UCD ACoRD
Joint Committee on Health and Children
27/2/2014
Academic Centre on Rare Diseases
ACoRD
UCD School of Medicine
Scoil an Leighis agus
& Medical Science
Eolaíocht An Leighis UCD
Room C3.29, 3rd Floor
An triú h-urlár, Seomra C3.29
Health Sciences Building
Ionad Eolaíocht Sláinte UCD
University College Dublin
An Coláiste Ollscoile Baile Átha Cliath
Belfield, Dublin 4
Belfield, Baile Átha Claith 4
T +353 1 716 6685
ACoRD@ucd.ie
F +353 1 716 6585
http://bit.ly/UCDACoRD
Joint Committee on Health and Children
27th February 2014
Opening Statement on Rare Diseases
by
Dr. Seán Ennis
Director of
UCD’s Academic Centre on Rare Diseases (ACoRD)
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UCD ACoRD
Joint Committee on Health and Children
27/2/2014
1. Introduction
1.1. I am Dr. Seán Ennis, Director of UCD’s Academic Centre on Rare Diseases(ACoRD).
1.2. Awarded formal University academic status in June 2013, the UCD Academic Centre
on Rare Diseases (ACoRD) brings together a small but highly focused set of
researchers active in the area of rare diseases. The aim of the Centre is to develop
critical mass around the area of Rare Diseases. It is aligned with UCD School of
Medicine & Medical Science’s research strategy. The Centre is a hub for the
interaction of many inter-disciplinary research links between Clinical geneticists,
non-clinical geneticists, bioinformaticians, computer scientist, cell biologists,
molecular diagnostic clinical scientists and pharmacologists.
1.3. The focus of the centre is to investigate rare genetic diseases, particularly those
affecting the Irish population and the Irish Traveller population.
1.4. The Centre is focused on the study of the genetic basis of rare diseases, with a view
to the identification of the mutation(s) causing the disease. Once a causal
mutation(s) is established, the objective is to develop diagnostic tests for translation
back into a clinical setting.
1.5. Once a gene is implicated, our scientists work to further investigate the gene
function and biological pathways involved in the condition with a view to having an
impact on patient management and improve health care for the patient. The
ultimate aim is to investigate those conditions and genes which might be amenable
to drug targeting or gene therapy.
2. Background
2.1. The current treatment options for many patients with Rare Diseases are limited.
They are not targeted or personalised and currently involve the management of
patient symptoms as opposed to directly treating the cause of the disease. In
recent years there has been revolution in the field of Genomics and genome
technology. At the same time there is now a growing awareness that having a rare
disease is a common event. It is estimated that some 6% to 8% of the population
have a rare disease and we have estimated more than 60 autosomal recessive
disorders in the Irish Traveller population. (Autosomal recessive disorders are
conditions which require two defective gene copies to exhibit the condition).
Despite being ‘rare’, these conditions take a disproportionate amount of the health
budget. We at ACoRD are applying modern advances in genomics to rare diseases.
And we are already beginning to have some success through our investigations.
2.2. The power and potential for research into rare Diseases is best illustrated by the
three examples below which are three conditions investigated with ACoRD;
 The story of the children born with no eyes
 The pigmentation / infection disorder story
 The LARS story
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UCD ACoRD
Joint Committee on Health and Children
27/2/2014
3. The story of the children born with no eyes.
3.1. Our first major breakthrough using modern ‘Omics’ technology was in a rare disease
where children are born with eyes that are either small or missing – a condition
called micro-anophthalmia. A child’s eyes will not develop fully in the womb if the
child has alterations in STRA6, a gene which is responsible for transporting vitamin A
into the cells.
3.2. Anophthalmia (absence of one or both eyes, occurs in around 1 in 100,000 births),
and its sister conditions microphthalmia (small eye) and coloboma (malformed eye),
arise during the development of the baby in the womb (occur in around 1 in 10,000
births). Although individually rare, these three major structural eye defects account
for 11% of all childhood visual impairments. They can also be associated with other
birth defects such as malformations of the heart, lungs and diaphragm.
3.3. Through our analysis of representative tissue/DNA/serum? Samples, we pinpointed
STRA6, a gene responsible for transporting vitamin A into cells. We went on to show
that the genetic mutation identified in these patients significantly impairs the ability
of STRA6 to transport vitamin A into the cells. And consequently, the amount of
vitamin A needed to support normal eye development in the embryo is lacking. This
has resulted in significant advances in the understanding of individual genes that
can cause anophthalmia, microphthalmia, and coloboma, and it also adds important
diagnostic criteria to the field of general eye malformations. Our findings suggest
that patients with eye defects of unknown cause should also be considered for
STRA6 testing.
