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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. [ABSTRACT FROM AUTHOR]

Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular disease, and genitourinary stones beginning in the fourth decade of life. Nitisinone, a potent inhibitor of the upstream enzyme, 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces HGA production. As such, nitisinone is a proposed treatment for alkaptonuria. A randomized clinical trial of nitisinone in alkaptonuria confirmed the biochemical efficacy and tolerability of nitisinone for patients with alkaptonuria but the selected primary outcome did not demonstrate significant clinical benefit. Given that alkaptonuria is a rare disease with slow progression and variable presentation, identifying outcome parameters that can detect significant change during a time-limited clinical trial is challenging. To gain insight into patient-perceived improvements in quality of life and corresponding changes in physical function associated with nitisinone use, we conducted a post-hoc per protocol analysis of patient-reported outcomes and a functional assessment. Analysis revealed that nitisinone-treated patients showed significant improvements in complementary domains of the 36-Item Short-Form Survey (SF-36) and 6-min walk test (6MWT). Together, these findings suggest that nitisinone improves both quality of life and function of patients with alkaptonuria. The observed trends support nitisinone as a therapy for alkaptonuria., Competing Interests: Declaration of competing interest KRS, FR, MBP, MAK, PS, KEO, JCB, WAG, and WJI have no conflicts of interest to declare. WFG and SF are employees of Cycle Pharmaceuticals Limited. Partial research support was received from Cycle Pharmaceuticals Limited through a cooperative research and development agreement with the NIH., (Published by Elsevier Inc.)

Aim: Report a case of alkaptonuria diagnosed following consultation with an otolaryngologist. Background: Alkaptonuria is a rare genetic disorder with an autosomal recessive inheritance pattern that leads to an increase in homogentisic acid (HGA). Our aim is to raise awareness about the otolaryngology manifestations of the disease and the treatment of this disease. Case description: A 75-year-old woman presented to an ear, nose, and throat (ENT) consultation with a history of progressive bilateral hearing loss and tinnitus. She had a history of joint pain and morning stiffness, which had previously been attributed to osteoarthritis. Physical examination revealed hyperpigmentation of the conchae, sclerae, and both hands. Laboratory tests showed significantly elevated levels of HGA in her urine, leading to a diagnosis of alkaptonuria. Conclusion and clinical significance: Alkaptonuria is a rare genetic disorder that can present with a variety of symptoms, including joint and cardiovascular problems. This case highlights the significance of recognizing unusual symptoms, such as blue discoloration of the ears, as potential indicators of alkaptonuria. [ABSTRACT FROM AUTHOR]

Thyroid cancer is one of the most common primary endocrine malignancies worldwide, and papillary thyroid carcinoma (PTC) is the predominant histological type observed therein. Although PTC has been studied extensively, our understanding of the altered metabolism and metabolic profile of PTC tumors is limited. We identified that the content of metabolite homogentisic acid (HGA) in PTC tissues was lower than that in adjacent non-cancerous tissues. We evaluated the potential of HGA as a novel molecular marker in the diagnosis of PTC tumors, as well as its ability to indicate the degree of malignancy. Studies have further shown that HGA contributes to reactive oxygen species (ROS) associated oxidative stress, leading to toxicity and inhibition of proliferation. In addition, HGA caused an increase in p21 expression levels in PTC cells and induced G1 arrest. Moreover, we found that the low HGA content in PTC tumors was due to the low expression levels of tyrosine aminotransferase (TAT) and p -hydroxyphenylpyruvate hydroxylase (HPD), which catalyze the conversion of tyrosine to HGA. The low expression levels of TAT and HPD are strongly associated with a higher probability of PTC tumor invasion and metastasis. Our study demonstrates that HGA could be used to diagnose PTC and provides mechanisms linking altered HGA levels to the biological behavior of PTC tumors. [ABSTRACT FROM AUTHOR]

Alkaptonuria is a rare autosomal recessive disease caused by a mutation in the homogentisate 1,2-dioxygenase (HGO) gene, leading to the accumulation of homogentisic acid (HGA). HGA polymerizes to form a black pigment that accumulates in connective tissue and joints (ochronosis), causing their destruction. In this work, we report a case of Achilles tendon rupture in a patient with a prior diagnosis of alkaptonuria. A 71-year-old man presented to the emergency department reporting pain in his posterior right ankle and dysfunction, evolving over three weeks after falling down a short flight of stairs. He had previously been diagnosed with alkaptonuria and had undergone five joint prostheses and an aortic valve replacement. A physical examination revealed right ankle edema, pain upon palpation, a palpable gap at the insertion of the tendon, and a positive Thompson test. An MRI confirmed an avulsive rupture at the insertion of the Achilles tendon. During surgical exploration, black pigmentation was observed in the tendon, which was reinserted using a double-row system reinforced with a percutaneous Bunnel stitch. The patient was discharged the following day with a cast splint, maintaining the foot in physiological plantar flexion for two weeks. In the subsequent two weeks, he used a non-weight-bearing walker boot, and finally, in the following two weeks, he began weight-bearing. Two months post-operation, he was walking without support. Twelve months after the intervention, the patient regained their previous functional status, being able to walk on tiptoes without difficulty. Spontaneous Achilles tendon rupture without associated trauma in patients with ochronosis is rare, with limited literature demonstrating successful outcomes post-surgery. Since the tendon becomes more fragile due to pigment accumulation, it was reinserted using a double-row system, increasing the contact area and more effectively distributing the load. There is no standard technique for treating these patients, but the patient's previous functional capacity was restored, with no new ruptures to date. The significant morbidity of alkaptonuria and potential complications, such as tendon ruptures, warrant future studies to discover and develop new prophylactic and therapeutic treatments., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fabião et al.)

Alkaptonuria is a rare hereditary condition in which homogentisic acid is deposited in collagenous tissues, leading to blackish discoloration, degenerative changes, restricted mobility, and pain in the affected part. The skeletal system is commonly affected, resulting in the stiffening of the vertebral spine, shoulders, knees, hip joints, and thoracic cage. Additionally, the degenerative process involves heart valves, endocardium, and kidneys, with associated pathophysiological changes. These patients present significant challenges in neuraxial anesthesia, airway management, and postoperative pain relief. In this report, we present the anesthetic management of a case of alkaptonuria undergoing total knee arthroplasty and discuss the encountered difficulties. We conclude that the perioperative anesthesia management of alkaptonuria patients requires thorough planning to effectively address the various challenges associated with the administration of anesthesia., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Barde et al.)

Alkaptonuria is an inborn error of metabolism inherited as an autosomal recessive disorder due to a mutation in the homogentisic acid dioxygenase gene. It occurs rarely (global prevalence of alkaptonuria is 1 in 100,000 to 250,000), and mainly affects the joints and connective tissue of the body due to deposition of homogentisic acid giving affected areas a blue-black discoloration (ochronosis).In this case report, we present a male patient, aged 47 years, with joint and scleral involvement. He had been diagnosed many years ago with the disease by gas chromatography. His symptoms kept progressively worsening since he was recently prescribed physiotherapy and vitamin C for his disease, which has not been shown to be an effective treatment. A main reason for his disease deterioration was also the lack of nitisinone availability in his home country, as well as in the subcontinent region generally. We also presen a summary of some previously reported cases and treatment regimens to compare our case and present the comparison as a learning source for future physicians., Competing Interests: Disclosures: The authors report no conflicts of interest or financial support related to this work., (Copyright © 2024 Marshfield Clinic Health System.)

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., Competing Interests: Conflict of Interest: Nil, (Copyright: © Indian Orthopaedic Research Group.)