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Endogenous ochronosis: Case report and a systematic review of the literature
Abstract
Endogenous ochronosis (EO) is a rare autosomal recessive disorder due to accumulation of oxidized and polymerized forms of homogentisic acid (HGA) in connective tissues, giving them a deep dark blue pigmentation.
Through a new Tunisian case of EO and a review of the literature, we aimed to define the epidemioclinical features of EO, its diagnostic criteria, and evolution.
Three hundred and forty patients were enrolled through 54 articles and four abstracts.
A 35-year-old woman, born in consanguineous parents, presented with blue-grey patches of fingernails, first interdigital spaces, and ears with brown conjunctival pigmentation. Urine specimen turned dark on standing overnight. The diagnosis of EO was confirmed by urinary high levels of HGA. Investigations revealed radiologic signs of ochronotic arthropathy.
EO is ubiquitary. Its prevalence was estimated at almost 6.5 cases/year. The mean age at diagnosis was 55.9 years (M/F: 1.85). Onset symptoms mainly consisted in cutaneous signs. Ochronotic arthropathy was the most frequently reported manifestation. Treatment was mainly symptomatic.
EO is often revealed in adulthood mainly after the fourth decade. Urinary darkening is the first sign of the disease but is rarely reported as an onset sign. Skin signs are the alerting features. Ochronotic arthropathy is insidious but may be debilitating. No specific medical treatment of EO is available.
Cutaneous manifestations are the hallmarks of OE. As vital organ involvement has been reported, close monitoring and continuous surveillance is warranted.
... Los niveles elevados de AHG en sangre dan lugar a su depósito en distintos tejidos, donde se oxida y polimeriza en pigmento ocronótico. Este tiene afinidad por el colágeno de la dermis y el cartílago, por lo que los principales órganos afectados son el sistema músculoesquelético, las válvulas cardíacas y la piel [4][5][6]. ...
... La OE es más frecuente en mujeres (ratio hombre: mujer de 1, 3 a 2, 5), [5]. El primer síntoma que se presenta es la aparición de orinas oscuras en el pañal, lo que permite que hasta el 21% de los casos de OE se diagnostiquen antes del año de edad [2]. ...
... Histológicamente, la imagen típica es el depósito en dermis de pigmento no melánico marrón-amarillento y curvilíneo en forma de plátano localizado entre los haces de colágeno de la dermis. Sin embargo, el diagnóstico se debe confirmar mediante la determinación de AHG elevado en orina de 24 horas, hallazgo patognomónico de esta enfermedad [2,5,6]. ...
Endogenous ochronosis (EO) or alkaptonuria is an inherited autosomal recessive disease caused by the insufficiency of the enzyme homogentisic acid dioxygenase. This disturbance causes an accumulation and increased renal excretion of homogentisic acid (AHG), which manifests as dark urine when it oxidizes on contact with air. Other clinical manifestations of OE are the result of the deposit of AHG in the form of ochronotic pigment at the level of collagen in the skin and cartilage, where it causes blue-gray cutaneous hyperpigmentation, degenerative arthropathy, valvular disease, and other multisystem effects. Despite the progressive and irreversible nature of OE and the lack of a curative treatment, the life expectancy is preserved. We report a new case of EO with cutaneous and joint involvement, in which a high clinical suspicion, confirmed by elevated AHG in urine was the key in the diagnosis.
... There are only a few reports in the literature of multiple rupture of the Achilles tendon. [1][2][3][4] We report a case who had a rupture of the Achilles tendon, followed by rupture of the quadriceps tendon one year later. ...
... The prevalence is lower than 1:250000. 3 The patients are usually asymptomatic till the third decade. By the second decade bluish grey pigmentation may appear in the sclera, cartilage of the ear, in the teeth, buccal mucosa and in the nails or skin. ...
... 1,2 This weakens the connective tissue, leading to rupture of tendons and early degeneration of the cartilage. 3,4 The most reported tendon rupture is the tendo-Achilles. ...
p>Alkaptonuria is a rare autosomal recessive disorder characterised by the absence of homogentisic acid oxidase, due to deficiency of an enzyme that degrades HGA in the tyrosine degradation pathway. Homogentisic acid (HGA) and its metabolites accumulate in the connective tissues leading to dark pigmentation of connective tissue in patients with alkaptonuria. HGA deposits in connective tissue causes weakness of the tendon and subsequent rupture, especially the large tendons in the body. Only few cases are reported in the literature with multiple tendon rupture but many case reports are available with isolated rupture of tendons. We report on a patient with sequential tendon ruptures in a patient. The case is reported for its rarity.</p
... There is no effective specific treatment. The main objective is to prevent ochronotic arthropathy that may require joint replacements (3,4). The patients must be followed up for possible involvement of the renal and cardiovascular systems (4). ...
... The main objective is to prevent ochronotic arthropathy that may require joint replacements (3,4). The patients must be followed up for possible involvement of the renal and cardiovascular systems (4). At present, the only treatment available is symptomatic. ...
... The intervertebral discs are the most frequently involved, where it results in calcification and intervertebral disc space narrowing. Severe spinal involvement can resemble ankylosing spondylitis due to formation of bony bridges between vertebral bodies, rigid spine, and morning stiffness (4,5). The physician should also consider diffuse idiopathic skeletal hyperostosis (DISH) as a differential diagnosis. ...
... Okronozis daha çok erkeklerde görülen, kalıtımsal bir rahatsızlıktır ve bir ailenin 3 ferdinde birden görüldüğü literatürde daha önce bildirilmiştir. [8] İskelet dışı özellikler pek çok hastada hemen göze çarpmadığından, okronozis tanısının ilk aşamada atlanması mümkündür. [5,9] Sunduğumuz olguda, tanının ancak ameliyat sırasında konulabilmesi mümkün olmuştur. ...
... Alkaptonurik hastalarda belirtilerin başlıca nedeni artropatidir. [3,8,10] Okronozis ise kıkırdakta homogentisik asidin uzun süre boyunca birikiminin ortaya çıkan sonucudur ve kemiğin daha kırılgan hale gelmesine, bunun sonucunda da fissür ve erken dejenerasyona yol açar. Artan apoptoz ile birlikte etkilenen kondrositlerden salınan nitrik asit ve etkilenen endotel dokudan salınan toksik granüller de hasara neden olabilir. ...
... [1] Daha sonraki aşamalarda, yaşamın 4. veya 5. dekadında ise hızla ilerleyen artrit bulguları ortaya çıkar. [8] Okronotik artropatinin tedavisi semptomatiktir. Hızlı ilerleyen doğasıyla üç kompartımanlı tutulum, artroskopik debridman veya yüksek tibial osteotomi gibi eklem kurtarıcı işlemlere izin vermez. ...
