762 results on '"Ochronosis"'
Search Results
2. Clinical Images: Ochronotic arthropathy.
- Author
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Jafri, Kashif, Gensler, Lianne S, and Link, Thomas M
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Spine ,Humans ,Spondylitis ,Ankylosing ,Joint Diseases ,Back Pain ,Alkaptonuria ,Ochronosis ,Diagnosis ,Differential ,Radiography ,Medical Illustration ,Middle Aged ,Female ,Spondylitis ,Ankylosing ,Diagnosis ,Differential - Published
- 2017
3. Ochronotic arthropathy in the context of spondyloarthritis differential diagnosis: a case-based review
- Author
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Tsvetelina Kostova, Zguro Batalov, Rositsa Karalilova, and Anastas Batalov
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Immunology ,Ascorbic Acid ,Alkaptonuria ,Dioxygenases ,Rheumatology ,Osteoarthritis ,Quality of Life ,Humans ,Spondylarthropathies ,Tyrosine ,Immunology and Allergy ,Joint Diseases ,Cartilage Diseases ,Homogentisic Acid ,Ochronosis ,Aged - Abstract
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.
- Published
- 2022
4. Alkaptonuria in an adolescent boy
- Author
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Jaippreetha Jayaraj, Senthil Chandran, Geminiganesan Sangeetha, and Swathi Ganesan
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Adolescent ,Case Report ,Ascorbic Acid ,030105 genetics & heredity ,Alkaptonuria ,Antioxidants ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Recessive inheritance ,Spinal osteoarthropathy ,medicine ,Humans ,Homogentisic acid ,Tyrosine Metabolism ,Ochronosis ,business.industry ,Genetic disorder ,General Medicine ,medicine.disease ,Dermatology ,Early Diagnosis ,chemistry ,Disease Progression ,Abnormality ,business ,030217 neurology & neurosurgery ,Sclera - Abstract
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.
- Published
- 2023
5. Sarcoidal granuloma on exogenous ochronosis
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M, Tene Ndiaye Diop, B, Seck, A, Diop, K, Diop, A, Deh, N, Ndour, C, Ndiaye, M, Sarr, S, Diadie, B, Ahy Diatta, M, Ndiaye, M, Diallo, and F, Ly
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Granuloma ,Humans ,Dermatology ,Alkaptonuria ,Ochronosis ,Hydroquinones - Published
- 2022
6. Hyperpigmentation: Looking beyond hydroquinone
- Author
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Naseem Ahmad, Charoo
- Subjects
Adult ,Hyperpigmentation ,Humans ,Dermatology ,Middle Aged ,Ochronosis ,Hydroquinones - Abstract
Hyperpigmentation is the most common complaint in the age group 40-45 years, seeking consultation for skin disorders. Hydroquinone is a commonly used depigmenting agent in clinical practice for treating hyperpigmentation. Prolonged use of hydroquinone has been associated with cancer risk and exogenous ochronosis. The CARES (The Coronavirus Aid, Relief, and Economic Security Act) Act of 2020 has instituted significant changes to hydroquinone containing OTC (over the counter) products, and consequently, many hydroquinone-based OTC products had to be withdrawn from the market. Henceforth, products containing hydroquinone would need US Food and Drug Administration approval via new drug application pathways for commercialization. Alternative treatment options to hydroquinone in clinical practice are reviewed in this paper with regard to their safety and efficacy vis a vis hydroquinone. Also, new potential treatment options such as thiamidol, Polypodium leucotomos, and glutathione are discussed. The review shows that these alternative depigmenting agents can be rationally combined to achieve desired treatment goals in the management of hyperpigmentation.
- Published
- 2022
7. Alkaptonuria with rapidly destructive arthropathy of the hip: A case report and literature review
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Yoshiki, Kitahara, Nobuhiro, Kaku, Hiroaki, Tagomori, and Hiroshi, Tsumura
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Male ,Orthopedic surgery ,Humans ,Femur Head ,Hip Joint ,Joint Diseases ,Alkaptonuria ,Ochronosis ,RD701-811 ,Aged - Abstract
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.
- Published
- 2021
8. Alkaptonuria in Russia
- Author
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Andrea Soltysova, Elena Samarkina, Andrea Zatkova, and Alexandr Kuzin
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Genetics ,Homogentisate 1,2-Dioxygenase ,Ochronosis ,Exons ,Biology ,Brief Communication ,Alkaptonuria ,medicine.disease ,Exon ,chemistry.chemical_compound ,chemistry ,medicine ,Humans ,Multiplex ligation-dependent probe amplification ,Homogentisic acid ,Joint Diseases ,Allele ,Homogentisic Acid ,Gene ,Genetics (clinical) ,Homogentisate 1,2-dioxygenase - Abstract
Alkaptonuria is characterized by the accumulation of homogentisic acid (HGA), part of which is excreted in the urine but the excess HGA forms a dark brown ochronotic pigment that deposits in the connective tissue (ochronosis), eventually leading to early-onset severe arthropathy. We analyzed a cohort of 48 Russian AKU families by sequencing all 14 exons (including flanking intronic sequences) of the homogentisate 1,2-dioxygenase gene (HGD) and Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. Nine novel likely pathogenic HGD variants were identified, which have not been reported previously in any other country. Recently, Bychkov et al. [1] reported on the variant spectrum in another cohort of 49 Russian AKU patients. Here we summarize complete data from both cohorts that include 82 Russian AKU families. Taken together, 31 different HGD variants were found in these patients, of which 14 are novel and found only in Russia. The most common variant was c.481G>A (p.(Gly161Arg)), present in almost 54% of all AKU alleles.
- Published
- 2021
9. Evaluating the aortic stenosis phenotype before and after the effect of homogentisic acid lowering therapy: Analysis of a large cohort of eighty-one alkaptonuria patients
- Author
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Lakshminarayan R. Ranganath, Michael Fisher, T. Heseltine, and Milad Khedr
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Nitisinone ,Endocrinology, Diabetes and Metabolism ,030105 genetics & heredity ,Alkaptonuria ,Severity of Illness Index ,Biochemistry ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Aortic valve replacement ,Internal medicine ,Genetics ,Humans ,Medicine ,Homogentisic acid ,Enzyme Inhibitors ,Molecular Biology ,Aged ,Ochronosis ,Cyclohexanones ,business.industry ,Aortic Valve Stenosis ,Middle Aged ,medicine.disease ,Stenosis ,Phenotype ,chemistry ,Nitrobenzoates ,Cohort ,Female ,business ,030217 neurology & neurosurgery ,Rare disease ,medicine.drug - Abstract
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.
