"From an early stage, the brain of AADC deficient patients are persistently exposed to 5-HTP which is either directly or indirectly toxic towards neuronal cells"

The Project hopes to provide:

New methods –  including improved diagnostic ability (plasma assay)
Better understanding of AADC enzyme – optimising activity
Documentation of biochemical changes following loss of AADC activity
Proposal of Novel treatment strategies
Publication
George Allen’s PhD

Dr Simon Heales introduced George Allen (PhD Student) who further elaborated on this subject.  George only began this project in October 2007, despite this, progress has been very encouraging, with the successful development of cultured AADC brain cells.

Dr Simon Heales and George Allen will keep us posted of any new developments.

The power point presentation on this subject is available on our Family Forum for registered members.

Speaker 2 - Biochemical and Clinical Aspects of AADC Deficiency
Professor Peter Clayton
Institute of Child Health and Great Ormond Street Hospital, London.

Thank  you to Professor Peter Clayton for stepping in at a moments notice and presenting a power point presentation on Biochemical and Clinical Aspects of AADC Deficiency.

Professor Clayton gave a more indepth explanation of AADC deficiency and provided supporting evidence that Pyridoxal Phosphate may be a more favoured B6 compound than Pyridoxine when treating children with AADC deficiency.  Pyridoxal Phosphate is a more active form of B6 and so the brain of an AADC child has less work to do to usefully metabolise it. In view of this, AADC deficient patients should be considered for treatment with pyridoxal phosphate.

The power point presentation on this subject is available on our Family Forum for registered members.

Speaker 3 - Oculogyric Crisis (OGC)
Professor Chris Harris
University of Plymouth, UK

Although Professor Harris has had little experience with OGC in children with AADC deficiency, his area of expertise may prove essential in describing how and why these episodes occur.

Professor Harris presented a power point presentation explaining the origins of Oculogyric Crisis, detailing how OGC occurs as a side affect in patients (not suffering AADC deficiency) using the following medications:

•      neuroleptics
•      amantadine
•      benzodiazepines
•      carbamazepine
•      gabapentin
•      chloroquine
•      cisplatin
•      diazoxide
•      influenza vaccine
•      cetirizine
•      levodopa
•      lithium
•      metoclopramide
•      nifedipine
•      pemoline
•      phencyclidine
•      reserpine
•      tricyclics
•      pentazocine

Other symptoms reported which accompany an OGC attack includes:

•      mutism
•      palilalia
•      blepharospasm
•      lacrimation
•      pupil dilation
•      drooling
•      respiratory dyskinesia
•      increased BP and heart rate
•      facial flushing
•      headache
•      vertigo
•      anxiety
•      agitation
•      compulsive thinking
•      paranoia
•      depression
•      recurrent fixed ideas depersonalization
•      violence
•      obscene language

OGC crisis in children with AADC is not the result of side effects from the use of the above medications.  The use of these medications in other conditions and the fact they cause OGC may give a clue as to why they happen in AADC deficiency.  Much more research is needed to better describe these episodes in children with AADC as they are an extremely problematic symptom of the disease.  The duration of an OGC can range from 1 to many hours and can be accompanied by symptoms described above.

The balance of the cholinergic and dopaminergic pathways may be the key to improving OGC’s.  How this is achieved is what we hope to discover.

Summary

Professor Harris concludes that the use of the following medications may be of some benefit to children with AADC deficiency.

?L-Dopa
Bromocriptine – dopamine agonist
Pergolide – dopamine agonist
Diphenhydramine ( benadryl) – antihistamine
Benztropine (cogentin) – anticholinergic/antihistamine
Procyclidine - anticholinergic

We do know that some of these medications have been tried in the treatment of AADC.  Reports of anticholinergic/antihistamine treatments are very mixed and a worsening of some AADC symptoms have been noted, so great care should be taken when using them.  We also know that Dopamine agonists and MAOI have provided some improvements in OGC’s for children who have been able to tolerate these medications.

Professor Harris is willing to collaborate in a study with the Trust involving observing OGC’s in children with AADC deficiency to help better describe this symptom and facilitate improved treatment strategies.  In order for us to progress with this project, we would need to enrol the assistance of our AADC families.   The Trust  would provide an information sheet to affected families to record every time their child suffers an OGC.  The information would include  what exactly preceded an OGC attack, duration, detailed symptoms and the recovery process.  In addition, timing of medications and feeding in relation to an attack are vital.

These reports would help the Trust collate information specific to OGC’s in AADC and enable us to plan Professor Harris’s time and travel more efficiently and cost effectively.

