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2.
Ned Tijdschr Geneeskd ; 1652021 01 27.
Article in Dutch | MEDLINE | ID: mdl-33651519

ABSTRACT

A 52-year-old men suffered from osteoarthritis of the knee. During knee replacement surgery, the remaining cartilage appeared black. This discoloration and early degeneration of the cartilage is characteristic for the metabolic disorder alkaptonuria in which homogentisic acid accumulates in the body.


Subject(s)
Alkaptonuria , Arthroplasty, Replacement, Knee , Cartilage/pathology , Knee Joint/pathology , Knee/pathology , Ochronosis , Alkaptonuria/complications , Alkaptonuria/metabolism , Alkaptonuria/surgery , Cartilage/metabolism , Cartilage/surgery , Color , Homogentisic Acid/metabolism , Humans , Incidental Findings , Knee/surgery , Knee Joint/metabolism , Knee Joint/surgery , Male , Middle Aged , Ochronosis/etiology , Ochronosis/metabolism , Ochronosis/surgery , Osteoarthritis/complications , Osteoarthritis/surgery
4.
J Inherit Metab Dis ; 43(4): 737-747, 2020 07.
Article in English | MEDLINE | ID: mdl-31609457

ABSTRACT

The clinical effects of alkaptonuria (AKU) are delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. Data from AKU patients from four studies were merged to form a single AKU group. A control group of non-AKU subjects was generated by merging data from two non-AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. There were 225 AKU patients in the AKU group and 52 in the non-AKU control group. Circulating HGA increased with age (P < 0.001), and was significantly associated with decreased HGA clearance (CLHGA ) (P < 0.001) and FEHGA (P < 0.001). CLHGA and FEHGA were increased beyond the theoretical maximum renal plasma flow, confirming renal production and emphasising the greater contribution of net tubular secretion than glomerular filtration to renal elimination of HGA. The kidneys are crucial to elimination of HGA. Elimination of HGA is impaired with age resulting in worsening disease over time. The kidney is an important site for production of HGA. Tubular secretion of HGA contributes more to elimination of HGA in AKU than glomerular filtration.


Subject(s)
Alkaptonuria/metabolism , Glomerular Filtration Rate , Homogentisic Acid/metabolism , Kidney/metabolism , Ochronosis/etiology , Adult , Alkaptonuria/physiopathology , Case-Control Studies , Creatinine/metabolism , Female , Humans , Linear Models , Male , Middle Aged , Ochronosis/physiopathology , Phenylalanine/metabolism , Sex Factors , Tyrosine/metabolism
5.
Rev Port Cir Cardiotorac Vasc ; 26(3): 225-227, 2019.
Article in Portuguese | MEDLINE | ID: mdl-31734977

ABSTRACT

Alkaptonuria is a rare genetic disorder related to tyrosine metabolism. The cardiovascular manifestations are rare being the aortic stenosis the most commonly reported. We present a case of 72-year-old women who underwent aortic valve replacement with intraoperative findings in the aortic valve and the aortic wall suggestive of Cardiac Ochronosis. Once it is a rare disease there are issues related to the natural history of the disorder that still unknown, namely the type of aortic prothesis in use. For this reason, we find essential the documentation and follow-up of all these rare cases.


A Alcaptonúria é uma doença genética rara, relacionada com o metabolismo da tirosina. As manifestações cardiovasculares são a forma de apresentação menos comum da doença, sendo a estenose aórtica a patologia mais frequentemente encontrada. No presente artigo, apresentamos o caso de uma doente do sexo feminino de 72 anos proposta para cirurgia eletiva de substituição valvular aórtica com alterações intraoperatórias sugestivas de Ocronose Cardíaca. Atendendo à raridade da doença, muito há por esclarecer acerca da sua história natural, nomeadamente no que se refere ao tipo de próteses utilizadas, motivo pelo qual é essencial a documentação e seguimento destes casos.


Subject(s)
Alkaptonuria/complications , Aortic Valve Stenosis/surgery , Ochronosis/pathology , Aged , Aortic Valve/pathology , Aortic Valve Stenosis/pathology , Female , Heart Valve Prosthesis Implantation , Humans , Ochronosis/etiology
6.
Skinmed ; 17(3): 161-170, 2019.
Article in English | MEDLINE | ID: mdl-31496470

ABSTRACT

Cutaneous deposition disorders represent an array of conditions resulting from the accumulation of endogenous and exogenous substances within the skin. Many of the deposition diseases resemble each other and can also be confused with disorders not related to deposition. Porphyria cutanea tarda (PCT) results from dysfunction particularly in the fifth enzyme of the heme synthesis pathway, leading to increased skin fragility and bullae among other abnormalities. Ochronosis develops from alkaptonuria or exogenous sources, creating deposition of ocher-colored pigment in the skin. Hemochromatosis is a systemic disorder that can be inherited or acquired, altering skin pigmentation in more than 90% of patients. PCT can be an initial manifestation of hemochromatosis. Argyria is an acquired disorder of silver deposition that can also cause pigmentation similar to ochronosis. These uncommon but not rare disorders may resemble and be confused with each other in multiple ways.