- Published
- 2021
10. Occupational Localized Cutaneous Argyria With Pseudo-Ochronosis in a Jeweler
- Author
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Bart Wagner, Effie Katsarma, Manuraj Singh, Patricia Goggin, Sarita Singh, and Nikki Georgiadou
- Subjects
Adult ,Chronic exposure ,Hand Dermatoses ,Dermatology ,Argyria ,Pathology and Forensic Medicine ,Fingers ,Pseudo-ochronosis ,Dermis ,Silver deposition ,medicine ,Humans ,Ochronosis ,medicine.diagnostic_test ,Chemistry ,General Medicine ,Anatomy ,Left middle finger ,medicine.disease ,medicine.anatomical_structure ,Dermatitis, Occupational ,Jewelry ,Skin biopsy ,Female - Abstract
A case of localized argyria in a 36-year-old female jeweler is described who presented with 2 discrete and asymptomatic bluish-black pigmented macules on the pulp of her left middle finger. A skin biopsy from both lesions demonstrated deposition of brown/black pigmented granules along the basement membrane zone of eccrine glands, blood vessels, nerves, and the dermo-epidermal junction fully in keeping with silver deposition. In addition, there was yellow-brown deposition seen within the interstitial dermis mimicking an early form of ochronosis, so called "pseudo-ochronosis." This latter feature is rarely described in cases of argyria. Transmission electron microscopy and energy dispersive x-ray spectroscopy confirmed the presence of electron dense particles up to 150 nm in diameter and the presence of silver, respectively. On further questioning, the patient had a history of localized and chronic exposure to silver, which specifically involved holding and manipulating silver wires and rings over the left middle finger. This case highlights an unusual and rare presentation of localized argyria in a jeweler. In addition, our case showed preferential silver deposition on dermal elastic fibers which has not been previously described in the literature.
- Published
- 2021
11. Inflammatory rheumatic diseases in patients with ochronotic arthropathy
- Author
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Fatos Onen, Ali Balci, Burcu Ozturk Hismi, Sadettin Uslu, Pelin Teke Kisa, Zumrut Arslan, Nur Arslan, Ulku Ucar, Tuba Yuce Inel, and Ismail Sari
- Subjects
Cartilage, Articular ,medicine.medical_specialty ,Alkaptonuria ,chemistry.chemical_compound ,Rheumatology ,hemic and lymphatic diseases ,Internal medicine ,Osteoarthritis ,medicine ,Humans ,In patient ,Homogentisic acid ,Ochronotic arthropathy ,Ankylosing spondylitis ,Ochronosis ,business.industry ,medicine.disease ,Dermatology ,Spine ,eye diseases ,chemistry ,Rheumatoid arthritis ,business - Abstract
Ochronotic arthropathy (OcA) refers to excessive homogentisic acid (HGA) deposition in the musculoskeletal system. Our current understanding of OcA is limited, as there are less than a thousand alkaptonuria (AKU) cases reported in the literature. Herein, we investigated the rheumatological manifestations of OcA in a group of adult AKU patients.Adult AKU patients with symptoms suggestive of OcA were included. Patients underwent a detailed rheumatological assessment. Laboratory testing, including autoantibodies and radiological investigations such as conventional X-rays, andEight out of 12 (66%) patients had symptoms consistent with OcA. The median age at OcA symptoms was 36 (27-48) years, and the presenting symptom was back pain in 87.5% of the patients. All patients had chronic back pain, and three (37.5%) had an inflammatory type of pain character. Radiographic sacroiliitis based on X-rays was present in 2 (25%) cases. MRI of the sacroiliac joints documented bone marrow edema in five (62.5%), and spinal MRI identified corner inflammatory lesions in three patients (37.5%). One patient (12.5%) had rheumatoid arthritis. Extra-articular involvement, including enthesitis (The frequent occurrence of OcA-related inflammatory manifestations in our patients contradicts the conventional concept of OcA as a non-inflammatory disorder. The activation of inflammatory pathways, possibly by the HGA products, may responsible for this condition.Significance and innovationsAbout three-fourths of adult ochronotic arthropathy (OcA) patients in our group had associated inflammatory disease.OcA associated inflammatory diseases were showing a severe phenotypeNearly half of the OcA patients required early prosthesis operations compared to their healthy counterparts.
- Published
- 2021
12. Homogentisic acid induces cytoskeleton and extracellular matrix alteration in alkaptonuric cartilage
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Annalisa Santucci, Otilia V. Vieira, Maria Serena Milella, Laura Salvini, Silvia Galderisi, Vittoria Cicaloni, Alvaro H. Crevenna, Laura Tinti, Michela Geminiani, Lia Millucci, Cristina Tinti, Ottavia Spiga, and Liliana S. Alves
- Subjects
Cartilage, Articular ,0301 basic medicine ,Physiology ,extracellular matrix ,Clinical Biochemistry ,Vimentin ,Microtubules ,Alkaptonuria ,Extracellular matrix ,03 medical and health sciences ,chemistry.chemical_compound ,Chondrocytes ,0302 clinical medicine ,medicine ,Humans ,Homogentisic acid ,Cytoskeleton ,Homogentisate 1,2-dioxygenase ,alkaptonuria ,Ochronosis ,biology ,Cartilage ,cytoskeleton ,Cell Biology ,homogentisic acid ,medicine.disease ,Actins ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,cartilage ,Extracellular Matrix ,Homogentisic Acid ,biology.protein ,Articular - Abstract
Alkaptonuria (AKU) is an ultra-rare disease caused by the deficient activity of homogentisate 1,2-dioxygenase enzyme, leading the accumulation of homogentisic acid (HGA) in connective tissues implicating the formation of a black pigmentation called "ochronosis." Although AKU is a multisystemic disease, the most affected tissue is the articular cartilage, which during the pathology appears to be highly damaged. In this study, a model of alkaptonuric chondrocytes and cartilage was realized to investigate the role of HGA in the alteration of the extracellular matrix (ECM). The AKU tissues lost its architecture composed of collagen, proteoglycans, and all the proteins that characterize the ECM. The cause of this alteration in AKU cartilage is attributed to a degeneration of the cytoskeletal network in chondrocytes caused by the accumulation of HGA. The three cytoskeletal proteins, actin, vimentin, and tubulin, were analyzed and a modification in their amount and disposition in AKU chondrocytes model was identified. Cytoskeleton is involved in many fundamental cellular processes; therefore, the aberration in this complex network is involved in the manifestation of AKU disease.
