English AKU-Info http://www.dsaku.de/hilfe-bei-alkaptonurie/english-aku-info-/ de-de www.dsaku.de Fri, 25 Aug 2017 16:29:15 +0200 English AKU-Info http://www.dsaku.de http://www.dsaku.de Alkaptonuria (AKU) in English Introduction Alkaptonuria (AKU, ochronosis, omim 203500 , ORPHA56 ) is a rare genetic disease that requires two gene mutations - one from eacht parent - in order to occur. Thus, it is an autosomal recessive disorder. AKU affects the final breakdown of proteins as it is caused by an enzymatic deficiency of the tyrosine metabolism. Hence, patients accumulate the metabolite homogentisic acid at (HGA) about 2000 times the normal rate (1,2). Oxidation of HGA to BQA results in darkening of urine (Figure 1), cartilage degradation and symptoms similar to early-onset osteoarthritis. A unique feature of AKU patients is blackening of cartilage and other connective tissues such as tendons, ligaments, muscles, heart valve, auricles and eye sclera, also referred to as ochronotic pigmentation (Figure 2). This process is called ochronoses and results in oxidative stress, producing radical oxygen species (ROS), inflammation and secondory amyloidosis AA (5, 6). Therefore, as a chronic systemic disease, AKU requires age-dependent surveillance and subsequent therapeutic interventions as summarised in Table 1. Severity and disease progress can be monitored by the AKU-Severity-Score- Index, developed by Prof. Ranganath and Prof. Cox (2-4). Currently, there is no cure available and treatment entails symptom relief such as pain management, physiotherapy and surgery involving joint replacement. Presently, a FP7-funded clinical trial ( developAKUre ) is being conducted to investigate the drug nitisinone for the curative treatment of AKU as illustrated in Table 3 (2). Gait analysis has shown to be a powerful tool to assess onset of AKU-associated arthropathy and to monitor gait impairments for recommendations of effective therapeutic interventions (7). The worldwide prevalence of alkaptonuria is currently 4 - 10 : 1,000,000, however, there are so-called hotspots such as Slovakia, Jordan, India, the Dominican Republic and Berlin (8,9). The highest frequency is found in Slovakia with 1:19,000. Figure 1: Oxidation of homogentisic acid (HGA) to BQA causes darkening of the urine when exposed to air (8). Figure 2: AKU-symptoms due to ochronosis. Ochronotic pigmentation of the connective tissue causes arthropathy of the spine and joints, discolouration of eye and ear as well as aortic stenosis (1-3, 10, 11). AKU-Symtoms: Darkening of urine (brown - black) Darkening of cartilage (brown - black) Systemic Amyloidosis AA Blue -greyish discolourisation of ear pinna (~30 years) Brown - black spots in eye sclera Spondyloarthropathy with calcification of intervertebral disc space at ~30 years Age-dependent gait-impairments at ~30 years Rapid progressive polyarthropathy (ochronotic arthropathy) associated with pain at ~40 years Ruptures of tendons, muscles and ligaments Aortic stenosis at ~50 years Kidney- / prostate stones at ~60 years Figure 3: Summary of AKU associated symptoms. The first sign of AKU is darkening of urine upon exposure to the air. In early adulthood ochronosis begins, resulting in arthropathy of the spine and mainly larger joints, pigmentation of eye sclera and outer ear, aortic stenosis and kidney- / prostate-stones. Monitoring and Diagnostics: Surveillance of AKU-symptoms can be monitored as summarised in talbe 2 (1-4, 10, 12-14). Severity and disease progression is determined according to the AKU-Severity-Score-Index (AKUSSI) , developed