RESUMO
BACKGROUND: Ochronotic arthropathy (OcA) refers to excessive homogentisic acid (HGA) deposition in the musculoskeletal system. Our current understanding of OcA is limited, as there are less than a thousand alkaptonuria (AKU) cases reported in the literature. Herein, we investigated the rheumatological manifestations of OcA in a group of adult AKU patients. METHODS: Adult AKU patients with symptoms suggestive of OcA were included. Patients underwent a detailed rheumatological assessment. Laboratory testing, including autoantibodies and radiological investigations such as conventional X-rays, and magnetic resonance imaging (MRI) were performed. RESULTS: Eight out of 12 (66%) patients had symptoms consistent with OcA. The median age at OcA symptoms was 36 (27-48) years, and the presenting symptom was back pain in 87.5% of the patients. All patients had chronic back pain, and three (37.5%) had an inflammatory type of pain character. Radiographic sacroiliitis based on X-rays was present in 2 (25%) cases. MRI of the sacroiliac joints documented bone marrow edema in five (62.5%), and spinal MRI identified corner inflammatory lesions in three patients (37.5%). One patient (12.5%) had rheumatoid arthritis. Extra-articular involvement, including enthesitis (n = 1; 12.5%), interstitial lung disease (n = 1; 12.5%), and scleritis (n = 1; 12.5%), was also noted. CONCLUSION: The frequent occurrence of OcA-related inflammatory manifestations in our patients contradicts the conventional concept of OcA as a non-inflammatory disorder. The activation of inflammatory pathways, possibly by the HGA products, may responsible for this condition.Significance and innovationsAbout three-fourths of adult ochronotic arthropathy (OcA) patients in our group had associated inflammatory disease.OcA associated inflammatory diseases were showing a severe phenotypeNearly half of the OcA patients required early prosthesis operations compared to their healthy counterparts.
Assuntos
Ocronose , Osteoartrite , Alcaptonúria/complicações , Alcaptonúria/diagnóstico por imagem , Cartilagem Articular , Humanos , Ocronose/complicações , Ocronose/diagnóstico por imagem , Coluna VertebralRESUMO
ApreciseKUre is a multi-purpose digital platform facilitating data collection, integration and analysis for patients affected by Alkaptonuria (AKU), an ultra-rare autosomal recessive genetic disease. We present an ApreciseKUre plugin, called AKUImg, dedicated to the storage and analysis of AKU histopathological slides, in order to create a Precision Medicine Ecosystem (PME), where images can be shared among registered researchers and clinicians to extend the AKU knowledge network. AKUImg includes a new set of AKU images taken from cartilage tissues acquired by means of a microscopic technique. The repository, in accordance to ethical policies, is publicly available after a registration request, to give to scientists the opportunity to study, investigate and compare such precious resources. AKUImg is also integrated with a preliminary but accurate predictive system able to discriminate the presence/absence of AKU by comparing histopatological affected/control images. The algorithm is based on a standard image processing approach, namely histogram comparison, resulting to be particularly effective in performing image classification, and constitutes a useful guide for non-AKU researchers and clinicians.
Assuntos
Alcaptonúria , Alcaptonúria/diagnóstico por imagem , Cartilagem/diagnóstico por imagem , Bases de Dados Factuais , Ecossistema , Humanos , Medicina de PrecisãoRESUMO
AIM: To study the efficacy of low dosage of nitisinone in alkaptonuria. BACKGROUND: Alkaptonuria (AKU) is a rare genetic disease which induces deposition of homogentisic acid (HGA) in connective inducing premature arthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures and osteopenia. Recent studies showed that nitisinone decreases HGA and is a beneficial therapy in AKU. This treatment induces an increase in tyrosine levels which can induces adverse effects as keratopathy. METHODS: We described the evolution HGA excretion and tyrosine evolution in 3 AKU patients treated by very low dosage of nitisinone with regards to their daily protein intakes. We also described the first pregnancy in an AKU patient treated by nitisinone. RESULTS: We found mild clinical signs of alkaptonuria on vertebra MRI in two young adults and homogentisate deposition in teeth of a 5â¯years old girl. Very low dose of nitisinone (10% of present recommended dose: 0.2â¯mg/day) allowed to decrease homogentisic acid by >90% without increasing tyrosine levels above 500⯵mol/ in these three patients. INTERPRETATIONS: The analysis of the follow-up data shows that, in our three patients, a low-dosage of nitisinone is sufficient to decrease urinary HGA without increasing plasma tyrosine levels above the threshold of 500⯵mol/L.
