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Cells Jun 2023Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring... (Clinical Trial)
Clinical Trial
Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out. Evaluation of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway, showed that the compound had innate activity against Gram-positive and Gram-negative bacteria, which was lost following conversion into the degradation product benzoquinone acetic acid (BQA). Anti-staphylococcal activity of HGA can be attributed to effects on bacterial membranes. Despite an absence of haemolytic activity, the compound was cytotoxic to human HepG2 cells. We conclude that the antibacterial activity and in vitro safety profile of HGA render it more suitable for use as a topical agent or for inclusion in a small-molecule medicinal chemistry program.
Topics: Humans; Alkaptonuria; Anti-Bacterial Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Homogentisic Acid; Prospective Studies
PubMed: 37443717
DOI: 10.3390/cells12131683 -
JIMD Reports Jul 2023Amongst a cohort of 88 alkaptonuria (AKU) patients attending the United Kingdom National Alkaptonuria Centre (NAC), four unrelated patients had co-existing Parkinson's...
Amongst a cohort of 88 alkaptonuria (AKU) patients attending the United Kingdom National Alkaptonuria Centre (NAC), four unrelated patients had co-existing Parkinson's disease (PD). Two of the NAC patients developed PD before receiving nitisinone (NIT) while the other two developed overt PD during NIT therapy. NIT lowers redox-active homogentisic acid (HGA) and profoundly increases tyrosine (TYR). A further unpublished case of a Dutch patient with AKU and PD on deep brain stimulation is included in this report. A Pubmed search revealed a further five AKU patients with PD, all without NIT usage. The prevalence of PD in AKU in the NAC appears to be nearly 20-times higher than in the non-AKU population ( < 0.001) even when adjusted for age. We propose that life-long exposure to redox-active HGA may account for the higher prevalence of PD in AKU. Furthermore, the appearance of PD in AKU patients during NIT therapy may be due to unmasking dopamine deficiency in susceptible individuals, as a result of the tyrosinaemia during NIT therapy inhibiting the rate-limiting brain tyrosine hydroxylase.
PubMed: 37404676
DOI: 10.1002/jmd2.12367 -
Journal of Inherited Metabolic Disease Sep 2023Until now, only a few studies have focused on the early onset of symptoms of alkaptonuria (AKU) in the pediatric population. This prospective, longitudinal study is a...
Until now, only a few studies have focused on the early onset of symptoms of alkaptonuria (AKU) in the pediatric population. This prospective, longitudinal study is a comprehensive approach to the assessment of children with recognized AKU during childhood. The study includes data from 32 visits of 13 patients (five males, eight females; age 4-17 years) with AKU. A clinical evaluation was performed with particular attention to eye, ear, and skin pigmentation, musculoskeletal complaints, magnetic resonance imaging (MRI), and ultrasound (US) imaging abnormalities. The cognitive functioning and adaptive abilities were examined. Molecular genetic analyses were performed. The most common symptoms observed were dark urine (13/13), followed by joint pain (6/13), and dark ear wax (6/13). In 4 of 13 patients the values obtained in the KOOS-child questionnaire were below the reference values. MRI and US did not show degenerative changes in knee cartilages. One child had nephrolithiasis. Almost half of the children with AKU (5/13) presented deficits in cognitive functioning and/or adaptive abilities. The most frequent HGD variants observed in the patients were c.481G>A (p.Gly161Arg) mutation and the c.240A>T (p.His80Gln) polymorphism. The newly described allele of the HGD gene (c.948G>T, p.Val316Phe) which is potentially pathogenic was identified.
Topics: Child; Male; Female; Humans; Child, Preschool; Adolescent; Alkaptonuria; Homogentisate 1,2-Dioxygenase; Prospective Studies; Longitudinal Studies; Mutation
PubMed: 37395296
DOI: 10.1002/jimd.12647 -
Molecular Genetics and Metabolism Jul 2023A 6-yr-old female orangutan presented with a history of dark urine that turned brown upon standing since birth. Repeated routine urinalysis and urine culture were...
A 6-yr-old female orangutan presented with a history of dark urine that turned brown upon standing since birth. Repeated routine urinalysis and urine culture were unremarkable. Urine organic acid analysis showed elevation in homogentisic acid consistent with alkaptonuria. Sequence analysis identified a homozygous missense variant, c.1081G>A (p.Gly361Arg), of the homogentisate 1,2-dioxygenase (HGD) gene. Familial studies, molecular modeling, and comparison to human variant databases support this variant as the underlying cause of alkaptonuria in this orangutan. This is the first report of molecular confirmation of alkaptonuria in a nonhuman primate.
Topics: Animals; Humans; Female; Alkaptonuria; Pongo abelii; Homogentisic Acid; Mutation, Missense; Homozygote
PubMed: 37354891
DOI: 10.1016/j.ymgme.2023.107628 -
Journal of Cutaneous Pathology Sep 2023
Topics: Humans; Argyria; Elastic Tissue; Ochronosis; Alkaptonuria
PubMed: 37316955
DOI: 10.1111/cup.14476 -
Cureus May 2023Alkaptonuria (AKU) is a rare hereditary disorder of tyrosine degradation. The disorder is characterized by the accumulation of a pigment called homogentisic acid. Its...