by Prof. Ranganath and Prof. Cox and outlined in Table 3 (2-4). Table 2:Summary of monitoring AKU-symptoms (1-4, 11-15) Symptoms Age Diagnostic Interventions Dark urine 0 HGA determination, Mutation-analyses, kidney function Bone metabolism Healthy lifestyle, moderate protein intake, avoidance of sports and labour with high impact Pigmentation of skin, outer ear and sclera 30 Examination, documentation No special interventions are necessary Back pain due to degenerate arthropathy 30 X-rays, MRT, bone isotope scan Pain therapy, physiotherapy, physical exercises, surgery if indicated Ruptures of muscles, tendons and ligaments 30 MRT, ultrasound Strengthening of muscles/joints by moderate sport activities, , surgery if indicated Arthropathy of large joints 40 X-rays, MRT, bone isotope scan Pain therapy, physiotherapy, physical exercises, surgery, joint replacement if indicated Kidney-stones 50 Ultrasound, CT, laboratory diagnostics Surgical removal of kidney stones Prostate-stones 50 Ultrasound, CT Surgical removal of prostate stones Aortic stenosis 50 Echocardiogram, ECG Replacement of heart valves Depression / Isolation 30 Medical history, clarification of the causes Patients’ support-group DSAKU, psychotherapy, antidepressants Table 2: AKU-Severity-Score-Index (AKUSSI) as developed by Prof. Ranganath and Cox (2-4). *, eye conjunctiva: none, slight, moderate/marked; §, sclera:none, slight, moderate/marked; #, number of fracture or rupture. Therapy Table 3: Summary of symptomatic and curative therapies (2,11). Therapy / Counselling Treatment Summary Symptomatic Therapies: Nutrition Vitamin C Efficacy unproven Low Protein Diet Efficacy in adults unproven, compliance problematic Life style counselling Excercise Low impact sports, e.g. swimming, are recommended Choice of job Avoid jobs with heavy labour Family Planning Professional Genetic Counselling Disability Often difficult to obtain to to lack of knowledge about AKU Invalidity Therapies by health professionals Physiotherapy Underused, recommended to maintain mobility Occupational Therapy Underused, recommended to maintain work Pain management Tailored pain therapy Widely used palliative therapy, incompletely effective Surveillance Diagnostics Lack of knowledge prevents utilisation Surgery Organ replacement Probably unjustified in a disease with relatively preserved lifespan Palliative Surgery Effective but invasive, not universally available HGA-lowering curative Therapies: Substrate reduction therapy Nitisinon Currently under investigations ( www.developAKUre.eu ) Gene-therapy HGD-gene Not yet available Enzyme replacement HGD-enzyme Not yet available Disease Management: Table 4: Recommentations of disease management in AKU at all ages and life-circumstances (2,11-18). *Recommended by DSAKU e.V.,**possible symptoms or problems, Deutsche Rheuma-Liga = German League against Rheumatism, Unabhängige Patientenberatung Deutschland = independent patient-counselling Germany.*, great degree of variation; **, may occur. Age (±) Possible symptoms / problems Recommended interventions + treatment methods Infancy Identification* Laboratory analysis HGA Childhood Laboraty diagnostics* Surveillance of kidney functions Childhood Diet* Healthy low protein Childhood Sport activity* Avoidance diet of sport activity with high impact Adolescence Choice of occupation* Avoidance of jobs with heavy labour Adulthood Family planning* Genetic counselling 20 - 30 + Back pain* Physiotherapy, pain therapy, physical exercises 30 + Felt Isolation** Contacts with other AKU-patients via DSAKU e.V. 40 + Joint