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International Journal of Molecular... Dec 2022Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine...
Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine degradation. AKU patients carry variants within the gene coding for homogentisate-1,2-dioxygenase (HGD), which are responsible for reducing the enzyme catalytic activity and the consequent accumulation of HGA and formation of a dark pigment called the ochronotic pigment. In individuals with alkaptonuria, ochronotic pigmentation of connective tissues occurs, leading to inflammation, degeneration, and eventually osteoarthritis. The molecular mechanisms underlying the multisystemic development of the disease severity are still not fully understood and are mostly limited to the metabolic pathway segment involving HGA. In this view, untargeted metabolomics of biofluids in metabolic diseases allows the direct investigation of molecular species involved in pathways alterations and their interplay. Here, we present the untargeted metabolomics study of AKU through the nuclear magnetic resonance of urine from a cohort of Italian patients; the study aims to unravel molecular species and mechanisms underlying the AKU metabolic disorder. Dysregulation of metabolic pathways other than the HGD route and new potential biomarkers beyond homogentisate are suggested, contributing to a more comprehensive molecular signature definition for AKU and the development of future adjuvant treatment.
Topics: Humans; Alkaptonuria; Metabolomics; Homogentisic Acid; Biomarkers; Dioxygenases; Magnetic Resonance Spectroscopy
PubMed: 36555443
DOI: 10.3390/ijms232415805 -
Indian Journal of Dermatology,... 2013
Topics: Alkaptonuria; Glycolates; Humans; Male; Middle Aged; Ochronosis
PubMed: 23760323
DOI: 10.4103/0378-6323.113086 -
Annals of Medicine and Surgery (2012) Aug 2022Alkaptonuria is a rare hereditary disease with a defective enzyme that results in increased homogentisic acid levels in the body. Homogentisic acid accumulates in...
Alkaptonuria is a rare hereditary disease with a defective enzyme that results in increased homogentisic acid levels in the body. Homogentisic acid accumulates in multiple body parts and initializes tissue damage. Clinical manifestations such as pigmentation of the skin areas and joint destruction result in ochronosis. Nitisinone decreases serum and urinary homogentisic acid levels, improving morbidity by preventing and slowing the progression of alkaptonuria. Nitisinone-induced hypertyrosinemia causes keratopathy and mental ill effects, which can be managed by diet restriction and regular check-ups. A personalized approach is required for treatment by nitisinone. Low-dose oral nitisinone is associated with overall good results and a better safety profile.
PubMed: 36045846
DOI: 10.1016/j.amsu.2022.104340 -
Annals of Translational Medicine Dec 2018The 21 century is an exciting time to be in the field of metabolic medicine. As with many fields, one of the keys to anticipating the future is to understand the past.... (Review)
Review
The 21 century is an exciting time to be in the field of metabolic medicine. As with many fields, one of the keys to anticipating the future is to understand the past. The term "inborn error of metabolism" was first coined in 1908 by Sir Archibald Garrod, in reference to four disorders (alkaptonuria, pentosuria, cystinuria and albinism). The first (and still most definitive) textbook on the subject, "The Metabolic Basis of Inherited Disease" was initially published in 1960 and covered 80 disorders in 1,477 pages. After the eighth edition of this text became unwieldy at 6,338 pages in 4 volumes covering more than 1,000 disorders, the book was changed to an online reference text with 259 chapters and is still growing. Current newborn screening on a few dried blood spots on filter paper identifies more than 1 in 2,000 newborns as having a metabolic disorder. The availability of metabolomic and genomic analyses is resulting in the diagnosis of many new disorders. Enzyme replacement therapy (ERT) has provided treatments for previously untreatable metabolic disorders, and the promise of gene therapy on the near horizon will certainly revolutionize the field.