- Published
- 2021
13. Perforating and granulomatous exogenous ochronosis
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Adam I. Rubin, Susan Pei, Andrew S. Fischer, Heather Milbar, Rosalie Elenitsas, and Brian C Capell
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Pathology ,medicine.medical_specialty ,Ochronosis ,Histology ,Exogenous ochronosis ,business.industry ,Dermatology ,Middle Aged ,Alkaptonuria ,medicine.disease ,Pathology and Forensic Medicine ,medicine ,Humans ,Female ,business ,Skin - Published
- 2021
14. [Ochronosis: A case report]
- Author
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K, Erraoui, K, Nassar, and S, Janani
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Radiography ,Knee Joint ,Humans ,Alkaptonuria ,Ochronosis ,Homogentisic Acid ,Aged - Abstract
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.
- Published
- 2022
15. Descemet's membrane folds in ochronosis: a case report
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Otavio de Azevedo Magalhaes and Dunia Abdel Rahman Abu Hwas
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Aged, 80 and over ,Cornea ,Male ,Visual Acuity ,Humans ,General Medicine ,Descemet Membrane ,Homogentisic Acid ,Ochronosis ,Aged - 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.
- Published
- 2022
16. Ocular Ochronosis in Alkaptonuria
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Fabrizio Giansanti, Stefano Mercuri, and Daniela Bacherini
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Ophthalmology ,Humans ,Alkaptonuria ,Ochronosis - Published
- 2022
17. THE USE OF NEAR INFRARED SPECTROSCOPY IN ALKAPTONURIA - THE MISLEADING OCHRONOSIS - A CASE REPORT AND LITERATURE REVIEW
- Author
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Mateus, Carolina, Carvalho, Ana Filipa, and Fonte Boa, Ana
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Spectroscopy, Near-Infrared ,Cerebrovascular Circulation ,Humans ,Female ,Oximetry ,Alkaptonuria ,Ochronosis - Abstract
Introduction: Near infrared spectroscopy is a non-invasive method to assess regional oxygenation and is being used in transcatheter aortic valve implantation to document periods of cerebral hypoperfusion, where cerebrovascular events are one of the most feared complications. Alkaptonuria is a rare metabolic disease characterized by accumulation of homogentisic acid in tissues and body fluids. The accumulation of pigment might interfere with the absorption of near infrared light, used in near infrared spectroscopy monitoring. We present a case of near infrared spectroscopy failing to accurately monitor cerebral oximetry in a woman, with alkaptonuria, undergoing a transcatheter aortic valve implantation., Portuguese Journal of Cardiac Thoracic and Vascular Surgery, Vol. 28 No. 4 (2021): October - December
- Published
- 2022
18. Long-term follow-up of alkaptonuria patients: single center experience
- Author
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Ayse Ergul Bozaci, Havva Yazici, Ebru Canda, Sema Kalkan Uçar, Merve Saka Guvenc, Afig Berdeli, Sara Habif, and Mahmut Coker
- Subjects
Adult ,Male ,Homogentisate 1,2-Dioxygenase ,alkaptonuria ,ochronosis ,Ascorbic-Acid ,Endocrinology, Diabetes and Metabolism ,Alcaptonuria ,homogentisic acid ,Urine ,Gene ,osteoarthritis ,Endocrinology ,Pediatrics, Perinatology and Child Health ,Humans ,Tyrosine ,Female ,Ochronotic Arthropathy ,Nitisinone ,Child ,Mutations ,Follow-Up Studies ,Retrospective Studies - Abstract
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.
- Published
- 2022
19. Homogentisic acid affects human osteoblastic functionality by oxidative stress and alteration of the Wnt/β‐catenin signaling pathway
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Giulia Bernardini, Ranieri Rossi, Annalisa Santucci, Maria Lucia Schiavone, Barbara Marzocchi, Daniela Giustarini, and Lia Millucci
- Subjects
AB_258242 AB_90264 ,0301 basic medicine ,Physiology ,AB_303014 ,Clinical Biochemistry ,Inflammation ,medicine.disease_cause ,Bone and Bones ,Alkaptonuria ,AB_331729 ,AB_569332 ,alkaptonuria ,bone diseases ,osteoblast ,oxidative stress ,SCR_014246 ,β-catenin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,Homogentisic acid ,Homogentisic Acid ,Wnt Signaling Pathway ,Cells, Cultured ,beta Catenin ,Homogentisate 1,2-dioxygenase ,Melanins ,Ochronosis ,Osteoblasts ,Pigmentation ,Wnt signaling pathway ,Cell Biology ,medicine.disease ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,medicine.symptom ,Signal transduction ,Oxidation-Reduction ,Oxidative stress ,Signal Transduction - Abstract
Alkaptonuria (AKU) is a rare disease correlated with deficiency of the enzyme homogentisate 1,2 dioxygenase, which causes homogentisic acid (HGA) accumulation. HGA is subjected to oxidation/polymerization reactions, leading to the production of a peculiar melanin-like pigmentation (ochronosis) after chronic inflammation, which is considered as a triggering event for the generation of oxidative stress. Clinical manifestations of AKU are urine darkening, sclera pigmentation, early severe osteoarthropathy, and cardiovascular and renal complication. Despite major clinical manifestations of AKU being observed in the bones and skeleton, the molecular and functional parameters are so far unknown in AKU. In the present study, we used human osteoblasts supplemented with HGA as a AKU cellular model. We observed marked oxidative stress, and for the first time, we were able to correlate HGA deposition with an impairment in the Wnt/β-catenin signaling pathway, opening a range of possible therapeutic strategies for a disease still lacking a known cure.
- Published
- 2020
20. Dogliotti and Phillips classifications are unsuitable for grading the histopathological findings of exogenous ochronosis
- Author
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Maximiliano Ramia de Cap, Xenia Parisi, and Steven R. Tahan
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Histology ,Humans ,Dermatology ,Alkaptonuria ,Ochronosis ,Pathology and Forensic Medicine ,Skin - Abstract
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.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.Clinical-histopathological concordance was seen in 80% and 60% of EO lesions when graded according to the Dogliotti and Phillips classifications, respectively.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.
- Published
- 2021
21. Musculoskeletal manifestations in Alkaptonuria
- Author
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Khan, Aysha Habib, Afroze, Bushra, Majid, Hafsa, Zaidi, Yusra, Jamil, Azeema, and Jafri, Lena
- Subjects
Adult ,Male ,alkaptonuria ,musculoskeletal ,Adolescent ,Observational Study ,Infant ,homogentisic acid ,Middle Aged ,Alkaptonuria ,Young Adult ,Cross-Sectional Studies ,Child, Preschool ,Humans ,Pakistan ,Female ,Joint Diseases ,Child ,Musculoskeletal System ,Ochronosis ,Research Article ,Aged - Abstract
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.