pain* Tailored pain therapy, physical therapy, 40 + Surveillance of kidney / prostate* Annual ultrasound + laboratory diagnostics 40 + Surveillance of heart / arteries* Annual ECG + Echocardiogram 40 + Working with AKU** Support by DSAKU + Deutsche Rheuma 1 50 + Stiffness + joint pain** Orthopaedic surveillance, surgery if required such as joint replacement 50 + Kidney- + prostate-stones** Surgical removal of kidney- / prostate-stones if required 50 + Aortic stenosis** Replacement of heart valves if required 50 + Possible occupational disability / invalidity** Support by DSAKU + Deutsche Rheuma-Liga 1 + Unabhängige Patientenberatung Deutschland References Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., and Gahl, W. A. (2002) Natural history of alkaptonuria. N.Engl.J.Med. 347, 2111-2121. Ranganath, L. R., Jarvis, J. C., and Gallagher, J. A. (2013) Recent advances in management of alkaptonuria (invited review; best practice article) J Clin.Pathol. 66, 367-373. Ranganath, L. R. and Cox, T. F. (2011) Natural history of alkaptonuria revisited: analyses based on scoring systems. J Inherit.Metab Dis. 34, 1141-1151. Cox, T. F. and Ranganath, L. (2011) A quantitative assessment of alkaptonuria : Testing the reliability of two disease severity scoring systems. J.Inherit.Metab Dis. 34, 1153-1162. Braconi, D., Millucci, L., Bernardini, G., Santucci, A. (2015) Oxidative stress and mechanisms of ochronosis in alkaptonuria. Free Radic Biol Med. 88 (Pt A), 70-80. Millucci, L., Ghezzi, L., Bernardini, G., Braconi, D., Lupetti, P., Perfetto, F., Orl,andini, M., Santucci, A. (2014) Diagnosis of secondary amyloidosis in alkaptonuria. Diagn Pathol. 9 ,185-189. Barton, G.J., King, S.L., Robinson, M.A., Hawken, M.B., and Ranganath, L.R. (2015) Age-Related Deviation of Gait from Normality in Alkaptonuria . JIMD Rep. 24 , 39-44. pubmed Zatkova, A. (2011) An update on molecular genetics of Alkaptonuria (AKU). J Inherit.Metab Dis. 34, 1127-1136. Mönch, E. and Link, R. (2006) Alkaptonurie. In Mönch, E. and Link, R., editors. Diagnostik und Therapie bei angeborenen Stoffwechselstörungen , SPS-Verlag, Heilbronn. pp. Richter, P., Halle, D., Le Guillou, D., Wagner, L. (2012) www.youtube.com/watch?v=t5EgHvSYDPM Hannoush, H., Introne, W. J., Chen, M. Y., Lee, S. J., O'Brien, K., Suwannarat, P., Kayser, M. A., Gahl, W. A., and Sachdev, V. (2012) Aortic stenosis and vascular calcifications in alkaptonuria. Mol.Genet.Metab 105, 198-202. Vinjamuri, S., Ramesh, C. N., Jarvis, J., Gallagher, J. A., and Ranganath, L. L. (2011) Nuclear medicine techniques in the assessment of alkaptonuria. Nucl.Med.Commun. 32, 880-886. Pettit, S. J., Fisher, M., Gallagher, J. A., and Ranganath, L. R. (2011) Cardiovascular manifestations of Alkaptonuria. J Inherit.Metab Dis. 34, 1177-1181. Introne, W. J., Kayser, M. A., and Gahl, W. A. (1993) Alkaptonuria. In Pagon, R.A.B.T.D.D.C.R.S.K., editor. GeneReviews [Internet] , University of Washington, Seattle, 1993-2003. Kayser, M. A., Introne, W., and Gahl, W. A. (2009) Chapter 92: Alkaptonuria. In Vale, D., Beaudet, A. L., Vogelstein, B., Kinzler, K. W., Antonarakis, S. E., Ballabio, A., Scriver, C. R., Sly, W. S., and Childs, B., editors. The Scriver's Online Metabolic & Molecular Bases of Inherited Diseases , McGrawHill Companies, Columbus, 1-30. Perry, M. B., Suwannarat, P., Furst, G. P., Gahl, W. A., and Gerber, L. H. (2006) Musculoskeletal findings and disability in alkaptonuria. J.Rheumatol. 