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Revista Espanola de Cirugia Ortopedica... 2021Ochronosis is a rare genetic disease of phenylamine and tyrosine metabolism in which an accumulation of homogentisic acid occurs. The accumulation of HGA causes...
Ochronosis is a rare genetic disease of phenylamine and tyrosine metabolism in which an accumulation of homogentisic acid occurs. The accumulation of HGA causes alkaptonuria and deposition in the connective tissue causing a dark colouring of the tissue. In the joints, it can lead to early and very disabling arthropathy, known as ochronotic arthropathy. We present the case of a patient diagnosed with ochronosis and ochronotic arthropathy of the left knee, in which we describe the intraoperative process with the macroscopic and microscopic anatomopathological findings. The patient made good progress after implantation of a total knee prosthesis (TKP), PS type, and was able to follow the same rehabilitation protocol used in patients without ochronotic arthropathy undergoing TKP. The patient showed improvement in the different functional scales, as well as disappearance of pain.
PubMed: 32192929
DOI: 10.1016/j.recot.2020.01.005 -
The Application of Clinical Genetics 2020The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate... (Review)
Review
The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate dioxygenase (HGD), the enzyme involved in metabolism of tyrosine, and is characterized by the presence of dark ochronotic pigment in the connective tissue that is formed, due to high levels of circulating homogentisic acid. Almost 120 years ago, Sir Archibald Garrod used AKU to illustrate the concept of Mendelian inheritance in man. In January 2019, the phase III clinical study SONIA 2 was completed, which tested the effectiveness and safety of nitisinone in the treatment of AKU. Results were positive, and they will serve as the basis for the application for registration of nitisinone for treatment of AKU at the European Medicines Agency. Therefore, AKU might become a rare disease for which a cure will be found by 2020. We understand the natural history of the disease and the process of ochronosis much more, but at the same time there are still unanswered questions. One of them is the issue of the factors influencing the varying severity of the disease, since our recent genotype-phenotype study did not show that differences in residual homogentisic acid activity caused by the different mutations was responsible. Although nitisinone has proved to arrest the process of ochronosis, it has some unwanted effects and does not cure the disease completely. As such, enzyme replacement or gene therapy might become a new focus of AKU research, for which a novel suitable mouse model of AKU is available already. We believe that the story of AKU is also a story of effective collaboration between scientists and patients that might serve as an example for other rare diseases.
PubMed: 32158253
DOI: 10.2147/TACG.S186773 -
Federal Practitioner : For the Health... Jan 2020Although commonly detected early in life, alkaptonuria, a rare congenital metabolic disorder, can be challenging to diagnosis and treat in older patients.
Although commonly detected early in life, alkaptonuria, a rare congenital metabolic disorder, can be challenging to diagnosis and treat in older patients.
PubMed: 32047356
DOI: No ID Found -
Case Reports in Orthopedics 2019Ochronosis arthropathy (OcA) is a rare condition which may be treated with total knee arthroplasty (TKA) at the end stage. The condition is often discovered only...
INTRODUCTION
Ochronosis arthropathy (OcA) is a rare condition which may be treated with total knee arthroplasty (TKA) at the end stage. The condition is often discovered only intraoperatively and the ideal choice of TKA is unknown.
CASE PRESENTATION
A 54-year-old male with worsening chronic bilateral mechanical knee pain had failed conservative therapy. Posterior stabilised (PS), cemented TKA and patella resurfacing was performed. Intraoperatively, collagenous structures such as the menisci and cartilage were noted to be black. Histological examination showed deposition of large amorphous brown material suggestive of ochronosis. He recovered well and underwent TKA of the contralateral knee the following year. At 2 years postindex TKA, his outcome scores improved and he was satisfied.
DISCUSSION AND CONCLUSION
With increasing TKA performed worldwide, a surgeon may eventually be surprised by the above findings once in their lifetime. However, OcA may be considered a likely diagnosis and it is safe to proceed with TKA. There is no particular TKA design that proved to be superior in our systematic review of 19 publications regarding TKA as all reported good outcomes. However, as the pathogenesis of OcA appears to be inflammatory in nature, we suggest using cemented PS TKA with resurfacing of the patella.
