Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria.

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.

ARTHROPLASTY IN ALKAPTONURIC OCHRONOSIS.

Ochronotic degenerative arthropathy occurs in patients with alkaptonuria. Alkaptonuria disorder is an extremely rare disease characterized by black pigmentation of various tissues (e.g., cartilage and connective tissue). Ochronotic arthropathy is a disabling disease that primarily affects the large joints. Like other metabolic diseases that involve the musculoskeletal system, care must be taken with regard to the quality of the affected bones, tendons and ligaments, and therefore the stability and survival of joint prosthesis. The following is a report of a 66-year-old man affected by several musculoskeletal manifestations of alkaptonuria with severe joints disruption, who was successfully treated with total left hip and total right knee replacements. Surgical, anesthesiological and postoperative management of these patients may require more vigilance due to the associated comorbidities of this disorder.

An update on the role of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases.

BACKGROUND: Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/ß-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/ß-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies. DATA SOURCES: The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria. RESULTS: We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed. CONCLUSIONS: The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.

A new integrated and interactive tool applicable to inborn errors of metabolism: Application to alkaptonuria.

This paper describes our experience with the development and implementation of a database for the rare disease Alkaptonuria (AKU, OMIM: 203500). AKU is an autosomal recessive disorder caused by a gene mutation leading to the accumulation of homogentisic acid (HGA). Analogously to other rare conditions, currently there are no approved biomarkers to monitor AKU progression or severity. Although some biomarkers are under evaluation, an extensive biomarker analysis has not been undertaken in AKU yet. In order to fill this gap, we gained access to AKU-related data that we carefully processed, documented and stored in a database, which we named ApreciseKUre. We undertook a suitable statistical analysis by associating every couple of potential biomarkers to highlight significant correlations. Our database is continuously updated allowing us to find novel unpredicted correlations between AKU biomarkers and to confirm system reliability. ApreciseKUre includes data on potential biomarkers, patients' quality of life and clinical outcomes facilitating their integration and possibly allowing a Precision Medicine approach in AKU. This framework may represent an online tool that can be turned into a best practice model for other rare diseases.

Anesthetic management of two patients with alkaptonuric ochronosis for total knee arthroplasty / Manejo anestésico de dois pacientes com ocronose alcaptonúrica para artroplastia total do joelho

Abstract The current case report describes two cases of alkaptonuric ochronosis for anesthetic management. Alkaptonuria is a rare genetic orphan disease of tyrosine metabolism characterized by an accumulation of homogentisic acid in cartilage and connective tissues. Patients present most commonly for orthopedic joint surgery due to progressive arthropathy that can be misdiagnosed many a times. However respiratory, airway, cardiovascular and genitourinary systems complications can occur with age progressing. Restricted range of motion of cervical spine may lead to difficulty with airway management. In addition, degenerative changes and stiffness of lumbar spine due to ochronosis would make neuraxial blockade challenging. Although this inherited condition is extremely rare, anesthesiologists should be aware of its existence and prepare for management of potential challenging problems. This report highlights special care and precautions that need to be taken during anesthetic management.

Resumo Este relato descreve o manejo anestésico em dois casos de ocronose alcaptonúrica. Alcaptonúria é uma doença genética rara do metabolismo de tirosina caracterizada por acúmulo de ácido homogentísico em cartilagem e tecidos conjuntivos. Os pacientes geralmente recorrem à cirurgia ortopédica devido à artropatia progressiva, que, muitas vezes, pode ser diagnosticada incorretamente. No entanto, complicações das vias respiratórias, cardiovasculares e geniturinárias podem ocorrer com o avanço da idade. A restrição de mobilidade da coluna cervical pode levar ao manejo difícil das vias aéreas. Além disso, as alterações degenerativas e a rigidez da coluna lombar devido à ocronose podem tornar o bloqueio neuroaxial um desafio. Embora essa condição hereditária seja extremamente rara, os anestesiologistas devem estar cientes de sua existência e se preparar para o manejo de potenciais problemas desafiadores. Este relato destaca os cuidados e as precauções especiais que devem ser tomadas durante o manejo anestésico.

Interpreting sources of variation in clinical gait analysis: A case study.

OBJECTIVE: To illustrate and discuss sources of gait deviations (experimental, genuine and intentional) during a gait analysis and how these deviations inform clinical decision making. METHODS: A case study of a 24-year old male diagnosed with Alkaptonuria undergoing a routine gait analysis. A 3D motion capture with the Helen-Hayes marker set was used to quantify lower-limb joint kinematics during barefoot walking along a 10m walkway at a self-selected pace. Additional 2D video data were recorded in the sagittal and frontal plane. The patient reported no aches or pains in any joint and described his lifestyle as active. RESULTS: Temporal-spatial parameters were within normal ranges for his age and sex. Three sources of gait deviations were identified; the posteriorly rotated pelvis was due to an experimental error and marker misplacement, the increased rotation of the pelvis in the horizontal plane was genuine and observed in both 3D gait curves and in 2D video analysis, finally the inconsistency in knee flexion/extension combined with a seemingly innocuous interest in the consequences of abnormal gait suggested an intentional gait deviation. CONCLUSIONS: Gait analysis is an important analytical tool in the management of a variety of conditions that negatively impact on movement. Experienced gait analysts have the ability to recognise genuine gait adaptations that forms part of the decision-making process for that patient. However, their role also necessitates the ability to identify and correct for experimental errors and critically evaluate when a deviation may not be genuine.

