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Background: Cardiac ochronosis, presenting as a rare manifestation of alkaptonuria, an autosomal recessive disorder, is characterised by black pigmentation of calcified cardiac valves and atherosclerotic plaques. We report an intraoperative dilemma on the discovery on the black aortic valve in a case of an old lady with degenerative calcific aortic stenosis. Case presentation: A 60-year-old lady was electively admitted for valve replacement with a bioprosthetic valve for severe aortic stenosis. She was symptomatic with complaints of headache and giddiness and had a pressure gradient of 113/17mmhg across the aortic valve. Intraoperatively, she was found to have cardiac ochronosis on the discovery of pigmented aortic intima extending to the valve leaflets and underwent valve replacement with a mechanical prosthetic valve. She was post-operatively evaluated for the same and diagnosed with alkaptonuria. Though the surgery went uneventful and the patient was discharged without any complication, she was advised to be on regular follow-up to assess valve gradients, paravalvular leaks and to monitor the disease progression. Conclusion: The presented case sheds light on the rare cardiac manifestation of alkaptonuria. In the absence of definitive pre-operative diagnosis, intraoperative findings played a pivotal role in guiding the surgical approach and choice of prosthetic valve. The decision to use a mechanical valve was influenced by the potential risks associated with bioprosthetic valves in the setting of ochronosis. Ongoing follow-up and monitoring are essential to assess the durability of the chosen prosthetic valve and to manage any long-term consequences of the underlying metabolic condition. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiac ochronosis, presenting as a rare manifestation of alkaptonuria, an autosomal recessive disorder, is characterised by black pigmentation of calcified cardiac valves and atherosclerotic plaques. We report an intraoperative dilemma on the discovery on the black aortic valve in a case of an old lady with degenerative calcific aortic stenosis. Case presentation A 60-year-old lady was electively admitted for valve replacement with a bioprosthetic valve for severe aortic stenosis. She was symptomatic with complaints of headache and giddiness and had a pressure gradient of 113/17mmhg across the aortic valve. Intraoperatively, she was found to have cardiac ochronosis on the discovery of pigmented aortic intima extending to the valve leaflets and underwent valve replacement with a mechanical prosthetic valve. She was post-operatively evaluated for the same and diagnosed with alkaptonuria. Though the surgery went uneventful and the patient was discharged without any complication, she was advised to be on regular follow-up to assess valve gradients, paravalvular leaks and to monitor the disease progression. Conclusion The presented case sheds light on the rare cardiac manifestation of alkaptonuria. In the absence of definitive pre-operative diagnosis, intraoperative findings played a pivotal role in guiding the surgical approach and choice of prosthetic valve. The decision to use a mechanical valve was influenced by the potential risks associated with bioprosthetic valves in the setting of ochronosis. Ongoing follow-up and monitoring are essential to assess the durability of the chosen prosthetic valve and to manage any long-term consequences of the underlying metabolic condition.

Alkaptonuria (AKU) is a genetic disorder that affects connective tissues of several body compartments causing cartilage degeneration, tendon calcification, heart problems, and an invalidating, early-onset form of osteoarthritis. The molecular mechanisms underlying AKU involve homogentisic acid (HGA) accumulation in cells and tissues. HGA is highly reactive, able to modify several macromolecules, and activates different pathways, mostly involved in the onset and propagation of oxidative stress and inflammation, with consequences spreading from the microscopic to the macroscopic level leading to irreversible damage. Gaining a deeper understanding of AKU molecular mechanisms may provide novel possible therapeutical approaches to counteract disease progression. In this review, we first describe inflammation and oxidative stress in AKU and discuss similarities with other more common disorders. Then, we focus on HGA reactivity and AKU molecular mechanisms. We finally describe a multi-purpose digital platform, named ApreciseKUre, created to facilitate data collection, integration, and analysis of AKU-related data. [ABSTRACT FROM AUTHOR]

Alkaptonuria is an inborn error of metabolism inherited as an autosomal recessive disorder due to a mutation in the homogentisic acid dioxygenase gene. It occurs rarely (global prevalence of alkaptonuria is 1 in 100,000 to 250,000), and mainly affects the joints and connective tissue of the body due to deposition of homogentisic acid giving affected areas a blue-black discoloration (ochronosis). In this case report, we present a male patient, aged 47 years, with joint and scleral involvement. He had been diagnosed many years ago with the disease by gas chromatography. His symptoms kept progressively worsening since he was recently prescribed physiotherapy and vitamin C for his disease, which has not been shown to be an effective treatment. A main reason for his disease deterioration was also the lack of nitisinone availability in his home country, as well as in the subcontinent region generally. We also presen a summary of some previously reported cases and treatment regimens to compare our case and present the comparison as a learning source for future physicians. [ABSTRACT FROM AUTHOR]