Ochronotic arthropathy mainly involves the spine and large joints. Along with blackening of the joint, degeneration rapidly progresses mostly in the knee, resulting in symptoms by the 4th or 5th decade. As the role of medical treatment and joint conservation surgeries are limited in the early stages, joint replacement is the only effective option in one third of patients. We present a case of the unique complication of patellar ligament rupture during total knee replacement (TKR) of an ochronotic joint. A 51-year-old male presented with bilateral severe tricompartmental osteoarthritis with varus deformities and restriction of motion. Bilateral TKR was performed. At the 28-month follow-up, the patient was walking pain free with acceptable position of implants in radiographs. To our knowledge this is the first report of rupture of the patellar ligament during TKR of an ochronotic joint. We propose appropriate preoperative preparation and greater care in the handling of the tendon during TKR of an ochronotic joint in order to avoid complication.
... Clinically and radiologically ochronotic cartilage destruction closely imitates anklyosating spondylitis additionally affecting the big peripheral joints and making joint replacement necessary at young age [3,10]. Pigment accumulation further leads to ocular affection, skin darkening, cardiac valve impairment and several other less frequent affections [3,10,15]. Many clinical aspects of ochronosis have been assessed in detail [3] and a recent review aims to estimates their frequencies [15]. ...
... Pigment accumulation further leads to ocular affection, skin darkening, cardiac valve impairment and several other less frequent affections [3,10,15]. Many clinical aspects of ochronosis have been assessed in detail [3] and a recent review aims to estimates their frequencies [15]. However, attempts to assess the nature of the ocular signs in ochronosis date back at least to the 1950s and are rather unsystematic [16][17][18]. ...
... Only a minority of patients is diagnosed due to the earliest sign of alkaptonuria: darkening of urine [3,10,15]. Most frequently diagnosis is set in adulthood when ochronosis becomes symptomatic [10,15]. ...
Ochronosis / Alkaptonuria is a tyrosine metabolism disorder where accumulation of homogentisic acid, in eye, skin, cartilage and several other connective tissues leads to a black pigmentation of the affected tissues. It is autosomal-recessive inherited in men with a frequency of 1-9/1,000,000. While it is clear that pigment deposits lead to joint destruction, renal stone formation and cardiac valvulopathy respectively, the significance of ocular findings is still unclear. We therefore aim to evaluate the frequency and clinical significance of ocular findings in ochronosis and discuss possible therapeutic options.
Systematic review of literature via Medline and Web of Science. Only case reports in English, German, French, Spanish or Italian documenting detailed ophthalmologic examination were included.
Our search revealed 36 case reports including 40 patients. Average age at the onset of ocular signs was 40.6 years. The most frequent sign was symmetric brown sclera pigmentation present in 82.5 percent of the patients. "Oil-drops", brown pigment spots in the limbus are generally considered pathognomonic but were a little less frequent (75 percent). Vermiform pigment deposits at the level of the conjunctiva or increased conjunctival vessel diameter is also frequent. We found an increased incidence of central vein occlusion and elevated intraocular pressure going along with chamber angle hyperpigmentation. Another condition observed twice is rapid progressive astigmatism attributable to corneoscleral pigment accumulation.
Our observations suggest that ocular findings are of double relevance. First, characteristic ocular findings can anticipate the time of diagnosis and second, ocular findings may complicate to various conditions putting sight at risk. Opthalmologists and general physicians should be aware of both. Therapeutic options include protein restriction, administration of high dose vitamin C or nitisonone. Evidence for all of them is limited.
... In our dataset, the number of positive case of AKU by gender (Male: Female) was 6:1 (Table 2), which is different from the theory. While another observation on 339 cases of AKU patients also reported an imbalanced ratio [29]. Unfortunately, the cause of the difference in disease severity is unknown so far. ...
Background
Inherited metabolic disorders (IMDs) usually occurs at young age and hence it severely threatening the health and life of young people. While so far there lacks a comprehensive study which can reveals China’s nationwide landscape of IMDs. This study aimed to evaluate IMDs incidence and regional distributions in China at a national and province level to guide clinicians and policy makers.
Methods
The retrospective study conducted from January 2012 to March 2021, we analyzed and characterized 372255 cases’ clinical test information and diagnostic data from KingMed Diagnostics Laboratory. The samples were from 32 provincial regions of China, the urine organic acids were detected by gas chromatography-mass spectrometry (GC–MS), amino acids and acylcarnitines in dried blood spots were detected by liquid chromatography-tandem mass spectrometry (LC–MS/MS). We did a statistical analysis of the distribution of the 16 most common IMDs in amino acid disorders and organic acidemias, and then paid special attention to analyze the age and regional distributions of different IMDs. The statistical analyses and visualization analysis were performed with the programming language R (version 4.2.1).
Results
There were 4911 positive cases diagnosed, which was 1.32% of the total sample during the ten-year study period. Most diseases tended to occur at ages younger than 18 year-old. The Ornithine Transcarbamylase Deficiency tended to progress on male infants who were less than 28 days old. While the peak of the positive case number of Citrin Deficiency disease (CD) was at 1–6 months. Different IMDs’ had different distribution patterns in China’s provinces. Methylmalonic Acidemias and Hyperphenylalaninemia had an imbalanced distribution pattern in China and its positive rate was significantly higher in North China than South China. Conversely, the positive rate of CD was significantly higher in South China than North China.
Conclusions
Results of this work, such as the differences in distribution pattern of different diseases in terms of age, region, etc. provide important insights and references for clinicians, researchers and healthcare policy makers. The policy makers could optimize the better health screening programs for covering children and infants in specific ages and regions based on our findings.
... 2 Endojen okronozis için ise tahmini sıklık 5.75 vaka/ yıl olarak raporlanmıştır. 3 Alkaptononüride idrarda artmış HGA atılımı ve buna bağlı idrarda renk değişikliği varken; okronoziste kıkırdak, tendon, intervertebral disk, göz kapakları, yanak mukozası gibi doku ve kardiyovasküler, ürogenital iç organlarda HGA ve metebolitlerinin birikimine bağlı kahverengi -siyah pigmentasyon ve bunun sonucu olarak kas iskelet ve iç organ patolojileri görülmektedir. 1,4,5 Alkaptonüri çoğunlukla çocukluk döneminde tanınırken, okronozis tanısı ileri yaşlarda konmaktadır. ...