Tyrosinase, could it be a missing link in ochronosis in alkaptonuria?

The hypothesis that is proposed is that tyrosinase, an enzyme widely found within the human body is implicated in the ochronosis that occurs in alkaptonuria; an autosomal recessive condition first used by Archibald Garrod to describe the theory of "Inborn Errors of Metabolism." The disease results from the absence of a single enzyme in the liver that breaks down homogentisic acid; this molecule becomes systemically elevated in sufferers. The condition is characterised by a clinical triad of symptoms; homogentisic aciduria from birth, ochronosis (darkening) of collagenous tissues (from ∼30years of age) and ochronotic osteoarthropathy in weight bearing joints due to long term ochronosis in them (from ∼40years of age). Tyrosinase, a polyphenol oxidase has been shown in many species to contribute to the darkening of tissues in many organisms; including humans in the production of melanin. Tyrosinase under the right conditions shows alterations in its substrate specificity and may contribute to the darkening seen in AKU where it moves away from polymerising tyrosine but also homogentisic acid, the causative molecule in alkaptonuria, that is present in excess.

Alkaptonuria Presenting with Impressive Osteoarticular Changes and Severe Aortic Stenosis.

Alkaptonuria, or ochronosis, a rare autosomal recessive metabolic disorder, causes an excess of homogentisic acid that results in dark pigmentation, calcification, and inflammation of cartilaginous and other tissues. Cardiovascular complications are also typical of the disease. We report the case of a 78-year-old male who presented with impressive osteoarticular changes and aortic stenosis associated with alkaptonuria.

Alkaptonuria: An example of a "fundamental disease"--A rare disease with important lessons for more common disorders.

"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.

Oxidative stress and mechanisms of ochronosis in alkaptonuria.

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.

Nine cases of Alkaptonuria in one family in southern Jordan.

Alkaptonuria is a rare autosomal recessive metabolic disorder characterized by a deficiency of homogentisate 1,2-dioxygenase (HGO) in the liver. This results in excretion of large quantities of homogentisic acid (HGA) (also called alkapton) in the urine and a slowly progressive deposition of homogentisic acid and its oxidative product in connective tissues. Clinical characteristic features of alkaptonuria are darkening of urine, bluish-dark pigmentation of connective tissues (ochronosis) and arthritis of large joints and spine. Cardiovascular and genitourinary systems may also be affected. In this report, we present the initial results of screening family members with history of alkaptonuria in southern region of Jordan. We present 9 cases of alkaptonuria (two males and seven females) in one Jordanian family. The history, signs and symptoms, diagnostic techniques and treatment options of alkaptonuria are reviewed in this article.

The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria.

OBJECTIVE: Alkaptonuria is a genetic disorder of tyrosine metabolism, resulting in elevated circulating concentrations of homogentisic acid. Homogentisic acid is deposited as a polymer, termed ochronotic pigment, in collagenous tissues, especially cartilages of weight-bearing joints, leading to a severe osteoarthropathy. We undertook this study to investigate the initiation and progression of ochronosis from the earliest detection of pigment through complete joint failure. METHODS: Nine joint samples with varying severities of ochronosis were obtained from alkaptonuria patients undergoing surgery and compared to joint samples obtained from osteoarthritis (OA) patients. Samples were analyzed by light and fluorescence microscopy, 3-dimensional scanning electron microscopy (SEM), and the quantitative backscattered electron mode of SEM. Cartilage samples were mechanically tested by compression to determine Young's modulus of pigmented, nonpigmented, and OA cartilage samples. RESULTS: In alkaptonuria samples with the least advanced ochronosis, pigment was observed intracellularly and in the territorial matrix of individual chondrocytes at the boundary of the subchondral bone and calcified cartilage. In more advanced ochronosis, pigmentation was widespread throughout the hyaline cartilage in either granular composition or as blanket pigmentation in which there is complete and homogenous pigmentation of cartilage matrix. Once hyaline cartilage was extensively pigmented, there was aggressive osteoclastic resorption of the subchondral plate. Pigmented cartilage became impacted on less highly mineralized trabeculae and embedded in the marrow space. Pigmented cartilage samples were much stiffer than nonpigmented or OA cartilage as revealed by a significant difference in Young's modulus. CONCLUSION: Using alkaptonuria cartilage specimens with a wide spectrum of pigmentation, we have characterized the progression of ochronosis. Intact cartilage appears to be resistant to pigmentation but becomes susceptible following focal changes in calcified cartilage. Ochronosis spreads throughout the cartilage, altering the mechanical properties. In advanced ochronosis, there is aggressive resorption of the underlying calcified cartilage leading to an extraordinary phenotype in which there is complete loss of the subchondral plate. These findings should contribute to better understanding of cartilage-subchondral interactions in arthropathies.

