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Frontiers in Surgery 2022Alkaptonuria is a rare autosomal recessive metabolic disorder which leads to accumulation of homogentisic acid in the body.
INTRODUCTION
Alkaptonuria is a rare autosomal recessive metabolic disorder which leads to accumulation of homogentisic acid in the body.
CASE PRESENTATION
We report a rare case of an alkaptonuria-related knee arthritis who underwent left total knee arthroplasty and received postoperative systematic physical therapy in a 57-year-old male patient. The patient has suffered from bilateral knee pain for over 4 years. The patient developed melanin pigmentation on the skin of the whole body, especially on the face and auricle. He self-reported that fresh urine was normal color but after standing overnight, the color deepened to black or soy color. He underwent routine urine examination for many times, but no obvious abnormality was found. The patient has suffered from low back pain for more than 20 years. He had been considered for lumbar disc herniation and ankylosing spondylitis after many in-hospital visits. After symptomatic medication, there was no obvious relief. We followed the patient for 4 years after surgery.
RESULT
The patient presented with pain relief and enhanced range of motion at the 4-year follow-up. The improvements of daily living and the pain relief suggest that the surgery is appropriate for this rare disease.
CONCLUSION
It is rare that the knee pain is diagnosed as alkaptonuria. After total knee arthroplasty and physical therapy, the patient had a good outcome. This case provides experience for the diagnosis and treatment of alkaptonuria-related knee arthritis.
PubMed: 36684325
DOI: 10.3389/fsurg.2022.913120 -
Journal of Pharmaceutical Policy and... Apr 2021We considered the extent of the contribution of publicly funded research to the late-stage clinical development of pharmaceuticals and medicinal products, based on the...
BACKGROUND
We considered the extent of the contribution of publicly funded research to the late-stage clinical development of pharmaceuticals and medicinal products, based on the European Commission (EC) FP7 research funding programme. Using two EC FP7-HEALTH case study examples-representing two types of outcomes-we then estimated wider public and charitable research funding contributions.
METHODS
Using the publicly available database of FP7-HEALTH funded projects, we identified awards relating to late-stage clinical development according to the systematic application of inclusion and exclusion criteria, classified them according to product type and clinical indication, and calculated total EC funding amounts. We then identified two case studies representing extreme outcomes: failure to proceed with the product (hepatitis C vaccine) and successful market authorisation (Orfadin® for alkaptonuria). Total public and philanthropic research funding contributions to these products were then estimated using publicly available information on funding.
RESULTS
12.3% (120/977) of all EC FP7-HEALTH awards related to the funding of late-stage clinical research, totalling € 686,871,399. Pharmaceutical products and vaccines together accounted for 84% of these late-stage clinical development research awards and 70% of its funding. The hepatitis C vaccine received total European Community (FP7 and its predecessor, EC Framework VI) funding of €13,183,813; total public and charitable research funding for this product development was estimated at € 77,060,102. The industry sponsor does not consider further development of this product viable; this now represents public risk investment. FP7 funding for the late-stage development of Orfadin® for alkaptonuria was so important that the trials it funded formed the basis for market authorisation, but it is not clear whether the price of the treatment (over €20,000 per patient per year) adequately reflects the substantial public funding contribution.
CONCLUSIONS
Public and charitable research funding plays an essential role, not just in early stage basic research, but also in the late-stage clinical development of products prior to market authorisation. In addition, it provides risk capital for failed products. Within this context, we consider further discussions about a public return on investment and its reflection in pricing policies and decisions justified.
PubMed: 33910624
DOI: 10.1186/s40545-021-00317-8 -
Journal of Orthopaedic Case Reports Nov 2022Ochronosis is a rare metabolic disorder, characterized by accumulation of homogentisic acid in the connective tissues due to the lack of the enzyme homogentisic acid...
INTRODUCTION
Ochronosis is a rare metabolic disorder, characterized by accumulation of homogentisic acid in the connective tissues due to the lack of the enzyme homogentisic acid oxidase. The musculoskeletal manifestation of alkaptonuria is black pigmentation of cartilage of the knee and the hip leading to arthropathy.