- Published
- 2021
22. Disc calcifications: Think of ochronosis
- Author
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Daniel, Wendling
- Subjects
Rheumatology ,Humans ,Calcinosis ,Intervertebral Disc ,Ochronosis ,Intervertebral Disc Displacement - Published
- 2022
23. Basophilic, Thickened Collagen Bundles Seen in Late-Stage Exogenous Ochronosis
- Author
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Vanden L, Grube, Laura, Huang, and Farhaan, Hafeez
- Subjects
Humans ,Collagen ,Dermatology ,General Medicine ,Alkaptonuria ,Ochronosis ,Pathology and Forensic Medicine - Published
- 2022
24. Exogenous ochronosis associated with hydroquinone: a systematic review
- Author
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Shari R. Lipner and Stephanie Ishack
- Subjects
Ochronosis ,medicine.medical_specialty ,Side effect ,Hydroquinone ,business.industry ,Papillary dermis ,MEDLINE ,Dermatology ,Middle Aged ,medicine.disease ,Alkaptonuria ,Hydroquinones ,chemistry.chemical_compound ,symbols.namesake ,chemistry ,medicine ,symbols ,Humans ,Histopathology ,Female ,business ,Adverse effect ,Fisher's exact test - Abstract
Exogenous ochronosis is a potential side effect associated with hydroquinone, and treatment is often unsatisfactory. Our study objectives were to review data on hydroquinone-associated ochronosis to determine risk factors for patients experiencing this adverse event. On September 27, 2020 (MEDLINE/PubMed), and October 30, 2020 (Scopus and Web of Science), databases were searched for "ochronosis + hydroquinone" by both authors to reduce risk basis. PRISMA reporting guidelines were used to select 56 articles with a total of 126 patients with hydroquinone-associated ochronosis. Included articles described hydroquinone-associated ochronosis. Articles were excluded if they had irrelevant content, were non-English language text, and were non-case studies. Full text articles were assessed and recorded. Cross-tabulation analysis was performed on categorical data, and Fisher exact test was performed. Ochronosis was most often reported in middle-aged women (53.2%), of African descent (45.2%), Black races (55.5%), and Fitzpatrick skin types V-VI (52.4%). It was most frequently reported with unknown and hydroquinone concentrations greater than 4% (32.5 and 35.7% cases, respectively). Median duration of use was 5 years, with only four cases reported with courses 3 months or shorter and eight cases reported with use 1 year or less. All patients presented with facial blue-black or gray-blue macules in a reticulate, lace-like fashion. Histopathology consistently showed solar elastosis and brownish-yellow, 'banana-shaped' fibers between degenerated collagen fibers of the papillary dermis. Based on these findings, we conclude that hydroquinone in concentrations above 4% and in treatment courses longer than 3 months may be associated with new-onset ochronosis.
- Published
- 2021
25. A molecular spectroscopy approach for the investigation of early phase ochronotic pigment development in Alkaptonuria
- Author
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Fabrizio Manetti, Andrea Bernini, Elena Petricci, Maria Camilla Baratto, Andrea Atrei, and Annalisa Santucci
- Subjects
Male ,Magnetic Resonance Spectroscopy ,Alkaptonuria, molecular spectroscopy, ochronotic pigment, homogentisic acid HGA, 1,4-benzoquinone acetic acid BQA, radical species ,Acetates ,Alkaptonuria ,Biochemistry ,chemistry.chemical_compound ,ochronotic pigment ,Benzoquinones ,Homogentisic Acid ,chemistry.chemical_classification ,Multidisciplinary ,Hydroquinone ,Middle Aged ,molecular spectroscopy ,visual_art ,visual_art.visual_art_medium ,Medicine ,Female ,Early phase ,Oxidation-Reduction ,Adult ,radical species ,4-benzoquinone acetic acid BQA ,Science ,Urinalysis ,Article ,Acetic acid ,Pigment ,homogentisic acid HGA ,medicine ,Humans ,Homogentisic acid ,Homogentisate 1,2-dioxygenase ,Aged ,Homogentisate 1,2-Dioxygenase ,Electron Spin Resonance Spectroscopy ,medicine.disease ,Dynamic Light Scattering ,Enzyme ,chemistry ,Case-Control Studies ,Mutation ,Spectrophotometry, Ultraviolet ,Ochronosis ,Chemical modification - Abstract
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.
- Published
- 2021
26. Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria
- Author
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Silvia Galderisi, Maria Serena Milella, Martina Rossi, Vittoria Cicaloni, Ranieri Rossi, Daniela Giustarini, Ottavia Spiga, Laura Tinti, Laura Salvini, Cristina Tinti, Daniela Braconi, Lia Millucci, Pietro Lupetti, Filippo Prischi, Giulia Bernardini, and Annalisa Santucci
- Subjects
Cartilage, Articular ,Homogentisate 1,2-Dioxygenase ,Homogentisate 1 ,Biophysics ,Apoptosis ,Alkaptonuria ,Biochemistry ,Cell Line ,Oxidative Stress ,Cartilage ,Chondrocytes ,2-Dioxygenase ,Autophagy ,Humans ,Molecular Biology ,Homogentisic Acid ,Ochronosis ,Homogentisic acid ,Oxidative stress ,Biomarkers ,Signal Transduction ,Articular - Abstract
Alkaptonuria (AKU) is an ultra-rare genetic disease caused by a deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD) leading to the accumulation of homogentisic acid (HGA) on connective tissues. Even though AKU is a multi-systemic disease, osteoarticular cartilage is the most affected system and the most damaged tissue by the disease. In chondrocytes, HGA causes oxidative stress dysfunctions, which induce a series of not fully characterized cellular responses. In this study, we used a human chondrocytic cell line as an AKU model to evaluate, for the first time, the effect of HGA on autophagy, the main homeostasis system in articular cartilage. Cells responded timely to HGA treatment with an increase in autophagy as a mechanism of protection. In a chronic state, HGA-induced oxidative stress decreased autophagy, and chondrocytes, unable to restore balance, activated the chondroptosis pathway. This decrease in autophagy also correlated with the accumulation of ochronotic pigment, a hallmark of AKU. Our data suggest new perspectives for understanding AKU and a mechanistic model that rationalizes the damaging role of HGA.