Alkaptonüri tirozin metabolizmasında yer alan homogentisik asit oksidaz enzim eksikliğine bağlı olarak idrarda homogentisik asit atılımıyla karakterize nadir görülen bir hastalıktır. Enzim eksikliğine bağlı biriken metabolitlerin doku ve iç organlarda birikmesi olarak tanımlanan okronozis, ilgili dokuda pigmentasyon artışına ve organ patolojilerine sebep olmaktadır. Benzer klinik tablolar oluşturması nedeniyle spondiloartropati, diffüz idiopatik iskelet hiperostozis, juvenil idiopatik artrit, osteoartrit gibi pek çok hastalığın ayırıcı tanısına girebilmektedir. Özgün bir tedavi yöntemi henüz olmamakla birlikte diyet modifikasyonu, ağrı kontrolü, hasta eğitimi ve uygun egzersiz programı oluşturulması tedavi seçeneklerini oluşturmaktadır. Bu vaka sunumunda boyun, bel ağrısı ve dizde artrit öyküsü olan hastada okronozisin spondiloartropati ve artrit ayırıcı tanısında akılda bulundurulması gerektiğine dikkat çekmek istedik.
... Homogentisic acid accumulates and is polymerized into a melanin-like pigment that is ultimately deposited in connective tissue over the years, where it associates with collagen fibers, especially in eyes, skin, bones, tendons, articular cartilages, lungs, valves, and kidneys [2]. Patients with AKU are usually asymptomatic until the fourth decade [3]. ...
Background
We present this report of a new ophthalmic finding in a patient with ochronosis.
Case presentation
An 85-year-old Caucasian male patient with bilateral dark temporal and nasal pigmentation of conjunctiva and sclera was referred to our hospital owing to low visual acuity. On biomicroscopic examination, bilateral horizontal Descemet’s membrane folds were observed. Corneal tomography revealed irregular and asymmetric “against-the-rule” astigmatism in both eyes. Anterior segment optical coherence tomography demonstrated numerous central Descemet’s without edema or other corneal structure alterations.
Conclusion
This is the first report of Descemet’s membrane folds in ochronosis. These corneal findings suggest that the accumulation of homogentisic acid in the sclera leads to thickening and stiffness of this region. These alterations could remarkably decrease visual acuity owing to topographic corneal curvature alterations, especially in elderly patients.
... Historical treatment included analgesics, anti-inflammatories, and steroids. 9 Our aim is to present two patients who were seen in an Otology clinic. They both had ochronosis, which was not the cause of their coexisting otologic diseases that brought them to the Otologist's office. ...
Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous and one endogenous in etiology. The first was caused by minocycline use for severe acne, and the second was caused by congenital alkaptonuria. There are several physical examination findings indicative of ochronosis in Otolaryngology. Although these discoveries can be alarming, they are not harmful and can be observed. When young patients are found to have ochronosis, a newly discovered medication can be taken to lessen the development of these physical manifestations.
... El cambio del color de la orina, alcaptonuria, es el único hallazgo clínico evidente en edades tempranas (5) . La orina fresca tiene color normal por lo que el individuo no percibe ninguna alteración (6) . La sintomatología relevante de este trastorno, se manifiesta a partir de la cuarta década donde las pigmentaciones en el cartílago de las orejas, los dedos y las escleras (Signo de Osler) (7) . ...
Resumen La ocronosis es una secuela de la alcaptonuria (AKU), trastorno hereditario autosómico recesivo causado por la deficiencia de la enzima homogentisiato 1,2 dioxigenasa (HGD). Esta patología provoca pigmenta-ción del tejido conectivo por depósito del ácido homogentísico (HGA), incluyendo el cartílago articular, lo cual provoca una artropatía ocronótica (AO). La AO es un trastorno poco común, en Ecuador, se des-conoce la tasa de prevalencia de esta enfermedad. Su diagnóstico se lo realiza tardíamente, por lo que el tratamiento efectivo, en la mayoría de casos, consiste en la artroplastia total. Su diagnóstico y tratamiento terapéutico temprano pueden disminuir la incidencia de sus complicaciones. A continuación presentamos el caso de un varón de 61 años con artropatía ocronótica de ambas rodillas y cadera derecha, diagnosticada por examen histopatológico post-operatorio y confirmada a partir de los hallazgos del cuadro clínico. Palabras clave: Artropatía ocronótica, alcaptonuria, homogentisiato 1,2 dioxidasa, ácido homogentísico, ar-troplastia. Abstract Ochronosis is a sequel to the alkaptonuria (AKU), an autosomal recessive inherited disorder caused by deficiency of the enzyme homogentisiate 1,2 dioxygenase (HGD). This condition causes pigmentation of the connective tissue by the deposition of homogentisic acid (HGA), including articular cartilage, which causes a ochronotic arthropathy (AO). AO is a uncommon disorder in Ecuador, the prevalence rate of the disease is unknown. Its diagnosis is performed lately, so that effective treatment, in most cases, is the total arthroplasty. Its early diagnosis and therapeutic treatment can reduce the incidence of complications. We present the case of a 61 year old male with ochronotic arthropathy of both knees and right hip, diagnosed by histopathology and postoperative confirmed the findings from the clinical picture.
... It is a progressive disease characterized by a classical triad of dark urine since birth, ochronosis becoming evident at around fourth decade, and osteoarthritis of major joints developing at around sixth decade of life. 1,2 There are no reports of dermoscopy of EO in the literature. Here, authors evaluated the dermoscopic patterns of EO. ...
... Progressive arthropathy of the large weight bearing joints particularly knee, followed by the hip and shoulder, is the most common clinical feature of ochronosis, appearing after the fourth decade. [1][2][3][4][5]21,22] The polymerized, deposited HGA discolors and weakens the connective tissue and cartilage, which is easily disrupted, fragmented, creates loose shards and finally leads to chronic inflammation, joint space narrowing, sclerosis and eventually osteoarthritis, which stimulates other osteoarthritic pattern with a small inflammatory component due to synovial irritation. [23] Although the smaller joints do not appear to develop arthritis, the cartilage within these joints also demonstrates pigmentation. ...
Alkaptonuria is a rare autosomal recessive disorder caused by defective metabolism of homogentisic acid (HGA) which on accumulation in the connective tissues causes arthritis, darkening of urine and connective tissue pigmentation. Knee is most commonly affected joint whereas pigment deposition is seen in entire body causing cardiovascular, genitourinary, ocular, cutaneous, and musculoskeletal complications. We here report such a case of bilateral ochronotic arthropathy, who was diagnosed to be alkaptonuric only during joint exploration. He sustained a cardiac catastrophic stroke on 3 rd post operative day of the left knee replacement which was done one week after the right knee replacement. With prompt treatment and good hospital care, the patient was revived successfully, without valvulotomy or valvular replacement. The spectrum of clinical manifestations are discussed in the report with emphasis on thorough history and clinical examination of the patient, before taking the patient to the total knee replacement to make accurate diagnosis before hand and be prepared for the complications or catastrophic by a multidisciplinary approach.
