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.

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.

Descemet's membrane folds in ochronosis: a case report.

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.

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.

[Ochronosis: A case report]. / Ochronose : une observation.

INTRODUCTION: 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. CASE REPORT: 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. CONCLUSION: Alkaptonuria is a degenerative arthropathy that leads to reduction of functional ability. The use of molecular analysis and genetic research is useful.

[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.

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.

Musculoskeletal manifestations in Alkaptonuria: A cross-sectional study.

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 ±â€Š24.5 years (range 0.2-66 years) and male to female ratio of 2:1. Of the total, only 9 were adults (mean age, 44 ±â€Š12 years). Most adult patients had musculoskeletal involvement, with joint pain (n = 9) and ochronotic pigmentation (n = 6), whereas all patients presented with a history of urine darkening on standing (21/21 cases).The high prevalence of musculoskeletal involvement observed in patients with albuminuria is likely to be missed by physicians unless specifically tested for in such cases.

Alkaptonuria 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.

[Severe spine lesion following alkaptonuria. Case report]. / Tyazheloe porazhenie pozvonochnika pri alkaptonurii. Opisanie klinicheskogo sluchaya.

Alkaptonuria is a rare autosomal recessive disease. In these patients, melanin-like compounds as the final products of impaired metabolism of homogentisic acid are deposited mainly in connective tissue, including cartilage tissue of intervertebral discs. Similar to other degenerative spine diseases, lumbar segment is often damaged. The authors report a 67-year-old patient with alkaptonuria. Compression of cauda equina by damaged cartilage masses of intervertebral discs and spine ligaments with deposits of ochronotic pigment is described. Previously diagnosed alkaptonuria in this patient was confirmed by surgical findings (black pigmentation) and histological data.

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.

Alkaptonuria in an adolescent boy.

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.

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.

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.

Characterising the arthroplasty in spondyloarthropathy in a large cohort of eighty-seven patients with alkaptonuria.

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 << .0001) and ochronosis (R = 0.54; P < .0001) was seen. Nitisinone had no significant effect on incident arthroplasty. Arthroplasty due to ochronosis and SPOND is common in AKU. Nitisinone decreased ochronosis but had no effect on arthroplasty in this cohort.

[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.