- Published
- 2021
27. The color of skin: black diseases of the skin, nails, and mucosa
- Author
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Connie C. Qiu, Ashley E. Brown, Gabriella R. Lobitz, Akshay Shanker, and Sylvia Hsu
- Subjects
Mucous Membrane ,Skin Neoplasms ,Tattooing ,Calciphylaxis ,Skin Diseases, Papulosquamous ,Dermatology ,Prognosis ,Plaque, Atherosclerotic ,Diagnosis, Differential ,Nevus, Spindle Cell ,Nail Diseases ,Lupus Erythematosus, Discoid ,Carcinoma, Basal Cell ,Hyperpigmentation ,Nevus, Blue ,Dermatomycoses ,Humans ,Mucormycosis ,Acanthosis Nigricans ,Keratosis, Seborrheic ,Melanoma ,Ochronosis - Abstract
Gradations in skin color are a consequence of differing amounts of melanin and their varying distribution. Although many darkly pigmented skin lesions are melanocytic and can be attributed to melanin content, the color of a black lesion can also be due to blood, necrotic tissue, or exogenous pigment. The source, pattern, and distribution of the color in black lesions usually offer important insight into its etiology. This contribution reviews conditions that can take on a black color, discussing the cause of the hue and any additional impact sun exposure may have.
- Published
- 2019
28. [A male with black cartilage]
- Author
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David, Visser and Jan A N, Verhaar
- Subjects
Male ,Incidental Findings ,Cartilage ,Knee Joint ,Osteoarthritis ,Color ,Humans ,Knee ,Middle Aged ,Alkaptonuria ,Arthroplasty, Replacement, Knee ,Homogentisic Acid ,Ochronosis - Abstract
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.
- Published
- 2021
29. A Mimic of Ankylosing Spondylitis, Ochronosis: Case Report and Review of the Literature
- Author
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Maria C Cuellar, Philip Chu, Teresa K. Tarrant, and Sonali J. Bracken
- Subjects
musculoskeletal diseases ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Immunology ,Osteoarthritis ,Alkaptonuria ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Animals ,Humans ,Spondylitis, Ankylosing ,Homogentisic acid ,030223 otorhinolaryngology ,Homogentisic Acid ,Homogentisate 1,2-dioxygenase ,Sacroiliac joint ,Ankylosing spondylitis ,Ochronosis ,business.industry ,medicine.disease ,Hyperpigmentation ,medicine.anatomical_structure ,030228 respiratory system ,chemistry ,medicine.symptom ,business - Abstract
Ochronosis and alkaptonuria are manifestations of the same condition—a rare autosomal recessive disorder resulting from a constitutional lack of homogentisate 1,2-dioxygenase (HGD) with the consequent accumulation of homogentisic acid (HGA). In ochronosis, HGA undergoes autoxidation as well as enzymatic oxidation to form an ochronotic pigment that accumulates in cartilage and connective tissues. In the beginning, there is homogentisic aciduria and pigmentation of cartilages and other connective tissues. In later years, generalized osteoarthritis of the spine and large joints, termed ochronotic arthropathy, develops. The diagnosis is confirmed by quantitative measurement of HGA in urine and mutation analysis of the HGD gene. One of the differential diagnoses for the skin findings is exogenous ochronosis, a limited hyperpigmentation of skin caused by some chemicals. As for the lumbar spine findings, there can be radiographic similarities with ankylosing spondylitis (AS) including reduced intervertebral disc spaces and loss of lumbar lordosis; however, ochronosis will spare the sacroiliac joint, and the lumbar spine will show dense, wafer-like disk calcification with a vacuum disc phenomenon and broad syndesmophytes. Here, we present a case of a patient with probable ochronosis that was treated many years as ankylosing spondylitis without response, and we provide a review of the current literature on ochronosis pathogenesis, diagnosis, and treatment.
- Published
- 2021
30. Ochronosis
- Author
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Berardo Di Matteo and MAURILIO MARCACCI
- Subjects
Male ,Homogentisate 1,2-Dioxygenase ,Tibia ,Loss of Function Mutation ,Humans ,General Medicine ,Femur ,Patella ,Middle Aged ,Alkaptonuria ,Arthroplasty, Replacement, Knee ,Ochronosis - Published
- 2021
31. Exogenous ochronosis associated with dimethoxytolyl propylresorcinol (UP302)
- Author
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Steven R. Tahan, Xenia Parisi, and Maximiliano Ramia de Cap
- Subjects
medicine.medical_specialty ,Exogenous ochronosis ,business.industry ,Dermatology ,General Medicine ,medicine.disease ,Alkaptonuria ,Hydroquinones ,medicine ,Humans ,business ,Ochronosis - Published
- 2021
32. Characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients
- Author
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Milad Khedr, Sobhan Vinjamuri, Lakshminarayan R. Ranganath, and James A. Gallagher
- Subjects
Male ,medicine.medical_specialty ,Nitisinone ,Spondyloarthropathy ,Alkaptonuria ,Severity of Illness Index ,Cohort Studies ,03 medical and health sciences ,Lumbar ,Internal medicine ,Positron Emission Tomography Computed Tomography ,Genetics ,Medicine ,Humans ,Homogentisic Acid ,Genetics (clinical) ,030304 developmental biology ,Aged ,0303 health sciences ,Ochronosis ,business.industry ,Cyclohexanones ,030305 genetics & heredity ,Middle Aged ,medicine.disease ,Spine ,United Kingdom ,medicine.anatomical_structure ,Phenotype ,Joint pain ,Nitrobenzoates ,Cohort ,Linear Models ,Upper limb ,Female ,Joints ,medicine.symptom ,business ,medicine.drug - Abstract
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
- Published
- 2021
33. Variant Analysis of Alkaptonuria Families with Significant Founder Effect in Jordan
- Author
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Raida Khalil, Eman Albsoul, Nesrin Mwafi, Arwa Alsaraireh, Ibrahim Al Sbou, Dema Ali, and Loiy Obeidat
- Subjects
Male ,0301 basic medicine ,Oligonucleotides ,030105 genetics & heredity ,Alkaptonuria ,chemistry.chemical_compound ,Exon ,Medicine ,Missense mutation ,Child ,Homogentisic Acid ,Sanger sequencing ,Genetics ,Metabolic disorder ,Exons ,General Medicine ,Middle Aged ,Founder Effect ,Pedigree ,Child, Preschool ,symbols ,Female ,Research Article ,Adult ,Heterozygote ,Adolescent ,Article Subject ,Mutation, Missense ,Genes, Recessive ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,03 medical and health sciences ,symbols.namesake ,Humans ,Homogentisic acid ,Family Health ,Homogentisate 1,2-Dioxygenase ,Ochronosis ,Jordan ,General Immunology and Microbiology ,business.industry ,Genetic Variation ,Sequence Analysis, DNA ,medicine.disease ,030104 developmental biology ,chemistry ,business ,Founder effect - Abstract
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).
