Tyrosine Degradation Study (TyDeS )
Research type
Research Study
Full title
A stable isotopes study of tyrosine degradation in alkaptonuria patients, before and after nitisinone, compared to healthy volunteers
IRAS ID
216041
Contact name
Lakshminarayan Ranganath
Contact email
Sponsor organisation
Royal Liverpool Hospital
Duration of Study in the UK
1 years, 0 months, 2 days
Research summary
Alkaptonuria (AKU) is a rare inborn error of tyrosine metabolism, caused by an enzyme deficiency that leads to increased circulating homogentisic acid (HGA) in body fluids and tissues. This results in the formation of a black pigment in a process called ochronosis. \nOchronosis gives rise to the various manifestations of AKU. These include features such as stones (kidney, prostate, salivary and gall bladder), ruptures (tendons, muscle, ligaments), hearing impairment, external ear and eye ochronosis, cardiac (mainly aortic) valve disease, fractures and most significantly, arthritis.\n\nUntil recently the main treatment for this condition was analgesia, which was mostly ineffective, and joint replacement surgery in severely affected cases. A new treatment employing a drug, called nitisinone, can decrease homogentisic acid production to near zero. Nitisinone is already licensed and has been used for over two decades for the treatment of hereditary tyrosinaemia 1 (HT1) in children. Since 2012, nitisinone is also being used off-label in the NHS England designated National Alkaptonuria Centre (NAC) at the Royal Liverpool University Hospital. All AKU patients from England and Scotland attend the NAC annually and receive nitisinone as part of their standard care.\n\nNitisinone, however, can cause an increase in tyrosine in AKU patients. This can results in tyrosine keratopathy which spontaneously resolve upon discontinuation of nitisinone. Since nitisinone is the only potential HGA lowering therapy available at present, the tyrosinaemia will need to be better understood and managed. An important first step is to characterise the tyrosinaemia post nitisinone. Little is known about the quantitative analysis of tyrosine pathway in AKU pre and post nitisinone. Understanding the flux of metabolites is central to employing future therapies.\n\nUsing stable isotopes, this study will investigate the tyrosine pathway in AKU patients before and after treatment with nitisinone. It will also compare it with tyrosine degradation in healthy volunteers.\n
REC name
North West - Liverpool Central Research Ethics Committee
REC reference
17/NW/0032
Date of REC Opinion
16 Feb 2017
REC opinion
Further Information Favourable Opinion