RESUMO
Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs due to a deficiency in functional levels of the enzyme homogentisate 1,2-dioxygenase (HGD), required for the breakdown of HGA, because of mutations in the HGD gene. Over time, HGA accumulation causes the formation of the ochronotic pigment, a dark deposit that leads to tissue degeneration and organ malfunction. Such behaviour can be observed also in vitro for HGA solutions or HGA-containing biofluids (e.g. urine from AKU patients) upon alkalinisation, although a comparison at the molecular level between the laboratory and the physiological conditions is lacking. Indeed, independently from the conditions, such process is usually explained with the formation of 1,4-benzoquinone acetic acid (BQA) as the product of HGA chemical oxidation, mostly based on structural similarity between HGA and hydroquinone that is known to be oxidized to the corresponding para-benzoquinone. To test such correlation, a comprehensive, comparative investigation on HGA and BQA chemical behaviours was carried out by a combined approach of spectroscopic techniques (UV spectrometry, Nuclear Magnetic Resonance, Electron Paramagnetic Resonance, Dynamic Light Scattering) under acid/base titration both in solution and in biofluids. New insights on the process leading from HGA to ochronotic pigment have been obtained, spotting out the central role of radical species as intermediates not reported so far. Such evidence opens the way for molecular investigation of HGA fate in cells and tissue aiming to find new targets for Alkaptonuria therapy.
Assuntos
Acetatos/urina , Alcaptonúria/urina , Benzoquinonas/urina , Homogentisato 1,2-Dioxigenase/metabolismo , Ácido Homogentísico/urina , Ocronose/metabolismo , Ocronose/urina , Adulto , Idoso , Alcaptonúria/enzimologia , Alcaptonúria/genética , Estudos de Casos e Controles , Difusão Dinâmica da Luz , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Homogentisato 1,2-Dioxigenase/genética , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Ocronose/enzimologia , Ocronose/genética , Oxirredução , Espectrofotometria Ultravioleta , UrináliseAssuntos
Alcaptonúria/diagnóstico , Doenças Ósseas Metabólicas/diagnóstico por imagem , Vértebras Cervicais/diagnóstico por imagem , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Ocronose/diagnóstico , Compressão da Medula Espinal/diagnóstico por imagem , Espondilose/diagnóstico por imagem , Adulto , Alcaptonúria/complicações , Alcaptonúria/urina , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Ácido Homogentísico/urina , Humanos , Deslocamento do Disco Intervertebral/etiologia , Deslocamento do Disco Intervertebral/fisiopatologia , Masculino , Ocronose/complicações , Ocronose/urina , Doenças da Esclera/etiologia , Doenças da Esclera/patologia , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/fisiopatologia , Espondilose/etiologia , Espondilose/fisiopatologia , Incontinência Urinária/etiologia , Incontinência Urinária/fisiopatologiaRESUMO
In this study the authors report the first example of spinal pseudarthrosis in a patient with ochronosis, and they describe the application of posterior-only 360° surgery as an alternative approach to combined anterior-posterior surgery in the management of pseudarthrosis of an ankylosed spine, regardless of its etiology. Spinal involvement in ochronosis produces loss of flexibility and ankylosis of thoracic and lumbar segments. Pseudarthrosis is a serious complication of the diseases that present with ankylosis of the spine. However, its occurrence in ochronotic spine has not been reported previously. Evaluation of progressive paraparesis in a 68-year-old man with ochronosis revealed pseudarthrosis at the T11-12 level. Circumferential dural sac decompression, debridement of the disc space, interbody fusion, and screw-rod fixation were all done via a posterior-only approach. Postoperatively the patient exhibited a marked recovery in terms of pain and neurological status. At the 3-month follow-up, he was able to walk independently. Ochronosis should be included in the etiology of pseudarthrosis. With aggravation of back pain and the appearance of neurological deficits in an already stable patient with any ankylosing disease, pseudarthrosis should be suspected. Furthermore, single-stage, 360°, posterior-only surgery may obviate the need for single-stage or staged anterior-posterior surgical intervention in patients with pseudarthrosis of the thoracic and lumbar spine.