Background: Increased homogentisic acid (HGA) in alkaptonuria (AKU) causes severe arthritis. Nitisinone reduces the production of HGA, but whether it also decreases arthroplasty was examined in 237 AKU patients. Patients and methods: Patients attending the United Kingdom National Alkaptonuria Centre (NAC) and the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) study were studied. Assessments included questionnaires eliciting details of arthroplasty. Nitisinone was administered from baseline, 2 mg in the NAC and 10 mg in SONIA 2. In SONIA 2, subgroups consisted of those with baseline arthroplasty on and not on nitisinone (BR + N+, BR + N-), as well as those without baseline arthroplasty on and not on nitisinone (BR-N+, BR-N-). Results: In the SONIA2 subgroups, new joint replacement (JR) probabilities after baseline were significantly different (BR + N+, BR + N-, BR-N+, BR-N-) (χ2 = 23.3, p

Background: Alkaptonuria (AKU) is a rare autosomal recessive disease characterized by a deficiency in an enzyme involved in the tyrosine and phenylalanine degradation. Patients suffering from this disorder develop a black coloration of cartilages known as ochronosis, leading to debilitating cartilage and arthritis at early ages. The spine is commonly involved but reports of lumbar disc disease are rare. Methods: We present a case of a lumbar disc herniation secondary to ochronosis, and we also provide a comparative analysis with other cases documented in the literature. For the literature search we selected manuscripts published in PubMed, Embase, Scopus, Ovid, and Science Direct between 1963 and 2022. Results: The mean age of the 25 included patients was 44.2 years (range: 22–69), and most of them were males (n = 19). The most common presentations were back pain and leg pain (n = 10), followed by lumbar radiculopathy (n = 9). Cauda equina syndrome (n = 2), thoracic myelopathy (n = 2), and cervical radiculopathy (n = 1) were less frequently observed. The lumbar region was the most affected area, with L4-L5 being the most affected level (n = 7), followed by L5-S1 (n = 4). Conclusion: AKU can lead to ochronotic spondyloarthropathy and, rarely, disc herniation, particularly in the lower lumbar region. Surgeons should note that black cartilage during a discectomy indicates likely ochronotic disc involvement. Diagnosis requires histopathologic and biochemical analyses of blood and urine, usually done retrospectively. Genetic confirmation is crucial due to the multisystem nature of alkaptonuria. Our case contributes to the literature on this rare condition, emphasizing the need for comprehensive diagnostics.

Alkaptonuria is a metabolic disorder characterized by homogentisic acid accumulation in connective tissue. Ochronotic arthropathy, a rare condition reported in alkaptonuria, mostly affects the knee joint. In this study we reported a 57-year-old male patient presented with bilateral hip pain. During the operation, black bone tissue and tendons were observed. We examined the patient for alkaptonuria after the operation and the diagnosis was confirmed. In fact, alkaptonuria was not detected until the operation. Therefore, our study suggests that orthopedic surgeons be suspicious of atypical arthropathy in order to avoid being overwhelmed by the appearance of black cartilage during surgery.

Alkaptonuria is a rare genetic disease caused by defect in the phenylalanine and tyrosine metabolism due to a deficiency in homogentisate 1,2-dioxygenase enzyme. The formation of ochronotic brownish-black pigment is the hallmark of the disease and at later stage AKU patients complain of recurrent renal calculi formation. In this report, we describe the case of 48 years old man who is previously diagnosed with alkaptonuria and is suffering from recurrent renal stones formation. We analysed the chemical composition of his AKU-stones by Fourier transform infrared spectroscopy (FTIR) and Inductively coupled plasma-mass spectrometry (ICP-MS) respectively and compared them with non-AKU stones obtained from 48 years old non-AKU man. Our results showed that sulphur content was 33 folds higher in AKU stones compared to non-AKU sample. This provides an evidence that sulphur-rich protein is a critical component for stone formation and growth from calcium oxalate monohydrate (COM) crystals. Accordingly, a model was proposed for the formation and growth of ochronotic renal stones in AKU patients with protein stimulated COM aggregation based on the generation of adducts between benzoquinone acetate and sulphur-rich proteins. Overall, the outcomes of this study shed a new light on the disease pathogenesis at the molecular level and opened new perspective which might orient the physicians to find a convenient therapeutic intervention or at least prophylactic measures to avoid recurrent formation of calculi in AKU patients. [ABSTRACT FROM AUTHOR]

Background: Ochronotic Arthropathy is very rare disorder (around one in million people). It is due to deficiency of enzyme homogentisic acid oxidase which leads to accumulation of homogentisic acid (HGA) and causes damage of several connective tissues. Case report: 53 years old male presented with pain and stiffness in both hip and knee since last 10 years, knees were more painful than hips. In last 6 months his condition deteriorated which hampered his daily routine activities. There is history of consanguineous marriage in family, his two sons also suffering from same problems. Intra-operative we found blackish discolouration of soft tissue and cartilage. Conclusion: Fabulous results have been seen after bilateral hip and knee replacement at 18 months of follow up without any complications.

Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that turns black upon standing. Though rarely fatal, joint degradation is a common sequela, and many patients require multiple large joint arthroplasties throughout their lifetime. Though many aspects of the pathophysiological mechanisms of the disease have been described, questions remain, such as how the initiation of ochronotic pigmentation is prompted and the specific circumstances that make some tissues more resistant to pigmentation-related damage than others. In this report, we present the case of an 83-year-old female previously diagnosed with alkaptonuria including high-quality arthroscopic images displaying the fraying of articular cartilage. We also offer a summary of the latest literature on the pathophysiological mechanisms of the disease, including cellular-level changes observed in ochronotic chondrocytes, biochemical and mechanical alterations to the cartilaginous extracellular matrix, and patterns of pigmentation and joint degradation observed in humans and mice models. With these, we present an overview of the mechanisms of ochronotic chondropathy and joint degradation as the processes are currently understood. While alkaptonuria itself is rare, it has been termed a "fundamental disease," implying that its study and greater understanding have the potential to lead to insights in skeletal biology in general, as well as more common pathologies such as osteoarthritis and their potential treatment mechanisms. [ABSTRACT FROM AUTHOR]

Background: Alkaptonuria is a rare metabolic autosomal recessive disorder. Its aetiology involves homogentisate 1,2 dioxygenase (HGD) deficiency resulting in homogentisic acid accumulation in the connective tissues (ochronosis). The classic triad of the disease is: i) homogentisic aciduria, ii) bluish-black pigmentation in tissues such as the sclera, cornea, cartilage and skin, and iii) degenerative arthropathy usually in the fourth decade of life. Case: In this case report, we present a 41-year-old man with diffuse musculoskeletal pain and additional clinical features in tissues such as the ear and urinary tract who was diagnosed late (>30 years). He was diagnosed with alkaptonuria based on clinical findings and elevated urinary homogentisic acid levels. Conclusion: This case report underscores the need for early diagnosis of alkaptonuria, which can help in managing symptoms and improving the quality of life of patients. Further research is needed to develop more targeted therapies for alkaptonuria, which can help slow down the progression of joint degeneration and improve overall patient. [ABSTRACT FROM AUTHOR]

Exogenous ochronosis is a stigmatizing dermatosis characterized by asymptomatic, bluish-black, or grayish macules in photoexposed areas. Associated with the prolonged use of hydroquinone for the treatment of dyschromias, it has a broad therapeutic arsenal, but the results are unsatisfactory and/or costly. We report the case of a female patient with histologically proven exogenous ochronosis who underwent dermabrasion associated with the use of tretinoin and topical corticosteroids with surprising results after three months of follow-up to demonstrate the possibility of therapeutic success with a low-cost technique and an outpatient clinic procedure.

Background: Alkaptonuria is a rare metabolic autosomal recessive disorder. Its aetiology involves homogentisate 1,2 dioxygenase (HGD) deficiency resulting in homogentisic acid accumulation in the connective tissues (ochronosis). The classic triad of the disease is: i) homogentisic aciduria, ii) bluish-black pigmentation in tissues such as the sclera, cornea, cartilage and skin, and iii) degenerative arthropathy usually in the fourth decade of life. Case: In this case report, we present a 41-year-old man with diffuse musculoskeletal pain and additional clinical features in tissues such as the ear and urinary tract who was diagnosed late (>30 years). He was diagnosed with alkaptonuria based on clinical findings and elevated urinary homogentisic acid levels. Conclusion: This case report underscores the need for early diagnosis of alkaptonuria, which can help in managing symptoms and improving the quality of life of patients. Further research is needed to develop more targeted therapies for alkaptonuria, which can help slow down the progression of joint degeneration and improve overall patient.