Subject(s)
Argyria/diagnosis , Hemochromatosis/diagnosis , Ochronosis/diagnosis , Porphyria Cutanea Tarda/diagnosis , Argyria/etiology , Argyria/pathology , Diagnosis, Differential , Hemochromatosis/etiology , Hemochromatosis/pathology , Humans , Ochronosis/etiology , Ochronosis/pathology , Porphyria Cutanea Tarda/etiology , Porphyria Cutanea Tarda/pathology
7.
Unfallchirurg ; 122(11): 905-910, 2019 Nov.
Article in German | MEDLINE | ID: mdl-31332451

ABSTRACT

This article presents the case of a 53-year-old male patient born in Sri Lanka, who presented to the outpatient unit with the suspicion of empyema of the knee joint. Within the framework of knee arthroscopy, the diagnosis of ochronosis was made and later confirmed by histopathological biopsy. The alkaptonuria is caused by a homogentisate 1,2-dioxygenase deficiency and leads to an accumulation of homogentisic acid, a degradation product of tyrosine. This leads to the characteristic appearance of ochronosis with bluish-black deposits in the tissue (e.g. in connective tissue, sclera and ear cartilage) and a black coloration of the urine.


Subject(s)
Alkaptonuria/complications , Knee Joint/surgery , Ochronosis/surgery , Alkaptonuria/diagnosis , Arthroscopy , Biopsy , Humans , Knee Joint/pathology , Male , Middle Aged , Ochronosis/diagnosis , Ochronosis/etiology , Ochronosis/pathology
8.
J Glaucoma ; 28(7): e112-e114, 2019 07.
Article in English | MEDLINE | ID: mdl-31274704

ABSTRACT

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.


Subject(s)
Alkaptonuria/complications , Conjunctival Diseases/etiology , Glaucoma, Open-Angle/etiology , Ochronosis/etiology , Scleral Diseases/etiology , Aged , Alkaptonuria/diagnosis , Conjunctival Diseases/diagnosis , Glaucoma, Open-Angle/diagnosis , Gonioscopy , Homogentisic Acid/urine , Humans , Intraocular Pressure/physiology , Male , Ochronosis/diagnosis , Scleral Diseases/diagnosis , Slit Lamp Microscopy , Tonometry, Ocular
9.
Dermatol Online J ; 25(4)2019 Apr 15.
Article in English | MEDLINE | ID: mdl-31046911

ABSTRACT

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.


Subject(s)
Alkaptonuria/diagnosis , Homogentisic Acid/urine , Hyperpigmentation/etiology , Joint Diseases/etiology , Ochronosis/diagnosis , Alkaptonuria/complications , Alkaptonuria/urine , Female , Humans , Middle Aged , Ochronosis/etiology
11.
Ann Thorac Surg ; 108(4): e257-e259, 2019 10.
Article in English | MEDLINE | ID: mdl-30926473

ABSTRACT

Alkaptonuria is rare genetic disorder of tyrosine metabolism manifesting with signs of tissue pigmentation, dark urine, and ochronotic arthropathies. Commonly undiscovered by late adulthood, alkaptonuria can manifest as cardiac ochronosis with cardiovascular disorders such as valvulopathies, but rarely coronary artery disease. This case report describes 2 patients with aortic stenosis and coronary artery disease in whom alkaptonuria was diagnosed during open heart surgery.


Subject(s)
Alkaptonuria/complications , Aortic Valve Stenosis/etiology , Coronary Artery Disease/etiology , Ochronosis/etiology , Aged , Alkaptonuria/diagnosis , Aortic Valve Stenosis/surgery , Coronary Artery Disease/surgery , Female , Humans , Middle Aged , Ochronosis/pathology
12.
Clin Dermatol ; 37(5): 447-467, 2019.
Article in English | MEDLINE | ID: mdl-31896402

ABSTRACT

Gradations in skin color are a consequence of differing amounts of melanin and their varying distribution. Although many darkly pigmented skin lesions are melanocytic and can be attributed to melanin content, the color of a black lesion can also be due to blood, necrotic tissue, or exogenous pigment. The source, pattern, and distribution of the color in black lesions usually offer important insight into its etiology. This contribution reviews conditions that can take on a black color, discussing the cause of the hue and any additional impact sun exposure may have.


