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Journal of Clinical Medicine Jun 2023Exogenous ochronosis is a rare dyschromia that primarily impacts those with skin of color. It is characterized by blue-black pigmentation and is associated with the...
Exogenous ochronosis is a rare dyschromia that primarily impacts those with skin of color. It is characterized by blue-black pigmentation and is associated with the long-term application of skin-lightening creams containing hydroquinone. Commonly confused with other dyschromias, the use of skin lightening topicals can cause paradoxical skin darkening in patients with known exogenous ochronosis. This is highly distressing to patients, often worsening the underlying dyschromia and making treatment more difficult. A 10-year retrospective analysis was conducted that revealed 25 patients with exogenous ochronosis. The average patient used a skin lightening cream for 9.2 years, with exogenous ochronosis most commonly arising on the cheeks (68%), forehead (24%), and temples (20%). Furthermore, this study identified that patients with exogenous ochronosis may respond well to treatment with Q-switched Alexandrite laser and microneedling. The incidence of exogenous ochronosis is likely to increase as demographics shift and access to a wide range of over-the-counter topicals becomes more available, both in the United States and worldwide. Therefore, it is imperative to better characterize exogenous ochronosis to identify best treatment practices for all patients.
PubMed: 37445377
DOI: 10.3390/jcm12134341 -
Journal of Inherited Metabolic Disease Mar 2020Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy.... (Observational Study)
Observational Study
Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700 μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. Elevated tyrosine (813 μmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3, 274.8, and 144.3 μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 μmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.
Topics: Alkaptonuria; Animals; Cyclohexanones; Diet, Protein-Restricted; Female; Humans; Male; Mice; Nitrobenzoates; Phenylalanine; Tyrosine; Tyrosinemias
PubMed: 31503358
DOI: 10.1002/jimd.12172 -
Current Allergy and Asthma Reports Mar 2021Ochronosis and alkaptonuria are manifestations of the same condition-a rare autosomal recessive disorder resulting from a constitutional lack of homogentisate... (Review)
Review
PURPOSE OF REVIEW
Ochronosis and alkaptonuria are manifestations of the same condition-a rare autosomal recessive disorder resulting from a constitutional lack of homogentisate 1,2-dioxygenase (HGD) with the consequent accumulation of homogentisic acid (HGA). In ochronosis, HGA undergoes autoxidation as well as enzymatic oxidation to form an ochronotic pigment that accumulates in cartilage and connective tissues. In the beginning, there is homogentisic aciduria and pigmentation of cartilages and other connective tissues. In later years, generalized osteoarthritis of the spine and large joints, termed ochronotic arthropathy, develops.
RECENT FINDINGS
The diagnosis is confirmed by quantitative measurement of HGA in urine and mutation analysis of the HGD gene. One of the differential diagnoses for the skin findings is exogenous ochronosis, a limited hyperpigmentation of skin caused by some chemicals. As for the lumbar spine findings, there can be radiographic similarities with ankylosing spondylitis (AS) including reduced intervertebral disc spaces and loss of lumbar lordosis; however, ochronosis will spare the sacroiliac joint, and the lumbar spine will show dense, wafer-like disk calcification with a vacuum disc phenomenon and broad syndesmophytes. Here, we present a case of a patient with probable ochronosis that was treated many years as ankylosing spondylitis without response, and we provide a review of the current literature on ochronosis pathogenesis, diagnosis, and treatment.
Topics: Alkaptonuria; Animals; Homogentisic Acid; Humans; Ochronosis; Spondylitis, Ankylosing
PubMed: 33666743
DOI: 10.1007/s11882-021-01002-1 -
Rheumatology and Immunology Research Jun 2021Osteoarthritis (OA) is one of the major causes of disability and pain worldwide, yet despite a massive international research effort, no effective disease-modifying... (Review)
Review
Osteoarthritis (OA) is one of the major causes of disability and pain worldwide, yet despite a massive international research effort, no effective disease-modifying drugs have been identified to date. In this review, we put forward the proposition that greater focus on rarer forms of OA could lead to a better understanding of the pathogenesis of more common OA. We have investigated the severe osteoarthropathy of the ultra-rare disease alkaptonuria (AKU). In addition to the progress made in finding a treatment for AKU, our research has revealed important lessons for more common OA, including the identification of high-density mineralized protrusions (HDMPs), new pathoanatomical structures which may play an important role in joint destruction and pain in AKU and in OA. AKU is an inherited disorder of tyrosine metabolism, caused by genetic lack of the enzyme homogentisate 1,2 dioxygenase (HGD), which leads to failure to breakdown homogentisic acid (HGA). While most HGA is excreted over time, some of it is deposited as a pigment in connective tissues, a process described as ochronosis. Ochronotic pigment alters the mechanical properties of tissues, leading to inevitable joint destruction and frequently to cardiac valve disease. Until recently, there was no effective therapy for AKU, but preclinical studies demonstrated that upstream inhibition of tyrosine metabolism by nitisinone, a drug previously used in hereditary tyrosinaemia 1 (HT1), completely prevented ochronosis in AKU mice. This was followed by successful clinical trials which have resulted in nitisinone being approved for therapy of AKU by the European Medicines Agency, making AKU the only cause of OA for which there is an effective therapy to date. Study of other rare causes of OA should be a higher priority for researchers and funders to ensure further advances in understanding and eventual therapy of OA.