Endogenous ochronosis/Alkaptonuria is a rare, genetic metabolic disease presenting with cutaneous hyperpigmentation, disabling arthropathy, and homogentisic aciduria. The dermoscopic features of this entity have a good correlation with the histopathological findings, and its knowledge can facilitate early diagnosis to decrease long-term morbidity and improve the quality of life. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endogenous ochronosis or alkaptonuria is a rare disease of autosomal recessive inheritance, which manifests with a brown or ocher hue caused by the insufficiency of the homogentisic acid oxidase enzyme causing its accumulation in the connective tissues. CLINICAL CASE: A 56-year-old female patient, with a history of renal lithiasis, presenting with one year evolution of ocher, erythematous and grayish-blue macules on the ears and hands, asymptomatic. The biopsy showed yellowish-brown material in the shape of a banana, with the presence of choluria when performing the urinary alkalinization test with bicarbonate; the imaging studies showed lumbar spondyloarthrosis and annular disc protrusion with foraminal involvement. CONCLUSIONS: Alkaptonuria is a disease with multiple clinical manifestations, it is characteristic the darkening in the urine, the presence of multiple ocher-toned macules and multiple joint conditions; the definitive diagnosis is stablished by measuring the levels of homogentisic acid in urine or with a genetic study; it is recommended to perform biopsies in the macules in search of the characteristic pigment and to carry out an integral approach with paraclinical studies such as magnetic resonance imaging, echocardiography, and ultrasound studies, the treatment is mainly symptomatic. [ABSTRACT FROM AUTHOR]

Ochronosis is a cutaneous disorder caused by the accumulation of phenols, either endogenously as homogentisic acid in patients with alkaptonuria (autosomal recessive disorder with deficiency of the enzyme homogentisic acid oxidase), or exogenously in patients using phenol products such as topical creams containing hydroquinone or the intramuscular application of antimalarial drugs. Exogenous ochronosis (EO) typically affects the face and was reported in patients with dark skin such as Black South Africans or Hispanics who use skin-lightening products containing hydroquinone for extended periods. Recently more cases have been reported worldwide even in patients with lighter skin tones, to include Eastern Indians, Asians, and Europeans. However, just 39 cases of EO have been reported in the US literature from 1983 to 2020. Here we present two cases; a 69 and a 45-year-old female who were seen for melasma, given hydroquinone 4% cream daily and tretinoin 0.05%. Both patients noticed brown spots on their cheeks, which progressively enlarged and darkened in color. The diagnosis of ochronosis was confirmed by characteristic histopathological features on the punch biopsy. Unfortunately, neither patient responded to multiple treatments (to include, tazarotene 0.1% gel and pimecrolimus ointment, topical corticosteroids, and avoidance of hydroquinone containing products). We also present a case of classic (endogenous) ochronosis in a patient with alkaptonuria to picture the histological similarities of these two entities. EO is an important clinical consideration because early diagnosis and treatment may offer the best outcome for this notoriously refractory clinical diagnosis.

Endogenous ochronosis/Alkaptonuria is a rare, genetic metabolic disease presenting with cutaneous hyperpigmentation, disabling arthropathy, and homogentisic aciduria. The dermoscopic features of this entity have a good correlation with the histopathological findings, and its knowledge can facilitate early diagnosis to decrease long-term morbidity and improve the quality of life.

Abstract 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.

Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. It is characterized by homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and arthropathy of large joints. Less common manifestations include cardiovascular abnormalities, renal, urethral and prostate calculi. Bone fractures are unusual in ochronosis. In this report, we describe a woman, 72 years of age, with a history of severe arthropathy requiring total joint replacement in both of her hips and left Knee. During the Left Total Knee Replacement, an intra operative observation of a bluish-black discoloration of the knee joint and the surrounding soft tissue raised the diagnosis of Alkaptonuria. We review the etiology, pathogenesis, clinical presentation, diagnosis and treatment of alkaptonuric ochronosis. Early detection is important for prevention and treatment of multiple systems. [ABSTRACT FROM AUTHOR]

Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine degradation. AKU patients carry variants within the gene coding for homogentisate-1,2-dioxygenase (HGD), which are responsible for reducing the enzyme catalytic activity and the consequent accumulation of HGA and formation of a dark pigment called the ochronotic pigment. In individuals with alkaptonuria, ochronotic pigmentation of connective tissues occurs, leading to inflammation, degeneration, and eventually osteoarthritis. The molecular mechanisms underlying the multisystemic development of the disease severity are still not fully understood and are mostly limited to the metabolic pathway segment involving HGA. In this view, untargeted metabolomics of biofluids in metabolic diseases allows the direct investigation of molecular species involved in pathways alterations and their interplay. Here, we present the untargeted metabolomics study of AKU through the nuclear magnetic resonance of urine from a cohort of Italian patients; the study aims to unravel molecular species and mechanisms underlying the AKU metabolic disorder. Dysregulation of metabolic pathways other than the HGD route and new potential biomarkers beyond homogentisate are suggested, contributing to a more comprehensive molecular signature definition for AKU and the development of future adjuvant treatment. [ABSTRACT FROM AUTHOR]

