Final Report for REMEDI
Project Heading: Medical Risk Factors in Autism: A systematic search
for associated medical risk factors in a total population of children with
autism and other pervasive developmental disorders
Participants: grant holders and collaborators
Dr Gillian Baird Consultant Paediatrician – Guy’s and St Thomas NHS
Foundation Trust - Honorary Professor in Neurodisability, Kings College
London
Professor Emily Simonoff – Professor of Child & Adolescent Psychiatry,
Institute of Psychiatry, Kings College London
Dr Tony Charman – Reader in Psychology,Behavioural Sciences Unit
Institute of Child Health London
Professor Andrew Pickles – Professor of Epidemiology and Social Statistics,
Department of Bio-statistics, University of Manchester.
Dr Neil Dalton – Senior Biochemist, Kings College London
Dr Michael Champion – Consultant Paediatrician in Metabolic Medicine,
Guy’s & St Thomas NHS Foundation Trust
Dr Charles Turner – Clinical Biochemist, Kings College London
Dr Peter Sullivan – Consultant Gastroenterologist, John Radcliffe Hospital,
Oxford
Background to the project
In 2000 The Wellcome Trust funded a study looking at the prevalence of
autism and spectrum of autistic conditions in the South Thames Region.
The Wellcome Trust did not fund any medical tests other than physical
examination and chromosome analysis. At an early stage REMEDI
supported our application to look at other medical factors in this population
representative cohort of children then aged between 10 and 11 years.
Subsequent to the REMEDI support the Department of Health gave
additional funding for another control group of children with special needs
who did not have autism to be enrolled and the National Association of
Autism Research (NAAR), an American charity at that time, gave additional
funding for a group of children from mainstream school who had no
developmental abnormalities to be recruited. These two subsequent
applications were for different biomedical investigations, namely measles
virology and a broad immunological screen, respectively. Remedi’s support
was crucial in getting other funders ‘on board’. However, as a consequence
this has been a large ambitious project with 4 grants running
simultaneously and whilst the initial timescale of the Remedi funded
component was 3 years the data collection continued for a full 5 years until
the end of 2005. However, we anticipate that overall the study including the
Author: Dr Gillian Baird – Report for Remedi Website
Date: 21st September 2006
component funded by Remedi will make a significant contribution to the
autism field.
Reasons for researching this particular area.
There has long been a concern about possible medical causes of autism
which are unrecognised by the medical community and which might lead to
potential treatments. Public awareness and anxiety were particularly raised
over a report in 1998 in the Lancet of an association of autism with
regression following the MMR immunisation and a bowel disorder. The
direct consequence of this was a marked drop in immunisation with MMR of
the nation’s children with consequent severe outcomes as vulnerable patient
groups found themselves exposed to measles with devastating effect.
Subsequent epidemiological studies have not shown any cause for concern
about the MMR but parents have still been concerned to have their children
directly investigated. In addition it was clear that none of the research
studies to date had examined in a large enough sample using a case control
design, of the prevalence of bowel problems. This was also an opportunity to
directly assess whether there was any evidence of the postulated leaky gut
and escape of peptides across the gut barrier again in a case control series.
Another postulated association with autism has been the work carried out in
Sunderland by the University of Sunderland. Dr Paul Shattock and team
claiming that there is a specific substance secreted in the urine of those with
autism called indoloylacryloylglycine (IAG). This is a test parents pay for
and subsequently are encouraged to make judgements about whether or not
a child should be placed on a special diet depending on the results. Since
this cohort were going to be so well defined in terms of phenotype, we judged
it important to try to look at IAG and also the immunological impairments
also postulated to be different in children with autism. We added a range of
metabolic conditions including abnormalities of B12, purines and
pyrimidines and a general screen using a tandem mass spectrometer. We
also explored any gastrointestinal problems, obtained diet histories and
sought family histories of auto-immune diseases.
The Remedi support was absolutely crucial in enabling this part of the
project to go ahead.
How did we spend the Remedi money?
Remedi agreed to fund the laboratory work costed per test. We had to
purchase the pure IAG and set up an analysis. We had to set up a method of
analysing gut permeability. All laboratory processes need checking and
rechecking so samples have been rerun as different batches after the control
groups were collected. Remedi also funded storage of samples in a suitable
refrigerator. In 2003 I wrote to Patrick Mesquita asking if we could use some
of the money to support salary for Neil Daltons lab and this was agreed by
Remedi.