Subject(s)
Hyperpigmentation/diagnosis , Hyperpigmentation/etiology , Lupus Erythematosus, Discoid/diagnosis , Melanoma/diagnosis , Nevus, Blue/diagnosis , Skin Neoplasms/diagnosis , Acanthosis Nigricans/diagnosis , Acanthosis Nigricans/etiology , Acanthosis Nigricans/therapy , Calciphylaxis/diagnosis , Calciphylaxis/drug therapy , Carcinoma, Basal Cell/diagnosis , Carcinoma, Basal Cell/pathology , Dermatomycoses/complications , Dermatomycoses/diagnosis , Diagnosis, Differential , Humans , Hyperpigmentation/therapy , Keratosis, Seborrheic/diagnosis , Lupus Erythematosus, Discoid/drug therapy , Melanoma/etiology , Melanoma/therapy , Mucormycosis/complications , Mucormycosis/diagnosis , Mucormycosis/therapy , Mucous Membrane , Nail Diseases/diagnosis , Nevus, Blue/surgery , Nevus, Spindle Cell/diagnosis , Nevus, Spindle Cell/pathology , Ochronosis/diagnosis , Ochronosis/etiology , Plaque, Atherosclerotic/complications , Plaque, Atherosclerotic/diagnosis , Prognosis , Skin Diseases, Papulosquamous/diagnosis , Skin Diseases, Papulosquamous/etiology , Skin Neoplasms/etiology , Skin Neoplasms/pathology , Skin Neoplasms/surgery , Tattooing
13.
J Neurol Surg A Cent Eur Neurosurg ; 80(2): 131-133, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30477028

ABSTRACT

Alkaptonuria is a rare metabolic disease caused by deficiency of homogentisic acid oxidase and characterized by bluish-black discoloration of cartilages and skin (ochronosis). Defective production of this enzyme results in the accumulation of homogentisic acid (HGA), a tyrosine degradation product, in the bloodstream. Accumulation of HGA and its metabolites in tissues causes ochronosis. The word ochronosis refers to the dark bluish-black discoloration of connective tissues including the sclera, cornea, auricular cartilage, heart valves, articular cartilage, tendons, and ligaments. Neurogenic claudication resulting from focal hypertrophy of the ligamentum flavum in the lumbar spine due to ochronotic deposits has only been previously reported once in the literature. In this article, we present a 71-year-old male patient with alkaptonuria-associated degenerative L3-L4-L5 stenosis, diagnosed after lumbar decompressive laminectomy.


Subject(s)
Alkaptonuria/complications , Ligamentum Flavum/pathology , Lumbar Vertebrae , Ochronosis/etiology , Aged , Alkaptonuria/pathology , Humans , Male , Ochronosis/pathology
14.
Ann Thorac Surg ; 106(1): e19-e20, 2018 07.
Article in English | MEDLINE | ID: mdl-29501639

ABSTRACT

Cardiac ochronosis is a rare complication of alkaptonuria, a disorder of tyrosine metabolism characterized by a triad of dark urine, pigmentation of tissues, and ochronotic arthropathies. When present, cardiac ochronosis generally affects the aortic valve, resulting in aortic stenosis. More rarely, it may affect the mitral valve and the coronary arteries. This report describes the case of a 67-year-old woman with a history of alkaptonuria with severe ochronosis of the coronary arteries and mitral valve who required coronary artery bypass and mitral valve replacement.


Subject(s)
Alkaptonuria/complications , Coronary Artery Bypass , Coronary Vessels/pathology , Heart Valve Prosthesis Implantation , Mitral Valve/pathology , Ochronosis/surgery , Tricuspid Valve/pathology , Aged , Coronary Vessels/surgery , Dyspnea/etiology , Elective Surgical Procedures , Female , Humans , Mitral Valve/surgery , Mitral Valve Insufficiency/etiology , Mitral Valve Insufficiency/surgery , Ochronosis/etiology , Thoracic Arteries/pathology , Tricuspid Valve/surgery , Tricuspid Valve Insufficiency/etiology , Tricuspid Valve Insufficiency/surgery , Vascular Calcification/etiology , Vascular Calcification/surgery
15.
Calcif Tissue Int ; 101(1): 50-64, 2017 07.
Article in English | MEDLINE | ID: mdl-28271171