Alkaptonuria is a disease often forgotten because of its rarity. Its pathogenic mechanism is the deficiency of one of the enzymes of the tyrosine degradation pathway—homogentisate-1, 2-dioxygenase, which sequelae is accumulation and deposition of its metabolite homogentisic acid in connective tissues and urine. Alkaptonuria presents as a clinical triad—darkening urine upon prolonged exposure to air, pigmentation of connective tissues and debilitating arthropathy. We present a case report of a 67-year old patient with alkaptonuria who presented with the clinical triad, but was mistakenly diagnosed as having ankylosing spondylitis in the past. Currently there is no treatment for the disease hence the management strategy was focused on symptoms control with analgesics, physical therapy, dietary modification, vitamin C supplementation, and joint arthroplasty. Alkaptonuria's clinical features are extensively described in the literature and despite the fact that it is a rare disease, due to the similar radiographic changes with spondyloarthropathies, it should be included in the differential diagnosis in young patients presenting with severe joint involvement. Early recognition of the disease is necessary since its natural evolution is joint destruction leading to significant reduction in the quality of life. Alkaptonuria's articular features in the spine and peripheral tissues are well described using the classical imaging techniques. Musculoskeletal ultrasonography shows a characteristic set of findings in the soft tissues, including synovium, cartilage, tendons and entheses. [ABSTRACT FROM AUTHOR]

Alkaptonuria is rare autosomal recessive multisystem disease, caused by mutations in the homogentisine oxidase gene, which leads to the deposition of metabolites of homogentisic acid in organs and tissues (ochronosis).The purpose: to study spectrum of ophthalmic manifestations of alkaptonuria in Russian cohort of patients of different ages.Material and methods. Ophthalmological examination of 9 patients: 5 adults aged from 39 to 64 years and 4 children aged from 3 to 6 years with confirmed diagnosis of “alkaptonuria” was performed.Results. In all adult patients bilateral brown-black scleral pigmentation and yellow-brown deposits in the conjunctiva in the region of the palpebral fissure were detected paralymbally, the severity of which correlated with age, tortuosity and vasodilation of the conjunctiva in areas of deposits. In 1 out of 4 children minimal deposits of yellow pigment were found in the conjunctiva of the limb. In patients older than 60 years typical small brownish deposits were observed in the cornea near the limb in the region of the palpebral fissure.Conclusion. Eye changes are one of the most common clinical manifestations of alkaptonuria. Typical manifestations are the sclera’s pigmentation, conjunctiva and cornea in the limb. Ophthalmological examination is non-invasive informative method that can help in early diagnosis, differential diagnostics, assessment of the dynamics of the disease and the effectiveness of the therapy.

Abstract Background Ochronotic arthropathy affecting the hip and knee joints is one of the musculoskeletal manifestations of alkaptonuria which results from a tyrosine amino acid metabolism disorder. The condition has no definitive management; however, end-stage joint arthritis is well treated by total joint replacement. Case presentation We present a case of a healthy male patient who presented with left hip and bilateral knee (more on the left side) progressive pain and limitation of motion how was diagnosed as having advanced arthritis and was treated by total hip and total knee replacement for the left hip and knee joints respectively. Intraoperatively, the tissues had blackish discoloration characterizing ochronosis. This patient was diagnosed as having ochronotic arthropathy based on the intraoperative findings. Conclusions Accurate diagnosis of ochronotic arthropathy could only be reached intraoperatively; furthermore, end-stage joint arthritis could be treated efficiently by total joint replacement surgery.

Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that turns black upon standing. Though rarely fatal, joint degradation is a common sequela, and many patients require multiple large joint arthroplasties throughout their lifetime. Though many aspects of the pathophysiological mechanisms of the disease have been described, questions remain, such as how the initiation of ochronotic pigmentation is prompted and the specific circumstances that make some tissues more resistant to pigmentation-related damage than others. In this report, we present the case of an 83-year-old female previously diagnosed with alkaptonuria including high-quality arthroscopic images displaying the fraying of articular cartilage. We also offer a summary of the latest literature on the pathophysiological mechanisms of the disease, including cellular-level changes observed in ochronotic chondrocytes, biochemical and mechanical alterations to the cartilaginous extracellular matrix, and patterns of pigmentation and joint degradation observed in humans and mice models. With these, we present an overview of the mechanisms of ochronotic chondropathy and joint degradation as the processes are currently understood. While alkaptonuria itself is rare, it has been termed a “fundamental disease,” implying that its study and greater understanding have the potential to lead to insights in skeletal biology in general, as well as more common pathologies such as osteoarthritis and their potential treatment mechanisms.

