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1.
Nat Rev Dis Primers ; 10(1): 16, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453957

RESUMO

Alkaptonuria is a rare inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase activity. The consequent homogentisic acid (HGA) accumulation in body fluids and tissues leads to a multisystemic and highly debilitating disease whose main features are dark urine, ochronosis (HGA-derived pigment in collagen-rich connective tissues), and a painful and severe form of osteoarthropathy. Other clinical manifestations are extremely variable and include kidney and prostate stones, aortic stenosis, bone fractures, and tendon, ligament and/or muscle ruptures. As an autosomal recessive disorder, alkaptonuria affects men and women equally. Debilitating symptoms appear around the third decade of life, but a proper and timely diagnosis is often delayed due to their non-specific nature and a lack of knowledge among physicians. In later stages, patients' quality of life might be seriously compromised and further complicated by comorbidities. Thus, appropriate management of alkaptonuria requires a multidisciplinary approach, and periodic clinical evaluation is advised to monitor disease progression, complications and/or comorbidities, and to enable prompt intervention. Treatment options are patient-tailored and include a combination of medications, physical therapy and surgery. Current basic and clinical research focuses on improving patient management and developing innovative therapies and implementing precision medicine strategies.


Assuntos
Alcaptonúria , Ocronose , Masculino , Humanos , Feminino , Alcaptonúria/complicações , Alcaptonúria/diagnóstico , Alcaptonúria/terapia , Qualidade de Vida , Ocronose/complicações , Ocronose/diagnóstico , Rim/metabolismo , Ácido Homogentísico/metabolismo
2.
Nat Rev Dis Primers ; 10(1): 17, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38453968
3.
J Clin Lab Anal ; 37(21-22): e24976, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37877521

RESUMO

OBJECTIVE: Homogentisic acid (HGA) is excreted in excessive amounts in the urine of patients with alkaptonuria, which is a hereditary metabolic disorder of phenylalanine and tyrosine. Therefore, the detection of HGA in urine is useful for the diagnosis of alkaptonuria. To evaluate the detection of HGA, we confirmed the color shift of HGA solutions and analyzed them by electrospray ionization mass spectrometry (ESI-MS). METHODS: We observed the color change of the HGA solutions under different pH conditions (pH 6.0, 7.0, and 8.0) and examined the influences of adding potassium hydroxide (KOH) and ascorbic acid (AA) to the HGA solutions. Then, we analyzed the chemical reaction in HGA solutions using ESI-MS. RESULTS: The HGA solution at pH 8.0 became brown after incubation at room temperature for 24 h and became darker brown with the addition of KOH; however, HGA solutions at pH 6.0 and 7.0 showed no color changes. The brown color change of the HGA solution at pH 8.0 was also inhibited by AA. Moreover, all HGA sample solutions showed the deprotonated molecular ion peak at m/z 167.035 in the negative ion mode after incubation at room temperature for 24 h and with the addition of KOH and AA. CONCLUSION: We identified the molecular ion of HGA in all sample solutions by ESI-MS, regardless of different pH conditions, color changes, or the presence of AA. These results suggest that spectral analysis by ESI-MS is suitable for the detection of HGA and the diagnosis of alkaptonuria.


Assuntos
Alcaptonúria , Humanos , Alcaptonúria/diagnóstico , Alcaptonúria/urina , Espectrometria de Massas por Ionização por Electrospray , Ácido Homogentísico/urina , Hidróxidos , Ácido Ascórbico
4.
BMJ Case Rep ; 16(10)2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37880174

RESUMO

Alkaptonuria is a very rare disorder in which homogentisic acid accumulates due to a deficiency in the activity of homogentisic acid 1,2 dioxygenase. This deficiency results in deposition of a yellowish-brown pigment in connective tissue. Such deposition is termed 'ochronosis' and leads to deterioration in the formation and structure of proteoglycans in hyaline cartilage. These actions lead to fragmentation and rapid destructive arthritis. Often, ochronotic arthritis appears at 40-60 years of age, and many patients are treated symptomatically. Here, we report two patients (three ankles) with ochronotic arthritis who were treated with ankle arthrodesis. In all cases, the postoperative clinical score improved, but the time needed for fusion was prolonged and symptomatic subtalar arthropathy developed in the early postoperative period.