... Postinflammatory hyperpigmentation [22] Medication-induced Amiodarone [23] Antimalarials [1, 3] Bismuth [2] Clofazimine [2] Gold [24, 25] Mercury [2, 26] Methylene blue [27] Minocycline [28, 29] Phenothiazines [4, 30] Phenol [31] Silver [32] Systemic disorders Addison's disease [32] Alkaptonuria [33] Blue toe syndrome [34] DRESS syndrome (post baclofen, piracetam, and mitoxantrone) [35] Hemochromatosis [36] Melanosis cutis (diffuse) [37] Ochronosis (endogenous) [38] POEMS syndrome (associated with Castleman's disease) [39] DRESS drug rash with eosinophilia and systemic signs, POEMS polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes responsibility for the integrity of the work as a whole. ...
Hydroxychloroquine may result in cutaneous dyschromia. Older individuals who are the victims of elder abuse can present with bruising and resolving ecchymoses.
The features of hydroxychloroquine-associated hyperpigmentation are described, the mucosal and skin manifestations of elder abuse are reviewed, and the mucocutaneous mimickers of elder abuse are summarized.
An elderly woman being treated with hydroxychloroquine for systemic lupus erythematosus developed drug-associated black and blue pigmentation of her skin. The dyschromia was misinterpreted by her clinician as elder abuse and Adult Protective Services was notified. The family was eventually cleared of suspected elder abuse. A skin biopsy of the patient's dyschromia confirmed the diagnosis of hydroxychloroquine-associated hyperpigmentation.
Hyperpigmentation of skin, mucosa, and nails can be observed in patients treated with antimalarials, including hydroxychloroquine. Elder abuse is a significant and underreported problem in seniors. Cutaneous findings can aid in the discovery of physical abuse, sexual abuse, and self-neglect in elderly individuals. However, medication-associated effects, systemic conditions, and accidental external injuries can mimic elder abuse. Therefore, a complete medical history and appropriate laboratory evaluation, including skin biopsy, should be conducted when the diagnosis of elder abuse is suspected.
Blue nail discoloration is a distinctive clinical presentation, and diagnosis is challenging given the broad differential diagnosis. A comprehensive review of the literature describing blue discoloration of one or multiple nails was performed using the PubMed, Embase, Scopus, and Web of Science databases. A total of 245 publications were included and grouped based on involvement of a single nail (monodactylic) or multiple nails (polydactylic). Monodactylic blue discoloration was associated with tumors or benign nevi, most commonly glomus tumors, followed by blue nevi and less commonly melanomas. Polydactylic blue discoloration was frequently associated with medications (such as minocycline, zidovudine, and hydroxyurea), toxic and exogenous exposures (such as silver), and other medical conditions (such as HIV/AIDS and systemic lupus erythematous). Patients presenting with blue nail discoloration warrant a thorough history, physical examination, and workup to rule out malignancy, systemic disease, or toxic exposure. We present diagnostic algorithms for monodactylic and polydactylic blue nail discoloration to guide workup and treatment plans.
When looking for diseases of the skin, this is usually done in a holistic way, automatically and unconsciously, by recognizing localization, distribution, and appearance of the primary or secondary skin lesions. When Robert Willan (1757-1812) introduced the concept of morphology of skin lesions, it became the basis for the classification of dermatoses. Apart from ethnic factors, the various dermatoses comprise a rainbow of colors ranging from the most common red color to yellow, blue, brown, silver, green, black, and white.
Purpose:
To report a case of alkaptonuria (AKU) in a patient with bilateral conjunctival and scleral black colorization who was diagnosed with glaucoma thereafter.
Methods:
This is a single case report.
Results:
A 67-year-old male patient with bilateral black colorization of conjunctiva and sclera was referred to our hospital. In the biomicroscopic examination, globular dark pigmentation was observed in the conjunctiva, sclera, and limbal cornea. The patient was diagnosed with a nuclear cataract in both eyes. He also had gray skin pigmentation at his nose and paranasal area. Corneal topography examination revealed irregular astigmatism. Intraocular pressure values were 29 and 31 mm Hg, in the right and left eye, respectively, with Goldmann applanation tonometry. The diagnosis of AKU was made after pathologic assessment of conjunctival biopsy by the internal medicine department.
Conclusions:
AKU is characterized by the accumulation of homogentisic acid in the connective tissues of many organs including the eye. Patients should be carefully examined in ophthalmology clinics in order to not miss systemic diagnoses. It should be kept in mind that AKU may cause iridocorneal angle pigmentation, which leads to glaucoma, and patients should be treated with proper medication when presenting with elevated intraocular pressure values.
Background
Endogenous ochronosis (EO) is an autosomal recessive inherited disorder where there is incomplete oxidation of tyrosine and phenylalanine due to a lack of the enzyme homogentisic acid oxidase.
Objective
We report a singular observation of EO with a fatal outcome.
Case Report
We report the case of a 46-year-old man born to consanguineous parents with a medical history of recurrent renal colic and chronic nonspecific arthropathy. On clinical examination, slate blue pigmentation was seen on the cheeks, forehead, and nose, as well as blue-gray patches on all fingernails and bluish discoloration of the gums. Familial investigation revealed that his sister had similar pigmentation on the ears, hands, and fingernails. Histologic examination of a biopsy specimen from a pigmented lesion showed a dermal deposit of an acellular, eosinophilic material without cell reaction. Based on the clinical and histopathologic data, combined with the family medical history, our patient was considered to have EO with mucocutaneous, articular, and renal involvement. Unfortunately, the diagnosis was late because our patient died a few months later of terminal renal failure.
Conclusion
Skin signs are the hallmarks of EO and must alert the clinician to look for involvement of vital organs.
Renseignements de base
L'ochronose endogène (OE) est une affection héréditaire récessive autosomique où il se produit une oxydation incomplète de la tyrosine et de la phénylalanine en raison d'un manque d'oxydase de l'acide homogentisique.
Objectif
Nous présentons une observation singulière d'OE dont l'issue a été fatale.
Rapport de cas
Nous exposons le cas d'un homme de 46 ans né de parents consanguins ayant des antécédents médicaux de coliques néphrétiques récurrentes et une arthropathie chronique non spécifique. À l'examen clinique, nous avons observé une pigmentation bleu ardoise au niveau des joues, du front, et du nez, ainsi que des plaques bleu gris sur tous les ongles de doigts et une décoloration bleuâtre des gencives. Une étude des antécédents familiaux a révélé que sa sœur présentait une pigmentation semblable au niveau des oreilles, des mains, et des ongles de doigts. L'examen histologique de l'échantillon de la biopsie pratiquée sur une lésion pigmentée a montré un dépôt cutané de matériel éosinophile acellulaire sans réaction cellulaire. Selon les données cliniques et histopathologiques, combinées aux antécédents médicaux familiaux, notre patient présentait une OE avec une atteinte rénale, articulaire, et muco-cutanée. Malheureusement, le diagnostic a été tardif puisque notre patient est décédé quelques mois plus tard d'insuffisance rénale terminale.