Alkaptonuria (AKU) is a rare hereditary disorder of tyrosine degradation. The disorder is characterized by the accumulation of a pigment called homogentisic acid. Its accumulation can lead to the breakdown of connective tissue, including tendons. This report presents a 46-year-old male with a history of bilateral total knee arthroplasty (TKA) who sustained bilateral patellar tendon rupture after an acute injury. A single-stage bilateral knee revision with direct repair of the extensor mechanism augmented with Achilles allograft was performed. The procedure was successful, and the patient had an excellent post-operative outcome at one year post-operatively. This case attempts to highlight the possible complications from AKU in order to better counsel patients with this condition who are undergoing TKA.
PubMed: 37288202
DOI: 10.7759/cureus.38597 -
Advances in Clinical Chemistry 2023Alkaptonuria (AKU) is an ultra-rare inherited inborn error of metabolism that afflicts the tyrosine metabolic pathway, resulting in the accumulation of homogentisic acid... (Review)
Review
Alkaptonuria (AKU) is an ultra-rare inherited inborn error of metabolism that afflicts the tyrosine metabolic pathway, resulting in the accumulation of homogentisic acid (HGA) in the circulation, and significant excretion in urine. Clinical manifestations, typically observed from the third decade of life, are lifelong and significantly affect the quality of life. This review provides a comprehensive overview of the natural history of AKU, including clinical, biochemical and genetic perspectives. An update on the major advances on studies in murine models and human subjects, providing mechanistic insight into the molecular and biochemical processes that underlie pathophysiology and its response to treatment are presented. The impact of treatment with nitisinone is also presented with a specific emphasis on hypertyrosinemia, as uncertainty on this topic remains. Future perspectives are explored, such as novel approaches to treat hypertyrosinemia including the use of binding agents and amino acid transporter inhibitors, as well as advanced potentially curative gene and cell therapy initiatives.
Topics: Humans; Animals; Mice; Alkaptonuria; Quality of Life; Tyrosinemias; Homogentisic Acid; Tyrosine
PubMed: 37268334
DOI: 10.1016/bs.acc.2023.02.005 -
Orthopedic Research and Reviews 2023Alkaptonuric shoulder arthropathy is a challenging clinical entity in arthroplasty. In this report, we describe an atypical presentation, technical considerations, a...
IMPORTANCE
Alkaptonuric shoulder arthropathy is a challenging clinical entity in arthroplasty. In this report, we describe an atypical presentation, technical considerations, a literature review, and some recommendations of significant benefits to shoulder surgeons.
OBJECTIVE
The author's objective in this report is to illustrate the deleterious metabolic effects of ochronosis on cartilage and the development of early arthritis.
DESIGN
This is a case report study, done in May 2021.
SETTING
Middle East, Jordan.
INTRODUCTION
Alkaptonuria is a metabolic disease of amino acid metabolism that can affect multiple organ systems, including the musculoskeletal system. The musculoskeletal system manifestations usually involve the spine, knee, and, uncommonly, the shoulder. Tissue ochronosis caused by alkaptonuria can cause significant damage to the joint and surrounding soft tissue envelope. In this case, we presented a patient who has end-stage glenohumeral arthritis and rotator cuff arthropathy secondary to ochronosis.
CASE PRESENTATION
In this case report, we present a 42-year-old male patient who presented to the clinic with severe right shoulder pain and limitations of the range of motion, especially with abduction. The patient underwent radiographic assessment, which showed a rotator cuff arthropathy combined with advanced degenerative changes of the right glenohumeral joint. The patient underwent reverse total shoulder arthroplasty. After the surgery and on follow-up later on for a period of one year and after a period of physiotherapy and rehabilitation, the patient showed remarkable improvement in the pain and range of motion.
CONCLUSION
Alkaptonuria can have a detrimental effect on the articular cartilage and the surrounding soft tissue envelope, which might manifest clinically as early degenerative arthritis changes in a young adult patient. Shoulder involvement is extremely rare and can manifest with substantial injury to the glenohumeral joint; whenever such extensive damage is present, shoulder arthroplasty is the best treatment.
PubMed: 37091223
DOI: 10.2147/ORR.S402214 -
Cureus Mar 2023Alkaptonuria is a rare genetic metabolic disorder of autosomal recessive inheritance characterised by the accumulation of homogentisic acid in the body. It is diagnosed...
Alkaptonuria is a rare genetic metabolic disorder of autosomal recessive inheritance characterised by the accumulation of homogentisic acid in the body. It is diagnosed upon identification of characteristic symptoms, using various biochemical investigations, radiographic pictures, and a variety of specialised tests. Here we are discussing the case of an 80-year-old female patient with incidental findings of alkaptonuria. It is crucial to understand the fundamental diagnostic investigations that can be used in low-income nations or facilities where investigations like genetic testing, gas chromatography, and mass spectrometry are not readily available for the diagnosis of alkaptonuria.
PubMed: 37025736
DOI: 10.7759/cureus.35792