Alkaptonuria is a rare disorder, an autosomal recessive condition with genetic determinism and hereditary transmission, having a prevalence of 1 per 1 million population in USA. The pathogenesis includes the deficiency of the homogentisate 1,2-dioxygenase (HGD) enzyme, an intermediary enzyme in phenylalanine and tyrosine catabolism. Mutations in HGD gene leads to deficient levels of functional HGD and an excess of homogentisic acid (HGA). Although HGA is rapidly excreted by the kidneys, it slowly accumulates in various tissues. Due to HGA oxidase deficiency, HGA turns into melanin-like pigment which determines: alkaptonuria, accumulation in the connective tissues, in the joints, or can make cardiovascular and genitourinary deposits. The chronic accumulation of HGA destroys the affected tissue, leading to the characteristic black-blue colour and to clinical symptoms of alkaptonuria. The aim of this paper is to investigate the particularities of rheumatic manifestations in a rare metabolic disease and to support the correct diagnosis. A 58-year-old male patient was admitted to our clinic in 2019 for bilateral knee and left shoulder pain. In 2008 he was diagnosed with polyarticular ochronosis having dorsal and lumbar pain, mixed scapulohumeral pain, lumbar intervertebral disk calcifications; at that time, a diagnosis of ankylosing spondylitis or Forestier disease was excluded. At the current admission, the patient has been thoroughly reassessed to obtain a proper diagnosis and to determine the severity of the disease. The ochronotic axial damage caused important differential diagnosis problems with ankylosing spondylitis. Pigment deposition in the eyes, ears and skin does not cause problems to patients, but cardiovascular and genitourinary deposition leads to important complications. Kinetotherapy and NSAIDs are beneficial for pain symptoms. There is no specific medication for stopping the disease progression. Conclusions. Ochronosis is a rare disease which can cause a lot of problems regarding a proper diagnosis and treatment. When differential diagnosis with AS is difficult, the HLA-B27 genotyping is recommended. Final diagnosis is based on qualitative and quantitative urinary tests. The treatment includes only symptomatic drugs such as NSAIDs and kinetotherapy to improve joint mobility and muscle toning.

ABSTRACT: Ochronosis is a syndrome characterized by bluish black discoloration due to the deposition of polymerized products of homogentisic acid (HGA) in the connective tissues. The endogenous variety (alkaptonuria), is a rare autosomal recessive metabolic disorder. The disorder is manifested by deficiency of the enzyme homogentisate 1,2-dioxygenase. The characteristic of the condition is a triad of pigmentation of skin, cartilage, and sclera; ochronotic arthropathies and homogentisic aciduria (resulting in darkening of urine). More rarely, it may affect the breast. This rare and interesting case of a woman with ochronosis of both breasts and chest wall, prompted us to write this case report.

Introduction: alkaptonuria is a very rare metabolic disease with autosomal recessive inheritance due to HGA oxidase deficiency. Classically described and diagnosed in the third to fourth decade of life, affecting both men and women; Its diagnostic impression is clinical based on the blue/black coloration of the conjunctivae, however it is confirmed by the specific analysis of the enzyme in the urine, to date there is no cure and its treatment is palliative and symptomatic. Material and methods: descriptive, observational, case series study, the primary objective of which is to describe the progression of the disease and its involvement in the musculoskeletal system. Results: two clinical cases are presented in women and men in which the broad clinic is illustrated, its progressive advance and the different alterations that it can generate in the musculoskeletal system. Conclusions: alkaptonuria is a rare disease which leads to a severe secondary arthropathy, currently without a specific management which is based on treating the symptoms, in its final stages joint replacements are a management option with satisfactory results for the relief of pain. [ABSTRACT FROM AUTHOR]