Conclusion
Les signes cutanés constituent les caractéristiques de l'OE et ceux-ci doivent alerter le clinicien de manière à ce qu'il cherche la contribution des organes vitaux.
Ochronosis is a rare disease characterised clinically by bluish-grey skin discolouration and histologically by yellow-brown pigment deposits in the dermis. It occurs in endogenous and exogenous forms. Endogenous ochronosis, also known as alkaptonuria, is an autosomal recessive disease of tyrosine metabolism, resulting in the accumulation and deposition of homogentisic acid in connective tissue. We report a case of facial endogenous ochronosis and coexistent photodamage, which was successfully treated with erbium-doped yttrium aluminium garnet laser resurfacing and deep focal point treatment to remove areas of residual deep pigment.
Ochronosis is dark pigmentation of connective tissue in patients with alkaptonuria. The dark pigmentation is caused by accumulation of homogentisic acid (HGA) and its metabolites in the connective tissues, due to deficiency of an enzyme that degrades HGA in the tyrosine degradation pathway. The deposition of HGA in connective tissue causes weakness of the tendon and subsequent rupture, especially the large tendons in the body. Rupture of isolated tendons has been reported in many case reports in the literature. We report on a patient with multiple sequential tendon ruptures, and review the literature to see if there is a way of preventing subsequent tendon ruptures after an initial rupture in this condition.
Background:
Endogenous ochronosis (EO) is an autosomal recessive inherited disorder where there is incomplete oxidation of tyrosine and phenylalanine due to a lack of the enzyme homogentisic acid oxidase.
Objective:
We report a singular observation of EO with a fatal outcome.
Case report:
We report the case of a 46-year-old man born to consanguineous parents with a medical history of recurrent renal colic and chronic nonspecific arthropathy. On clinical examination, slate blue pigmentation was seen on the cheeks, forehead, and nose, as well as blue-gray patches on all fingernails and bluish discoloration of the gums. Familial investigation revealed that his sister had similar pigmentation on the ears, hands, and fingernails. Histologic examination of a biopsy specimen from a pigmented lesion showed a dermal deposit of an acellular, eosinophilic material without cell reaction. Based on the clinical and histopathologic data, combined with the family medical history, our patient was considered to have EO with mucocutaneous, articular, and renal involvement. Unfortunately, the diagnosis was late because our patient died a few months later of terminal renal failure.
Conclusion:
Skin signs are the hallmarks of EO and must alert the clinician to look for involvement of vital organs.
In a 69-year-old man with ochronosis, circumscribed brown-black scleral spots with injection of conjunctival vessels and some small pigmentations of the peripheral superficial cornea occurred. Ochronosis is an autosomal recessive chronic disease, whereby early detection of cardiac valvular defects and arthritis is important particularly in patients who are older than 40 years.
Ochronosis is a dark pigmentation of connective tissues in patients with alkaptonuria. We report a 35-year-old fit male who presented with a rupture of the Achilles tendon while walking. He was diagnosed as a patient of alkaptonuria when he was young following black discoloration of his urine. To the authors knowledge, this is the first case of ochronotic Achilles tendon rupture reported in literature.
To assess the involvement of the recently identified human homogentisate 1,2-dioxygenase gene (HGO) in alkaptonuria (AKU) in two unrelated patients with ochronosis of the conjunctiva, sclera, and cornea.
A mutation screen of the entire coding region of the HGO gene was performed using single stranded conformational analysis after polymerase chain reaction with oligonucleotide primers flanking all 14 exons of the HGO gene. Fragments showing aberrant mobility were directly sequenced.
Two homozygous missense mutations, L25P and M368V, were identified, each of which leads to the replacement of a highly conserved amino acid in the HGO protein.
The authors describe a novel mutation, L25P, in the German population and bring to 18 the total number of known HGO mutations.
The patient, a 43 year old woman with a 35 year history of alkaptonuria (fig 1A), presented to the orthopaedic clinic for pain in the right shoulder. Clinical examination demonstrated an important reduction of shoulder mobility with, on radiographic evaluation, a greatly destroyed joint (fig 1B). The patient was admitted to hospital to obtain a …
Alkaptonuria is a rare single-gene disorder characterized by black pigmentation of cartilage and other connective tissues. Premature degenerative arthritis affects the large joints in many of these of patients. Medical treatment is limited to a protein-restricted diet (phenylalanine and tyrosine) with surgery reserved for end-stage joint disease. As in other metabolic bone diseases, there are concerns about the quality and strength of affected bones and therefore the suitability and longevity of replacement arthroplasty. The histopathology and outcome of joint replacement for alkaptonuric arthritis is unknown and limited to sporadic case reports.
We describe 11 joint replacements in 3 patients with alkaptonuric polyarthropathy, including shoulder and elbow replacements not previously reported. No prosthetic failures occurred in up to 12 years of follow-up.
Total joint replacement is an acceptable treatment for degenerative joint disease in alkaptonuric patients, with implant survival comparable to that found in patients with osteoarthritis.
The biomedical literature on alcaptonuria, ochronosis and ochronotic joint disease, including 604 cases reported from thirty-five countries, is reviewed. The history of the development of our knowledge concerning this hereditary metabolic disorder, from 1584 to 1962, is recapitulated. The nature of the biochemical defect, a deficiency of homogentisic acid oxidase, in alcaptonuria is described and the pattern of genetic transmission traced. The geographic and racial distribution, and the multisystemic clinical manifestations of ochronosis are summarized. The diagnostic features and differential diagnostic considerations are presented. The gross, histopathologic and electron microscopic changes as well as pathogenesis are discussed. The various types of treatment attempted, without success, are mentioned.
Alcaptonuria is a rare hereditary disease, characterized by an abnormal blackish coloration of the urine and dark pigmentation of the conjunctive tissue which is due to a deficiency in homogentisate 1,2-dioxygenase (HGO), a phenylalanine catabolizing enzyme. An accumulation of homogentisate (HGA) is then formed, and is responsible for the dark coloration which only occurs after the urine has been exposed to air over a period of time. Signs of this disorder therefore frequently remain unnoticed during childhood, because the urine requires a relatively long exposure to air before it changes color. Diagnosis is generally made at a later date, during adulthood, following complications such as ochronosis, inflammatory arthritis, or urinary calculi.
Case report
In this study, the case has been described of alcaptonuria diagnosed in a five-month old infant. No efficient cure has yet been found, although certain treatments, including high doses of vitamin C, do seem to have a beneficial effect on limiting the complications associated with this disorder. Early diagnosis whenever possible is therefore important.