33, 2280-2285. Deutsche-Rheuma-Liga (2012) www.rheuma-liga.de . Unabhängige Patientenberatung Deutschland (2016) www.patientenberatung.de http://www.dsaku.de/hilfe-bei-alkaptonurie/english-aku-info-/_part1211 Frau Leona Wagner Fri, 25 Aug 2017 16:29:15 +0200 part1211 Introduction Alkaptonuria (AKU, ochronosis, omim 203500 , ORPHA56 ) is a rare genetic disease that requires two gene mutations - one from eacht parent - in order to occur. Thus, it is an autosomal recessive disorder. AKU affects the final breakdown of proteins as it is caused by an enzymatic deficiency of the tyrosine metabolism. Hence, patients accumulate the metabolite homogentisic acid at (HGA) about 2000 times the normal rate (1,2). Oxidation of HGA to BQA results in darkening of urine (Figure 1), cartilage degradation and symptoms similar to early-onset osteoarthritis. A unique feature of AKU patients is blackening of cartilage and other connective tissues such as tendons, ligaments, muscles, heart valve, auricles and eye sclera, also referred to as ochronotic pigmentation (Figure 2). This process is called ochronoses and results in oxidative stress, producing radical oxygen species (ROS), inflammation and secondory amyloidosis AA (5, 6). Therefore, as a chronic systemic disease, AKU requires age-dependent surveillance and subsequent therapeutic interventions as summarised in Table 1. Severity and disease progress can be monitored by the AKU-Severity-Score- Index, developed by Prof. Ranganath and Prof. Cox (2-4). Currently, there is no cure available and treatment entails symptom relief such as pain management, physiotherapy and surgery involving joint replacement. Presently, a FP7-funded clinical trial ( developAKUre ) is being conducted to investigate the drug nitisinone for the curative treatment of AKU as illustrated in Table 3 (2). Gait analysis has shown to be a powerful tool to assess onset of AKU-associated arthropathy and to monitor gait impairments for recommendations of effective therapeutic interventions (7). The worldwide prevalence of alkaptonuria is currently 4 - 10 : 1,000,000, however, there are so-called hotspots such as Slovakia, Jordan, India, the Dominican Republic and Berlin (8,9). The highest frequency is found in Slovakia with 1:19,000. Figure 1: Oxidation of homogentisic acid (HGA) to BQA causes darkening of the urine when exposed to air (8). Figure 2: AKU-symptoms due to ochronosis. Ochronotic pigmentation of the connective tissue causes arthropathy of the spine and joints, discolouration of eye and ear as well as aortic stenosis (1-3, 10, 11). AKU-Symtoms: Darkening of urine (brown - black) Darkening of cartilage (brown - black) Systemic Amyloidosis AA Blue -greyish discolourisation of ear pinna (~30 years) Brown - black spots in eye sclera Spondyloarthropathy with calcification of intervertebral disc space at ~30 years Age-dependent gait-impairments at ~30 years Rapid progressive polyarthropathy (ochronotic arthropathy) associated with pain at ~40 years Ruptures of tendons, muscles and ligaments Aortic stenosis at ~50 years Kidney- / prostate stones at ~60 years Figure 3: Summary of AKU associated symptoms. The first sign of AKU is darkening of urine upon exposure to the air. In early adulthood ochronosis begins, resulting in arthropathy of the spine and mainly larger joints, pigmentation of eye sclera and outer ear, aortic stenosis and kidney- / prostate-stones. Monitoring and Diagnostics: Surveillance of AKU-symptoms can be monitored as summarised in talbe 2 (1-4, 10, 12-14). Severity and disease progression is determined according to the AKU-Severity-Score-Index (AKUSSI) , developed by Prof. Ranganath and Prof. Cox and outlined in Table 3 (2-4). Table 2:Summary of monitoring