CASE REPORT
In this article, we report three patients with involvement of hip, knee, and spine, but with more severe involvement of the hips. Bilateral hip arthroplasty was done in one out of the three patients.
CONCLUSION
Being a rare disorder and often missed, the functional outcome of hip arthroplasty in these patients is similar to primary osteoarthritis. The importance lies in correct diagnosis and anticipation of intraoperative difficulties.
PubMed: 37013237
DOI: 10.13107/jocr.2022.v12.i11.3400 -
Journal of Cardiothoracic Surgery Jun 2024Alkaptonuria is a rare congenital metabolic disorder characterized by homogentisic acid accumulation in body cartilage and connective tissues due to a deficient...
BACKGROUND
Alkaptonuria is a rare congenital metabolic disorder characterized by homogentisic acid accumulation in body cartilage and connective tissues due to a deficient homogentisic acid dioxygenase enzyme. This disorder manifests in various clinical symptoms, including spondyloarthropathy, ocular and dermal pigmentation, genitourinary tract obstruction by ochronosis stones, and cardiovascular system involvement. Cardiac ochronosis is a rare manifestation of alkaptonuria that may present as aortic stenosis, sometimes accompanied by other cardiovascular complications.
CASE PRESENTATION
We report an unexpected case of ochronosis diagnosed during cardiac surgery. Due to the fragile, thin, and atheromatous nature of the ascending aorta in patients with ochronosis, we opted for a sutureless aortic valve replacement procedure. This approach appears to be more suitable for patients with ochronosis.
CONCLUSIONS
Although cardiac ochronosis is rare, surgeons should remain vigilant and consider the possibility of this condition when examining patients with aortic valve stenosis, paying close attention to the clinical manifestations of alkaptonuria.
Topics: Humans; Ochronosis; Aortic Valve Stenosis; Alkaptonuria; Heart Valve Prosthesis Implantation; Aortic Valve; Male; Sutureless Surgical Procedures; Female; Aged
PubMed: 38918861
DOI: 10.1186/s13019-024-02834-4 -
Genes & Diseases Jul 2022Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD...
Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous knockout ( ) mice to model the wider metabolic effects of deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from AKU ( = 15) and non-AKU control ( = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in were further investigated in AKU mice ( = 18) and patients from the UK National AKU Centre ( = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of C-labelled HGA to ( = 4) and ( = 4) mice (Experiment 3) to confirm direct association with HGA. mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism.
PubMed: 35685462
DOI: 10.1016/j.gendis.2021.02.007 -
The American Journal of Case Reports Sep 2020BACKGROUND Alkaptonuria (AKU) is a rare metabolic disease caused by a deficiency in homogentisic acid oxidase, which leads to the accumulation of homogentisic acid dark...
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 tendons. 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.
Topics: Alkaptonuria; Diskectomy; Female; Humans; Low Back Pain; Middle Aged; Ochronosis; Spinal Cord Diseases
PubMed: 32908119
DOI: 10.12659/AJCR.924575 -
Concentric lamellae - novel microanatomical structures in the articular calcified cartilage of mice.Scientific Reports Aug 2019The structure, ultrastructure and function of hyaline articular cartilage (HAC) and subchondral bone (SCB), and their involvement in the pathogenesis of osteoarthritis...
The structure, ultrastructure and function of hyaline articular cartilage (HAC) and subchondral bone (SCB), and their involvement in the pathogenesis of osteoarthritis (OA) have been extensively researched. However, much less attention has been focused on the intervening tissue, articular calcified cartilage (ACC) and its role in the initiation and progression of OA. Using both light microscopy (LM) and transmission electron microscopy (TEM), a study of ACC in wild type (WT) mice, and mice with genetic osteoarthropathies (AKU) was undertaken to further understand the role played by ACC in the early stages of OA.Tibio-femoral joints were obtained from BALB/c WT and BALB/c AKU mice aged between 7 and 69 weeks. One joint was processed for routine histological analysis. The tip of the medial femoral condyle (MFC), which contained HAC, ACC, and SCB, was dissected from the contra-lateral joint and processed for TEM.In WT and AKU mice novel microanatomical structures, designated concentric lamellae, were identified surrounding chondrocytes in the ACC. The lamellae appeared to be laid down in association with advancement of the tidemark indicating they may be formed during calcification of cartilage matrix. The lamellae were associated with hypertrophic chondrocytes throughout the ACC.Novel microanatomical structures, termed concentric lamellae, which were present around hypertrophic chondrocytes in the ACC are described for the first time. Their apparent association with mineralisation, advancement of the tidemark, and greater abundance in a model of osteoarthropathy indicate their formation could be important in the pathogenesis of OA and AKU.
