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Metabolites Jun 2024In the original publication [...].
In the original publication [...].
PubMed: 38921482
DOI: 10.3390/metabo14060339 -
Cells Jun 2024Alkaptonuria (AKU) is a genetic disorder that affects connective tissues of several body compartments causing cartilage degeneration, tendon calcification, heart... (Review)
Review
Alkaptonuria (AKU) is a genetic disorder that affects connective tissues of several body compartments causing cartilage degeneration, tendon calcification, heart problems, and an invalidating, early-onset form of osteoarthritis. The molecular mechanisms underlying AKU involve homogentisic acid (HGA) accumulation in cells and tissues. HGA is highly reactive, able to modify several macromolecules, and activates different pathways, mostly involved in the onset and propagation of oxidative stress and inflammation, with consequences spreading from the microscopic to the macroscopic level leading to irreversible damage. Gaining a deeper understanding of AKU molecular mechanisms may provide novel possible therapeutical approaches to counteract disease progression. In this review, we first describe inflammation and oxidative stress in AKU and discuss similarities with other more common disorders. Then, we focus on HGA reactivity and AKU molecular mechanisms. We finally describe a multi-purpose digital platform, named ApreciseKUre, created to facilitate data collection, integration, and analysis of AKU-related data.
Topics: Alkaptonuria; Humans; Oxidative Stress; Homogentisic Acid; Inflammation; Animals
PubMed: 38920699
DOI: 10.3390/cells13121072 -
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 -
Journal of Orthopaedic Case Reports Jun 2024Alkaptonuria is a rare autosomal recessive genetic disorder found in 2-5/million live births. It results in dark brown pigmentation of connective tissues including...
INTRODUCTION
Alkaptonuria is a rare autosomal recessive genetic disorder found in 2-5/million live births. It results in dark brown pigmentation of connective tissues including cartilage and joint capsule that can often lead to arthropathy of large joints. However, bone fractures are unusual. This article describes a fracture neck of the femur in a patient with undiagnosed alkaptonuria managed at a rural center.
CASE REPORT
A 60-year-old daily wage laborer with previously pain-free hips presented with sudden onset pain in the left hip while walking with no prior history of trauma. Radiographs showed a displaced fracture of the neck of the left femur. She underwent Left hip hemiarthroplasty. Intraoperatively, her soft-tissue including the joint capsule and the femoral head had dark brown pigmentation. Postoperatively, her urine was tested and the same turned black supporting the clinical diagnosis of alkaptonuria. At her 1-year follow-up, she had a painless, stable, and mobile hip.
CONCLUSION
We report a rare and unique case of neck of femur fracture in a patient with alkaptonuria treated with hemiarthroplasty in a resource-limited hospital in rural India. It is essential to consider the possibility of this condition when we come across a patient with an atypical fracture presentation. This article also presents an overview of alkaptonuria with a discussion on etiopathogenesis, clinical presentation, diagnosis, and management.
PubMed: 38910974
DOI: 10.13107/jocr.2024.v14.i06.4508 -
Cornea Jun 2024To report the association of Pseudofilariasis as a presenting sign of Alkaptonuria.
PURPOSE
To report the association of Pseudofilariasis as a presenting sign of Alkaptonuria.
METHOD
Case Report.
RESULTS
A 49-year-old Indian man was referred because of wormlike objects in his left conjunctiva. Ocular and family history was non-contributory. He had not been to India in 15 years. Past medical history revealed hypertension, hypercholesterolemia, arthritis, and a myocardial infarct. He had undergone two stents, bilateral Achilles tendon repairs and bilateral knee replacements. ROS showed longstanding back stiffness and pain. On ocular examination the vision was 20/25 in each eye and positive findings were in the left eye bulbar conjunctival which showed stationary black vermiform (filarial in appearance) foreign bodies along with 2 small corneal limbal pigmented deposits. Conjunctival biopsy showed dilated lymph channels with interstitial proteinaceous material of a light brown color consistent with Ochronotic pigment; hence diagnostic of Alkaptonuria.
CONCLUSIONS
Pseudofilariasis may be a presenting sign of Alkaptonuria and occur years before a clinical diagnosis is made. Filariasis is always involves white worms and never black. Knowing the ophthalmic signs of this rare disease may lead to an accurate diagnosis earlier thusly avoiding unnecessary tests and examinations.
PubMed: 38900710
DOI: 10.1097/ICO.0000000000003587 -
Joint replacement risk is markedly increased in alkaptonuria (AKU) in those with prior arthroplasty.Molecular Genetics and Metabolism... Sep 2024Increased homogentisic acid (HGA) in alkaptonuria (AKU) causes severe arthritis. Nitisinone reduces the production of HGA, but whether it also decreases arthroplasty was...
BACKGROUND
Increased homogentisic acid (HGA) in alkaptonuria (AKU) causes severe arthritis. Nitisinone reduces the production of HGA, but whether it also decreases arthroplasty was examined in 237 AKU patients.
PATIENTS AND METHODS
Patients attending the United Kingdom National Alkaptonuria Centre (NAC) and the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) study were studied. Assessments included questionnaires eliciting details of arthroplasty. Nitisinone was administered from baseline, 2 mg in the NAC and 10 mg in SONIA 2. In SONIA 2, subgroups consisted of those with baseline arthroplasty on and not on nitisinone (BR + N+, BR + N-), as well as those without baseline arthroplasty on and not on nitisinone (BR-N+, BR-N-).