- Published
- 2021
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34. Black cartilage: Incidentally discovered articular ochronosis during arthroplasty
- Author
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Belinda Campos-Xavier, Despina Christina Pavlidou, Julien Stanovici, Emmelie Chaibi, Christel Tran, and Camille Kumps
- Subjects
Male ,Incidental Findings ,medicine.medical_specialty ,Ochronosis ,business.industry ,medicine.medical_treatment ,Cartilage ,Middle Aged ,Alkaptonuria ,medicine.disease ,Arthroplasty ,Surgery ,medicine.anatomical_structure ,Genetics ,medicine ,Humans ,Joint Diseases ,Arthroplasty, Replacement, Knee ,business ,Homogentisic Acid ,Genetics (clinical) - Published
- 2021
35. Characterising the arthroplasty in spondyloarthropathy in a large cohort of eighty-seven patients with alkaptonuria
- Author
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James A. Gallagher, Lakshminarayan R. Ranganath, Sobhan Vinjamuri, and John S. Davidson
- Subjects
Male ,medicine.medical_specialty ,Nitisinone ,Joint replacement ,Spondyloarthropathy ,medicine.medical_treatment ,Alkaptonuria ,Arthroplasty ,Cohort Studies ,Internal medicine ,Positron Emission Tomography Computed Tomography ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Aged ,Ochronosis ,business.industry ,Cyclohexanones ,Incidence (epidemiology) ,Middle Aged ,medicine.disease ,United Kingdom ,Nitrobenzoates ,Cohort ,Linear Models ,Spondylarthropathies ,Female ,business ,medicine.drug - Abstract
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 <
- Published
- 2020
36. [Ochronosis of the Entire Aortic Root in Alkaptonuria;Report of a Case]
- Author
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Hiroaki, Komatsu, Hitoshi, Kanamitsu, and Makoto, Mohri
- Subjects
Heart Valve Prosthesis Implantation ,Aortic Valve ,Humans ,Female ,Aortic Valve Stenosis ,Alkaptonuria ,Ochronosis ,Aged - Abstract
Alkaptonuria is a rare hereditary disorder of phenylalanine and tyrosine metabolism, which results in ochronosis of cardiovascular structures including valves, aortic intima, and coronary arteries. Aortic valve disease is the most frequently reported cardiac sequela of alkaptonuria. We report a case of 77-year-old woman with known alkaptonuria who underwent aortic valve replacement for severe aortic stenosis. Operative findings showed impressive ochronosis of the aortic valve and the aortic intima. The post-operative course was uneventful and she was discharged 25 days after the surgery.
- Published
- 2020
37. Hydroquinone: myths and reality
- Author
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Faisal R. Ali, Tamara Searle, and Firas Al-Niaimi
- Subjects
medicine.medical_specialty ,Tyrosinase ,Dermatology ,Administration, Cutaneous ,Ointments ,030207 dermatology & venereal diseases ,03 medical and health sciences ,chemistry.chemical_compound ,Retinoids ,0302 clinical medicine ,Adrenal Cortex Hormones ,Hyperpigmentation ,medicine ,Triple combination ,Humans ,Hydroquinone ,business.industry ,Exogenous ochronosis ,Monophenol Monooxygenase ,Hydroquinones ,chemistry ,030220 oncology & carcinogenesis ,Drug Therapy, Combination ,business ,Ochronosis - Abstract
Hydroquinone has pharmacological uses in disorders of pigmentation because of its ability to competitively inhibit the enzyme tyrosinase. Our contemporary review presents the strongest evidence supporting the use of hydroquinone with the most effective and tolerable formulations combining hydroquinone, retinoid and corticosteroid (modified Kligman formula or 'triple combination cream'). The risk of exogenous ochronosis is low if prescribed concentrations of ≤ 5 for a limited period with regular monitoring. Dermatologists should reassure patients that with controlled use, hydroquinone can be well-tolerated and safe for a range of hyperpigmentary conditions.
- Published
- 2020
38. Total Knee Replacement in Alkaptonuric Ochronosis
- Author
-
Cesar, Pesciallo, German, Garabano, Joaquin, Rodriguez, German, Viale, Fernando, Tillet, and Hernan, Del Sel
- Subjects
Humans ,Pain ,Joint Diseases ,Alkaptonuria ,Arthroplasty, Replacement, Knee ,Ochronosis - Abstract
Alkaptonuria is a rare disease characterized by the accumulation of homogentisic acid (HGA). Over time, these patients may develop disabling ochronotic arthropathy. We present 2 cases of patients with end-stage arthropathy treated with total knee arthroplasty (TKA).Both patients complained of disabling knee pain and reported limited walking distance (200-300 m). One had a history of osteotomy for medial knee arthtritis and ignored his underlying condition. The other presented with valgus gonoarthrosis and diagnosis of alkaptonuria.Intraoperatively, the characteristic dark-blue color in the joint was observed. Both patients evolved favorably after TKA with excellent results according to the Knee Society Scores (KSS) at three years of follow-up.We believe TKA is the right treatment for patients with end-stage disease because it offers considerable relief from pain and allows patients to recover function.
- Published
- 2020
39. Cervical Myelopathy Due to Ochronosis: An Intraoperative Suspicion
- Author
-
Amer Alqaisi, Fadi Hadidi, Tareq Kanaan, Munther Al-Saber, Mohammed S Alisi, and Ahmed A. Abdulelah
- Subjects
medicine.medical_specialty ,Anterior cervical discectomy and fusion ,Alkaptonuria ,Spinal Cord Diseases ,chemistry.chemical_compound ,Myelopathy ,medicine ,Back pain ,Humans ,Homogentisic acid ,Neck pain ,Ochronosis ,Neck Pain ,business.industry ,Articles ,General Medicine ,Middle Aged ,medicine.disease ,Low back pain ,chemistry ,Female ,Radiology ,medicine.symptom ,business ,Low Back Pain ,Diskectomy - Abstract
Patient: Female, 55-year-old Final Diagnosis: Alkaptonuria Symptoms: Neck pain Medication:— Clinical Procedure: — Specialty: Neurosurgery • Orthopedics and Traumatology Objective: Rare disease Background: Alkaptonuria (AKU) is a rare metabolic disease caused by a deficiency in homogentisic acid oxidase, which leads to the accumulation of homogentisic acid dark pigments in tissues such as bones, ligaments, and ten-dons. Long-term duration of this condition, termed ochronosis, can result in degenerative arthropathy involving the spine and large joints. Case Report: This report describes a 55-year-old Jordanian woman presenting with chronic neck and lower back pain. History, physical examination, and radiological imaging indicated cervical myelopathy and lumbar spine degeneration. Two-level anterior cervical discectomy and fusion was performed successfully. Intra-operatively, the cervical discs were observed to be black, suggesting a diagnosis of alkaptonuria, which was later confirmed by genetic testing. A detailed history and physical examination revealed the absence of classical features of AKU. Conclusions: Intraoperative detection of black disc material suggests the need for further tests to diagnose AKU, especially in indolent patients who did not have classical clinical features. Surgical management may improve outcomes in patients with cervical myelopathy due to ochronosis.