Assuntos
Alcaptonúria/diagnóstico por imagem , Alcaptonúria/tratamento farmacológico , Cicloexanonas/administração & dosagem , Nitrobenzoatos/administração & dosagem , Adulto , Pré-Escolar , Dieta , Relação Dose-Resposta a Droga , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Tirosina/sangue , Adulto JovemRESUMO
STUDY DESIGN: Case report and literature review. OBJECTIVE: To characterize the rare presentation of myelopathy occurring secondary to alkaptonuria and to evaluate the available evidence regarding its treatment. SUMMARY OF BACKGROUND DATA: Alkaptonuria is an autosomal recessive genetic condition with an estimated incidence of 1 in 250,000 to 1 in 1,000,000 people. Mutation of the enzyme homogentisate 1,2-dioxygenase leads to the production of high levels of homogentisic acid, with subsequent deposition in ligaments, cartilage, and menisci. Involvement of the spine is termed "ochronotic spondyloarthropathy," of which myelopathy is an uncommon presentation. METHODS: We present the case of a 57-year-old man with alkaptonuria-associated myelopathy, who underwent surgical decompression. Ten additional cases were identified in the literature by a systematic search of PubMed and Google Scholar. RESULTS: In a patient presenting with myelopathy, alkaptonuria may be suspected because of medical history, family history, symptoms (including darkened urine, pigmented ear cartilage, and sclera), or radiographic changes, such as multilevel disc collapse, progressive wafer-like disc calcification, extensive osteophyte formation, and spinal deformity. The diagnosis can be confirmed by urine homogentisic acid testing. Of the 11 patients presented here or identified in the literature, 2 were treated nonoperatively, 8 were treated with decompressive spinal surgery, and treatment of the myelopathy was not discussed for 1 patient. In all cases in which outcomes were reported, substantial improvement in the patient's condition was seen. CONCLUSION: Alkaptonuria is a rare cause of myelopathy, but one that clinicians should understand. Although no disease-modifying treatment currently exists for alkaptonuria, the use of symptomatic treatments and, particularly, surgical decompression is recommended to address myelopathy if it develops. LEVEL OF EVIDENCE: 4.
Assuntos
Alcaptonúria/diagnóstico por imagem , Alcaptonúria/cirurgia , Ocronose/diagnóstico por imagem , Ocronose/cirurgia , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/cirurgia , Alcaptonúria/complicações , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/diagnóstico por imagem , Doenças da Medula Óssea/cirurgia , Calcinose/complicações , Calcinose/diagnóstico por imagem , Calcinose/cirurgia , Descompressão Cirúrgica/métodos , Humanos , Tinta , Masculino , Pessoa de Meia-Idade , Ocronose/complicações , Doenças da Medula Espinal/complicações , Espondiloartropatias/complicações , Espondiloartropatias/diagnóstico por imagem , Espondiloartropatias/cirurgiaRESUMO
Alkaptonuria is a rare inborn metabolic disorder due to a mutation in the homogentisic acid oxidase enzyme (HGO) gene on chromosome 3q. As HGO is deficient in alkaptonuria patients, there is an accumulation of homogentisic acid in the blood and urine. Homogentisic acid gets deposited in the soft tissues, tendons, cartilages, large joints and intervertebral discs. Ochronosis usually affects the dorsolumbar spine and typically spares the cervical spine and sacroiliac joints. However, in this case of isolated ochronosis, we report co-existent extensive cervical spine degenerative changes and cervical vertebral fusion, which has not been described in the literature so far.
