Alkaptonuria.

Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation in body fluids and tissues leads to a multisystemic and highly debilitating disease whose main features are dark urine, ochronosis (HGA-derived pigment in collagen-rich connective tissues), and a painful and severe form of osteoarthropathy. Other clinical manifestations are extremely variable and include kidney and prostate stones, aortic stenosis, bone fractures, and tendon, ligament and/or muscle ruptures. As an autosomal recessive disorder, alkaptonuria affects men and women equally. Debilitating symptoms appear around the third decade of life, but a proper and timely diagnosis is often delayed due to their non-specific nature and a lack of knowledge among physicians. In later stages, patients' quality of life might be seriously compromised and further complicated by comorbidities. Thus, appropriate management of alkaptonuria requires a multidisciplinary approach, and periodic clinical evaluation is advised to monitor disease progression, complications and/or comorbidities, and to enable prompt intervention. Treatment options are patient-tailored and include a combination of medications, physical therapy and surgery. Current basic and clinical research focuses on improving patient management and developing innovative therapies and implementing precision medicine strategies.

Arthroscopic ankle arthrodesis in two alkaptonuria patients.

Alkaptonuria is a very rare disorder in which homogentisic acid accumulates due to a deficiency in the activity of homogentisic acid 1,2 dioxygenase. This deficiency results in deposition of a yellowish-brown pigment in connective tissue. Such deposition is termed 'ochronosis' and leads to deterioration in the formation and structure of proteoglycans in hyaline cartilage. These actions lead to fragmentation and rapid destructive arthritis. Often, ochronotic arthritis appears at 40-60 years of age, and many patients are treated symptomatically. Here, we report two patients (three ankles) with ochronotic arthritis who were treated with ankle arthrodesis. In all cases, the postoperative clinical score improved, but the time needed for fusion was prolonged and symptomatic subtalar arthropathy developed in the early postoperative period.

Effects of Nitisinone on Oxidative and Inflammatory Markers in Alkaptonuria: Results from SONIA1 and SONIA2 Studies.

Nitisinone (NTBC) was recently approved to treat alkaptonuria (AKU), but there is no information on its impact on oxidative stress and inflammation, which are observed in AKU. Therefore, serum samples collected during the clinical studies SONIA1 (40 AKU patients) and SONIA2 (138 AKU patients) were tested for Serum Amyloid A (SAA), CRP and IL-8 by ELISA; Advanced Oxidation Protein Products (AOPP) by spectrophotometry; and protein carbonyls by Western blot. Our results show that NTBC had no significant effects on the tested markers except for a slight but statistically significant effect for NTBC, but not for the combination of time and NTBC, on SAA levels in SONIA2 patients. Notably, the majority of SONIA2 patients presented with SAA > 10 mg/L, and 30 patients in the control group (43.5%) and 40 patients (58.0%) in the NTBC-treated group showed persistently elevated SAA > 10 mg/L at each visit during SONIA2. Higher serum SAA correlated with lower quality of life and higher morbidity. Despite no quantitative differences in AOPP, the preliminary analysis of protein carbonyls highlighted patterns that deserve further investigation. Overall, our results suggest that NTBC cannot control the sub-clinical inflammation due to increased SAA observed in AKU, which is also a risk factor for developing secondary amyloidosis.

Minocycline induced discoloration of the aortic intima and valve: A case report.

CASE REPORT: Ochronosis refers to the blue-black discoloration of connective tissue. While cardiovascular ochronosis has been described resulting from alkaptonuria, it may also result from chronic minocycline use which is exceedingly rare. Cardiovascular ochronosis often presents with insidious development, often identified incidentally during aortic valve replacement (AVR). Herein, we describe the case of a 71-year-old male undergoing AVR and coronary artery bypass grafting found to have minocycline-induced ochronosis of the aortic valve and aorta. CONCLUSIONS: Given the rarity of this case, descriptions of cardiovascular ochronosis cases secondary to minocycline use are imperative in ensuring that it is on the differential diagnosis when identified by others in future cases. Additional care must be taken intraoperatively to ensure that the correct anatomy is identified as discoloration hinders visualization of the anatomy potentially resulting in unintentional consequences such as heart block or perivalvular leak as traditional visual cues for suture placement are distorted.

Ochronotic arthropathy in the context of spondyloarthritis differential diagnosis: a case-based review.

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.

The black root: Aortic valve sparing in alkaptonuria.

We report an unusual case of black discoloration of an aortic root aneurysm and aortic valve cusps due to homogentisic acid deposition in a patient suffering from alkaptonuria. The patient underwent a valve-sparing aortic root replacement after careful and objective evaluation of the valve cusps. Despite alkaptonuria is classically associated with aortic valve stenosis and replacement, in the present case, the affected valve cusps were suitable for repair. To our knowledge, this is the first reported case of aortic valve-sparing procedure performed in a patient with alkaptonuria.

[Alkaptonuria: evolution and course of the disease towards ochronotic arthropathy. Series of cases managed with joint replacement]. / Alcaptonuria: evolución y curso de la enfermedad hacia artropatía ocronótica. Serie de casos manejados con reemplazo articular.

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.

