Download Rare disease research in York

Rare disease research in York
Scientists and clinicians at the University of York/ Department of Biology (Biol)/
Centre for Immunology and Infection (CII)/ HYMS and York Teaching Hospital (YTH)
tackle important questions to better understand, diagnose and treatment for patients
with rare diseases. This poster shows selected examples of these research activities.
Please feel free to visit: www.york.ac.uk/biology/research
IgG4-Related Disease
Rett Syndrome
Jawad Fazal – Rheumatology YTH
IgG4-related disease is a newly recognised immune mediated condition. It was only in 2003 when it
was recognised as a multiorgan disease. Experts have described it as a “black crow flying through
the dark night” as it escaped recognition through the history of medicine for over a century.
Epidemiology of IgG4-RD is not well known because of insufficient awareness. Studies from Japan
estimated prevalence of 60 per million. It typically occurs in middle aged and elderly men.
Dr Darren Goffin – Department of Biology
Rett syndrome is a devastating autism spectrum disorder affecting 1 in 10,000 females and
is caused by mutations in the X-linked gene encoding Methyl-CpG Binding Protein 2
(MeCP2). The development of mice carrying MeCP2 mutations revealed the presence of
neurological phenotypes resembling those observed in Rett syndrome patients. Moreover,
reintroduction of MeCP2 into behaviourally affected MeCP2 knockout mice is sufficient to
rescue Rett syndrome-like phenotypes raising the exciting possibility that Rett syndrome
may be a curable disorder.
Commonly presents as
Mutations found in Rett
syndrome prevent MeCP2
from binding to DNA properly
T Kamisawa et al
2015
tumor like swelling of the involved organ
can mimic malignancy, infections or inflammatory disorders
Can involve almost any organ
IgG4-RD comprises a spectrum of disorders which were once considered
as separate entities. Those at high risk are Pancreatitis of Unknown origin,
Bilateral salivary gland swelling, Orbital Pseudotumor, Sclerosing
Cholangitis and Retroperitoneal fibrosis.
Diagnostic Criteria: Primary: Histology - Lymphoplasmacytic Infiltrate,
Storiform fibrosis, Obliterative Phlebitis. Secondary : IgG4+ cells >10/HPF, IgG4+/IgG > 40%,
Serum IgG4 > 135mg/dl. Awareness of IgG4-RD is essential as it is a treatable disease. Early
recognition can change the management significantly.
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Darren Goffin (Departments of Biology and Psychology, University of York) has been
awarded C2D2/Welcome Trust funds to identify new insights into understanding
the mechanisms by which mutations in MeCP2 lead to the manifestation of Rett syndrome.
Congenital Disorders of Glycosylation (CDG)
Human T Lymphotropic Virus
Dr Daniel Ungar – Department of Biology
Dr Fabiola Martin – CII/HYMS
In the UK most patients are diagnosed through blood donation
services. More than 699 new HTLV diagnoses have been
made so far:
65% were women around the age of 52.
There are some treatment options for
ATLL but no specific treatment for HAM/TSP.
North East Retrovirology Referral Centre (NERRC): Dr Fabiola Martin and her team look after HTLV
positive people at York Teaching Hospital.
HTLV research Laboratory: Dr Fabiola Martin set up the HTLV laboratory at the Centre for
Immunology and Infection. Research has been focusing on mucosal and mother to child transmission
and has attracted funding from Hull and York Medical School and C2D2/Wellcome Trust.
Cystic Fibrosis (CF)
Dr Rebecca Thomas – Respiratory Medicine YTH
Professor Mike Brockhurst – Department of Biology
Cystic Fibrosis (CF) affects over 10,000 people in
the UK. It is a lifelong condition affecting every
organ in the body.
CF is an inherited disease, where a faulty gene means mucus becomes
thick and sticky, clogging up the lungs and digestive system, making it
hard to breathe and digest food.
The lungs are also infected more easily, and research at York University is
helping to understand how bacteria adapt to life in the CF lung.
CF is also a relative success story – in the 1950s most
people died before the age of 5, but now the average life
expectancy is 43. We aim that people born with CF today
will live to retirement.
The adult and paediatric CF teams at York work to provide a high quality,
local service. If you want to know more about CF, or the service we offer
here in York, go to www.cfyork.org.uk or contact the team on cystic.
[email protected]
Trypanosoma brucei - African Sleeping Sickness (HAT)
Dr Pegine Walrad – CII/Department of Biology
Investigating parasite proteins for new therapeutic interventions
displaying sugar structures in blue
How do we know sugars are important?
Disruption of glycans causes a group of rare diseases
called Congenital Disorders of Glycosylation (CDG).