3.4. What is the impact of this finding so far?
Having identified the genetic basis of this condition we have developed a diagnostic
genetic test. Next month sees the formal introduction of this genetic test to the
diagnostic laboratory at the National Centre for Medical Genetics (NCMG), a key
resource for Irish clinicians and parents. The molecular laboratory at NCMG offers
carrier testing for genetic disorders common in the population and this condition will
now be added to the testing panel.
3.5. Impact Patient Management
Accurate carrier testing and genetic counselling can be offered to those individuals
planning to have children. If identified, the couples can receive advice and
counselling about the implications of carrying the gene alteration for their present
and future children.
3.6. Improve Health care
Currently there is no clinical treatment for micro-anophthalmia (the absence of one
or both eyes), and children born with the condition must have prosthetic eyes fitted
to help their face and skull to develop naturally. Ultimately, this work may be used to
develop preventive measures or possible treatments in the future,
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Joint Committee on Health and Children
27/2/2014
4. The pigmentation / infection story
4.1. This was the study of what was originally thought to be three separate syndromes
occurring in overlapping family groups presenting at three different types of clinics.
The first syndrome was characterised by a natural killer (NK) cell deficiency, this
deficiency probably accounts for the patients' recurrent viral illnesses. The second
syndrome showed evidence of an atypical Fanconi's type DNA breakage disorder, in
which molecular tests supported a diagnosis of mosaic Fanconi's anaemia, but the
patients did not present with any of the expected clinical features of the disorder.
The third syndrome showed features of familial glucocorticoid deficiency (FGD).
However, the symptomatic presentation of FGD was delayed in onset.
4.2. It wasn’t until one of our clinicians made the astute observation that all three of
these syndromes segregate together, that we could test the theory that the NK cell
deficiency, DNA repair disorder and FGD were all caused by a single genetic event.
We identified a single mutation which affected two overlapping genes MCM4 and
PRKDC. The biology of the genes was consistent with the observed syndromes.
4.3. The findings suggest that clinicians should consider this disorder in those patients
with failure to thrive who develop pigmentation or who have recurrent infections.
4.4. Impact of identification of STRA6 mutations
4.4.1. What is the impact of this finding so far?
Having identified the genetic basis of this condition we have developed a diagnostic
genetic test. Next month sees the formal introduction of the genetic test to the
diagnostic laboratory at the National Centre for Medical Genetics (NCMG). The
National Centre for Medical Genetics offers carrier testing for genetic disorders
common in the population and this condition will now be added to the testing panel.
4.4.2. Impact Patient Management
Having a simple diagnostic DNA test now avoids the hazardous ‘synacthen test’ a
chemical test to check the function of the adrenal glands which is both invasive and
painful in Children. There is also a psychological benefit to patients in having genetic
counselling available for a condition.
4.4.3. Improve Health care
Early diagnosis allows the earlier use of Hydrocortisone before the onset of ‘ACTH
resistance’ symptoms. This in turn delays onset of symptoms in these children
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UCD ACoRD
Joint Committee on Health and Children
27/2/2014
5. The LARS story
5.1. This was originally thought to be a mitochondrion disease (that is a dysfunction in
the body’s cell ‘battery packs’) due to the presence of multi system organ failure. In
our studies, we identified the gene (LARS) and the genetic mutation responsible.
This led eventually to the understanding that this was primarily a potentially-fatal
infantile liver failure disease. These children have liver failure in their first few
months and they continue to have liver dysfunction when they become ill.
5.2. What is the impact of this finding so far?
Having identified the genetic basis of this condition we have developed and clinically
validated a simple blood-based genetic test for LARS which has already proven beneficial
to patient health. Next month sees the formal introducing the genetic test to the
diagnostic laboratory at the National Centre for Medical Genetics (NCMG). The
molecular laboratory at NCMG offers carrier testing for genetic disorders common in the
population and this condition will now be added to the testing panel.
The benefit to patient health is a reduction in the time to diagnosis by ~3.7 years. It
avoids unnecessary investigations which includes invasive muscle/skin/liver biopsies at a
time when these children are sick.
5.3. Impact Patient Management
Since this discovery, we have also made advancements in understanding the disease
mechanism and are investigating the hypothesis that the patients can be treated by
means of a new nutritional approach. Our findings led to a significant change in patient
management. Previously, the families were advised to avoid protein when unwell, as
protein can exacerbate liver function. However, as LARS is involved in amino acid
incorporation, we now know that the disorder in these children is specifically one of
protein synthesis and that the patients need high levels of protein when ill. Dietary
changes have already been suggested to the patient families and have helped to avoid
repeat episodes of liver dysfunction in these children.
5.4. Improve Health care
Each family and their local medical unit have also been given a personalised emergency
plan so that clinicians are aware of the complications and urgency to test liver function
in these ‘at-risk’ LARS children when they have a minor illness. These children can
quickly deteriorate from minor cold to liver failure and their emergency plan has helped
to heighten awareness of the specific assessments and treatments that need to
administered.
