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Journal of Orthopaedic Case Reports Jul 2021Ochronotic arthropathy in patients with alkaptonuria is a rare hereditary disorder. The altered metabolism causes the homogentesic acid derivatives to deposit in various...
INTRODUCTION
Ochronotic arthropathy in patients with alkaptonuria is a rare hereditary disorder. The altered metabolism causes the homogentesic acid derivatives to deposit in various connective tissues causing characteristic pigmentation. Due to the close clinical resemblance to that of a degenerative disorder, diagnosis of ochronotic arthropathy usually occurs intraoperatively. We report arthroscopic findings of a 50-year-old female with ochronotic arthropathy.
CASE REPORT
A 50-year-old woman came with complaints of pain and swelling in the left knee. Clinical examination and MRI findings were correlated to reveal a tear of lateral meniscus. On arthroscopic examination, the blackish pigmentation of the meniscus and the articular cartilage led to the diagnosis of ochronotic arthropathy.
CONCLUSION
Arthroscopy plays an important role in diagnosis and treatment of patients with ochronotic arthropathy. The characteristic arthroscopic finding may aid diagnosis even in patients who do not have other systemic manifestations. Timely arthroscopic intervention can help delay the disease progression.
PubMed: 34790614
DOI: 10.13107/jocr.2021.v11.i07.2334 -
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 -
Metabolites May 2022Background: Nitisinone-induced hypertyrosinaemia is well documented in Alkaptonuria (AKU), and there is uncertainty over whether it may contribute to a decline in...
Background: Nitisinone-induced hypertyrosinaemia is well documented in Alkaptonuria (AKU), and there is uncertainty over whether it may contribute to a decline in cognitive function and/or mood by altering neurotransmitter metabolism. The aim of this work was to evaluate the impact of nitisinone on the cerebrospinal fluid (CSF) metabolome in a murine model of AKU, with a view to providing additional insight into metabolic changes that occur following treatment with nitisinone. Methods: 17 CSF samples were collected from BALB/c Hgd−/− mice (n = 8, treated with nitisinone—4 mg/L and n = 9, no treatment). Samples were diluted 1:1 with deionised water and analysed using a 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time-of-flight mass spectrometry (Agilent, Cheadle, UK). Raw data were processed using a targeted feature extraction algorithm and an established in-house accurate mass retention time database. Matched entities (±10 ppm theoretical accurate mass and ±0.3 min retention time window) were filtered based on their frequency and variability. Experimental groups were compared using a moderated t-test with Benjamini−Hochberg false-discovery rate adjustment. Results: L-Tyrosine, N-acetyl-L-tyrosine, γ-glutamyl-L-tyrosine, p-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)lactic acid were shown to increase in abundance (log2 fold change 2.6−6.9, 3/5 were significant p < 0.05) in the mice that received nitisinone. Several other metabolites of interest were matched, but no significant differences were observed, including the aromatic amino acids phenylalanine and tryptophan, and monoamine metabolites adrenaline, 3-methoxy-4-hydroxyphenylglycol, and octopamine. Conclusions: Evaluation of the CSF metabolome of a murine model of AKU revealed a significant increase in the abundance of a limited number of metabolites following treatment with nitisinone. Further work is required to understand the significance of these findings and the mechanisms by which the altered metabolite abundances occur.
PubMed: 35736410
DOI: 10.3390/metabo12060477 -
Ugeskrift For Laeger Sep 2020Alkaptonuria (AKU) is a rare autosomal-recessive disease in the tyrosine metabolism pathway. AKU is due to a mutation of a gene coding for homogentisate dioxygenase,...
Alkaptonuria (AKU) is a rare autosomal-recessive disease in the tyrosine metabolism pathway. AKU is due to a mutation of a gene coding for homogentisate dioxygenase, causing accumulation of homogentisic acid leading to a painful multisystemic disease. Damage to cartilage tissue is especially significant, and weight-bearing joints often require arthroplasty. Nitisinone, a drug already used in treatment of hereditary tyrosinaemia, could be approved for treatment of AKU. This case report describes the occurrence of AKU discovered in two brothers in connection with hip and knee arthroplasty.
Topics: Alkaptonuria; Arthroplasty, Replacement, Knee; Homogentisic Acid; Humans; Male; Mutation
PubMed: 33000720
DOI: No ID Found -
Scientific Reports Oct 2019Hereditary tyrosinemia type 1 (HT1) and alkaptonuria (AKU) are inherited metabolic disorders caused by defective enzymes involved in tyrosine catabolism. Nitisinone, an...
