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Sclerouveitis as Part of Multiple Autoimmune Syndrome in a Patient with Alkaptonuria: A Case Report.Ocular Immunology and Inflammation Feb 2023To present a novel association of multiple autoimmune syndrome (MAS) in a patient with sclerouveitis and alkaptonuria.
PURPOSE
To present a novel association of multiple autoimmune syndrome (MAS) in a patient with sclerouveitis and alkaptonuria.
CASE REPORT
A 68-year-old female with alkaptonuria, Hashimoto's thyroiditis, and familial autoimmunity presented with decreased VA, red eye, foreign body sensation, and ocular pain. Ophthalmological examination: OD conjunctival hyperemia, ochronosis, a reddish-violet scleral nodule, keratic precipitates, 2+ cells in the anterior chamber, 0.5+ vitreous cells, and mild vitreous haze. The patient was diagnosed with anterior uveitis and anterior nodular scleritis. Due to the associated sicca symptoms, a salivary gland biopsy was ordered, confirming Sjögren's syndrome. Then, MAS was diagnosed, and immunomodulatory medications were started; however, as she was refractory to more than two of them, it was suggested to start biological treatment.
CONCLUSION
We present a novel MAS-type 2 pattern consisting of Hashimoto's thyroiditis, sclerouveitis, and Sjögren's syndrome. Its diagnosis and management represent a challenge, so a multidisciplinary approach should be provided.
PubMed: 36821816
DOI: 10.1080/09273948.2023.2179498 -
Cureus Jan 2023Ochronosis is a rare metabolic disorder characterized by homogentisic acid deposition in the large joints and spine, resulting in progressive degeneration. We present...
Ochronosis is a rare metabolic disorder characterized by homogentisic acid deposition in the large joints and spine, resulting in progressive degeneration. We present two cases of ochronotic arthritis of the knee subjected to cemented total knee arthroplasty (TKA). These cases were diagnosed intraoperatively and later confirmed with a histopathologic examination. Orthopedic surgeons should be aware of the condition as the intraoperative finding of darkened cartilage might surprise them. After a five-year TKA follow-up, both of our cases showed better mobility and function.
PubMed: 36779093
DOI: 10.7759/cureus.33523 -
World Journal of Clinical Cases Jan 2023Ochronosis, also known as alkaptonuria, is a rare autosomal recessive self-metabolic disease arising from deficiency of homogentisate 1,2 dioxygenase enzyme. It affects...
BACKGROUND
Ochronosis, also known as alkaptonuria, is a rare autosomal recessive self-metabolic disease arising from deficiency of homogentisate 1,2 dioxygenase enzyme. It affects several organs and muscoskeletal structures. We herein report a case of a patient who presented with severe hip arthropathy complicated with late stage ochronosis.
CASE SUMMARY
A 56-year-old male patient was admitted in our department in 2019 with complaints of chronic low backache and left hip pain. After the required investigations were done, lumbar disc herniation and severe hip arthritis were the initial diagnosis. A total left hip arthroplasty was performed. Ochronotic osteoarthritis was only obtained post-surgery as confirmatory diagnosis. He was again admitted mid 2022 with the same complaints on the right hip. Subsequently, he underwent a total right hip arthroplasty. Post-operative recovery and follow-ups were deemed very satisfactory.
CONCLUSION
Ochronosis is an unusual diagnosis for a patient who presents with typical hip arthritis. Thus, unless meticulous history taking and advanced laboratory tests, the diagnosis can easily be missed by surgeons.
PubMed: 36687193
DOI: 10.12998/wjcc.v11.i1.210 -
Case Reports in Dermatological Medicine 2023The cosmetic use of skin bleaching products is common among women in sub-Saharan Africa despite numerous reported cutaneous and systemic complications. We report the...