Assuntos
Ocronose/complicações , Ocronose/cirurgia , Pseudoartrose/etiologia , Pseudoartrose/cirurgia , Vértebras Torácicas/cirurgia , Idoso , Descompressão Cirúrgica/métodos , Diagnóstico Diferencial , Evolução Fatal , Humanos , Fixadores Internos , Masculino , Ocronose/patologia , Ocronose/urina , Pseudoartrose/patologia , Pseudoartrose/urina , Fusão Vertebral/métodos , Vértebras Torácicas/diagnóstico por imagemAssuntos
Alcaptonúria/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Disco Intervertebral/diagnóstico por imagem , Ocronose/diagnóstico por imagem , Doenças da Esclera , Doenças da Coluna Vertebral/diagnóstico por imagem , Alcaptonúria/urina , Humanos , Masculino , Pessoa de Meia-Idade , Ocronose/urina , RadiografiaRESUMO
OBJECTIVE: Alkaptonuria (AKU) is a rare inborn error of metabolism of aromatic amino acids and considered to be an autosomal recessive trait caused by mutations in the homogentisate 1,2-dioxygenase (HGD) gene. A dominant pattern of inheritance has been reported but was attributed to extended consanguinity in many cases. However, we have observed a non-consanguineous family segregating AKU in a dominant manner over three generations. RESULTS: All affected individuals presented with typical features of AKU including darkening of the urine, ochronosis, arthropathy, and elevated urinary excretion of homogentisic acid. Sequence analysis of the HGD gene from genomic DNA of two affected individuals, uncle and niece, revealed a heterozygous missense mutation (M368V) in the uncle that was not present in his niece. Microsatellite genotyping demonstrated that both were heterozygous at the HGD locus and shared one haplotype. This haplotype did not contain a detectable HGD mutation. The haplotype was also found in a healthy son of the niece, making a dominant HGD mutation unlikely. Moreover, sequencing of cDNA from lymphoblastoid cells of the niece did not reveal an HGD mRNA with a potentially dominant-negative effect. CONCLUSION: Rare causes of the uncommon AKU inheritance in this family have to be considered, ranging from the coincidence of undetectable HGD mutations to a dominant mutation of a second, hitherto unknown AKU gene.
Assuntos
Alcaptonúria/diagnóstico , Homogentisato 1,2-Dioxigenase/genética , Mutação de Sentido Incorreto , Ocronose/diagnóstico , Adulto , Idoso , Alcaptonúria/enzimologia , Alcaptonúria/genética , Alcaptonúria/urina , Biomarcadores/urina , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Hereditariedade , Heterozigoto , Ácido Homogentísico/urina , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Ocronose/enzimologia , Ocronose/genética , Ocronose/urina , Linhagem , FenótipoAssuntos
Calcinose/etiologia , Dor Lombar/etiologia , Ocronose/complicações , Ocronose/diagnóstico , Transtornos da Pigmentação/etiologia , Doenças da Coluna Vertebral/etiologia , Bochecha , Mãos , Ácido Homogentísico/urina , Humanos , Disco Intervertebral , Masculino , Pessoa de Meia-Idade , Ocronose/urina , EscleraRESUMO
The deficiency of homogentisic acid oxidase, an enzyme that is mainly found in hepatocytes, is associated with alkaptonuria and ochronosis. We report a patient with clinical and radiologic findings of ochronotic arthropathy in whom alkaptonuria disappeared and the progressive course of the disease stopped after liver transplantation for hepatitis B-related cirrhosis.
