Research

George Allen invited to give oral presentation at the SSIEM meeting in Lisbon!
24 July 2008

George Allen’s PhD project is progressing extremely well and there have been a number of key developments/achievements arising directly from his research which commenced in October 2007.  These are summarised as follows:- 

Determination of blood AADC enzyme activity is now possible in the UK.  Previously this test, essential for a definitive diagnosis of AADC deficiency to be made, was only available in laboratories outside of the UK.  However, as a result of George’s work, the Neurometabolic Unit in London can now be added to the list of specialist centres offering this test.  Already, this year two new patients have been diagnosed in the UK by this test.

In the laboratory, brain cells have successfully been grown.  These are being used to create a model of AADC deficiency and will allow for investigations to be performed that will give valuable insight into the altered biochemistry that occurs in the brain of AADC deficient patients.

A new high performance liquid chromatography (HPLC) system has been installed for AADC research.  This system was 50% funded by the AADC research Trust and 50% by the NHS Best Research for Best Health initiative.  HPLC is an extremely sensitive technique and is being used, by George, to measure very low concentrations of brain chemicals such as dopamine.  Consequently, it is an essential piece of equipment for AADC research.  Having a dedicated system will have a dramatic and positive effect upon George’s research.

George’s latest research findings were submitted for consideration to be presented at the forthcoming (September 2008) Society for the Study of Inborn Errors of Metabolism (SSIEM) meeting in Lisbon.  Not only was the research accepted but George has been invited to give an oral presentation at this meeting.  Furthermore, he has been awarded a travelling scholarship, from the SSIEM, to cover all his costs associated with attending this meeting.  Both the invitation to give a presentation and the award of a scholarship are  prestigious and are based on scientific merit – Well done George !    A copy of the scientific abstract submitted to the SSIEM can be found below.

Simon Heales PhD

SSIEM Abstract:-

PYRIDOXAL PHOSPHATE AVAILABILITY AND AROMATIC AMINO ACID DECARBOXYLASE ACTIVITY. IMPLICATIONS FOR AADC DEFICIENCY AND INBORN ERRORS OF VITAMIN B6 METABOLISM
Allen G¹ , Clayton P² , Land J³ , Hyland K⁴ , Heales S^3
1Institute of Neurology (UCL), London, United Kingdom , ²Institute of Child Health (UCL), London, United Kingdom , ³Neurometabolic Unit, National Hospital, London, United Kingdom , ⁴Medical Neurogenetics, Atlanta, United States

Pyridoxal 5'-phosphate (PLP) is an essential cofactor for aromatic amino acid decarboxylase (AADC). In addition to facilitating substrate decarboxylation, PLP may have another role by acting as a chaperone to prevent enzyme degradation. To investigate this possibility, we determined plasma AADC activity (in the presence of saturating substrate and PLP concentrations) in two patients with pyridox(am)ine-5' phosphate oxidase (PNPO) deficiency, a disorder where plasma PLP concentrations are low. In one child AADC activity was clearly decreased;14 pmol/min/ml (Ref Range; 36 – 129). In the second child, AADC activity was just below the lower limit of the reference range; 35 pmol/min/ml. For this second patient, additional kinetic analysis revealed an apparent Km for PLP of 15 uM. The Km for control plasma was 6uM. These findings suggest that PLP availability may have a direct effect upon measured AADC activity, possibly by influencing enzyme degradation and kinetic properties. Furthermore, the marked differences in AADC activity observed here may provide an explanation for the variable CSF dopamine and serotonin metabolite levels reported in PNPO deficiency. With regards to AADC deficiency, our data would support the concept that PLP administration may be of benefit, i.e. by stimulating both residual AADC activity and limiting its degradation. We are grateful to the AADC research Trust, UK (www.aadcresearch.org) for supporting our work.