- Published
- 2020
40. Exogenous Ochronosis as an Elastotic Disease: A Light-Microscopic Approach
- Author
-
Jonathan D. Ho, Lynne J. Goldberg, and Neelam A. Vashi
- Subjects
Pathology ,medicine.medical_specialty ,Exogenous ochronosis ,business.industry ,Patient demographics ,Connective tissue ,Small sample ,Dermatology ,General Medicine ,Elastic Tissue ,Stain ,Pathology and Forensic Medicine ,Hydroquinones ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,Humans ,Medline database ,business ,Ochronosis ,Retrospective Studies - Abstract
Background Exogenous ochronosis (EO) is a deposition disease associated with application of hydroquinone-containing preparations. Characteristic ochronotic bodies (OBs) arise from endogenous connective tissues, most often reported as collagen. We highlight a significant role for elastic fibers as a precursor tissue. Objective To evaluate elastic tissue pathology in EO, specifically as it relates a precursor role in ochronotic body formation. Methods In this retrospective observational study, a literature review using PubMed/MEDLINE database was conducted to ascertain the most commonly ascribed precursor connective tissue. Eleven histopathologic cases of EO were identified. Patient demographics and clinical characteristics were recorded. Slides were reviewed for the presence and grade of solar elastosis (SE), the relationship of OBs to elastotic material, the presence of elastotic fibers transitioning to OBs, and positivity of bodies with Verhoeff-van Gieson elastic tissue stain. Results Elastic fibers are uncommonly reported as the major precursor tissue of OBs. SE was uniformly present in our cases, and the majority demonstrated heavy/high-grade elastosis. Elastotic fibers transitioning to OBs were observed in all cases, and the bodies demonstrated Verhoeff-van Gieson positivity. Limitations Small sample size. Conclusions Ochronotic body formation is associated with SE, and bodies appear to arise from damaged elastic fibers.
- Published
- 2020
41. Pigmentation Chemistry and Radical-Based Collagen Degradation in Alkaptonuria and Osteoarthritic Cartilage
- Author
-
Lakshminarayan R. Ranganath, James A. Gallagher, Robert Bittl, Christian Teutloff, Melinda J. Duer, Hartmut Oschkinat, Brendan P. Norman, Wing Ying Chow, and Norman B. Roberts
- Subjects
Cartilage, Articular ,Magnetic Resonance Spectroscopy ,Collagen helix ,Osteoarthritis ,Alkaptonuria ,Catalysis ,fibrous proteins ,chemistry.chemical_compound ,Pigment ,NMR spectroscopy ,Spinal osteoarthropathy ,Fibrous Proteins | Hot Paper ,medicine ,Humans ,Homogentisic acid ,Homogentisic Acid ,Ochronosis ,Pigmentation ,Cartilage ,Communication ,500 Naturwissenschaften und Mathematik::530 Physik::530 Physik ,Electron Spin Resonance Spectroscopy ,General Chemistry ,Pigments, Biological ,medicine.disease ,radicals ,Communications ,medicine.anatomical_structure ,chemistry ,Biochemistry ,visual_art ,visual_art.visual_art_medium ,sense organs ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie, Therapeutik ,Oxidation-Reduction ,metabolism ,EPR spectroscopy - Abstract
Alkaptonuria (AKU) is a rare disease characterized by high levels of homogentisic acid (HGA); patients suffer from tissue ochronosis: dark brown pigmentation, especially of joint cartilage, leading to severe early osteoarthropathy. No molecular mechanism links elevated HGA to ochronosis; the pigment's chemical identity is still not known, nor how it induces joint cartilage degradation. Here we give key insight on HGA‐derived pigment composition and collagen disruption in AKU cartilage. Synthetic pigment and pigmented human cartilage tissue both showed hydroquinone‐resembling NMR signals. EPR spectroscopy showed that the synthetic pigment contains radicals. Moreover, we observed intrastrand disruption of collagen triple helix in pigmented AKU human cartilage, and in cartilage from patients with osteoarthritis. We propose that collagen degradation can occur via transient glycyl radicals, the formation of which is enhanced in AKU due to the redox environment generated by pigmentation., Alkaptonuria is a rare disease that leads to striking pigmentation and mechanical failure of cartilage tissue. DNP‐enhanced solid‐state NMR enabled us to observe disruption of interstrand hydrogen bonding in collagen proteins from alkaptonuria patient tissue. A mechanism involving transient glycyl radicals is proposed as basis of the degradation and pigmentation of cartilage tissue in alkaptonuria.
- Published
- 2020
42. Aortic Valve Replacement In Alkaptonuric Ochronosis
- Author
-
Elisa Landín, Rey, Amparo Martínez, Monzonís, Aurora, Bajula, José M Suárez, Peñaranda, and Angel L, Fernández
- Subjects
Aortic Valve ,Heart Valve Prosthesis ,Humans ,Alkaptonuria ,Ochronosis - Abstract
Alkaptonuria is an autosomal recessive inborn error of metabolism of the aromatic amino acids. Deficiency of the homogentisate1,2-dioxygenase leads to an increased blood and urinary concentration of homogentisc acid resulting in a slow accumulation of its oxidation products in the connective tissues (ochronosis). The most common clinical manifestation of ochronosis is arthropathy whereas cardiac involvement is very infrequent. We report the case of a patient with ochronotic involvement of the aortic valve who underwent a valve replacement. Some aspects of pathogenesis, and treatment are discussed.