Assuntos
Alcaptonúria , Doenças das Cartilagens , Osteoartrite , Humanos , Alcaptonúria/complicações , Alcaptonúria/cirurgia , Tornozelo , Ácido Homogentísico , Artrodese
5.
Sci Rep ; 13(1): 14374, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37658095

RESUMO

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a deficient HGD enzyme with the consequent accumulation of homogentisic acid (HGA) in different tissues causing complications in various organs, particularly in joints, heart valves and kidneys. The genetic basis of AKU in Egypt is completely unknown. We evaluated the clinical and genetic spectrum of six pediatric and adolescents AKU patients from four unrelated Egyptian families. All probands had a high level of HGA in urine by qualitative GC/MS before genetic confirmation by Sanger sequencing. Recruited AKU patients were four females and two males (median age 13 years). We identified four different pathogenic missense variants within HGD gene. Detected variants included a novel variant c.1079G > T;p.(Gly360Val) and three recurrent variants; c.1078G > C;p.(Gly360Arg), c.808G > A;p.(Gly270Arg) and c.473C > T;p.(Pro158Leu). All identified variants were properly segregating in the four families consistent with autosomal recessive inheritance. In this study, we reported the phenotypic and genotypic spectrum of alkaptonuria for the first time in Egypt. We further enriched the HGD-variant database with another novel pathogenic variant. The recent availability of nitisinone may promote the need for genetic confirmation at younger ages to start therapy earlier and prevent serious complications.


Assuntos
Alcaptonúria , Dioxigenases , Adolescente , Feminino , Masculino , Humanos , Criança , Alcaptonúria/genética , Egito , Homogentisato 1,2-Dioxigenase/genética , Fenilacetatos , Ácido Homogentísico
6.
J Inherit Metab Dis ; 46(5): 916-930, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37395296

RESUMO

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.


Assuntos
Alcaptonúria , Criança , Masculino , Feminino , Humanos , Pré-Escolar , Adolescente , Alcaptonúria/diagnóstico , Alcaptonúria/genética , Alcaptonúria/patologia , Homogentisato 1,2-Dioxigenase/genética , Estudos Prospectivos , Estudos Longitudinais , Mutação
7.
Int J Mol Sci ; 24(13)2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37446173

RESUMO

Nitisinone has been approved for treatment of alkaptonuria (AKU). Non-invasive biomarkers of joint tissue remodelling could aid in understanding the molecular changes in AKU pathogenesis and how these can be affected by treatment. Serological and urinary biomarkers of type I collagen and II collagen in AKU were investigated in patients enrolled in the randomized SONIA 2 (NCT01916382) clinical study at baseline and yearly until the end of the study (Year 4). The trajectories of the biomarkers over time were observed. After treatment with nitisinone, the biomarkers of type I collagen remodelling increased at Year 1 (19% and 40% increase in CTX-I and PRO-C1, respectively), which was potentially reflected in the higher degree of mobility seen following treatment. The biomarkers of type II collagen remodelling decreased over time in the nitisinone group: C2M showed a 9.7% decline at Year 1, and levels then remained stable over the following visits; CTX-II showed a 26% decline at Year 3 and 4 in the nitisinone-treated patients. Nitisinone treatment induced changes in biomarkers of bone and cartilage remodelling. These biomarkers can aid patient management and deepen our knowledge of the molecular mechanisms of this rare disease.


Assuntos
Alcaptonúria , Humanos , Alcaptonúria/tratamento farmacológico , Biomarcadores , Cartilagem/patologia , Colágeno Tipo I
8.
Cells ; 12(13)2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37443717

RESUMO

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.


Assuntos
Alcaptonúria , Humanos , Alcaptonúria/tratamento farmacológico , Alcaptonúria/metabolismo , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas , Ácido Homogentísico/metabolismo , Estudos Prospectivos
9.
Adv Clin Chem ; 114: 47-81, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37268334

RESUMO

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.


Assuntos
Alcaptonúria , Tirosinemias , Humanos , Animais , Camundongos , Alcaptonúria/diagnóstico , Alcaptonúria/tratamento farmacológico , Alcaptonúria/metabolismo , Qualidade de Vida , Ácido Homogentísico/metabolismo , Tirosina/metabolismo , Tirosina/urina
11.
Mol Genet Metab ; 139(3): 107628, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37354891

RESUMO

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.


Assuntos
Alcaptonúria , Pongo abelii , Animais , Humanos , Feminino , Alcaptonúria/diagnóstico , Alcaptonúria/genética , Pongo abelii/genética , Ácido Homogentísico , Mutação de Sentido Incorreto , Homozigoto
12.
Ophthalmic Plast Reconstr Surg ; 39(5): e139-e142, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37010051

RESUMO

Exogenous ochronosis refers to accumulation of homogentisic acid metabolites in tissues, manifesting as pigmentation of affected tissues. Phenolic compounds are most commonly implicated, including hydroquinone, quinine, phenol, resorcinol, mercury, and picric acid. The affected connective tissues exhibit brownish discoloration when heavily pigmented and the histopathological appearance is characteristic with "banana-shaped" ochre-colored pigment deposits. Herein, the authors describe a rare case of exogenous ochronosis involving the conjunctiva, sclera and skin, as a result of chronic use of Teavigo (94% epigallocatechin gallate), a polyphenol compound with postulated antioxidant and antiapoptotic activity.