L'ochronose ou alcaptonurie est une maladie héréditaire autosomique récessive rare. Elle est due à l'absence de l'acide homogentisique-oxydase conduisant à l'accumulation d'acide homogentisique dans les tissus. Nous rapportons l'observation d'une patiente de 69 ans qui présentait des lombalgies chroniques d'allure mécanique et une radiculalgie. L'examen clinique montrait une perte de la lordose lombaire, une raideur rachidienne lombaire, et une limitation de la mobilité des genoux. Sur le plan extra-articulaire, on notait une coloration bleuâtre des pavillons des oreilles et des angles internes des yeux. L'imagerie du rachis (scanner lombaire) objectivait un vide avec calcifications discales lombaires étagées et des ponts ostéophytiques. Le diagnostic d'ochronose était posé sur des critères cliniques et radiologiques. L'alcaptonurie est à l'origine d'une arthropathie dégénérative pouvant mettre en jeu le pronostic fonctionnel. Le dépistage par analyse moléculaire et étude génétique prennent un grand intérêt. Ochronosis, also known as alkaptonuria, is a rare autosomal recessive disease. It is caused by a lack of homogentisic acid oxidase, which causes homogentisic acid deposition in the tissues. We report a 69-year-old patient who presented with chronic mechanical low back and radicular pain. The clinical examination revealed lumbar lordosis loss, lumbar spinal stiffness, and knee joint limitations of range of motion. On an extra-articular level, the pavilions of the ears and the internal angles of the eyes had a bluish color. Extensive lumbar disc calcifications, vacuum discal phenomenon and osteophytic bridges were demonstrated on standard radiographs of the spine. Clinical and radiographic criteria were used to make the diagnosis of ochronosis. Alkaptonuria is a degenerative arthropathy that leads to reduction of functional ability. The use of molecular analysis and genetic research is useful. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Changes in the phenylalanine (PHE)/tyrosine (TYR) pathway metabolites before and during homogentisic acid (HGA)-lowering by nitisinone in the Suitability of Nitisinone in Alkaptonuria (AKU) 2 (SONIA 2) study enabled the magnitude of the flux in the pathway to be examined. SONIA 2 was a 48-month randomised, open-label, evaluator-blinded, parallel-group study performed in the UK, France and Slovakia recruiting patients with confirmed AKU to receive either 10 mg nitisinone or no treatment. Site visits were performed at 3 months and yearly thereafter. Results from history, photographs of eyes/ears, whole body scintigraphy, echocardiography and abdomen/pelvis ultrasonography were combined to produce the Alkaptonuria Severity Score Index (cAKUSSI). PHE, TYR, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and HGA metabolites were analysed by liquid chromatography/tandem mass spectrometry in 24 h urine and serum samples collected before and during nitisinone. Serum metabolites were corrected for total body water (TBW), and the sum of 24 h urine plus total body water metabolites of PHE, TYR, HPPA, HPLA and HGA were determined. The sum of urine metabolites (PHE, TYR, HPPA, HPLA and HGA) were similar pre- and peri-nitisinone. The sum of TBW metabolites and sum TBW + URINE metabolites were significantly higher peri-nitisinone (p < 0.001 for both) compared with pre-nitisinone baseline. Significantly higher concentrations of metabolites from the tyrosine metabolic pathway were observed during treatment with nitisinone. Arguments for unmasking of the ochronotic pathway and biliary elimination of HGA are put forward. [ABSTRACT FROM AUTHOR]

Tendon injuries in the lower extremities are common in physically active individuals, although spontaneous Achilles tendon ruptures are linked to oral corticosteroid or fluoroquinolone use. Such ruptures are typically due to degenerative changes within the tendon and frequently occur during sudden dorsiflexion of a plantar-flexed foot. Bilateral spontaneous ruptures are especially prevalent in patients undergoing long-term corticosteroid therapy. Here, we present a rare case of bilateral spontaneous calcaneal avulsion in an otherwise healthy woman, ultimately diagnosed with alkaptonuria. This case underscores the importance of considering metabolic disorders in atraumatic tendon ruptures and highlights the diagnostic value of intraoperative findings., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Ochronosis is a rare metabolic disease caused by the deficiency of the homogentisic acid oxidase enzyme. It gives clinical findings related to the accumulation of homogentisic acid in soft tissues and excretion in urine. Patients with chronic arthropathy usually have some joint pain and inflammatory back pain. Although axial involvement radiologically resembles ankylosing spondylitis (AS), it is differentiated by the absence of typical syndesmophytes, facet involvement, sacroiliac erosion and fusion.Although there is no effective treatment for ochronosis disease; our patient was given a protein-poor diet, vitamin C supplementation (100 mg/kg/day) and analgesic treatment for symptoms recommended in the literature; and a reduction in joint complaints was observed. In this case, the aim is to diagnose the rare ochronotic arthropathy followed with the diagnosis of AS and to show that both axial and peripheral joint involvement can be together in this disease.

The aim of the study was to study the quality of life of patients with alkaptonuria.Material and methods. The study included 50 patients with a reliable diagnosis of alkaptonuria aged 18 to 78 years (mean age 58.2±10.8 years). Among them, men predominated (n=31; 62%), in most cases (98%) complaining of pain in the joints and/or spine. For the first time, the articular syndrome debuted at the age of 17 to 39 years (average age of debut – 29.4±4.76 years). The duration of clinical manifestations of the disease before diagnosis ranged from 7 to 47 years (mean 23.35±8.17 years). 74% of patients had a disability group. In the study cohort, the body mass index (BMI) was slightly higher than normal values and averaged 28.18±4.95 kg/m2. The quality of life of patients was assessed using the EuroQol-5D questionnaire (EQ-5D).Results. The quality of life corresponding to a satisfactory state of health according to EQ-5D was observed in 56% of patients. Their quality-of-life index (LQI) values were more than 0.5. 22% of patients had 0