Salary expenditure on laboratory technician and research assistants shared
across grants:
Transport costs for families shared across grants
Laboratory materials: £17,796.25
The investigations originally planned from the Remedi grant were:
Author: Dr Gillian Baird – Report for Remedi Website
Date: 21st September 2006
1. Related to gut function and the peptide theory of autism
Urine indoleacroylglycine
Gut permeability
Plasma and urine non-specific opiate drug screens
Bowel and other GI symptoms
Diet questionnaire
Full blood count
Coeliac antibodies
Family history of auto-immune disorders
2. Screening and specific tests for inherited metabolic diseases
Urinary methylmalonate
Plasma homocysteine
Plasma and urine uric acid
Urine orotic acid, uracil, thymine, dihydrouracil, and
dihydrothymine
Succinylamino-imidazole, carboxamide, ribotide,
succinyladenosine, and S-sulphocysteine
Plasma and urinary tryptophan and plasma acylcarnitines
Urinary organic acid screens to include quantitative
homovanillate, 3-hydroxy-4-methoxy mandelate, and 5hydroxyindoleacetate
Purines and pyrimidines
There have been some additions and changes made to this list either
because of changes in clinical priorities, or improved technology. Specifically:
1. Plasma and urine non-specific opiate drug screens have been
replaced by specific neuropeptide analysis
2. Plasma and urine sulphate have been added
3. Plasma and urine guanidinoacetate and creatine have been added,
together with urine ureidopropionate
4. Urinary methylmalonate has been replaced by plasma
methylmalonate
5. Urinary organic acid screens have been replaced by plasma and
urine MS scans in positive and negative ion mode and at low and
high voltages
In addition, with the support of the other grants, we have data on measles
and rubella antibodies, chromosome analyses, neuroimmunological
measures and a range of psychological and cognitive tests.
Impact on patient care: This is proving to be a highly illuminative and
influential study with findings that will inform clinician decisions for
investigation of children with autism world –wide and affect the advice we
can confidently give to parents. The reporting of results will be through peer
reviewed publications with full acknowledgement to Remedi.
Any unexpected problems?. We would like to have managed blood samples
on all children and have returned to some but as a research project we have
been totally respectful of the young peoples’ views. The initial participation
response was about 70% of potential families where children had statements
Author: Dr Gillian Baird – Report for Remedi Website
Date: 21st September 2006
of special needs which is satisfactory but not outstandingly good. We have
had enthusiastic participation from parents and young people once involved.
We have had delays in analysis of some lab work because we have gone back
to families for samples and they all have to be batch blind tested. Also
having to buy IAG and set up a totally new analysis was time consuming but
essential to test claims made by the Sunderland laboratory.Getting good lab
technicians was not easy. Integrating and analysing such a lot of data has
inevitably taken more time than we hoped but with the first paper out, we
are working on the next 5 currently.
The next step: The study has answered some important clinical questions
regarding theories relating to the pathogenesis of autism, provided scientific
evaluation of a range of autism specific biochemical tests, and generated
excellent population data on a range of old and new clinical tests. The
samples remain stored at -80oC and are an important resource to rapidly
test new theories of systemic causes of autism and validate any useful new
biomarkers.
The subjects in this study are contributing to the ongoing genetic studies.
The bowel symptoms require more research especially with a younger cohort.
In response to parental concern we are also looking at transition to post
school for this group and both mental and physical health needs.
Future plans: Each of these studies will be written up. At the moment one
paper reporting the prevalence in the Wellcome Trust and DoH study has
been published (Baird et al., 2006 – see below). We are now making progress
with writing up the more medical aspects which Remedi funded. Each result
will be placed in an appropriate journal and a summary paper of medical
testing in autism will also be written and submitted to an appropriate
journal. In each case Remedi support will be clearly acknowledged. We have
a further grant to look at cognitive links with behaviour and intend to apply
for funding for brain imaging.
We anticipate presentation of the entire findings to an appropriate parent
conference as well as professional conferences.
Remedi has been extremely helpful at a crucial moment in our study and we
are very grateful indeed for the contribution to this complex and lengthy
study that we believe will contribute to our understanding of the aetiology
and sequelae of autism and related disorders.
Reference: Baird G, Simonoff E, Pickles A, Chandler S, Loucas T,
Meldrum D, Charman T (2006), Prevalence of disorders of the autism
spectrum in a population cohort of children in South Thames: the Special
Needs and Autism Project (SNAP). Lancet 368:210-215
Author: Dr Gillian Baird – Report for Remedi Website
Date: 21st September 2006