Assuntos
Alcaptonúria/diagnóstico por imagem , Vértebras Cervicais/diagnóstico por imagem , Imagem Multimodal , Doenças da Coluna Vertebral/diagnóstico por imagem , Alcaptonúria/patologia , Vértebras Cervicais/patologia , Diagnóstico Diferencial , Humanos , Doenças da Coluna Vertebral/patologiaRESUMO
BACKGROUND: Ochronotic arthropathy related to alkaptonuria is a rare condition. Cervical spine involvement with myelopathic features has been even more rarely described, particularly related to atlantoaxial instability. As such, little is known about the optimal surgical management in these patients. CASE DESCRIPTION: We described the first case, to our knowledge, of a patient with alkaptonuria and related cervical spondylotic myelopathy from pannus formation at the atlantoaxial joint. We describe our choices in surgical management of this rare condition in a patient with an excellent outcome. CONCLUSION: Ochronotic cervical spondylotic myelopathy is a rare condition and may require additional considerations in surgical treatment compared to more common causes of cervical spondylotic myelopathy. In our case, we elected for decompression with posterior occipitocervical screw fixation and were able to achieve neurologic recovery with no complications, currently at 2-year follow-up.
Assuntos
Alcaptonúria/cirurgia , Vértebras Cervicais/cirurgia , Gerenciamento Clínico , Doenças da Medula Espinal/cirurgia , Espondilose/cirurgia , Idoso , Alcaptonúria/complicações , Alcaptonúria/diagnóstico por imagem , Vértebras Cervicais/diagnóstico por imagem , Seguimentos , Humanos , Masculino , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/etiologia , Espondilose/diagnóstico por imagem , Espondilose/etiologiaAssuntos
Alcaptonúria/diagnóstico por imagem , Dor nas Costas/diagnóstico por imagem , Artropatias/diagnóstico por imagem , Ocronose/diagnóstico por imagem , Radiografia , Alcaptonúria/complicações , Dor nas Costas/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Artropatias/complicações , Ilustração Médica , Pessoa de Meia-Idade , Ocronose/complicações , Coluna Vertebral/diagnóstico por imagem , Espondilite Anquilosante/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 , RadiografiaAssuntos
Alcaptonúria/diagnóstico por imagem , Antibacterianos/efeitos adversos , Hiperpigmentação/induzido quimicamente , Articulação do Joelho/diagnóstico por imagem , Minociclina/efeitos adversos , Dor/diagnóstico por imagem , Acne Vulgar/tratamento farmacológico , Antibacterianos/uso terapêutico , Artroscopia , Diagnóstico Diferencial , Humanos , Hiperpigmentação/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Minociclina/uso terapêuticoRESUMO
Alkaptonuria is a rare, hereditary metabolic disorder in which a deficiency in the homogentisate 1,2-dioxygenase enzyme results in an accumulation of homogentisic acid. Deposition of excess homogentisic acid in different intra- and extra-articular structures with high content of connective tissue causes brownish-black pigmentation and weakening, ultimately resulting in tissue degeneration and finally osteoarthritis. Ochronotic arthropathy is considered a rapidly progressive, disabling condition in which weight-bearing joints and the thoracolumbar spine are predominantly affected. Patients often require multiple joint replacements, such as in the case of the patient presented here. At present, there is no definitive cure for ochronosis, and management is predominantly symptomatic.
Assuntos
Alcaptonúria/diagnóstico por imagem , Artropatias/diagnóstico por imagem , Ocronose/diagnóstico por imagem , Alcaptonúria/complicações , Humanos , Artropatias/complicações , Masculino , Pessoa de Meia-Idade , Ocronose/complicações , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Alkaptonuria is a rare disease with autosomal recessive inheritance and variable expression. The weight-bearing joint involvement and spondylitis-like vertebral changes occur only after the 3rd decade. Musculoskeletal ultrasonographic findings in alkaptonuria were only rarely described, consisting mainly into enthesopathy and non-synovial tendon degeneration. We present the case of a 50 years old man with alkaptonuria and discuss the ultrasonographic findings and the relationship of the disease with chondrocalcinosis. The tendinous and synovial aspect may be peculiar and it could therefore allow recognition and screening for alkaptonuria, along with clinical and radiologic data.