Assuntos
Alcaptonúria , Ocronose , Transtornos da Pigmentação , Humanos , Ocronose/induzido quimicamente , Ocronose/diagnóstico , Ocronose/patologia , Alcaptonúria/patologia , Pele/patologia
13.
Molecules ; 28(6)2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36985595

RESUMO

Alkaptonuria (AKU) is a rare genetic autosomal recessive disorder characterized by elevated serum levels of homogentisic acid (HGA). In this disease, tyrosine metabolism is interrupted because of the alterations in homogentisate dioxygenase (HGD) gene. The patient suffers from ochronosis, fractures, and tendon ruptures. To date, no medicine has been approved for the treatment of AKU. However, physiotherapy and strong painkillers are administered to help mitigate the condition. Recently, nitisinone, an FDA-approved drug for type 1 tyrosinemia, has been given to AKU patients in some countries and has shown encouraging results in reducing the disease progression. However, this drug is not the targeted treatment for AKU, and causes keratopathy. Therefore, the foremost aim of this study is the identification of potent and druggable inhibitors of AKU with no or minimal side effects by targeting 4-hydroxyphenylpyruvate dioxygenase. To achieve our goal, we have performed computational modelling using BioSolveIT suit. The library of ligands for molecular docking was acquired by fragment replacement of reference molecules by ReCore. Subsequently, the hits were screened on the basis of estimated affinities, and their pharmacokinetic properties were evaluated using SwissADME. Afterward, the interactions between target and ligands were investigated using Discovery Studio. Ultimately, compounds c and f were identified as potent inhibitors of 4-hydroxyphenylpyruvate dioxygenase.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase , Alcaptonúria , Ocronose , Humanos , Alcaptonúria/tratamento farmacológico , Alcaptonúria/genética , Alcaptonúria/metabolismo , Simulação de Acoplamento Molecular , Ocronose/tratamento farmacológico , Ácido Homogentísico/metabolismo
14.
Endocr Regul ; 57(1): 61-67, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36966367

RESUMO

Alkaptonuria (AKU, OMIM, No. 203500) is a rare, slow-progressing, irreversible, multisystemic disease resulting from a deficiency of the homogentisate 1,2-dioxygenase enzyme, which leads to the accumulation of homogentisic acid (HGA) and subsequent deposition as pigment in connective tissues called ochronosis. As a result, severe arthropathy of large joints and spondyloarthropathy with frequent fractures, ligament ruptures, and osteoporosis develops in AKU patients. Since 2020, the first-time treatment with nitisinone has become available in the European Union. Nitisinone significantly reduces HGA production and arrests ochronosis in AKU patients. However, blocking of the tyrosine metabolic pathway by the drug leads to tyrosine plasma and tissue concentrations increase. The nitisinone-induced hypertyrosinemia can lead to the development of corneal keratopathy, and once it develops, the treatment needs to be interrupted. A decrease in overall protein intake reduces the risk of the keratopathy during nitisinone-induced hypertyrosinemia in AKU patients. The low-protein diet is not only poorly tolerated by patients, but over longer periods, leads to a severe muscle loss and weight gain due to increased energy intake from carbohydrates and fats. Therefore, the development of novel nutritional approaches is required to prevent the adverse events due to nitisinone-induced hypertyrosinemia and the negative impact on skeletal muscle metabolism in AKU patients.


Assuntos
Alcaptonúria , Ocronose , Tirosinemias , Humanos , Alcaptonúria/tratamento farmacológico , Alcaptonúria/metabolismo , Ocronose/tratamento farmacológico , Tirosina/uso terapêutico , Ácido Homogentísico/metabolismo
15.
Curr Protein Pept Sci ; 24(5): 380-392, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36880186

RESUMO

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs, which occurs because the homogentisate 1,2-dioxygenase (HGD) enzyme is not functional due to gene variants. Over time, HGA oxidation and accumulation cause the formation of the ochronotic pigment, a deposit that provokes tissue degeneration and organ malfunction. Here, we report a comprehensive review of the variants so far reported, the structural studies on the molecular consequences of protein stability and interaction, and molecular simulations for pharmacological chaperones as protein rescuers. Moreover, evidence accumulated so far in alkaptonuria research will be re-proposed as the bases for a precision medicine approach in a rare disease.