INTRODUCCIÓN: la alcaptonuria es una enfermedad metabólica inusual, de herencia autosómica recesiva dada por la deficiencia de la oxidasa de HGA. Clásicamente descrita y diagnosticada sobre la tercera a cuarta década de la vida, la cual tiene afectación en ambos sexos, su impresión diagnóstica es clínica, basándose en la coloración azul/negro de las conjuntivas; sin embargo, se confirma mediante el análisis específico de la enzima en la orina, actualmente no existe un tratamiento definitivo, sólo alternativas en cuanto a lo paliativo y sintomático. MATERIAL Y MÉTODOS: estudio descriptivo, observacional, de tipo serie de casos, como objetivo primario se describe la progresión de la enfermedad y su compromiso en el sistema musculoesquelético. RESULTADOS: se presentan dos casos clínicos en mujer y hombre, los cuales ilustran: variedad clínica, avance progresivo y las alteraciones que puede generar en el sistema musculoesquelético. CONCLUSIONES: la alcaptonuria es una enfermedad rara, la cual conlleva una artropatía secundaria severa, sin un tratamiento definitivo dirigido a tratar los síntomas, incluso en sus estadios finales los reemplazos articulares son una opción para proporcionar manejo del dolor obteniendo resultados satisfactorios.

Tale of a Black Heart!

Alkaptonuria is a rare condition of inborn error of metabolism. Association with aortic stenosis has been described; however, diagnosis at the time of valve replacement is infrequent. Recognition of this condition has potential management implications as the durability of prosthetic valves in such cases is unknown. We describe a case report that depicts these unique aspects.

Alkaptonuria with rapidly destructive arthropathy of the hip: A case report and literature review.

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.

Alkaptonuria: clinical manifestations and an updated approach to treatment of a rare disease.

Alkaptonuria (AKU) is a rare autosomal recessive disorder with a global incidence of 1 in 250 000 to 1 million people worldwide. It results from a deficiency of the enzyme homogentisic acid (HGA) oxidase which when absent, leads to an accumulation of HGA. Without this enzymatic degradation, HGA deposits in connective tissues resulting in pigmentation (ochronosis), plaque formation and accelerated cartilage destruction. With this, many patients who suffer from AKU develop ochronotic arthropathies, tendon ruptures, fractures, and chronic joint pain. Similarly, patients can develop cardiac valvular dysfunction and interstitial renal disease. Our two cases highlight the array of pathologies seen in AKU and, in light of newly published research, give us a platform from which we can discuss the developments in management of this rare disease.

Ochronotic heart disease leading to severe aortic valve and coronary artery stenosis.

Cardiac ochronosis is a rare disease, estimated to affect 1 in 250,000 persons. While there is extensive evidence of the musculoskeletal alterations of the disease, cardiac involvement has not been widely studied and most information we currently have derives from case reports and case series. We report the case of a 64-year old patient with a known history of alkaptonuria who presented with dyspnea and weight loss. On evaluation, he was found to have severe aortic stenosis, coronary artery disease, and interventricular septal hypertrophy. Surgery revealed extensive ochronotic pigment deposition affecting the cardiac septum, both internal thoracic arteries, the native coronary arteries, and the aortic valve. Ochronotic heart disease is an often disregarded presentation of alkaptonuria. More information is needed on the course of the disease, as well as long-term outcomes after valve replacement surgery and/or coronary artery bypass grafting in patients with alkaptonuria.

[A male with black cartilage]. / Een man met pijn en zwart kraakbeen.

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.

Inflammatory rheumatic diseases in patients with ochronotic arthropathy.

BACKGROUND: 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. METHODS: 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, and magnetic resonance imaging (MRI) were performed. RESULTS: Eight 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 (n = 1; 12.5%), interstitial lung disease (n = 1; 12.5%), and scleritis (n = 1; 12.5%), was also noted. CONCLUSION: 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.

A black heart: Aortic valve ochronosis secondary to alkaptonuria causing aortic stenosis.

Alkaptonuria is a rare autosomal recessive genetic disorder where an accumulation of homogentisic acid in the tissues leads to ochronosis-a pathological dark pigmentation. It can affect various tissues and the weight bearing joints of the body, leading to degenerative arthropathy. On the rare occasion, it causes cardiac manifestations. We describe a case of aortic valve stenosis due to ochronosis secondary to alkaptonuria requiring aortic valve replacement.

Minimally invasive endoscopic aortic valve replacement for alkaptonuria-associated severe aortic stenosis: a case report and literature review.

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.

[Ochronosis of the Entire Aortic Root in Alkaptonuria;Report of a Case].

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.

Clinical and radiological outcomes of total joint arthroplasty in patients with ochronotic arthropathy.

PURPOSE: Alkaptonuria is a rare metabolic disorder, and only a few case reports of total joint arthroplasty (TJA) for ochronotic arthropathy are described in the literature. We aim to analyse the functional and radiological outcomes of TJA in patients with ochronotic arthropathy. METHODS: We retrospectively collected the data of twenty-seven TJA in sixteen patients with ochronotic arthropathy from April 2007 to December 2017. We assessed the functional outcome through pre- and post-operative modified Harris hip score (HHS) and knee society score (KSS). The hip radiographs were analysed for migration and radiolucent zones, and the knee radiographs were assessed using knee society roentgenographic evaluation and scoring system. RESULTS: The mean follow-up was 39.4 months (12-132 months). Two patients died before the final follow-up. There was a statistically significant improvement in mean HHS from 17.8 preoperatively to 78 at the final follow-up (p < 0.001). Similarly, there was a significant improvement in mean KSS, following the surgery, from 27.2 preoperatively to 89.4 (p < 0.001). One patient developed deep infection, and another patient presented with aseptic loosening of the acetabular component after 7 years. In the radiological evaluation at the final follow-up, signs of lysis or loosening were not noted in any of the other patients. CONCLUSION: End-stage arthritis in ochronotic arthropathy is not uncommon. These patients can have multiple joint involvements, and the need for multiple surgeries should be considered. TJA in ochronotic arthropathy leads to a significant improvement in the functional outcome compared with the preoperative disability.