PubMed: 36465977
DOI: 10.2478/rir-2021-0011 -
The Thoracic and Cardiovascular Surgeon... Jan 2021Alkaptonuria is a rare autosomal recessive genetic disorder of tyrosine metabolism, which results in accumulation of homogentisic acid in various tissues, including...
Alkaptonuria is a rare autosomal recessive genetic disorder of tyrosine metabolism, which results in accumulation of homogentisic acid in various tissues, including the cardiovascular system. We report on a 64-year-old man with mixed aortic valve disease who underwent conventional aortic valve replacement. Intraoperative aortotomy revealed black pigmentation of the intima of the ascending aorta and the aortic valve was observed with thickened and calcified dark black leaflets. Histopathological diagnosis of ochronosis of the aortic valve was made. Despite several previous signs and symptoms, the diagnosis of alkaptonuria was not established until aortic valve replacement.
PubMed: 34194920
DOI: 10.1055/s-0041-1728721 -
SAGE Open Medical Case Reports 2020Alkaptonuria is a rare autosomal-recessive metabolic disorder of tyrosine degradation which results in elevated levels of circulating homogentisic acid. Ochronosis...
Alkaptonuria is a rare autosomal-recessive metabolic disorder of tyrosine degradation which results in elevated levels of circulating homogentisic acid. Ochronosis occurs when homogentisic acid polymerizes and deposits in connective tissue. Ochronotic lesions in the carotid arteries have not been described. In this report, we describe a 65-year-old man with alkaptonuria, with hypertension and hyperlipidemia, who underwent an uneventful carotid endarterectomy for an asymptomatic high-grade internal carotid artery stenosis. Histology revealed homogentisic acid deposits as black-brownish areas in the intima. He was noted to have an impressive heavily brown-black pigmented discoloration of the carotid plaque. Cardiovascular involvement is a rare consequence of alkaptonuria and is manifested by pigment deposition at the areas influenced by shear stress and turbulence.
PubMed: 32284865
DOI: 10.1177/2050313X20915411 -
Journal of Orthopaedic Case Reports Oct 2022Ochronotic arthropathy is a rapidly progressive sequelae of alkaptonuria. This is a rare autosomal recessive condition caused by a mutation in the homogentisate 1,2...
INTRODUCTION
Ochronotic arthropathy is a rapidly progressive sequelae of alkaptonuria. This is a rare autosomal recessive condition caused by a mutation in the homogentisate 1,2 dioxygenase (HGD) gene leading to HGD enzyme deficiency. Here, we report a case of neck femur fracture in a patient with ochronotic arthropathy managed by primary hip arthroplasty.
CASE REPORT
A 62-year-old gentleman presented with complaints of pain in his left groin area and difficulty in weight bearing on his left lower limb for 3 weeks. The pain was sudden in onset and started while he was on his morning walk. He did not have any problems with his left hip before this episode and he did not give a history of any significant trauma. History, radiological, and intraoperative findings revealed ochronotic hip arthropathy.
CONCLUSION
Ochronotic arthropathy is relatively rare and is seen in isolated communities. The treatment options are similar to primary osteoarthritis and the outcome is comparable to arthroplasty done for osteoarthritis.
PubMed: 36874893
DOI: 10.13107/jocr.2022.v12.i10.3346 -
Journal of Bone Metabolism Aug 2023Alkaptonuria is an extremely rare autosomal recessive metabolic disorder characterized by dark urine, ochronosis, and arthritis of the spine and major joints. We report...
Alkaptonuria is an extremely rare autosomal recessive metabolic disorder characterized by dark urine, ochronosis, and arthritis of the spine and major joints. We report a case of ochronotic arthritis observed during total knee replacement surgery in a 65-year-old male patient with no relevant medical history. Based on a literature review, this is the first case of ochronotic arthritis reported in Korea.
PubMed: 37718906
DOI: 10.11005/jbm.2023.30.3.283 -
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 -
Orthopedic Reviews Jun 2020Patients with alkaptonuria can present ochronotic degenerative arthropathy due to the accumulation of pigments in the cartilages. Ochronotic arthropathy initially...
Patients with alkaptonuria can present ochronotic degenerative arthropathy due to the accumulation of pigments in the cartilages. Ochronotic arthropathy initially affects the spine, then there is the involvement of the other large joints, with greater frequency of the knees. In this article we will present two patients with alkaptonuria who have been effectively treated with knee and hip replacement, comparing our experience with what is available in the literature.
PubMed: 32913615
DOI: 10.4081/or.2020.8687