Conclusion
This case report is interesting because of the early diagnosis involved. In the event of any abnormal coloration of the urine, diagnosis may be established via the addition of an alkylating agent, and the levels of HGA determined by chromatography.
Objectifs. – Confirmer le diagnostic de rhumatisme alcaptonurique par le dosage de l'acide homogentisique urinaire chez les 14 sujets examinés. Tenter d'établir une corrélation génotype–phénotype chez les cinq patients ayant bénéficié d'une étude moléculaire du gène de l'homogentisate 1,2-dioxygénase.
Méthodes. – Nous rapportons 14 observations d'alcaptonurie (dix hommes et quatre femmes) dans 11 familles algériennes. La consanguinité est connue dans seulement trois familles (F = 1/16). Les mutations du gène de l'homogentisate 1,2-dioxygénase ont été identifiées par séquençage de l'ADN génomique.
Résultats. – Le diagnostic d'alcaptonurie a toujours été confirmé par le dosage de l'acide homogentisique urinaire. Quatre mutations du gène de l'homogentisate 1,2-dioxygénase ont été mises en évidence : une mutation faux-sens, serine189isoleucine à l'état homozygote chez deux sœurs s'accompagnant d'un phénotype peu sévère ; une mutation au niveau du site d'excision–épissage de l'intron 1 (IVS1–1G>A) à l'état homozygote chez un homme associée à un phénotype sévère (décès à l'âge de 61 ans d'une insuffisance rénale) ; une mutation silencieuse, alanine470alanine à l'état hétérozygote chez un homme avec un phénotype peu sévère ; une délétion de G en position c.819 conduisant à un décalage du cadre de lecture après Gly217 (Gly217fs) puis à un codon stop en c.850. Cette mutation nouvelle est présente à l'état hétérozygote chez une femme de phénotype peu sévère.
Conclusions. – Les deux mutations à l'état homozygote s'accompagnant respectivement d'un phénotype peu sévère et sévère, aucune corrélation génotype–phénotype n'a pu être établie.
• 1.1. A review of the literature on ochronosis has been presented emphasizing the evolution of knowledge about this disease.
• 2.2. Alkaptonuria may be considered an inborn error of protein metabolism resulting in the excretion of a substance known as homogentisic acid in the urine; this substance probably represents an intermediate product of the normal metabolism of certain amino acids. The condition may also be the result of prolonged exposure to phenolic compounds. Ochronosis is the clinical state of pigmentation by the alkapton compounds with particular localization in the cartilaginous structures and the cardiovascular system.
• 3.3. The differential diagnosis of other diseases showing pigmentation has been stressed in detail, and the particular diagnostic features of ochronosis have been emphasized. A new observation on the fluorescent behavior of urine containing alkapton bodies has been made.
• 4.4. The case history of a patient with alkaptonuria and ochronosis has been presented.
Abstract Valvular heart disease has numerous etiologies. These range from congenital malformations to infectious and degenerative diseases. Clinically, these result in significant problems, the management of which can necessitate valve replacement with prosthetic heart valves. A rare cause is the deposition of foreign material in the valvular tissues, and these include inborn errors of metabolism of the essential amino acids. Alkaptonuria, an autosomal recessive trait, can result in the accumulation of excess homogentisic acid. This can manifest as pigmentation in the skin and other tissues, including heart valves. Accumulation of this pigment can lead to an inflammatory reaction and to progressive valve dysfunction.
Purpose: To report a rare case of bilateral asymmetrical melanin-like pigments found in the cornea, conjunctiva and sclera.
Methods: Systemic investigation with clinical and laboratory analysis.
Results: The case was diagnosed as one of alkaptonuria and ocular ochronosis.
Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively frequent nucleotide substitution in the coding sequence, exon 4, resulting in an amino acid change (H80Q). These data provide insight into the origin and evolution of the various AKU alleles.
A case report of a patient with ochronosis and simultaneously occurring renal, vesical, and prostatic calculi is presented. Literature review suggests an increased incidence of urinary calculi in this syndrome, yet stone composition in such cases is not remarkable.
Alkaptonuria is a rare genetic disorder in which the enzyme homogentisic acid oxidase is deficient, resulting in the accumulation of homogentisic acid in various bodily tissues. This is a multisystem disorder with a characteristic blue-black discoloration of the skin and cartilage, which is termed ochronosis. Herein we report a profound case of ochronosis secondary to alkaptonuria. Furthermore, we review the clinical manifestations of alkaptonuria and discuss the spectrum of ochronosis, both endogenous and exogenous.
Two patients with generalized ochronosis developed cardiovascular symptoms related to cardiac ochronosis with aortic valvular stenosis. One patient with a transvalvular pressure gradient of 150 mm Hg underwent emergency aortic valve replacement. The other patient with a transvalvular pressure gradient of 96 mm Hg underwent successful elective aortic valve replacement. Cardiac ochronosis is a rare disease that might be encountered, with the typical signs, during an elective, planned cardiac operation. The most frequent presenting feature of this disease seems to be aortic valvular stenosis.
Alkaptonuric ochronosis is a heritable disorder of tyrosine metabolism, with various systemic abnormalities related to pigment deposition and degeneration of collagen and other tissues, including the heart and aorta, though no cerebrovascular abnormalities have been reported. The authors report a patient with alkaptonuric ochronosis and multiple intracranial aneurysms presenting with subarachnoid hemorrhage. The ruptured aneurysm was surgically treated, with a satisfactory outcome. In view of the well-known association of other connective tissue disorders with intracranial aneurysms, a potentially causal relationship is suggested between cerebral aneurysms and alkaptonuric ochronosis.
Synovial fluid from a patient with ochronotic arthropathy and calcification of the capsule of the right knee contained calcium pyrophosphate crystals and dark debris. Microscopic examination of an unstained fresh preparation showed these dark fragments to have a brown or golden brown color typical of ochronotic pigment. By electron microscopy there were identifiable cartilage fragments in the synovial fluid. These contained clumps of dense material deposited on the surface of collagen fibers. Similar brown staining and electron dense material probably representing ochronotic pigment was seen in synovial membrane and synovial fluid cells. Some of the intracellular calcium pyrophosphate crystals were in close relation with probable pigment.
1. Four cases of ochronotic arthropathy have been studied and the related literature has been reviewed.
2. Ochronotic arthropathy is a rare condition resulting from an inborn error of metabolism occurring as a Mendelian recessive characteristic. Its incidence, however, may have been underestimated.
3. Problems of differential diagnosis are discussed and it is suggested that more widespread screening should be undertaken in order to assess the true incidence of the condition.