CDG patients, due to incorrect glycans, suffer from
many symptoms, for example:
• Poor growth
• Muscle problems
• Developmental delay
• Epilepsy-like fits
We research how glycans are made, what role(s)
they play in our bodies, and how this can go wrong
in a patient. We are also working on a new
diagnostic method.
Image: C. Bertozzi
Ten to 20 million people are infected with this retrovirus, which can be caught through unprotected
sex, breastfeeding and sharing needles. HTLV remains hidden in most infected. Only ~6% of people
develop disease: 3% Adult T Cell Leukemia (ATLL) and 3% HTLV-1 associated myelopathy/Tropical
Spastic Paraparesis (HAM/TSP). HTLV-1 is common in the Caribbean, Japan, Iran, Melanesia, South
America, and parts of Africa.
Sugar is a main energy-source for us, but our cells also build intricate sugar structures,
called glycans. Glycans cover the surface of every cell in nature, and affect growth,
behaviour and health. They are known to be different in most types of cells, such as
embryos, normal human cells and cancer cells.
Artist’s view of a cell’s surface,
Lowe Syndrome (Oculocerebrorenal Syndrome)
▪ Occurs only in males
▪ Found in 1 in 500,000 people
▪ Affects eyes (oculo), brain (cerebro) and kidney (renal)
Symptoms include:
•Glaucoma and cataracts
•Hypotonia (low muscle tone)
•Mental retardation
Dr Sean Sweeney – Department of Biology
• Seizures
• accumulation of acid due to kidney dysfunction
▪ Associated with mutations in the OCRL1 gene. Why loss of the OCRL1 gene causes Lowe
Syndrome is not known.
▪We have generated a Drosophila melanogaster
(fruit fly) model of Lowe syndrome
Lowe syndrome flies display:
Wildtype
OCRL1
Figure 1. OCRL1 mutant flies display black accumulations
caused by an immune responses. Observed here in larvae
A
B
C
• Weak muscles
• Abnormal neuron characteristics
• Reduced brain size • Activated immune responses
D
The Sweeney lab are now in a position to
identify cellular and physiological defects
caused by Lowe Syndrome. These
experiments are not possible in mammals
for reasons of genetic complexity.
Figure 2. By dissecting flie larvae we can observe the morphology and health of specific neurons and compare these between normal
and diseased animals. We particularly study the neuron that connects the brain to the muscle (C) and (D).
Neuroblastoma
Dr Gareth Evans – Department of Biology
What is neuroblastoma?
•a childhood developmental cancer caused by
neuronal stem cells forming tumours instead of
sympathetic neurons
•UK incidence: ~100 children under 5/year
How is neuroblastoma treated?
•surgery and chemo/radiotherapy
•20-50 % high risk patients do not respond to therapy
•some low risk patients (Stage 4S) are cured when
the cancer cells spontaneously revert back to
neurons, suggesting a route for new therapies
Tsetse fly
infecting bite
Parasite Blood invasion
Stage I
Encephalitis/Neural Disorders
Stage II
Research into the causes of neuroblastoma
The Evans group studies mechanisms of neuronal
development, with a view to understanding how
Stage 4S neuroblastoma patients often recover
without treatment. On the right are neuroblastoma cells treated with and without an enzyme
that might turn cancer cells back into neurons.
neuroblastoma cancer cells
Our research is funded by
neuroblastoma cells treated
with an enzyme that turns
them into harmless neurons
1. Dr Darren Goffin (Biol) and his group seek
5. Dr Sean Sweeney (Biol) and his group
to understand the molecular and cellular
study an inherited neurological disease,
basis of autism spectrum disorders including
Lowe Syndrome, using fruit flies.
Rett syndrome.
6. Dr Pegine Walrad (CII/Biol), Professor
Deborah Smith (CII/Biol) and colleagues
2. Dr Fabiola Martin (CII/HYMS) and her team
investigate the often hidden virus HTLV and
study proteins of the African Sleeping
look after infected patients.
Sickness parasite in search for therapies.
3. Dr Daniel Ungar (Biol) and his group focus
7. Dr Gareth Evans (Biol) and his group seek
on glycosylation disorders that are difficult
to understand how the diseased cells of a
to diagnose as they affect many organs.
rare childhood cancer, neuroblastoma, can
be turned into healthy neurons.
4. Dr Rebecca Thomas (YTH) and her team are
interested in providing quality care for cystic
fibrosis patients, while Professor Mike
Please feel free to visit:
Brockhurst (Biol) and colleagues research
www.york.ac.uk/biology/research/
bacteria causing infections in the patients.