RESULTS
In the SONIA2 subgroups, new joint replacement (JR) probabilities after baseline were significantly different (BR + N+, BR + N-, BR-N+, BR-N-) (χ = 23.3, < 0.001); mean (SD) was 3.8 (0.1) years in BR-N-, 3.7 (0.1) years in BR-N+, 3.4 (0.3) years in BR + N-, and 3.0 (0.3) years in BR + N+. Further, the BR + N- showed more JR than the BR-N- subgroup ( < 0.01), while BR + N+ similarly showed more JR than the BR-N+ subgroup ( < 0.001).In the NAC, the BR- group had a mean age of 51.6 7.0) years at baseline but 57.7 (8.7) years at final follow up during nitisinone therapy and showed only 7 incident JR. The BR+ group had an age at baseline of 57.4 (8.5) years and had undergone 94 JRs at baseline.
CONCLUSION
The incidence of arthroplasty was earlier and more frequent after the first JR and was not affected by nitisinone.
PubMed: 38846518
DOI: 10.1016/j.ymgmr.2024.101097 -
Clinical Neurology and Neurosurgery Jul 2024Alkaptonuria is a rare inborn disorder of phenylalanine and tyrosine metabolism. It is characterized by an accumulation of homogentisic acid and its oxidation products,... (Review)
Review
OBJECTIVES
Alkaptonuria is a rare inborn disorder of phenylalanine and tyrosine metabolism. It is characterized by an accumulation of homogentisic acid and its oxidation products, possibly resulting into connective tissue damaging. "Ochronosis" is a main feature, which is characterized by tissue discoloration and even alkaptonuric arthropathy. Cervical spine involvement is exceptional and there is a paucity of reports on surgical interventions in these patients. We explored the literature concerning cervical spine involvement in patients with alkaptonuria.
PATIENTS AND METHODS
We performed a review of the literature, in which patients with alkaptonuric degenerative changes of the cervical spine were examined. Articles were obtained from MEDLINE. Search terms included: "cervical", "alkaptonuria", "alkaptonuric changes" and "black disc". Additional studies were identified by checking reference lists. Furthermore, we present the case of a 46 year old patient with critical cervical spinal canal stenosis who underwent C6-C7 anterior cervical microdiscectomy and interbody fusion, in order to prevent myelopathic changes. CARE statement guidelines were followed.
RESULTS
Peroperatively, we did not encounter any macroscopic abnormalities of the skin, muscles or ligaments. A black discoloration of the nucleus pulposus was observed. Peroperative and postoperative course was uneventful.
CONCLUSION
Alkaptonuric degenerative abnormalities most commonly involve the lumbar spine, although the cervical spine can be affected in rare cases. Most frequently, the diagnosis of alkaptonuria can be made based on the clinical phenotype many years before symptoms secondary to ochronotic arthropathy develop. A retrospective diagnosis based on peroperative black discoloration of spinal structures has been described. A black discoloration of the intervertebral disc should encourage the neurosurgeon to further explore the possibility of alkaptonuria, even in the absence of a clear phenotype. Surgical results are mostly satisfactory. Further studies are required in order to better understand this pathology and its postoperative course.
Topics: Humans; Middle Aged; Alkaptonuria; Cervical Vertebrae; Diskectomy; Intervertebral Disc; Ochronosis; Spinal Fusion; Spinal Stenosis
PubMed: 38820945
DOI: 10.1016/j.clineuro.2024.108349 -
Annals of Medicine and Surgery (2012) May 2024Alkaptonuria is an autosomal extremely rare recessive metabolic disorder with incidence reported to occur as 1:100 000-1:250 000 live births worldwide. This rare...
INTRODUCTION
Alkaptonuria is an autosomal extremely rare recessive metabolic disorder with incidence reported to occur as 1:100 000-1:250 000 live births worldwide. This rare metabolic disorder is characterized by the accumulation of homogentisic acid due to a deficiency in homogentisic acid 1,2 dioxygenase. Homogentisic acid subsequently oxidizes and accumulates in the connective tissue. The knee is the most significant peripheral joint to be affected by the disorder. The authors present the first case of ochronotic arthropathy in Syria.
CASE PRESENTATION
A 46-year-old male presented with bilateral pain in the knees. the pain was affecting his day-to-day activities, and not responding to conservative management. Anteroposterior standing radiographs demonstrated extensive degenerative disease. Intraoperatively, the diagnosis was done after noticing that the quadriceps tendon and the articular cartilage of the femur, tibia, and patella were blackened during cemented total knee replacement of the knee.
CONCLUSION
Ochronotic arthropathy should be kept in mind in middle age patients with severe osteoarthritis to not be surprised by the rare alkaptonuria diagnosis if arthroplasty was indicated.
PubMed: 38694340
DOI: 10.1097/MS9.0000000000001775 -
Journal of Inherited Metabolic Disease Mar 2024Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway....
Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] μmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] μmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.
PubMed: 38487984
DOI: 10.1002/jimd.12728 -
Nature Reviews. Disease Primers Mar 2024Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation... (Review)
Review
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.
Topics: Male; Humans; Female; Alkaptonuria; Quality of Life; Ochronosis; Kidney; Homogentisic Acid
PubMed: 38453957
DOI: 10.1038/s41572-024-00498-x