Hereditary tyrosinemia type 1 (HT1) and alkaptonuria (AKU) are inherited metabolic disorders caused by defective enzymes involved in tyrosine catabolism. Nitisinone, an ex-herbicide and member of the β-triketone family, is therapeutically applied to prevent accumulation of toxic metabolites in patients by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). Here, we developed a colorimetric bacterial whole-cell screening system that allows quantifying the inhibitory effects of human HPD inhibitors in a high-throughput and a robust fashion. The principle of our screening system is based on the degradation of tyrosine through 4-hydroxyphenylpyruvate into homogentisate by human HPD expressed in E. coli and subsequent production of a soluble melanin-like pigment. With the aim to optimise the assay, we tested different E. coli strains, expression and reaction temperatures, and time-points for supplementing the substrate. We found that in our assay the addition of prototypical β-triketone HPD inhibitors decreases pigment production in a dose-dependent manner with increasing inhibitor concentrations. In addition, plate uniformity, signal variability and spatial uniformity assessment showed that we have developed a robust high-throughput screening assay that is simple to use, cost-effective and enables identification and evaluation of novel therapeutic human HPD inhibitors for the treatment of tyrosine-related metabolic disorders.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Calorimetry; Drug Discovery; Enzyme Inhibitors; Escherichia coli; High-Throughput Screening Assays; Humans; Melanins; Tyrosine
PubMed: 31578365
DOI: 10.1038/s41598-019-50533-1 -
JIMD Reports Sep 2020Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression.
BACKGROUND
Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression.
METHODS
Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V-1 (pre-baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24-hour urine samples were collected for measurement of HGA.
RESULTS
There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V-1 visit. Photographs of patients show increase in eye pigment between V-1 and V0, followed by decrease post-nitisinone at V1, V2, and V3. Ear and combined ochronosis semiquantitative scoring showed an increase between V-1 and V0 ( < .01), followed by a decrease at V1, V2, and V3, in the VAR group ( < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease ( < .05).
CONCLUSIONS
Nitisinone decreases HGA and partially reverses ochronosis.
PubMed: 32904992
DOI: 10.1002/jmd2.12137 -
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 -
Acta Orthopaedica Et Traumatologica... Dec 2021Alkaptonuria-related rapidly destructive arthropathy of the hip joint has not been reported in detail with both imaging and histopathological findings in the literature.... (Review)
Review
Alkaptonuria-related rapidly destructive arthropathy of the hip joint has not been reported in detail with both imaging and histopathological findings in the literature. We, herein, presented the case of a 79-year-old male patient who suddenly started experiencing marked right hip pain. Radiography showed that the femoral head was spherical; however, after 3 months, approximately half of the femoral head was destroyed despite there being almost no change in the acetabulum. Radiographs of the spine also showed fusion between multiple vertebrae. Significant osteoporosis was observed on roentgenography, together with decreased bone density. Urinary gas chromatography-mass spectrometry analysis revealed that a large amount of homogentisic acid was excreted. During total hip arthroplasty, gray and muddy contents were observed in the joint capsule, and the surface of the destroyed femoral head was black. Histopathologically, granulomatous foci containing fragmented bone and cartilage debris were found in the bone marrow space of the joint surface, and the cartilage tissue was pigmented brownish black. The patient was subsequently diagnosed with ochronotic hip joint destruction. The present case report is the first to demonstrate rapidly destructive coxopathy associated with alkaptonuria using both imaging and histopathological findings. These findings clearly show that severe hip joint destruction defined as rapidly destructive hip arthropathy can occur in a very short time period for patients with alkaptonuria.
Topics: Aged; Alkaptonuria; Femur Head; Hip Joint; Humans; Joint Diseases; Male; Ochronosis
PubMed: 34967747
DOI: 10.5152/j.aott.2021.21205 -
Turk Gogus Kalp Damar Cerrahisi Dergisi Jan 2022Alkaptonuria is a rare inherited metabolic disease caused by homogentisic acid oxidase enzyme deficiency. Homogentisic acid formed during phenylalanine and tyrosine...
Alkaptonuria is a rare inherited metabolic disease caused by homogentisic acid oxidase enzyme deficiency. Homogentisic acid formed during phenylalanine and tyrosine metabolism cannot be further metabolized and accumulates due to this enzyme deficiency. Some of the homogentisic acid that cannot be removed by metabolism is excreted with urine, some of it causes this accumulation known as ochronosis, which is characterized by dark pigmented color change in tissues. The classic clinical triad of the disease is darkening of the urine color, degenerative arthritis in the joints and dark colored pigmentation in the connective tissue. Herein, we present a case of ochronosis detected incidentally during aortic valve replacement with the diagnosis of aortic insufficiency.
PubMed: 35444851
DOI: 10.5606/tgkdc.dergisi.2022.20909 -
Indian Journal of Thoracic and... May 2021The commonest cardiac pathology in patients with alkaptonuria is aortic stenosis. Patients with alkaptonuria and aortic stenosis may remain asymptomatic until the 6th...
The commonest cardiac pathology in patients with alkaptonuria is aortic stenosis. Patients with alkaptonuria and aortic stenosis may remain asymptomatic until the 6th decade. Surgeons may have to deal with per-operative difficulties as alkaptonuria is a systemic disease. Proper preoperative planning is important. The mechanical valve prosthesis is advisable in a patient with alkaptonuria and aortic stenosis considering disease pathophysiology. We report a 70-year-old male diagnosed with alkaptonuria and aortic stenosis, who underwent aortic valve (mechanical valve prosthesis) and ascending aorta replacement.
PubMed: 33967422
DOI: 10.1007/s12055-020-01059-z