PubMed: 30740398
DOI: 10.21037/atm.2018.11.36 -
Journal of Industrial Microbiology &... Jul 2022Pyomelanin is a brown-black phenolic polymer and results from the oxidation of homogentisic acid (HGA) in the L-tyrosine pathway. As part of the research for natural and... (Review)
Review
Pyomelanin is a brown-black phenolic polymer and results from the oxidation of homogentisic acid (HGA) in the L-tyrosine pathway. As part of the research for natural and active ingredients issued from realistic bioprocesses, this work re-evaluates the HGA pigment and makes an updated inventory of its syntheses, microbial pathways, and properties, with tracks and recent advances for its large-scale production. The mechanism of the HGA polymerization is also well documented. In alkaptonuria, pyomelanin formation leads to connective tissue damage and arthritis, most probably due to the ROS issued from HGA oxidation. While UV radiation on human melanin may generate degradation products, pyomelanin is not photodegradable, is hyperthermostable, and has other properties better than L-Dopa melanin. This review aims to raise awareness about the potential of this pigment for various applications, not only for skin coloring and protection but also for other cells, materials, and as a promising (semi)conductor for bioelectronics and energy.
Topics: Homogentisic Acid; Humans; Melanins; Pigmentation; Tyrosine
PubMed: 35482661
DOI: 10.1093/jimb/kuac013 -
British Medical Journal Oct 1952
Topics: Alkaptonuria; Ochronosis; Pigmentation
PubMed: 12978317
DOI: 10.1136/bmj.2.4787.760 -
BMJ Case Reports Feb 2021Alkaptonuria 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...
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.
Topics: Adolescent; Alkaptonuria; Antioxidants; Ascorbic Acid; Disease Progression; Early Diagnosis; Humans; Male; Ochronosis; Sclera
PubMed: 33541951
DOI: 10.1136/bcr-2020-240147 -
Biomedicines Sep 2023Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that...
Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that turns black upon standing. Though rarely fatal, joint degradation is a common sequela, and many patients require multiple large joint arthroplasties throughout their lifetime. Though many aspects of the pathophysiological mechanisms of the disease have been described, questions remain, such as how the initiation of ochronotic pigmentation is prompted and the specific circumstances that make some tissues more resistant to pigmentation-related damage than others. In this report, we present the case of an 83-year-old female previously diagnosed with alkaptonuria including high-quality arthroscopic images displaying the fraying of articular cartilage. We also offer a summary of the latest literature on the pathophysiological mechanisms of the disease, including cellular-level changes observed in ochronotic chondrocytes, biochemical and mechanical alterations to the cartilaginous extracellular matrix, and patterns of pigmentation and joint degradation observed in humans and mice models. With these, we present an overview of the mechanisms of ochronotic chondropathy and joint degradation as the processes are currently understood. While alkaptonuria itself is rare, it has been termed a "fundamental disease," implying that its study and greater understanding have the potential to lead to insights in skeletal biology in general, as well as more common pathologies such as osteoarthritis and their potential treatment mechanisms.
PubMed: 37892999
DOI: 10.3390/biomedicines11102625 -
Quarterly Bulletin. Northwestern... 1958
Topics: Alkaptonuria; Cortisone; Humans; Ochronosis
PubMed: 13554742
DOI: No ID Found -
Angewandte Chemie (International Ed. in... Jul 2020Alkaptonuria (AKU) is a rare disease characterized by high levels of homogentisic acid (HGA); patients suffer from tissue ochronosis: dark brown pigmentation, especially...
Alkaptonuria (AKU) is a rare disease characterized by high levels of homogentisic acid (HGA); patients suffer from tissue ochronosis: dark brown pigmentation, especially of joint cartilage, leading to severe early osteoarthropathy. No molecular mechanism links elevated HGA to ochronosis; the pigment's chemical identity is still not known, nor how it induces joint cartilage degradation. Here we give key insight on HGA-derived pigment composition and collagen disruption in AKU cartilage. Synthetic pigment and pigmented human cartilage tissue both showed hydroquinone-resembling NMR signals. EPR spectroscopy showed that the synthetic pigment contains radicals. Moreover, we observed intrastrand disruption of collagen triple helix in pigmented AKU human cartilage, and in cartilage from patients with osteoarthritis. We propose that collagen degradation can occur via transient glycyl radicals, the formation of which is enhanced in AKU due to the redox environment generated by pigmentation.
Topics: Alkaptonuria; Cartilage, Articular; Electron Spin Resonance Spectroscopy; Homogentisic Acid; Humans; Magnetic Resonance Spectroscopy; Osteoarthritis; Oxidation-Reduction; Pigmentation; Pigments, Biological
PubMed: 32219972
DOI: 10.1002/anie.202000618