Assuntos
Alcaptonúria/complicações , Hepatite C/complicações , Cirrose Hepática/cirurgia , Transplante de Fígado , Vértebras Lombares , Ocronose/complicações , Espondilartrite/etiologia , Alcaptonúria/diagnóstico por imagem , Alcaptonúria/urina , Feminino , Seguimentos , Ácido Homogentísico/urina , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Pessoa de Meia-Idade , Ocronose/diagnóstico por imagem , Ocronose/urina , Radiografia , Espondilartrite/diagnóstico por imagem , Espondilartrite/urinaAssuntos
Alcaptonúria/complicações , Raquianestesia , Artroplastia de Quadril , Fraturas do Colo Femoral/cirurgia , Ocronose/etiologia , Idoso , Alcaptonúria/diagnóstico , Alcaptonúria/urina , Artrite/etiologia , Fraturas do Colo Femoral/complicações , Doenças das Valvas Cardíacas/etiologia , Ácido Homogentísico/urina , Humanos , Achados Incidentais , Masculino , Ocronose/diagnóstico , Ocronose/urina , Espaço SubaracnóideoRESUMO
No disponible
Assuntos
Masculino , Idoso , Humanos , Alcaptonúria/complicações , Raquianestesia , Artroplastia de Quadril , Fraturas do Colo Femoral/cirurgia , Ocronose/etiologia , Alcaptonúria/diagnóstico , Alcaptonúria/urina , Artrite/etiologia , Fraturas do Colo Femoral/complicações , Doenças das Valvas Cardíacas/etiologia , Ocronose/diagnóstico , Ocronose/urina , Achados Incidentais , Espaço Subaracnóideo , Ácido Homogentísico/urinaRESUMO
Alkoptunuria is an inherited autosomal recessive metabolic disorder which is caused by the lack of homogentisic acid-oxidase enzyme. It is associated with various systemic abnormalities and related to the deposition of homogentisic acid pigment in connective tissues. These pigmentary changes are termed "ochronosis". We describe two patients with ochronotic arthritis who presented with advanced degenerative changes in the lumbo-sacral spine, knee and hip. The literature, differential diagnosis and management of this rare condition are reviewed in this article.
Assuntos
Artrite/diagnóstico , Ocronose/diagnóstico , Idoso , Alcaptonúria/complicações , Alcaptonúria/diagnóstico , Artrite/etiologia , Artrite/cirurgia , Artrite Reumatoide/diagnóstico , Artroplastia de Quadril , Diagnóstico Diferencial , Feminino , Quadril/patologia , Humanos , Joelho/patologia , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Ocronose/complicações , Ocronose/cirurgia , Ocronose/urina , Osteoartrite/diagnósticoAssuntos
Doenças da Túnica Conjuntiva/diagnóstico , Ocronose/diagnóstico , Transtornos da Pigmentação/diagnóstico , Alcaptonúria/diagnóstico , Alcaptonúria/urina , Doenças da Túnica Conjuntiva/urina , Ácido Homogentísico/urina , Humanos , Masculino , Pessoa de Meia-Idade , Ocronose/urina , Transtornos da Pigmentação/urinaAssuntos
Cartilagem Articular/patologia , Cartilagem da Orelha/patologia , Ocronose/patologia , Articulação do Ombro/patologia , Membrana Sinovial/patologia , Adulto , Cartilagem Articular/diagnóstico por imagem , Feminino , Humanos , Ocronose/diagnóstico por imagem , Ocronose/urina , Radiografia , Articulação do Ombro/diagnóstico por imagemRESUMO
Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. It is characterized by homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and arthropathy of large joints. Less common manifestations include cardiovascular abnormalities, renal, urethral and prostate calculi. Bone fractures are unusual in ochronosis. In this report, we describe a woman, 69 years of age, with a history of dark urine since childhood and progressive pigmentation of the skin, sclera, and auricular cartilages. She had severe arthropathy requiring total joint replacement in both of her knees and right hip. She also had severe aortic stenosis requiring valve replacement, and asymptomatic nephrolithiasis. She presented with a low trauma fracture of the distal femur despite two years of alendroate therapy. We review the etiology, pathogenesis, clinical presentation, diagnosis and treatment of alkaptonuric ochronosis. Early detection is important for prevention and treatment of multiple systems. Nitisinone, a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces production and urinary excretion of homogentisic acid; however, the long-term efficacy and side effects of such therapy are unknown. Identifying the gene for alkaptonuria offers the potential for a new therapeutic approach (replacement therapy with a recombinant enzyme) in the treatment of alkaptonuric ochronosis.