BACKGROUND
The cosmetic use of skin bleaching products is common among women in sub-Saharan Africa despite numerous reported cutaneous and systemic complications. We report the first case of squamous cell carcinoma in a woman using skin bleaching products in Togo. . A 65-year-old woman with a 30-year history of skin bleaching products use consulted in dermatology for a tumor of the neck that had been evolving for 2 years. There was no personal or family history of cancer. The patient was obese (BMI = 38.3 kg/m) and had high blood pressure. Clinical examination noted multiple ulcerative and cauliflower tumors of the neck. The presence of stretch marks, skin atrophy, and ochronosis was noted in the examination of the rest of skin. There were no lymph nodes. HIV serology was negative. Histology of a tumor biopsy concluded to an invasive skin squamous cell carcinoma. The cervical, thoracic, abdominal, and pelvic TDM revealed pulmonary metastases. The patient underwent complete surgical removal of the right latero-cervical tumor. The left latero-cervical tumors were not removed because they infiltrated the large vessels. Chemotherapy before surgery was prescribed but not honored for financial reasons. The patient died 2 months after her first consultation in respiratory distress.
CONCLUSION
Squamous cell carcinoma is one of the complications of skin bleaching in sub-Saharan Africa. It is necessary to intensify awareness campaigns on the complications of this practice, in order to reduce their incidence, in our context where this practice is very frequent.
PubMed: 36684806
DOI: 10.1155/2023/8002896 -
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 -
Rheumatology and Immunology Research Jun 2022
PubMed: 36465319
DOI: 10.2478/rir-2022-0009 -
Scientific Reports Nov 2022Alkaptonuria (AKU) is a rare inborn error of metabolism caused by a defective homogentisate 1,2-dioxygenase (HGD), an enzyme involved in the tyrosine degradation...
Alkaptonuria (AKU) is a rare inborn error of metabolism caused by a defective homogentisate 1,2-dioxygenase (HGD), an enzyme involved in the tyrosine degradation pathway. Loss of HGD function leads to the accumulation of homogentisic acid (HGA) in connective body tissues in a process called ochronosis, which results on the long term in an early-onset and severe osteoarthropathy. HGD's quaternary structure is known to be easily disrupted by missense mutations, which makes them an interesting target for novel treatment strategies that aim to rescue enzyme activity. However, only prediction models are available providing information on a structural basis. Therefore, an E. coli based whole-cell screening was developed to evaluate HGD missense variants in 96-well microtiter plates. The screening principle is based on HGD's ability to convert the oxidation sensitive HGA into maleylacetoacetate. More precisely, catalytic activity could be deduced from pyomelanin absorbance measurements, derived from the auto-oxidation of remaining HGA. Optimized screening conditions comprised several E. coli expression strains, varied expression temperatures and varied substrate concentrations. In addition, plate uniformity, signal variability and spatial uniformity were investigated and optimized. Finally, eight HGD missense variants were generated via site-directed mutagenesis and evaluated with the developed high-throughput screening (HTS) assay. For the HTS assay, quality parameters passed the minimum acceptance criterion for Z' values > 0.4 and single window values > 2. We found that activity percentages versus wildtype HGD were 70.37 ± 3.08% (for M368V), 68.78 ± 6.40% (for E42A), 58.15 ± 1.16% (for A122V), 69.07 ± 2.26% (for Y62C), 35.26 ± 1.90% (for G161R), 35.86 ± 1.14% (for P230S), 23.43 ± 4.63% (for G115R) and 19.57 ± 11.00% (for G361R). To conclude, a robust, simple, and cost-effective HTS system was developed to reliably evaluate and distinguish human HGD missense variants by their HGA consumption ability. This HGA quantification assay may lay the foundation for the development of novel treatment strategies for missense variants in AKU.
Topics: Humans; Alkaptonuria; Homogentisate 1,2-Dioxygenase; Dioxygenases; Polymorphism, Single Nucleotide; High-Throughput Screening Assays; Escherichia coli; Homogentisic Acid
PubMed: 36376482
DOI: 10.1038/s41598-022-23702-y -
Journal of Cardiac Surgery Dec 2022Ochronosis refers to the blue-black discoloration of connective tissue. While cardiovascular ochronosis has been described resulting from alkaptonuria, it may also...