AKU-symptoms (1-4, 11-15) Symptoms Age Diagnostic Interventions Dark urine 0 HGA determination, Mutation-analyses, kidney function Bone metabolism Healthy lifestyle, moderate protein intake, avoidance of sports and labour with high impact Pigmentation of skin, outer ear and sclera 30 Examination, documentation No special interventions are necessary Back pain due to degenerate arthropathy 30 X-rays, MRT, bone isotope scan Pain therapy, physiotherapy, physical exercises, surgery if indicated Ruptures of muscles, tendons and ligaments 30 MRT, ultrasound Strengthening of muscles/joints by moderate sport activities, , surgery if indicated Arthropathy of large joints 40 X-rays, MRT, bone isotope scan Pain therapy, physiotherapy, physical exercises, surgery, joint replacement if indicated Kidney-stones 50 Ultrasound, CT, laboratory diagnostics Surgical removal of kidney stones Prostate-stones 50 Ultrasound, CT Surgical removal of prostate stones Aortic stenosis 50 Echocardiogram, ECG Replacement of heart valves Depression / Isolation 30 Medical history, clarification of the causes Patients’ support-group DSAKU, psychotherapy, antidepressants Table 2: AKU-Severity-Score-Index (AKUSSI) as developed by Prof. Ranganath and Cox (2-4). *, eye conjunctiva: none, slight, moderate/marked; §, sclera:none, slight, moderate/marked; #, number of fracture or rupture. Therapy Table 3: Summary of symptomatic and curative therapies (2,11). Therapy / Counselling Treatment Summary Symptomatic Therapies: Nutrition Vitamin C Efficacy unproven Low Protein Diet Efficacy in adults unproven, compliance problematic Life style counselling Excercise Low impact sports, e.g. swimming, are recommended Choice of job Avoid jobs with heavy labour Family Planning Professional Genetic Counselling Disability Often difficult to obtain to to lack of knowledge about AKU Invalidity Therapies by health professionals Physiotherapy Underused, recommended to maintain mobility Occupational Therapy Underused, recommended to maintain work Pain management Tailored pain therapy Widely used palliative therapy, incompletely effective Surveillance Diagnostics Lack of knowledge prevents utilisation Surgery Organ replacement Probably unjustified in a disease with relatively preserved lifespan Palliative Surgery Effective but invasive, not universally available HGA-lowering curative Therapies: Substrate reduction therapy Nitisinon Currently under investigations ( www.developAKUre.eu ) Gene-therapy HGD-gene Not yet available Enzyme replacement HGD-enzyme Not yet available Disease Management: Table 4: Recommentations of disease management in AKU at all ages and life-circumstances (2,11-18). *Recommended by DSAKU e.V.,**possible symptoms or problems, Deutsche Rheuma-Liga = German League against Rheumatism, Unabhängige Patientenberatung Deutschland = independent patient-counselling Germany.*, great degree of variation; **, may occur. Age (±) Possible symptoms / problems Recommended interventions + treatment methods Infancy Identification* Laboratory analysis HGA Childhood Laboraty diagnostics* Surveillance of kidney functions Childhood Diet* Healthy low protein Childhood Sport activity* Avoidance diet of sport activity with high impact Adolescence Choice of occupation* Avoidance of jobs with heavy labour Adulthood Family planning* Genetic counselling 20 - 30 + Back pain* Physiotherapy, pain therapy, physical exercises 30 + Felt Isolation** Contacts with other AKU-patients via DSAKU e.V. 40 + Joint pain* Tailored pain therapy, physical therapy, 40 + Surveillance of kidney / prostate* Annual ultrasound + laboratory diagnostics 40 + Surveillance of heart / arteries* Annual ECG + Echocardiogram 40 + Working with AKU** Support by DSAKU + Deutsche Rheuma 1 50 + Stiffness + joint pain** Orthopaedic surveillance, surgery if required such as joint replacement 50 + Kidney- + prostate-stones** Surgical removal of kidney- / prostate-stones if required 50 + Aortic stenosis** Replacement of heart valves if required 50 + Possible occupational disability / invalidity** Support by DSAKU + Deutsche Rheuma-Liga 1 + Unabhängige Patientenberatung Deutschland References Phornphutkul, C., Introne, W. J., Perry, M. B., Bernardini, I., Murphey, M. D., Fitzpatrick, D. L., Anderson, P. D., Huizing, M., Anikster, Y., Gerber, L. H., and Gahl, W. A. (2002) Natural history of alkaptonuria. N.Engl.J.Med. 347, 2111-2121. Ranganath, L. R., Jarvis, J. C., and Gallagher, J. A. (2013) Recent advances in management of alkaptonuria (invited review; best practice article) J Clin.Pathol. 66, 367-373. Ranganath, L. R. and Cox, T. F. (2011) Natural history of alkaptonuria revisited: analyses based on scoring systems. J Inherit.Metab Dis. 34, 1141-1151. Cox, T. F. and Ranganath, L. (2011) A quantitative assessment of alkaptonuria : Testing the reliability of two disease severity scoring systems. J.Inherit.Metab Dis. 34, 1153-1162. Braconi, D., Millucci, L., Bernardini, G., Santucci, A. (2015) Oxidative stress and mechanisms of ochronosis in alkaptonuria. Free Radic Biol Med. 88 (Pt A), 70-80. Millucci, L., Ghezzi, L., Bernardini, G., Braconi, D., Lupetti, P., Perfetto, F., Orl,andini, M., Santucci, A. (2014) Diagnosis of secondary amyloidosis in alkaptonuria. Diagn Pathol. 9 ,185-189. Barton, G.J., King, S.L., Robinson, M.A., Hawken, M.B., and Ranganath, L.R. (2015) Age-Related Deviation of Gait from Normality in Alkaptonuria . JIMD Rep. 24 , 39-44. pubmed Zatkova, A. (2011) An update on molecular genetics of Alkaptonuria (AKU). J Inherit.Metab Dis. 34, 1127-1136. Mönch, E. and Link, R. (2006) Alkaptonurie. In Mönch, E. and Link, R., editors. Diagnostik und Therapie bei angeborenen Stoffwechselstörungen , SPS-Verlag, Heilbronn. pp. Richter, P., Halle, D., Le Guillou, D., Wagner, L. (2012) www.youtube.com/watch?v=t5EgHvSYDPM Hannoush, H., Introne, W. J., Chen, M. Y., Lee, S. J., O'Brien, K., Suwannarat, P., Kayser, M. A., Gahl, W. A., and Sachdev, V. (2012) Aortic stenosis and vascular calcifications in alkaptonuria. Mol.Genet.Metab 105, 198-202. Vinjamuri, S., Ramesh, C. N., Jarvis, J., Gallagher, J. A., and Ranganath, L. L. (2011) Nuclear medicine techniques in the assessment of alkaptonuria. Nucl.Med.Commun. 32, 880-886. Pettit, S. J., Fisher, M., Gallagher, J. A., and Ranganath, L. R. (2011) Cardiovascular manifestations of Alkaptonuria. J Inherit.Metab Dis. 34, 1177-1181. Introne, W. J., Kayser, M. A., and Gahl, W. A. (1993) Alkaptonuria. In Pagon, R.A.B.T.D.D.C.R.S.K., editor. GeneReviews [Internet] , University of Washington, Seattle, 1993-2003. Kayser, M. A., Introne, W., and Gahl, W. A. (2009) Chapter 92: Alkaptonuria. In Vale, D., Beaudet, A. L., Vogelstein, B., Kinzler, K. W., Antonarakis, S. E., Ballabio, A., Scriver, C. R., Sly, W. S., and Childs, B., editors. The Scriver's Online Metabolic & Molecular Bases of Inherited Diseases , McGrawHill Companies, Columbus, 1-30. Perry, M. B., Suwannarat, P., Furst, G. P., Gahl, W. A., and Gerber, L. H. (2006) Musculoskeletal findings and disability in alkaptonuria. J.Rheumatol. 33, 2280-2285. Deutsche-Rheuma-Liga (2012) www.rheuma-liga.de . Unabhängige Patientenberatung Deutschland (2016) www.patientenberatung.de ]]>