemized aspartate, GAG, COMP and deamidated COMP (D-COMP). Unpaired AKU, OA and non-OA samples were compared by non-parametric Mann–Whitney U test. Results. Despite more extractable total protein being obtained from AKU cartilage than from OA or non-OA cartilage, there was significantly less extractable GAG, COMP and D-COMP in AKU samples compared with OA and non-OA comparators. Racemized Asx (aspartate and asparagine) was significantly enriched in AKU cartilage compared with in OA cartilage. Conclusions. These novel data represent the first examination of cartilage matrix components in a sample of patients with AKU, representing almost 10% of the known UK alkaptonuric population. Compared with OA and non-OA, AKU cartilage demonstrates a very low turnover state and has low levels of extractable matrix proteins.

Alkaptonuria is a rare metabolic disease caused by a partial or total deficiency of homogentisic acid oxidase, which results in excess homogentisic acid (HGA) levels. Homogentisic acid and its oxidation products can accumulate in hyaline cartilage, tendons, and ligaments. A 55-year-old male was admitted complaining of worsening chronic pain in his left knee. A radiographic evaluation showed tricompartmental end-stage osteoarthritis. A cemented total knee replacement was performed. At the 10-year follow-up, he had returned to full activity, had no knee pain, and was very satisfied with the outcome. No abnormality was observed in the femoral, tibial, or patellar components on radiography. We believe that total knee replacement is a good option in a patient with marked degenerative arthritis secondary to ochronotic arthritis.Keywords : Ochronotic Arthropathy,Alkaptonuria,Arthroplasty DOI: 10.3944/AOTT.2015.14.0117This abstract belongs to the un-edited version of the article and is only for informative purposes. Published version may differ from the current version., Alkaptonüri homojentisik asit oksidazın kısmen ya da tamamen eksikliği nedeniyle görülen nadir bir metabolik hastalık olup, artmış homojentisik asit (HGA) seviyeleri ile sonuçlanır. Homojentisik asit ve oksidasyon ürünleri hiyalin kıkırdak, tendon ve bağlarda birikebilir.55 yaşında erkek hasta, sol diz kronik ağrı şikayeti ile polikliğinimize başvurdu. Radyografik değerlendirmede trikompartmantal son dönem osteoartrit bulguları mevcuttu. Hastaya çimentolu total diz artroplastisi uygulandı. 10 yıllık takipte, hastanın günlük aktivitelerini tam olarak yapabildiği görüldü. Çekilen direkt grafilerde femoral ve tibial komponentlerde radyolojik olarak anormal görünüm izlenmedi.Total diz protezi uygulamasının, okronotik artropatiye ikincil gelişen dejeneratif osteoartritli hastaların tedavisinde iyi bir seçenek olduğunu düşünüyoruz.Alkaptonüri, nadir görülen otozomal resesif metabolik bir hastalıktır. 3. Kromozomda bulunan homojentizik 1,2 - dioksijenaz (HGO) geninde meydana gelen mutasyon nedeniyle artmış homojentisik asit (HGA) düzeyi ile karakterizedir.(1-3) İnsidansı 100.000-250.000 kişide bir görülmektedir.(3,4) Karaciğer ve böbreklerde bulunan homojentisik asit oksidazın kısmen ya da tamamen eksikliğinden kaynaklanır. Homogentisik asit oksidaz, HGA’ın fenilalanin ve tirozin katabolizmasından sorumludur. Homojentisik asit ve oksidasyon ürünleri hiyalin kıkırdak, tendon, bağ, sklera, deri, kalp kapakçıkları, burun ve kulaklar, böbrek tübül epitel hücreleri, pankreas ve arterlerde birikir.(4–6)Alkaptonüri teşhisi idrarda homojentisik asit miktarı ile teyit edilebilir. Günümüzde Alkaptonürinin bilinen medikal tedavisi yoktur. Tedavi semptomatik olup, fizyoterapi, analjezikler ve destek tedavisinden oluşur. Cerrahi tedavi seçenekleri arasında sinovektomi, artroskopik debridman ve artroplasti bulunur.(4,7,8) DOI: 10.3944/AOTT.2015.14.0117Bu özet, makalenin henüz redaksiyonu tamamlanmamış haline aittir ve bilgi verme amaçlıdır. Yayın aşamasında değişiklik gösterebilir.