PubMed: 31687244
DOI: 10.1155/2019/1871856 -
Human Molecular Genetics Dec 2019Alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase (HGD) deficiency. Circulating homogentisic acid (HGA) is elevated and deposits in connective...
Conditional targeting in mice reveals that hepatic homogentisate 1,2-dioxygenase activity is essential in reducing circulating homogentisic acid and for effective therapy in the genetic disease alkaptonuria.
Alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase (HGD) deficiency. Circulating homogentisic acid (HGA) is elevated and deposits in connective tissues as ochronotic pigment. In this study, we aimed to define developmental and adult HGD tissue expression and determine the location and amount of gene activity required to lower circulating HGA and rescue the alkaptonuria phenotype. We generated an alkaptonuria mouse model using a knockout-first design for the disruption of the HGD gene. Hgd tm1a -/- mice showed elevated HGA and ochronosis in adulthood. LacZ staining driven by the endogenous HGD promoter was localised to only liver parenchymal cells and kidney proximal tubules in adulthood, commencing at E12.5 and E15.5 respectively. Following removal of the gene trap cassette to obtain a normal mouse with a floxed 6th HGD exon, a double transgenic was then created with Mx1-Cre which conditionally deleted HGD in liver in a dose dependent manner. 20% of HGD mRNA remaining in liver did not rescue the disease, suggesting that we need more than 20% of liver HGD to correct the disease in gene therapy. Kidney HGD activity which remained intact reduced urinary HGA, most likely by increased absorption, but did not reduce plasma HGA nor did it prevent ochronosis. In addition, downstream metabolites of exogenous 13C6-HGA, were detected in heterozygous plasma, revealing that hepatocytes take up and metabolise HGA. This novel alkaptonuria mouse model demonstrated the importance of targeting liver for therapeutic intervention, supported by our observation that hepatocytes take up and metabolise HGA.
Topics: Alkaptonuria; Animals; Disease Models, Animal; Gene Knockout Techniques; Homogentisate 1,2-Dioxygenase; Homogentisic Acid; Liver; Male; Mice; Mice, Transgenic; Promoter Regions, Genetic
PubMed: 31600782
DOI: 10.1093/hmg/ddz234 -
Arthroplasty (London, England) Oct 2019The objective of this study is to share our experience in total hip replacement for the treatment of ochronotic hip arthritis, in particular to report how to establish...
BACKGROUND
The objective of this study is to share our experience in total hip replacement for the treatment of ochronotic hip arthritis, in particular to report how to establish the diagnosis and some tips to limit complications.
METHOD
A cohort comprised of 10 patients (12 hips) with alkaptonuric hip arthritis. There were six men and four women with the mean age of 62.80 ± 7.57 years. All patients had a stiff spine, grossly restricted movements of hip joints, and severely limited daily routine activities. Total hip replacement was performed in all patients. The patients were evaluated at 6, 12, and 24 months after surgery, as well as every 4 years thereafter. Harris hip score was used to assess the functional outcome. The level of significance was set at p < 0.05.
RESULTS
The mean follow-up lasted 16.70 ± 6.82 years (3 to 24 years). At the final available follow-up, nine patients returned to work, ambulate without an orthosis, and achieve complete pain relief. Harris hip score was improved from poor to excellent. One patient died 16 years after surgery due to breast cancer. No complication relating to prosthetic failures was detected.
CONCLUSION
Total hip replacement gives long-term satisfactory results in patients with alkaptonuric hip arthritis, resulting in comparable function of the hips in patients who undergo primary osteoarthrosis.
PubMed: 35240771
DOI: 10.1186/s42836-019-0010-8 -
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 -
Medicine Aug 2019Alkaptonuria (AKU) is a rare disease caused by deficiency of homogentisate 1,2-dioxygenase which results in deposition of homogentisic acid (HGA). Ochronotic arthritis,...
INTRODUCTION
Alkaptonuria (AKU) is a rare disease caused by deficiency of homogentisate 1,2-dioxygenase which results in deposition of homogentisic acid (HGA). Ochronotic arthritis, the deposition of excess oxidized HGA in the connective tissues, causes pigmentation and degeneration of the joint tissues ultimately resulting in chronic inflammation and osteoarthritis. The ochronotic arthritis has similar clinical features with osteoarthritis. There is currently no specific treatment for AKU and management is usually symptomatic. In severe cases, total joint arthroplasty is the major treatment approaches. It is rarely reported in China.
