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.

 

piaabbildung9.jpg

 Figure 1: Oxidation of homogentisic acid (HGA) to BQA causes darkening of the urine when exposed to air (8).


ochronosis_akusypmtoms.jpg

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
aku_summary_kopie.jpg

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.

akussi.jpgakussi.jpg

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 Rheuma1

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-Liga1 + Unabhängige Patientenberatung Deutschland

 


References

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  2. 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.
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  4. 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.
  5. 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.
  6. 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.
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