The project would include:

Observing OGCs carefully in AADC, especially onset as this may give clue to oculomotor mechanism.
Observe if AADC OGC is the same as other OGC’s?
Brain imaging
Test anticholinergic - antihistamine therapy
?DBS, implant

The power point presentation on this subject is available on our Family Forum for registered members.

Speaker 4 - Benefits of One Database
Profesor Nenad Blau
University Children’s Hospital, Switzerland

Professor Blau presented a power point presentation describing the extensive database held on the www.biopku.org web site for BIOPKU and BIOMD.  The same structure, within this site exists for PND’s and specifically AADC.  Although some AADC information is already held here, it remains very basic.

The AADC Database includes collection of:

Biochemical information

Neurotransmitter metabolites (5HIAA, HVA, 3OMD, l-Dopa, 5OH-Trp)

Prolactin

Organic acids (VLA)

AADC activity

Clinical information

Characteristic findings

Eye

GI

CNS

Other

Molecular genetics information

A problem with the collection of AADC Worldwide data can be with the reference ranges from Laboratory to Laboratory for the same test.  Initially, a dedicated person would need to accurately interpret these results and enter the data on the  biopku.org/AADC web site.  This requires absolute co-operation from all our Laboratories around the World.

Professor Blau hopes to employ the help of an MD Student (short term & non-funded) , looking for experience within the field of genetics, who can collect, interpret and input the AADC information on to the Database.

The AADC Research Trust will assist in the collection of the data and full co-operation was agreed from all those Professionals who attended the meeting.

Ultimately, this database will provide more extensive scientific and clinical information and will help in the Global understanding of AADC deficiency.  This information will assist the Trust (and other research groups) in their future research projects, by eliminating the need to collect AADC information from multi-locations around the World, which is both time consuming and costly.  Funds can then be spent on Project specifics.

The Trust will liase with Professor Blau on this subject.

You can visit www.biopku.org for more information on the AADC database.

The power point presentation on this subject is available on our Family Forum for registered members.

Speaker 5 - Neuroimaging findings in patients with AADC deficiency
Dr Wang Tso Lee
National Taiwan University Hospital, Taiwan

Dr Lee presented a power point presentation on neuroimaging findings in patients with AADC deficiency which high-lighted the possiblility of demylination of brain white matter in children with AADC deficiency.  This could hypothesise that AADC deficiency could potentially be a slow degenerative disease.  Patients in Taiwan have responded very poorly to current medications used for treating AADC deficiency and the survival rate has been low.  Currently Taiwan has the biggest population of AADC sufferers in the World.  Dr Lee has been studying AADC for some time, some of his neuromimaging findings were shared within this presentation.

From these findings it could also be hypothesised that demylination of the white matter could be prevented with the use of Folate supplementation.  Professor Peter Clayton shared the view that demylination of white matter can occur in children suffering Folate deficiency. 

Children suffering AADC deficiency excrete large amounts of L-Dopa which fail to convert to Dopamine as a result of absent AADC activity.  To eliminate this excessive build up of  L-Dopa, the body must use Folate to convert it to the metabolite 3-O-MethylDopa (3OMD).  The high level of 3OMD found in CSF of  AADC children is one of the indicative markers for AADC deficiency.

Converting excessive L-Dopa to 3OMD drains the folate pool in children with AADC deficiency, potentially leaving them peripherally deficient.  It is unknown at this time what symptoms may exisit as a result of this process.  Improvements of some AADC symptoms have been noted in one AADC child, who has been supplemented with Folinic Acid for the past 5 years.

The folate metabolite is not routinely measured in CSF of AADC children.  Folate measured in plasma for the child mentioned above was found to be in the low/normal reference range, but found to be deficient in CSF.  This result confuses the practioner’s picture when deciding whether to supplement an AADC child with Folinic Acid based on just plasma results.

Summary

It was not agreed by all those present at the meeting that Folinic Acid treatment would necessarily benefit AADC children by preventing the demylination of brain white matter.  However, it was unanimous that Folinic Acid supplementation should be tried in all AADC children as a result of the folate drain needed for converting the excessive L-Dopa to the metabolite 3OMD.

Folinic Acid (not folic acid) is the more favoured form of treament for AADC deficiency.

We await an AADC Project Proposal for funding consideration from Dr Lee for further research into AADC deficiency.

The power point presentation on this subject is available on our Family Forum for registered members.

Speaker 6 - The Importance of Genetic Pinpointing for IVF, CVS and Amniocentesis
Dr Roser Pons
Mitera Hospital, Greece

Dr Roser Pons presented a power point presentation based on The Importance of Genetic Pinpointing for IVF, CVS and Amniocentesis.  This was at the request of the Trust and we thank her for the time taken to prepare this presentation.