Assuntos
Alcaptonúria , Homogentisato 1,2-Dioxigenase , Humanos , Alcaptonúria/genética , Alcaptonúria/metabolismo , Dioxigenases/genética , Dioxigenases/metabolismo , Estudos de Associação Genética , Homogentisato 1,2-Dioxigenase/genética , Homogentisato 1,2-Dioxigenase/metabolismo , Ácido Homogentísico/metabolismo , Doenças Raras , Relação Estrutura-Atividade
16.
Am J Med Sci ; 365(4): 368-374, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36608845

RESUMO

BACKGROUND: The aim of the current study was to determine whether there is an association between alkaptonuria (AKU) and urinary tract infection (UTI) by exploring the bacterial quality of the urinary tract, as most of the patients with AKU present with frequent occurrence of urinary tract symptoms such as incomplete emptying of urinary bladder, dysuria and nocturia. METHODS: Study samples were collected from 22 participants; 9 from patients with AKU, 9 from individuals who were AKU carriers, and 4 people served as control. Confirmation of AKU diagnosis was established by the ferric chloride test and quantitative determination of urinary homogentisic acid (HGA) levels. RESULTS: In the ferric chloride test, the urine samples of AKU patients showed a characteristic black ring upon addition of few drops of ferric chloride solution. During urinary HGA determination, patients with AKU had increased levels of urinary HGA as compared to carriers and controls. The following 10 bacterial species were isolated from the urinary tract of AKU patients, carriers and controls: Sphingomonas paucimobilis, Escherichia coli, Francisella tularensis, Staphylococcus hominis, Staphylococcus haemolyticus, Leuconostoc mesenteroides, Dermacoccus nishinomiyaensis, Kytococcus sedentarius, Serratia fonticola and Granulicatella adiacens. The presence of S. paucimobilis was found in three male patients, and one female each from the carrier and control groups. Almost all study samples were positive for D. nishinomiyaensis and K. sedentarius. S. fonticola and G. adiacens were found only in AKU carrier females. CONCLUSIONS: The results deduced that males show symptoms of arthritis early and more severely than females and by this it appears that there is an association between these symptoms and the percentage of bacterial infection in males that requires more accurate diagnosis and treatment to clarify such relationship. In the current study, males (patients, carriers, and controls) were more likely to have bacterial infections than females (64% vs. 36%). The 16 and 2 bacterial isolates, detected in 7 males and 2 females AKU patients, respectively, revealed that male AKU patients had a 2.3-fold greater rate of bacterial infection than female AKU patients. Therefore, further studies are warranted to investigate if there's any relationship between higher incidence of bacterial infections and development of AKU-related clinical symptoms in the male population.


Assuntos
Alcaptonúria , Artrite , Sistema Urinário , Humanos , Masculino , Feminino , Alcaptonúria/tratamento farmacológico , Alcaptonúria/urina , Ácido Homogentísico/urina
18.
Orphanet J Rare Dis ; 18(1): 1, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36600285

RESUMO

Alkaptonuria is a rare inherited disorder for which there was no disease-modifying treatment. In order to develop a successful approved therapy of AKU multiple barriers had to be overcome. These included activities before the conduct of the study including deciding on the drug therapy, the dose of the drug to be used, clarify the nature of the disease, develop outcome measures likely to yield a positive outcome, have a strategy to ensure appropriate patient participation through identification, build a consortium of investigators, obtain regulatory approval for proposed investigation plan and secure funding. Significant barriers were overcome during the conduct of the multicentre study to ensure harmonisation. Mechanisms were put in place to recruit and retain patients in the study. Barriers to patient access following completion of the study and regulatory approval were resolved.


Assuntos
Alcaptonúria , Humanos , Alcaptonúria/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Cicloexanonas/uso terapêutico , Nitrobenzoatos/uso terapêutico , Ácido Homogentísico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
19.
Eur J Hum Genet ; 31(4): 485-489, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35110678

RESUMO

Until recently, mainly DNA sequencing has been used to identify variants within the gene coding for homogentisate dioxygenase (HGD, 3q13.33) that cause alkaptonuria (AKU), an autosomal recessive inborn error of metabolism of tyrosine. In order to identify possible larger genomic deletions we have developed a novel Multiplex Ligation-dependent Probe Amplification (MLPA) assay specific for this gene (HGD-MLPA) and tested it successfully in healthy controls and in patients carrying two known previously identified HGD deletions. Subsequently, we analysed 22 AKU patients in whom only one or none classical HGD variant was found by sequencing. Using HGD-MLPA and sequencing, we identified four larger deletions encompassing from 1 to 4 exons of this gene and we defined their exact breakpoints: deletion of exons 1-4 (c.1-8460_282 + 6727del), deletion of exons 5 and 6 (c.283-9199_434 + 1688del), deletion of exon 11 (c.775-1915_879 + 1293del), and deletion of exon 13 (c.1007-1709_1188 + 1121del). We suggest including MLPA in the DNA diagnostic protocols for AKU in cases where DNA sequencing does not lead to identification of both HGD variants.


Assuntos
Alcaptonúria , Humanos , Alcaptonúria/diagnóstico , Alcaptonúria/genética , Reação em Cadeia da Polimerase Multiplex , Homogentisato 1,2-Dioxigenase/genética , Genômica , Sequência de Bases
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