Ochronosis is the clinical manifestation of alkaptonuria, a rare inborn error of metabolism. It is characterized by widespread pigmentation of the fibroconnective tissues, arthritis, and passage of dark urine. Prostatic involvement is usually limited to the incidental finding of calculi within the gland. Herein, we report a case of diffuse ochronotic involvement of the prostate clinically presenting as a neoplasm.
A 75-year-old man was diagnosed with alcaptonuria by direct identification of homogentisic acid in the urine using gas chromatography-mass spectrometry. Complications included valvular heart disease with marked calcification detected by two-dimensional color-Doppler echocardiography and recurrent bacterial infection. Immunological analyses revealed a reduced number of T cells with compensatory expansion of CD56+, CD57+ natural killer (NK) cell population and impaired functions of cellular immunity such as phytohemagglutinin response, antibody-dependent cellular cytotoxicity, NK activity and interleukin-2 production. Humoral immunity and neutrophil functions were considered to be normal. This is the first reported case of alcaptonuria to our knowledge in which immunological abnormality was documented.
Alkaptonuric ochronosis is a rare inborn metabolic disorder. Because of the deficient activity of the enzyme homogentisic acid oxidase, homogentisic acid accumulates in plasma, is deposited in various tissues and is excreted in large amounts in urine. Dark brown discoloration of urine on exposure to air or after addition of alkaline solution is characteristic. We describe two brothers with typical alkaptonuric ochronosis with dark urine, blue pigmentation of auricles and axillae, focal brown hyperpigmentation of sclerae, and anthropathy.
To discuss the case of a patient with ochronotic arthropathy whose symptoms were treated with chiropractic care. An emphasis is placed on this condition's radiographic features.
A 59-year-old woman with pain in her low back, right knee, and left ankle sought chiropractic evaluation. Black pigmentation was found in the sclera of both eyes, and homogentisic acid was present in the urine. Orthopedic evaluation revealed uncomplicated, nonspecific joint pain, and radiographs demonstrated characteristic spinal changes.
The patient was treated with chiropractic manipulation, physiotherapy modalities, bracing, and exercises. This type of therapy was successful in reducing the symptoms and helped decrease the severity and frequency of acute exacerbations.
Ochronotic arthropathY is a rare metabolic disorder that can be diagnosed from spinal radiographs. Chiropractic care is an appropriate tool for reducing its symptomatology.
Alkaptonuria is an inherited metabolic disorder characterized by the absence of the enzyme homogentisic acid oxidase, which leads to the accumulation of homogentisic acid, produced during normal metabolism of phenylalanine and tyrosine. Ochronosis, which is the dark pigmentation of connective tissues in patients with long-lasting alkaptonuria, can cause severe cartilage destruction in large joints and the vertebral column. Knee joint involvement, which occurs at relatively early ages, can be quite restrictive. Arthroplasty may be the treatment of choice in these patients because of limited mobility and diffuse involvement of the joint. We report a 48-year-old man who had been treated with cementless total knee arthroplasty. Theoretically, there are no bone ingrowth deficits that might be detrimental for the stabilization of cementless prostheses in ochronotic arthropathy because the bone tissue is not primarily affected by the disease. The 4-year follow-up of cementless total knee arthroplasty was satisfactory without any evidence of loosening.
We describe a 37-year-old woman who presented with palmoplantar pigmentation, thickening and pitting of 4 years duration. Bluish pigmented patches were seen over the sclera of her eyes. Her lumbar spine showed typical calcification of the intervertebral discs. Addition of Benedict's reagent to a urine sample of the patient gave rise to greenish brown precipitate and brownish black supernatant. Alkalinization of urine turned it black. A biopsy of the palmar lesion demonstrated irregular breaking up, swelling and homogenization of collagen bundles in the reticular dermis. Yellow-brown (ochre coloured) pigment was seen lying within the collagen bundles and also freely in the deeper dermis confirming our clinical diagnosis of alkaptonuric ochronosis. To the best of our knowledge this is probably the second report of alkaptonuria presenting with palmoplantar pigmentation.
Unlabelled:
Alcaptonuria is a rare hereditary disease, characterized by an abnormal blackish coloration of the urine and dark pigmentation of the conjunctive tissue which is due to a deficiency in homogentisate 1,2-dioxygenase (HGO), a phenylalanine catabolizing enzyme. An accumulation of homogentisate (HGA) is then formed, and is responsible for the dark coloration which only occurs after the urine has been exposed to air over a period of time. Signs of this disorder therefore frequently remain unnoticed during childhood, because the urine requires a relatively long exposure to air before it changes color. Diagnosis is generally made at a later date, during adulthood, following complications such as ochronosis, inflammatory arthritis, or urinary calculi.
Case report:
In this study, the case has been described of alcaptonuria diagnosed in a five-month old infant. No efficient cure has yet been found, although certain treatments, including high doses of vitamin C, do seem to have a beneficial effect on limiting the complications associated with this disorder. Early diagnosis whenever possible is therefore important.
Conclusion:
This case report is interesting because of the early diagnosis involved. In the event of any abnormal coloration of the urine, diagnosis may be established via the addition of an alkylating agent, and the levels of HGA determined by chromatography.
Alkaptonuria (AKU) is an autosomal recessive disorder caused by the deficiency of homogentisate 1,2 dioxygenase (HGO) activity. AKU shows a very low prevalence (1:100,000-250,000) in most ethnic groups. One notable exception is in Slovakia, where the incidence of AKU rises to 1:19,000. This high incidence is difficult to explain by a classical founder effect, because as many as 10 different AKU mutations have been identified in this relatively small country. We have determined the allelic associations of 11 HGO intragenic polymorphisms for 44 AKU chromosomes from 20 Slovak pedigrees. These data were compared to the HGO haplotype data available in our laboratory for >80 AKU chromosomes from different European and non-European countries. The results show that common European AKU chromosomes have had only a marginal contribution to the Slovak AKU gene pool. Six of the ten Slovak AKU mutations, including the prevalent G152fs, G161R, G270R, and P370fs mutations, most likely originated in Slovakia. Data available for 17 Slovak AKU pedigrees indicate that most of the AKU chromosomes have their origins in a single very small region in the Carpathian mountains, in the northwestern part of the country. Since all six Slovak AKU mutations are associated with HGO mutational hot spots, we suggest that an increased mutation rate at the HGO gene is responsible for the clustering of AKU mutations in such a small geographical region.
A 45‐year‐old white woman presented with a 3‐year history of bluish discoloration of her ears ( Fig. 1 ). The patient had noted a bluish‐black staining of the armpit areas of her clothing for the prior 6 months. A review of systems and past medical history were significant for a history of constant right lower back pain and bilateral knee pain for approximately 1 year. A review of medications revealed daily use of conjugated estrogens and multivitamins and intermittent use of ibuprofen. A review of her family history revealed that a sister was affected with the same disorder, but the spouse and children were not. The patient's parents were not known to be consanguineous.