Assuntos
Alcaptonúria/complicações , Alcaptonúria/diagnóstico por imagem , Artrite/diagnóstico por imagem , Artrite/etiologia , Condrocalcinose/complicações , Condrocalcinose/diagnóstico por imagem , Ultrassonografia/métodos , Diagnóstico Diferencial , Humanos , Articulação do Joelho/diagnóstico por imagem , Masculino , Pessoa de Meia-IdadeRESUMO
Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene (HGD) that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense, and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8, and 13. We assessed the potential effect of all missense variations on protein function, using five bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT, and SNAP). We also analyzed the potential effect of splice-site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease.
Assuntos
Alcaptonúria/enzimologia , Alcaptonúria/genética , Homogentisato 1,2-Dioxigenase/genética , Mutação/genética , Alcaptonúria/diagnóstico por imagem , Alcaptonúria/patologia , Estudos de Coortes , Éxons/genética , Genótipo , Homogentisato 1,2-Dioxigenase/urina , Ácido Homogentísico/urina , Humanos , National Institutes of Health (U.S.) , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Radiografia , Irmãos , Estados UnidosRESUMO
Alkaptonuria is a rare recessive disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD) caused by mutations in the HGD gene. We report the case of a 38 year-old male with known alkaptonuria who was referred to an adult metabolic clinic after initially presenting to an emergency department with renal colic and subsequently passing black ureteric calculi. He complained of severe debilitating lower back pain, worsening over the last few years. A CT scan revealed marked degenerative changes and severe narrowing of the disc spaces along the entire lumbar spine. Sequencing of the HGD gene revealed that he was a compound heterozygote for a previously described missense mutation in exon 13 (G360R) and a novel missense mutation in exon 3 (K57N). Lys(57) is conserved among species and mutation of this residue is predicted to affect HGD protein function by interfering with substrate traffic at the active site. In summary, we describe an alkaptonuric patient and report a novel missense HGD mutation, K57N.
Assuntos
Alcaptonúria/genética , Homogentisato 1,2-Dioxigenase/genética , Mutação de Sentido Incorreto , Adulto , Alcaptonúria/diagnóstico por imagem , Alcaptonúria/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Homogentisato 1,2-Dioxigenase/química , Humanos , Masculino , Modelos Moleculares , Multimerização Proteica , Estrutura Quaternária de Proteína , Tomografia Computadorizada por Raios XRESUMO
Alkaptonuria is a rare autosomal recessive metabolic disorder that may present with multi-system involvement such as ochronotic arthropathy, renal, urethral and prostatic calculi, cardiac valvular lesions and pigmentation of the skin, sclera, cartilage and other connective tissues. An association of the disease with uveitis has never been reported. We report the first case of alkaptonuria with ochronotic arthropathy presenting with recurrent acute anterior uveitis as the initial manifestation. The possible common link with the HLA-B27 gene is discussed.
Assuntos
Alcaptonúria/complicações , Ocronose/complicações , Espondiloartropatias/complicações , Uveíte Anterior/etiologia , Doença Aguda , Alcaptonúria/diagnóstico por imagem , Alcaptonúria/tratamento farmacológico , Alcaptonúria/genética , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Diagnóstico Diferencial , Antígeno HLA-B27/genética , Humanos , Masculino , Pessoa de Meia-Idade , Midriáticos , Ocronose/diagnóstico por imagem , Ocronose/genética , Radiografia , Espondiloartropatias/diagnóstico por imagem , Espondiloartropatias/genéticaRESUMO
Alkaptonuria is a rare congenital metabolic disorder. A defect of the enzyme homogentisic oxidase results in a block of the metabolic pathway of the amino acids phenylalanine and tyrosine. Deposits of homogentisic acid polymers in connective tissue cause various organ manifestations, including musculoskeletal symptomatology. A 66 year-old woman was twice admitted to our Department because of progressive knee and low back pain. Physical examination and accessory investigations confirmed that her various complaints were caused by underlying alkaptonuria. We use this case and a review of literature to discuss orthopaedic problems in patients with alkaptonuria and describe the cardinal signs and symptoms of this disease, its diagnosis and treatment.