PATIENT CONCERNS
Here we reported a case of a patient with bilateral knee pain for more than 1 year. He complained of a 20-year history of chronic, nonspecific low back pain and stiffness. His urine was black since he was a child. Six years after the knee surgery, his Achilles tendon ruptured.
DIAGNOSIS
Specific radiographic and magnetic resonance imaging manifestations were observed. Darkly pigmented full-thickness cartilage and subchondral bone were found during the operation. Histological investigation also manifested dark stains in meniscus and synovial tissues. Black-denatured tendon tissue was also found during the operation. The patient was diagnosed as AKU.
INTERVENTIONS
Total knee arthroplasty and Achilles tendon repair were operated separately after the disease was diagnosed.
OUTCOMES
The patient recovered very well after the second surgery. He returned to full activities, described no knee pain, and presented to the clinic walking without any aid. Physical examination revealed 0 to 20 of plantar flexion and 0 to 15 of dorsiflexion of the ankle.
CONCLUSIONS
Ochronosis is a very rare disease in Asia. This paper supplies new information for study of this disease. The mechanism is still unknown right now. Further studies will be necessary.
Topics: Achilles Tendon; Alkaptonuria; Arthroplasty, Replacement, Knee; Cartilage, Articular; Disease Progression; Humans; Knee Joint; Magnetic Resonance Imaging; Male; Middle Aged; Ochronosis; Rupture, Spontaneous
PubMed: 31441856
DOI: 10.1097/MD.0000000000016837 -
The Journal of Clinical and Aesthetic... May 2019Melasma is a common hyperpigmentation disorder of the skin. Combination therapy of topical retinoids, corticosteroids, and hydroquinone has been effective in treating...
Melasma is a common hyperpigmentation disorder of the skin. Combination therapy of topical retinoids, corticosteroids, and hydroquinone has been effective in treating melasma, but long-term use is limited by corticosteroid atrophy and exogenous ochronosis. The aim of this pilot study (NCT02730819) was to determine the efficacy, safety, and tolerability of a novel composition (2013-MCN-333) comprising tazarotene 0.075%, azelaic acid 20%, tacrolimus 0.1%, and (microfine) zinc oxide 10% for the treatment of melasma. Sixteen patients with moderate-to-severe melasma were treated daily with sunscreen and 2013-MCN-333 for 20 weeks. Primary outcome measure was change in Melasma Area and Severity Index (MASI) score. Twenty-five percent of patients met the primary endpoint of a MASI score of less than eight points at Week 20. MASI score also decreased significantly from baseline (median: 18.9 points) through Week 4 (median: 17.3 points; =0.006), Week 12 (median: 16.0 points; =0.001), and Week 20 (median: 13.3 points; =0.001). Treatment-related adverse events were mild, most of which decreased or resolved over the course of the study. The small sample size and nonblinded nature of treatment intervention are potential limitations. Our results suggest daily 2013-MCN-333 could potentially be an effective, safe, and tolerable treatment for moderate-to-severe melasma.
PubMed: 31320976
DOI: No ID Found -
Dermatology Online Journal Apr 2019Exogenous ochronosis (EO) is an entity that manifests as black-bluish or grayish-brown cutaneous hyperpigmentation, which is a consequence of the deposition of...
Exogenous ochronosis (EO) is an entity that manifests as black-bluish or grayish-brown cutaneous hyperpigmentation, which is a consequence of the deposition of ochronotic pigment with characteristic banana-like morphology between the collagen fibers of the dermis. Both the clinical presentation and histopathology appearance are superimposable with endogenous ochronosis or alcaptonuria, a hereditary disease in which ochronotic pigment deposition occurs at a multisystemic level. The most frequent cause of EO is the use of facial depigmenting creams containing hydroquinone, a common practice among women with high phototypes. We present a woman who developed EO on the face, upper chest, and back after prolonged use of a depigmenting cream containing hydroquinone.
Topics: Antioxidants; Back; Facial Dermatoses; Female; Humans; Hydroquinones; Hyperpigmentation; Middle Aged; Ochronosis; Skin Lightening Preparations; Thorax
PubMed: 31046915
DOI: No ID Found