ABSTRACT

Alkaptonuria (AKU) is a hereditary disorder that results from altered structure and function of homogentisate 1,2 dioxygenase (HGD). This enzyme, predominantly produced by liver and kidney, is responsible for the breakdown of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway. A deficient HGD activity causes HGA levels to rise systemically. The disease is clinically characterized by homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and joint arthropathy. Additional manifestations are cardiovascular abnormalities, renal, urethral and prostate calculi and scleral and ear involvement. While the radiological aspect of ochronotic spondyloarthropathy is known, there are only few data regarding an exhaustive ultrastructural and histologic study of different tissues in AKU. Moreover, an in-depth analysis of tissues from patients of different ages, having varied symptoms, is currently lacking. A complete microscopic and ultrastructural analysis of different AKU tissues, coming from six differently aged patients, is here presented thus significantly contributing to a more comprehensive knowledge of this ultra-rare pathology.


Subject(s)
Alkaptonuria/pathology , Adult , Aged , Alkaptonuria/complications , Female , Humans , Male , Middle Aged , Ochronosis/etiology , Ochronosis/pathology
18.
Semin Cell Dev Biol ; 52: 53-7, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26891864

ABSTRACT

"Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis. In AKU, ochronotic pigment is deposited in cartilage when collagen fibrils become susceptible to attack by homogentisic acid (HGA). When HGA binds to collagen, cartilage matrix becomes stiffened, resulting in the aberrant transmission of loading to underlying subchondral bone. Aberrant loading leads to the formation of pathophysiological structures including trabecular excrescences and high density mineralised protrusions (HDMPs). These structures initially identified in AKU have subsequently been found in more common osteoarthritis and appear to play a role in joint destruction in both diseases.


Subject(s)
Alkaptonuria/diagnosis , Rare Diseases/diagnosis , Alkaptonuria/genetics , Alkaptonuria/physiopathology , Animals , Humans , Mice , Ochronosis/etiology , Ochronosis/physiopathology , Osteoarthritis/etiology , Osteoarthritis/physiopathology , Rare Diseases/genetics , Rare Diseases/physiopathology
19.
Free Radic Biol Med ; 88(Pt A): 70-80, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25733348

ABSTRACT

Alkaptonuria (AKU) is a rare metabolic disease due to a deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD), involved in Phe and Tyr catabolism. Due to such a deficiency, AKU patients undergo accumulation of the metabolite homogentisic acid (HGA), which is prone to oxidation/polymerization reactions causing the production of a melanin-like pigment. Once the pigment is deposited onto connective tissues (mainly in joints, spine, and cardiac valves), a classical bluish-brown discoloration is imparted, leading to a phenomenon known as "ochronosis", the hallmark of AKU. A clarification of the molecular mechanisms for the production and deposition of the ochronotic pigment in AKU started only recently with a range of in vitro and ex vivo human models used for the study of HGA-induced effects. Thanks to redox-proteomic analyses, it was found that HGA could induce significant oxidation of a number of serum and chondrocyte proteins. Further investigations allowed highlighting how HGA-induced proteome alteration, lipid peroxidation, thiol depletion, and amyloid production could contribute to oxidative stress generation and protein oxidation in AKU. This review briefly summarizes the most recent findings on HGA-induced oxidative stress in AKU, helping in the clarification of the molecular mechanisms of ochronosis and potentially providing the basis for its pharmacological treatment. Future work should be undertaken in order to validate in vivo the results so far obtained in in vitro AKU models.


Subject(s)
Alkaptonuria/physiopathology , Homogentisic Acid/metabolism , Ochronosis/physiopathology , Oxidative Stress , Humans , Ochronosis/etiology
20.
Dev Period Med ; 19(4): 508-10, 2015.
Article in English | MEDLINE | ID: mdl-26982762

ABSTRACT

Alkaptonuria is a rare inborn error of metabolism, identified over a century ago. But its basic pathomechanism (i.e. ochronosis) is still not completely explained. Though clinical onset of osteoarthropathy and complications from other organs (including: heart and blood vessels, skin, eyes, kidneys) occurs at adult age, the symptoms are progressive, cause severe pains and significantly limit everyday life of the patients. Until now no effective therapeutic methods have been known in alkaptonuria. Recently, thanks to an initiative of the international patient organization for alkaptonuria, a hope for a potential treatment availability, appears. So, alkaptonuria is an example of a role of multidysciplinary care, cooperation and ongoing progress in the area of rare diseases.


Subject(s)
Alkaptonuria/complications , Aortic Valve Stenosis/etiology , Ochronosis/etiology , Alkaptonuria/metabolism , Aortic Valve Stenosis/surgery , Heart Valve Prosthesis Implantation , Humans , Ochronosis/metabolism , Ochronosis/surgery
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