CASE REPORT
Ochronosis refers to the blue-black discoloration of connective tissue. While cardiovascular ochronosis has been described resulting from alkaptonuria, it may also result from chronic minocycline use which is exceedingly rare. Cardiovascular ochronosis often presents with insidious development, often identified incidentally during aortic valve replacement (AVR). Herein, we describe the case of a 71-year-old male undergoing AVR and coronary artery bypass grafting found to have minocycline-induced ochronosis of the aortic valve and aorta.
CONCLUSIONS
Given the rarity of this case, descriptions of cardiovascular ochronosis cases secondary to minocycline use are imperative in ensuring that it is on the differential diagnosis when identified by others in future cases. Additional care must be taken intraoperatively to ensure that the correct anatomy is identified as discoloration hinders visualization of the anatomy potentially resulting in unintentional consequences such as heart block or perivalvular leak as traditional visual cues for suture placement are distorted.
Topics: Male; Humans; Aged; Ochronosis; Minocycline; Heart Valve Prosthesis Implantation; Alkaptonuria; Aortic Valve; Aortic Valve Stenosis; Aorta
PubMed: 36335620
DOI: 10.1111/jocs.17129 -
Metabolites Oct 2022Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different...
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), resulting in ochronosis (pigmentation of the connective tissues) and severe ochronotic spondylo-arthropathy, which usually manifests in the mid-thirties. An earlier genotype−phenotype correlation study showed no differences in serum HGA levels, absolute urinary excretion of HGA, or in the clinical symptoms between patients carrying HGD variants leading to 1% or >30% residual HGD activity. Still, as reported previously, the variance of the excretion of the HGA was smaller within affected siblings that share a common genotype. The present study is the first ever to systematically analyze the baseline clinical data of 24 AKU sibling pairs/groups collected in the SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) study to evaluate phenotypical differences between patients carrying the same HGD genetic variants. We show that even between siblings there was considerable variability in the disease severity. This indicates that some other yet unidentified genetic, biomechanical, or environmental modifying factors may contribute to accelerated pigmentation and connective tissue damage observed in some patients.
PubMed: 36295892
DOI: 10.3390/metabo12100990 -
Metabolites Sep 2022Changes in the phenylalanine (PHE)/tyrosine (TYR) pathway metabolites before and during homogentisic acid (HGA)-lowering by nitisinone in the Suitability of Nitisinone...
Changes in the phenylalanine (PHE)/tyrosine (TYR) pathway metabolites before and during homogentisic acid (HGA)-lowering by nitisinone in the Suitability of Nitisinone in Alkaptonuria (AKU) 2 (SONIA 2) study enabled the magnitude of the flux in the pathway to be examined. SONIA 2 was a 48-month randomised, open-label, evaluator-blinded, parallel-group study performed in the UK, France and Slovakia recruiting patients with confirmed AKU to receive either 10 mg nitisinone or no treatment. Site visits were performed at 3 months and yearly thereafter. Results from history, photographs of eyes/ears, whole body scintigraphy, echocardiography and abdomen/pelvis ultrasonography were combined to produce the Alkaptonuria Severity Score Index (cAKUSSI). PHE, TYR, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and HGA metabolites were analysed by liquid chromatography/tandem mass spectrometry in 24 h urine and serum samples collected before and during nitisinone. Serum metabolites were corrected for total body water (TBW), and the sum of 24 h urine plus total body water metabolites of PHE, TYR, HPPA, HPLA and HGA were determined. The sum of urine metabolites (PHE, TYR, HPPA, HPLA and HGA) were similar pre- and peri-nitisinone. The sum of TBW metabolites and sum TBW + URINE metabolites were significantly higher peri-nitisinone (p < 0.001 for both) compared with pre-nitisinone baseline. Significantly higher concentrations of metabolites from the tyrosine metabolic pathway were observed during treatment with nitisinone. Arguments for unmasking of the ochronotic pathway and biliary elimination of HGA are put forward.
PubMed: 36295821
DOI: 10.3390/metabo12100920