Bluish patches are present on the ear overlying the cartilage
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Mucocutaneous examination was significant for bluish‐black patches on the ears in areas overlying cartilage. Larger bluish patches were also noted in the axillary vaults. Cardiac, ophthalmologic, and dental examinations were normal. An echocardiogram was normal. Orthopedic evaluation revealed limited spinal range of motion. Examination of lumbosacral X‐rays revealed marked degenerative disc disease at the T12–S1 levels and anterior osteophytosis at the T11–L2 levels. A bilateral knee X‐ray series was normal.
Complete blood count and serum chemistries were normal. A urine sample darkened upon standing for 1 day ( Fig. 2 , left side) as compared to a fresh urine specimen ( Fig. 2 , right side). A 0.5 cm ³ urine sample turned black immediately upon addition of 5 cm ³ of silver nitrate solution (3 g/100 cm ³ ) and alkalinization with three drops of dilute ammonia. Punch biopsy of the left ear demonstrated both degenerative change and focal yellow–brown pigmentation of the cartilage ( Fig. 3 ). A qualitative assay for urinary homogentisic acid (HGA) was positive (Fishberg test) (Fishberg EH. The instantaneous diagnosis of alkaptonuria on a single drop of urine. JAMA 1942; 119: 882). The presence of large amounts of urinary HGA was confirmed by gas chromatography and mass spectrometry.
A urine sample darkened upon standing for 1 day (left side of figure) as compared to a fresh urine specimen (right side of figure)
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A punch biopsy from the left ear demonstrates degenerative change of the cartilage with focal yellow–brown pigmentation (× 66)
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In alkaptonuria, homogentisate 1,2-dioxygenase deficiency causes tissue accumulation of homogentisic acid (HGA), followed by signs and symptoms of ochronosis. These include massive urinary excretion of HGA, arthritis and joint destruction, pigmentation of cartilage and connective tissue, and cardiac valve deterioration. We describe a 46-year-old man with alkaptonuria and diabetic renal failure whose plasma HGA concentration was twice that of any other alkaptonuria patient, and whose ochronosis progressed much more rapidly than that of his two alkaptonuric siblings. After renal transplantation, the plasma HGA normalized, and the daily urinary excretion of HGA decreased by 2-3g. This case illustrates the critical role of renal tubular secretion in eliminating HGA from the body, and suggests that renal transplantation in a uremic patient not only restores HGA excretion, but may also provide homogentisate 1,2-dioxygenase activity for the metabolism of HGA.
Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of alkaptonuria.
We evaluated 58 patients with alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively.
Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. Twenty-three new HGO mutations were identified. In a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone (7 days at a dose of 0.7 mg per day and 3 days at 2.8 mg per day). In a 59-year-old woman, urinary HGA fell from 6.4 g to 1.7 g per day after nine days of treatment with nitisinone (0.7 mg per day). Plasma tyrosine levels in these patients rose from approximately 1.1 mg per deciliter (60 micromol per liter) in both to approximately 12.8 mg per deciliter (700 micromol per liter) and 23.6 mg per deciliter (1300 micromol per liter), respectively, with no clinical signs or symptoms.
The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation.
There is no definitive treatment protocol for alkaptonuria. A patient with alkaptonuria was treated with ascorbic acid (0.5 g/day) from the age of 4 years. He developed episodes of severe recurrent joint pain at 9.5 years of age after which a protein-restricted diet (1.3 g/kg/day) was started. Protein restriction in combination with ascorbic acid therapy (1 g/day in two divided doses) resulted in a significant decrease but not a normalization of the urinary homogentisic acid excretion. Joint pain resolved and the radiological evidence of 'moth-eaten' irregularities on the articular surface in both knees disappeared. He is currently well, growing normally and in nitrogen balance. Our findings document a reversal of bone abnormalities and clinical symptoms in a case of alkaptonuria. The results should be confirmed in a larger study. We suggest that protein restriction should be applied in combination with ascorbic acid in affected patients as soon as joint pain occurs.
Aliberti G, Pulignano I, Schiappoli A, Minisola S, Romagnoli E, Proietta M (Università di Roma ‘La Sapienza’, Rome, Italy). Bone metabolism in ochronotic patients (Case report). J Intern Med 2003; 254: 296–300.
We investigated skeletal involvement in five male and two female patients with ochronosis, aged 26–82 years. The main parameters of mineral metabolism, together with biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and formation (serum bone isoenzyme of alkaline phosphatase and serum osteocalcin) were evaluated. In the same subjects lumbar spine and femoral bone mineral density (BMD) were also measured by dual energy X-ray absorptiometry. All patients but the younger 26-year-old patient had lower than normal bone mass at femoral neck and total hip, showing marked osteopenia in three cases and osteoporosis in the remaining three cases. However, at lumbar spine BMD measurement provided spuriously overestimated results, because of intervertebral disc calcification and osteophyte formation. As far as biochemical markers of bone turnover are concerned, the most relevant finding was the increased N-telopeptides of type I collagen urinary excretion. Our results suggest that ochronosis may be associated with increased bone resorption rate leading to an accelerated bone loss. A role of the homogentisic acid polymer deposit in bone matrix and cells, possibly with osteocyte damage and interference in collagen metabolism, might be hypothesized.
A 60-year-old woman presented with typical features of alkaptonuria.
The histopathological examination of an eye from a case of hereditary ochronosis is described. This is the fourth such account in the literature and the first examina-tion of an ochronotic globe removed during the life of the patient. The eye showed thrombotic glaucoma, which had led to enucleation, and ochro-nosis, characterized by intense golden-brown pigmentation in the anterior sclera in the horizontal plane at 3 and 9 o'clock, extending from the limbus to the region of the ora serrata. These areas showed swollen vermiform fibres in the episclera, granular masses lying immediately beneath, a deeply pigmented sclera, and amber structureless globules at the limbus. The staining reactions of these various components are reported in detail and reasons are given for supposing that the vermiform fibres are probably degenerate elastic fibres, while the staining reactions of the granular masses and pigmented sclera may have been due to ''elastotic degeneration'' of collagen. The nature of the limbal globules is unknown.
Ochronotic arthropathy is a disorder resulting from the deposition of homogentisic acid derivatives in the articular cartilage and the menisci. Large joints of the appendicular skeleton are preferentially affected. The clinical picture resembles that of degenerative joint disease. We present the arthroscopic findings in the shoulder and the knee in a 40-year-old man with ochronotic arthropathy and discuss the role of arthroscopy in the diagnosis and management of this rare metabolic disorder.