Assuntos
Alcaptonúria/complicações , Alcaptonúria/diagnóstico , Insuficiência da Valva Aórtica/etiologia , Fraturas do Fêmur/etiologia , Ocronose/complicações , Ocronose/diagnóstico , Idoso , Alcaptonúria/urina , Insuficiência da Valva Aórtica/cirurgia , Feminino , Fraturas do Fêmur/cirurgia , Próteses Valvulares Cardíacas , Humanos , Fixadores Internos , Ocronose/urinaRESUMO
Alkaptonuric ochronosis is rare disorder of tyrosin catabolism with an autosomal recessive trait. Alkaptonuric patients are deficient for homogentisate 1,2-dioxygenase. This enzymatic deficiency leads to the elimination of large amounts of homogentistic acid in the urine (Alkaptonuria) with accumulation of homogentistic acid oxidized pigment in the connective tissue (Ochronosis). The most common clinical features are dark brown discoloration of urine on exposure to air; ocular and cutaneous pigmentation; calcification of the intervertebral disc and cardiovascular ochronosis, especially calcification and stenosis of the aortic valve. The diagnosis is confirmed by detection of homogentistic acid in urine. We report a case of a 87 year old female which has all these clinical features mentioned above and pericardiac calcification, which had not been previously reported, to our knowledge.
Assuntos
Calcinose/diagnóstico por imagem , Dioxigenases , Cardiopatias/diagnóstico , Disco Intervertebral/diagnóstico por imagem , Ocronose/diagnóstico , Pericárdio/patologia , Doenças da Coluna Vertebral/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Alcaptonúria/diagnóstico , Alcaptonúria/urina , Feminino , Homogentisato 1,2-Dioxigenase , Ácido Homogentísico/urina , Humanos , Ocronose/urina , Oxigenases/deficiência , Radiografia AbdominalRESUMO
Ochronosis is a musculoskeletal manifestation of alkaptonuria, a rare hereditary metabolic disorder characterised by the absence of the enzyme homogentisic acid oxidase and associated with various systemic abnormalities related to the deposition of homogentisic acid pigment (ochronotic pigment). In this report, we describe a 53-year-old, HLA-B27(+) woman with ochronotic arthropathy. In addition to the typical clinical features of the disorder, she had bilateral hip involvement, which was improved by cementless total hip prosthesis.
Assuntos
Artroplastia de Quadril , Ocronose/cirurgia , Osteoartrite do Quadril/cirurgia , Espondilite Anquilosante/cirurgia , Feminino , Prótese de Quadril , Ácido Homogentísico/urina , Humanos , Cifose/diagnóstico por imagem , Cifose/urina , Lordose/diagnóstico por imagem , Lordose/urina , Região Lombossacral/diagnóstico por imagem , Pessoa de Meia-Idade , Ocronose/diagnóstico por imagem , Ocronose/urina , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/urina , Radiografia , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/urinaRESUMO
Hereditary ochronosis, or alkaptonuria, results from deficiency of homogentisic acid oxidase. It is an autosomal recessive condition found in geographically isolated populations. The excess homogentisic acid deposits in collagenous structures, leading to unusual pigmentation of the skin overlying cartilaginous structures, but on occasion pigment is also seen in the sclera, in sweat after oxidation, and classically, in urine when left standing at room temperature. This case report highlights the pathogenesis and expression of this rare disorder.
Assuntos
Artrite/diagnóstico , Hiperpigmentação/diagnóstico , Ocronose/diagnóstico , Descoloração de Dente/diagnóstico , Adulto , Artrite/genética , Cartilagem/patologia , Humanos , Hiperpigmentação/genética , Hiperpigmentação/patologia , Vértebras Lombares/diagnóstico por imagem , Masculino , Ocronose/diagnóstico por imagem , Ocronose/genética , Ocronose/urina , Radiografia , Descoloração de Dente/genéticaRESUMO
Alkoptonuria is an inherited metabolic disorder which is associated with various systemic abnormalities and related to the deposition of homogentisic acid pigment in connective tissues. These pigmentary changes are termed "ochronosis". We describe two patients with ochronotic arthropathy who presented with progressive and advanced degenerative changes in the lumbo-sacral spine. The literature, differential diagnosis and management of this rare condition are reviewed in this article. Management is usually conservative, but replacement surgery may be offered for severely affected major joints.