- Published
- 2020
43. Black symmetrical papular eruption of the zygomata
- Author
-
John F. Bourke, John G. White, and L Roche
- Subjects
Male ,Papular eruption ,medicine.medical_specialty ,Zygoma ,business.industry ,Administration, Topical ,Biopsy ,Skin Lightening Preparations ,Radiation-Protective Agents ,Dermatology ,Exanthema ,Middle Aged ,Alkaptonuria ,Hydroquinones ,Withholding Treatment ,medicine ,Humans ,business ,Ochronosis - Published
- 2020
44. Rare Hyperpigmentation of the Conjunctiva and Sclera: Ochronosis
- Author
-
Torsten Schlote and Ioannis Lamprakis
- Subjects
Ochronosis ,medicine.medical_specialty ,Conjunctiva ,business.industry ,medicine.disease ,Dermatology ,Hyperpigmentation ,Sclera ,Cornea ,Ophthalmology ,medicine.anatomical_structure ,medicine ,Humans ,medicine.symptom ,business - Published
- 2020
45. Minimally invasive endoscopic aortic valve replacement for alkaptonuria-associated severe aortic stenosis: a case report and literature review
- Author
-
Tatsuya Miyanaga, Shinichiro Taniguchi, and Takashi Shimada
- Subjects
Pulmonary and Respiratory Medicine ,Aortic valve ,Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Alkaptonuria ,03 medical and health sciences ,0302 clinical medicine ,Aortic valve replacement ,Internal medicine ,medicine.artery ,medicine ,Humans ,Aged ,Aorta ,business.industry ,General Medicine ,Aortic Valve Stenosis ,medicine.disease ,Cardiac surgery ,Stenosis ,medicine.anatomical_structure ,030228 respiratory system ,Cardiothoracic surgery ,Aortic Valve ,Heart Valve Prosthesis ,cardiovascular system ,Cardiology ,Surgery ,Cardiology and Cardiovascular Medicine ,business ,Ochronosis ,Calcification - Abstract
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.
- Published
- 2020
46. The 'dark side' is the key. Ochronosis by alkaptonuria
- Author
-
Karen Pastrana-Olaya and Kenny Buitrago-Toro
- Subjects
medicine.medical_specialty ,Ochronosis ,business.industry ,Medicine ,Humans ,General Medicine ,business ,medicine.disease ,Alkaptonuria ,Dermatology - Published
- 2020
47. Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial
- Author
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James A. Gallagher, Michael E. Briggs, Elizabeth Záňová, Birgitta Olsson, Ciarán Scott, Mattias Rudebeck, Sophie Taylor, Nadia Loftus, Nicolas Sireau, Brendan P. Norman, Roman Stančík, Jozef Rovenský, Alpesh Mistry, Andrew S. Davison, Elizabeth West, Richard Imrich, Nick Rhodes, Michael Fisher, Kim Hanh Le Quan Sang, Christa van Kan, Juliette H. Hughes, Emily Luangrath, J.P. Dillon, Jonathan C. Jarvis, Ol'ga Lukáčová, Eftychia E. Psarelli, Dinny Laan, Anthony K Hall, Trevor Cox, Andrea Zatkova, Anna M. Milan, Eva Vrtíková, Richard Fitzgerald, Jean Baptiste Arnoux, Helena Glasova, Jana Sedláková, Johan Szamosi, Lakshminarayan R. Ranganath, Daniela Braconi, Federica Genovese, Chris Webb, Milad Khedr, Anders Bröijersén, Vanda Mlynáriková, Helen Bygott, Annalisa Santucci, Sobhan Vinjamuri, Ella Shweihdi, and Andrew T. Hughes
- Subjects
Adult ,Male ,medicine.medical_specialty ,Internationality ,Nitisinone ,Endocrinology, Diabetes and Metabolism ,Urinary system ,Urine ,Alkaptonuria ,Drug Administration Schedule ,law.invention ,Excretion ,Endocrinology ,Randomized controlled trial ,law ,Internal medicine ,Internal Medicine ,Clinical endpoint ,medicine ,Humans ,Single-Blind Method ,Longitudinal Studies ,Enzyme Inhibitors ,Homogentisic Acid ,Aged ,Ochronosis ,business.industry ,Cyclohexanones ,Female ,Middle Aged ,Nitrobenzoates ,Treatment Outcome ,medicine.disease ,business ,medicine.drug - Abstract
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
- Published
- 2020
48. Family history of ochronotic arthropathy
- Author
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L, Gómez-Lechón Quirós, C, Hidalgo Calleja, M E, Acosta de la Vega, O, Compán Fernández, S, Pastor Navarro, and C, Montilla Morales
- Subjects
Cartilage, Articular ,Male ,Siblings ,Humans ,Osteoporosis ,Female ,Joint Diseases ,Alkaptonuria ,Low Back Pain ,Ochronosis ,Aged - Abstract
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.
- Published
- 2020
49. Localized argyria with pseudo-ochronosis
- Author
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Leslie Robinson-Bostom, Christopher DiMarco, Kaveri Korgavkar, and Jennifer Lee
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Histology ,Silver ,business.industry ,Biopsy ,Dermatology ,medicine.disease ,Alkaptonuria ,Argyria ,Pathology and Forensic Medicine ,Pseudo-ochronosis ,medicine ,Humans ,business ,Ochronosis ,Aged ,Skin - Published
- 2020
50. The color of skin: gray diseases of the skin, nails, and mucosa
- Author
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M. Badawy Abdel-Naser
- Subjects
medicine.medical_specialty ,Skin Neoplasms ,Lichen planus pigmentosus ,medicine.medical_treatment ,Color ,Dermatology ,Intense pulsed light ,Nevus of Ota ,Melanin ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Nail Diseases ,0302 clinical medicine ,Mongolian Spot ,Hyperpigmentation ,Metals, Heavy ,medicine ,Humans ,Incontinentia Pigmenti ,skin and connective tissue diseases ,030203 arthritis & rheumatology ,Ochronosis ,Mucous Membrane ,integumentary system ,medicine.diagnostic_test ,business.industry ,Mucous membrane ,Incontinentia pigmenti ,medicine.disease ,Anti-Bacterial Agents ,medicine.anatomical_structure ,Skin biopsy ,Drug Eruptions ,Hemochromatosis ,Erythema dyschromicum perstans ,business - Abstract
Gray diseases are a group of skin disorders characterized mainly by gray discoloration with or without involving the mucous membranes and nails. These diseases may be hereditary or acquired. Some of the better-known hereditary entities are dermal melanocytosis, incontinentia pigmenti, hypomelanosis of Ito, hemochromatosis, ochronosis, and silvery hair syndrome. Acquired diseases with gray coloring include late-stage organ failure, lichen planus pigmentosus, erythema dyschromicum perstans, and drug reactions. The discoloration is due to either increased epidermal and or dermal melanin or dermal deposition of a chromogen or a combination of both. Investigations are directed to determining the underlying medical condition and a skin biopsy is usually unnecessary. Likewise, treatment is directed mainly toward the underlying medical disease. Although bleaching (lightening) agents may diminish the discoloration, better results may be obtained from using a Q-switched laser and intense pulsed light, either alone or in combination with topical agents.
- Published
- 2020
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