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UCD ACoRD
Joint Committee on Health and Children
27/2/2014
6. Conclusion
6.1. These are just three of several examples where, by focusing on a rare disease in
related groups, research at UCD ACoRD has unveiled important genetic information
about rare conditions. These advancements in diagnostics, patient management
and therapeutics have only been made possible through isolation of the causative
disease gene and investigation of its disease mechanism. The success of our studies
has demonstrated the benefits of personalised ‘Omics’ research for patient care and
supports the use of an individualised approach to provide a diagnosis and
therapeutic options for families with a rare genetic disorder of unknown cause.
6.2. The identification of the genetic causes of a disorder provides us with new insights
into the mechanism of disease and opens up the potential for new targets for
therapeutics. These impact on patients and their families by allowing accurate
carrier testing and genetic counselling to be offered to those individuals planning to
have children. They can also add important diagnostic criteria to the field of general
malformations often with the rare case informing the broader situation.
6.3. As highlighted in the examples above there can be a direct impact on Patient
Management and an improvement in patient Health care. Ultimately, this work may
be used to develop preventive measures or possible treatments in the future
through drug targeting or gene therapy.
6.4. There is now an ambitious aim set among the international scientific community in
order to drive the field of research into Rare Diseases forward. That aim is to
develop and put in place a diagnostic genetic test for all of the ~7,000 known rare
diseases by the year 2020, and further to develop therapies for ~200 of these
conditions. We have aligned ourselves with these ambitions. Many countries have
united to tackle the area of rare diseases as no country can have expertise in all of
these conditions. We collaborate closely with our colleagues throughout Europe and
internationally in this regard.
6.4.1. Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Casey JP,
McGettigan P, Lynam-Lennon N, McDermott M, Regan R, Conroy J, Bourke B, O'Sullivan J,
Crushell E, Lynch S, Ennis S. Mol Genet Metab. 2012 Jul;106(3):351-8. Epub 2012 Apr 26.
PMID:22607940
6.4.2. Jillian P Casey, Michael Nobbs, Paul McGettigan, SallyAnn Lynch, Sean Ennis. Recessive
mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and
a disorder of DNA repair. J Med Genet 2012;49:242-245 doi:10.1136/jmedgenet-2012-100803
PMID:22499342
6.4.3. Casey J, Kawaguchi R, Morrissey M, Sun H, McGettigan P, Nielsen JE, Conroy J, Regan R, Kenny
E, Cormican P, Morris DW, Tormey P, Ní Chróinín M, Kennedy BN, Lynch S, Green A, Ennis S.
First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma:
A new dimension to the STRA6 phenotype. Hum Mutat. 2011 Sep 7. doi: 10.1002/humu.21590.
PMID:21901792
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UCD ACoRD
Joint Committee on Health and Children
27/2/2014
7. Recommendations for action
7.1. I would recommend that you, the committee, consider that the use of modern
‘Omics’ technology is highly effective in the study of Rare Diseases and will be of
increasing importance in an era of personalised medicine. That national expertise
exists in this arena and is making a contribution to managing Ireland’s Rare Disease
burden.
7.2. I would strongly urge you the committee to ‘be brave’ in your long term planning,
and to consider the widespread implementation of ‘Omics’ in Rare Diseases and
Personalised medicine. Relative to conventional pharmaceutical drug discovery,
research into Rare Diseases can have a relatively short time from gene discovery to
diagnostic test utility and a potentially high impact on patient’s lives. Many nations
are implementing or considering ambitious programmes. This is a field of rapid
advancement. Today’s ambitious move will soon be the standard of tomorrow. Such
an initiative in Health and Children in Ireland could have profound long term effects.
Surely our children deserve investment in their health.
7.3. Importance of basic research in biomedical science
Ireland has a sophisticated biomedical research environment with many multidisciplinary institutes on our main University campuses. Tragically, despite these
resources, Irish research funding agencies are increasingly abandoning fundamental
biomedical research in favour of more ‘applied’ and ‘enterprise-led research. While
this is important not all scientific advancements can be measured in economic
terms! Basic research in biomedical science needs to be supported as well as
enterprise-focused research.
7.4. Importance of Patient Biobanks
Key to progress in genomics-led research is the provision of well characterised
patient biobanks with associated clinical information. I would strongly recommend
support for DNA collections and biobanks being a routine feature of clinical care of
all new born babies. These samples need to be appropriately consented, coded or
anonymised, carefully stored and available to the research community for both
common and rare diseases.
7.5. National Centre for Medical Genetics
My colleagues in the National Centre for Medical Genetics currently operate under
extremely challenging resource constraints. Nevertheless they provide an
exceptional service to patients and parents both at Our Lady’s Children’s Hospital
Crumlin, at the Children’s University Hospital Temple Street and across the country.
In my opinion, regardless of its location, our new National Paediatric Hospital will
not be world class unless it has access to a well-resource truly national genetic
diagnostics service.
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