Topics: Alkaptonuria; Animals; Cartilage, Articular; Chondrocytes; Disease Models, Animal; Humans; Hypertrophy; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Osteoarthritis
PubMed: 31371812
DOI: 10.1038/s41598-019-47545-2 -
Frontiers in Medicine 2023Ochronosis is a rare autosomal recessive disorder of tyrosine metabolism characterized by multilevel spinal degeneration and arthritis of large weight-bearing joints,...
Ochronosis is a rare autosomal recessive disorder of tyrosine metabolism characterized by multilevel spinal degeneration and arthritis of large weight-bearing joints, which is referred to as ochronotic arthropathy. In this case report, we describe diagnosis and treatment of ochronotic arthropathy in a patient who underwent total hip arthroplasty (THA) and total knee arthroplasty (TKA). The Harris hip score was 26 preoperatively and 45, 68, 76, 90, 92, and 94 at 1, 3, 6, 9, 11, and 14 months, respectively, postoperatively. The forgotten joint score (FJS) of the hip was 27.8, 52.8, 81.1, 89.0, 90.6, and 92.4 at 1, 3, 6, 9, 11, and 14 months, respectively, postoperatively. TKA was performed 8 months after THA. The Knee Society Score was 36 before TKA and 74, 82, and 90 at 1, 3, and 6 months, respectively, after TKA. The FJS of the knee was 36.6, 63.9, and 84.5 at 1, 3, and 6 months, respectively, after TKA. The patient's knee range of motion returned to normal, with significant reduction in pain and improved satisfaction levels after TKA. THA and TKA can achieve good clinical outcomes in patients with ochronosis accompanied by severe joint pain.
PubMed: 37795417
DOI: 10.3389/fmed.2023.1212580 -
Journal of Orthopaedic Case Reports Oct 2021Alkaptonuria is a rare autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid (HGA) due to an inherited deficiency of the enzyme HGA...
INTRODUCTION
Alkaptonuria is a rare autosomal recessive metabolic disorder characterized by accumulation of homogentisic acid (HGA) due to an inherited deficiency of the enzyme HGA oxidase. Unlike rheumatoid arthritis which affects the small joints of the hands and feet, ochronotic arthropathy predominantly involves the large weight-bearing joints such as hips, knees, and spine. The knee is the most common joint to be affected. Ochronotic arthropathy is usually managed conservatively, but for severely affected hip and knee joints, replacement is considered.
CASE REPORT
This report describes a case of 57-year-old male who presented with bilateral knee osteoarthritis who was incidentally diagnosed with ochronosis intraoperatively during total knee arthroplasty, its challenges faced and post-operative functional outcome after 18 months follow-up.
CONCLUSION
This case report highlights the need for high index of suspicion for preoperative diagnosis of ochronotic arthropathy. Difficult spinal anesthesia should be anticipated. Friable and stiff tendon due to ochronotic involvement can put the extensor tendon at risk of rupture during retraction of patella intraoperatively. Post-operative active quadriceps rehabilitation should be done with caution due to friable tendon.
PubMed: 35415103
DOI: 10.13107/jocr.2021.v11.i10.2464 -
Acta Medica Portuguesa Jun 2023
Topics: Humans; Alkaptonuria; Aortic Valve; Aortic Valve Stenosis; Echocardiography; Treatment Outcome; Prosthesis Design
PubMed: 35713487
DOI: 10.20344/amp.17310