Background: Cutaneous exogenous ochronosis (EO) is frequently graded and staged according to the Dogliotti or Phillips classification system, both in research studies and in clinical practice. There are no data to support the use of these systems in either of these settings. These systems additionally purport that the clinical and histopathological findings of EO are concordant; however, anecdotal evidence suggests otherwise. We aimed to determine the clinical‐histopathological concordance rates in EO and to assess the suitability of the Dogliotti and Phillips classification systems for the grading and staging of EO lesions. Methods: Five cutaneous EO cases diagnosed at our institution were studied. Clinical and histopathological data were obtained by medical record and histopathology slide review. Each case was assigned a clinical and histopathological grade according to both the Dogliotti and Phillips classifications. Clinical‐histopathological concordance rates were determined for each classification. Results: Clinical‐histopathological concordance was seen in 80% and 60% of EO lesions when graded according to the Dogliotti and Phillips classifications, respectively. Conclusions: Cutaneous EO lesions do not consistently show clinical‐histopathological concordance. Although the Dogliotti and Phillips classifications may have clinical utility, they are not suitable to grade EO histopathologically. [ABSTRACT FROM AUTHOR]

Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous and one endogenous in etiology. The first was caused by minocycline use for severe acne, and the second was caused by congenital alkaptonuria. [ABSTRACT FROM AUTHOR]

Background: Ochronotic arthropathy affecting the hip and knee joints is one of the musculoskeletal manifestations of alkaptonuria which results from a tyrosine amino acid metabolism disorder. The condition has no definitive management; however, end-stage joint arthritis is well treated by total joint replacement. Case presentation: We present a case of a healthy male patient who presented with left hip and bilateral knee (more on the left side) progressive pain and limitation of motion how was diagnosed as having advanced arthritis and was treated by total hip and total knee replacement for the left hip and knee joints respectively. Intraoperatively, the tissues had blackish discoloration characterizing ochronosis. This patient was diagnosed as having ochronotic arthropathy based on the intraoperative findings. Conclusions: Accurate diagnosis of ochronotic arthropathy could only be reached intraoperatively; furthermore, end-stage joint arthritis could be treated efficiently by total joint replacement surgery. [ABSTRACT FROM AUTHOR]

Resumen: La ocronosis es una enfermedad genética rara del metabolismo de la fenilamina y de la tirosina en la que se produce una acumulación de ácido homogentísico. La acumulación de este provoca alcaptonuria y depósito en el tejido conectivo, provocando una coloración oscura del mismo. En las articulaciones puede provocar una artropatía temprana muy invalidante, conocida como artropatía ocronótica. Presentamos el caso de una paciente diagnosticada de ocronosis y artropatía ocronótica de la rodilla izquierda en la que describimos el proceso intraoperatorio con las características anatomopatológicas macroscópicas y microscópicas encontradas. La paciente presenta muy buena evolución tras la implantación de una prótesis total de rodilla tipo PS, siendo capaz de seguir el mismo protocolo de rehabilitación utilizado en pacientes sometidos a prótesis total de rodilla sin artropatía ocronótica. La paciente muestra mejoría de las distintas escalas funcionales, así como desaparición del dolor. Abstract: Ochronosis is a rare genetic disease of phenylamine and tyrosine metabolism in which an accumulation of homogentisic acid occurs. The accumulation of HGA causes alkaptonuria and deposition in the connective tissue causing a dark colouring of the tissue. In the joints, it can lead to early and very disabling arthropathy, known as ochronotic arthropathy. We present the case of a patient diagnosed with ochronosis and ochronotic arthropathy of the left knee, in which we describe the intraoperative process with the macroscopic and microscopic anatomopathological findings. The patient made good progress after implantation of a total knee prosthesis (TKP), PS type, and was able to follow the same rehabilitation protocol used in patients without ochronotic arthropathy undergoing TKP. The patient showed improvement in the different functional scales, as well as disappearance of pain.

Alkaptonuria is a rare autosomal recessive metabolic disorder. It is characterized by the accumulation of homogentisic acid in the body due to a lack of enzymes that degrade it. Over time, it results in joint degeneration and eventually leads to ochronosis. Ochronosis refers to bluish-black discoloration of connective and other tissues within the body. In this study, we present 5 distinct cases diagnosed with alkaptonuria. They have undergone 8 total joint replacement surgeries (4 hips and 4 knees) within 8 years (2010-2018). All patients had an excellent outcome over several years. The follow-up period ranged from 2 to 10 years. Although none of the presented cases had intraoperative or postoperative adverse sequelae, we must take care when dealing with patients with ochronotic arthropathy. They carry a higher risk of complications than other patients with osteoarthritis disease. These complications include fractures due to fragile bone quality, muscle or tendon rupture, joint instability, and anesthesia-related complications. Total joint arthroplasty is a valid and safe option in the management of hip and knee ochronotic arthropathy.