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.

BACKGROUND: Protein nutrition disorder in alkaptonuria (AKU), resulting in increased homogentisic acid (HGA) before nitisinone therapy and increased tyrosine (TYR) during nitisinone therapy, may benefit from dietetic intervention. The aim of this study was to characterise the diet and their effects prospectively in those who received formal dietetic intervention in the nitisinone-receiving National Alkaptonuria Centre (NAC) patients with those who did not in no-nitisinone Suitability of Nitisinone in Alkaptonuria 2 (SN2 N-) and nitisinone-treated SN2 (SN2 N+) randomised study groups.
METHODS: A total of 63, 69, and 69 AKU patients from the NAC, SN2 N-, and SN2 N+ were studied for anthropometric (weight, BMI), body composition (including muscle mass, %body fat, hand grip strength), chemical characteristics (serum TYR, serum phenylalanine, urine urea or uUREA, and urine creatinine or uCREAT), and corneal keratopathy. Nitisinone 2 mg and 10 mg were employed in the NAC and SN2 N+ groups, respectively. Dieticians managed protein intake in the NAC, while the SN2 N- and SN2 N+ groups only received advice on self-directed protein restriction during four years of study duration.
RESULTS: uUREA decreased in the NAC, SN2 N-, and SN2 N+ groups, showing that protein restriction was achieved in these groups. Body weight and BMI increased in the NAC and SN2 N+ groups. uCREAT decreased significantly in SN2 N- and SN2 N+ compared with the NAC over four years of study. Corneal keratopathy was less frequent in the NAC than in the SN2 N+ group. Active dietetic intervention in NAC stabilised lean body mass (muscle mass, hand grip strength) despite a decrease in uUREA and uCREAT, as well as sTYR.
CONCLUSIONS: Ongoing dietetic intervention prevented loss of lean body mass despite protein restriction and moderated serum tyrosine increase, leading to less prevalent corneal keratopathy. Protein restriction risks fat mass gain.

Alkaptonuria is a rare autosomal recessive congenital disorder of metabolism that affects 1 in 250,000 live births. It manifests as ochronosis and degenerative arthritis due to the accumulation of homogentistic acid in cartilage and heart valves along with precipitation of renal, salivary, pancreatic and gall bladder calculi. It is noted to cause cardiac valve stenosis and regurgitation secondary to calcification leading to cardiac failure in 10% of patients. Through this report, we present a successful perioperative anaesthetic management of a 74-year-old man with cardiac ochronosis, who underwent an aortic valve replacement with coronary artery bypass graft surgery at our centre.

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.

Alkaptonuria (AKU) is an ultra-rare autosomal recessive disease caused by a mutation in the homogentisate 1,2-dioxygenase gene. One of the main obstacles in studying AKU and other ultra-rare diseases, is the lack of a standardized methodology to assess disease severity or response to treatment. Based on that, a multi-purpose digital platform, called ApreciseKUre, was implemented to facilitate data collection, integration and analysis for patients affected by AKU. It includes genetic, biochemical, histopathological, clinical, therapeutic resources and Quality of Life (QoL) scores that can be shared among registered researchers and clinicians to create a Precision Medicine Ecosystem. The combination of machine learning applications to analyse and re-interpret data available in the ApreciseKUre clearly indicated the potential direct benefits to achieve patients\' stratification and the consequent tailoring of care and treatments to a specific subgroup of patients. In order to generate a comprehensive patient profile, computational modeling and database construction support the identification of potential new biomarkers, paving the way for more personalized therapy to maximize the benefit-risk ratio. In this work, different Machine Learning implemented approaches were described.

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.

A rare metabolic condition called alkaptonuria (AKU) is caused by a decrease in homogentisate 1,2 dioxygenase (HGO) activity due to a mutation in homogentisate dioxygenase (HGD) gene. Homogentisic acid is a byproduct of the catabolism of tyrosine and phenylalanine that darkens the urine and accumulates in connective tissues which causes an agonizing arthritis. Employing the use of deep learning artificial intelligence (AI) drug design, this study aims to alleviate the current toxicity of the AKU drugs currently in use, particularly nitisinone, by utilizing the natural flavanol kaempferol molecule as a 4-hydroxyphenylpyruvate dioxygenase inhibitor. Kaempferol was employed to generate three effective de novo drug candidates targeting the enzyme 4-hydroxyphenylpyruvate dioxygenase using an AI drug design tool. We present novel AIK formulations in the present study. The AIK\'s (Artificial Intelligence Kaempferol) examination of drug-likeliness among the three led to its choice as a possible target. The toxicity assessment research of AIK demonstrates that it is not only safer to use than other treatments, but also more efficient. The docking of the AIGT with 4-hydroxyphenylpyruvate dioxygenase, which revealed a binding affinity of around -9.099 kcal/mol, highlights the AIK\'s potential as a therapeutic candidate. An innovative approach to deal with challenging circumstances is thus presented in this study by new formulations kaempferol that have been meticulously designed by AI. The results of the in vitro tests must be confirmed in vivo, even though AI-designed AIK is effective and sufficiently safe as computed.

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.

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.

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.
METHODS: 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.