Nuclear medicine techniques in the assessment of alkaptonuria.

Alkaptonuria is a rare autosomal recessive disorder due to a lack of the enzyme homogentisate dioxygenase, leading to ochronosis, a process of accumulation of a melanin-like polymer of homogentisic acid in cartilage and other collagenous structures. Patients develop severe osteoarthropathy that resembles osteoarthritis. Although the diagnosis of alkaptonuria is not particularly challenging in view of the blue-black discolouration of visible connective tissue and the presence of homogentisic acid in urine, the natural history of alkaptonuria remains poorly understood. Patients would benefit immensely from an objective assessment of their disease status and from a clearer understanding of the pathophysiology and associated physical changes. Isotope bone scans, which are commonly used to identify the extent of involvement of bones in cancerous processes, have also been increasingly used for characterizing the extent of arthropathy in conditions such as osteoarthritis and rheumatoid arthritis. Semiquantitative scores based on the extent of involvement of joints have been used to describe the involvement of large joints in the context of symptomatic treatment for osteoarthritis. A similar semiquantitative isotope bone scan score depending on the involvement of the number of large joints in patients with alkaptonuria can be formulated and validated in a suitable cohort of patients. Bone densitometry measurement using dual-energy X-ray absorptiometry scanning is an internationally accepted tool to assess the risk and extent of osteoporosis, and is increasingly used to assess the additional fracture risk in patients with arthropathy. We believe that, currently, nuclear medicine techniques can provide useful information, which can be incorporated into disease severity scores for alkaptonuria. Once the biological basis for alkaptonuria is better understood, it is feasible that nuclear medicine techniques of even greater sensitivity and specificity can be developed, thereby taking advantage of the vast advances in the fields of radiochemistry, radiopharmacy, positron emission tomography-computed tomography and positron emission tomography-magnetic resonance imaging scanning.

Estenosis aórtica y cardiopatía coronaria en alcaptonuria. Presentación de un caso / Aortic stenosis and coronary artery disease in alkaptonuria. case report

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Alkaptonuria and intramedullary calcification.

Alkaptonuria is a rare disorder of metabolism caused by deficiency of homogentisic acid oxidase enzyme and characterized by triad of homogentisic aciduria (dark urine), relentlessly progressive arthritis and ochronosis. We have documented a case with typical features of alkaptonuria along with intramedullary calcification which has not been reported in the literature before.

Musculoskeletal findings and disability in alkaptonuria.

OBJECTIVE: To describe the musculoskeletal (MSK) findings in patients with alkaptonuria and to show which of these factors are associated with disability in this population. METHODS: This is a prospective cross-sectional MSK assessment of subjects. Participants included 53 patients with alkaptonuria across the life span, 22 female and 31 male, mean age 43.6 years (10-80 yrs), participating in a natural history study supported by the National Human Genome Research Institute (NHGRI). Assessments included objective measures of the MSK system (range of motion, radiographic assessment of joints and spine, etc.) and questionnaires including the Human Activity Profile (HAP), Health Assessment Questionnaire (HAQ), SF-36 health survey, and the Fatigue Assessment Instrument. RESULTS: There were 18 patients with kyphosis, 16 with scoliosis, 16 with marked reduction in range of motion of at least one major joint, 15 with joint replacements of major joints, 11 with tendon ruptures. A positive Schober's test was highly correlated with substantial functional loss and associated with disability as measured by the HAP (p < or = 0.0001), HAQ (p < or = 0.0001), and the physical component summary (p < or = 0.0001) of the SF-36 health survey. Severity of lumbar spine involvement had the greatest correlation with disability measures (p < or = 0.0001). All objective and subjective physical measures worsened with age. CONCLUSION: Disability is common and severe in patients with alkaptonuria and correlates well with physical findings. Disability does not correlate with self-reports of mental competencies. Aging with alkaptonuria is associated with progressive disability.

Ochronosis and lumbar disc herniation.

Alkaptonuria is a rare, autosomal recessive metabolic disorder in which the homogentisic acid oxidase activity is absent. Its incidence is as low as 0.001%. Ochronosis is the pigmentation of connective tissues and this pigmentation leads to degenerative changes in alkaptonuric patients. Alkaptonuria most prominently involves the lumbar region, but lumbar disc herniation as the presenting feature of alkaptonuria is not common. Only a few patients required surgical intervention. Herewith we report an alkaptonuric patient, who was operated on for lumbar disc herniation. His discectomy material was black and the metabolic disorder was diagnosed retrospectively. This metabolic disease is often recognized on physical re-examination after the black disc material was seen during the operation. Therefore urinalysis for homogentisic acid should be performed in all patients with degenerative changes of the vertebral column. The results of disc surgery in this patient group is successful.