AADC affected families talk of the problems involved in future pregnancies and in particular how do they avoid further possible AADC pregnancies?  Dr Roser Pons explained that very little is known about the success of measuring CVS and Amino fluid in pregnant families who previously parented a child with AADC deficiency.  Therefore it cannot report it as either a success or failure, but more a risk.  How these collections are made and risks involved are:

Chorionic villus (CVS)

8th-12th weeks gestation
Placenta tissue cells
A small amount of placental tissue is sucked out by a tube inserted through the abdominal wall or through the vagina
Risks of miscarriage 1/100 – 1/200

 

Amniotic fluid

~16th week of gestation (14-22)
Cells that have been shed from the fetus into the amniotic fluid
A small volume of this fluid can be removed using a needle inserted through the abdominal wall
Risks of miscarriage  1/250 -1/300

Biochemical Analysis of these samples is made, but the metabolite or the enzyme may  not be detectable in amniotic fluid or CV and culturing cells may be necessary which is time consuming and difficult.  Gene Anaylsis can only be made if the gene causing the disease is known or if the mutation in the gene is known.

IVF treament also requires the pinpointing of the AADC gene mutations.  This method does provide an early form of pre-natal diagnosis:

In vitro fertilization (IVF)

Genetic testing of embryos generated by in vitro fertilization(IVF) = early form of prenatal diagnosis
Embryos created in vitro can be analysed for genetic defects
Those free of the defects are transferred into the womb
Avoids the need for potential termination

In the event of a pregnancy and in the absence of AADC gene mutation anaylsis, a fetal liver biopsy can measure AADC activity.  An AADC carrier status fetus was detected using this method in 1992.  This carries a high risk of miscarriage and only two centres currently in the World are able to perform this test.

If a child is diagnosed with AADC deficiency, it is advisable to ask a practioner or geneticist for an AADC DNA mutation anaylsis for the family.  Once the mutations have been pinpointed, a family can make the most informed decision about future pregnancies.  It is also important to detect the heterzygote/homozygote status of parents of an AADC child, as this affects the outcome of these tests.

The power point presentation on this subject is available on our Family Forum for registered members.

Speaker 7 - New Blood Sample Protocol in UK
Dr Simon Heales & Dr John Land
National Hospital, UK

Dr John Land shared the good news that measurement of  ‘Plasma AADC Activity’ is now offered as a service at the UK Neurometabolic Unit SAS Laboratory.

The power point presentation on this subject is available on our Family Forum for registered members.

Speaker 8 - Availability of AADC Clinical, Scientific and Patient Information
David Gaze
St Georges Hospital, UK 

David Gaze presented a power point presentation on the availability of Scientific , Clinical and Patient Information, relating to AADC deficiency.

Exploring AADC deficiency using the Internet as a tool, leads you to web sites such as AADC Research.org , PND Assoc.org and BH4.org.  David high-lighted that these sites can be found using search words such as ‘AADC’ and/or ‘Aromatic Amino Acid Decarboxylase Deficiency’.  The need for basic, but detailed, Professional/Patient information is very evident, as all these sites still focus primarily on the scientific aspects of the disease.   

The Trust will prepare the most up to date information sheets which affected families can understand and share with their treating Professionals.  Collaboration and Endorsements of these information sheets is required by our Medical and Scientific Advisory Members (at least 2 member approvals).  All those at the meeting agreed to provide such endorsements.  David will help collate and prepare these sheets including:

Ergot Dopamine Agonists Vs Non-Ergot Dopamine Agonists
Parnate and Aneasthetic
Aneasthetic Risk in AADC Deficiency (Pre and Post Diagnosis)
Benefits of Folinic Acid
What do positive AADC results mean and how to interpret them
AADC and Future Pregnancies
Should high ‘Tyramine’ foods be avoided when using MAOI in AADC deficiency
Etc… Etc…

David also explained how we have improved our web site by adding a forum facility which enables affected families, Professionals and Health Care Providers to visit and share information/experience about the disease.

The power point presentation on this subject is available on our Family Forum for registered members.

AADC Meeting Summary

Overall and following the very positive feed back, the meeting was a great success, bringing AADC deficiency to the forefront of Professional’s minds and a top topic for discussion.  We have since heard that AADC projects are being prepared in three seperate countries for the Trust to consider for funding, which is a real endorsement of the success of this meeting.  These include:

Development of an AADC mouse model
Clincial and Scientific follow up of AADC patients
The study of Oculogyric Crisis in children with AADC deficiency.

I and the Trust Directors, whole heartedly thank all who participated in this meeting and we look forward to working closely with you in the future.

Thank you, on behalf of the Trust and its families, for your involvement with AADC Research.