RARE NEUROLOGICAL CONDITIONS IN IRELAND:

SUPPORTING RESEARCH AND PRACTICE

Orla Hardiman BSc MD FRCPI MRIAProfessor of Neurology

Academic Director, Trinity Biomedical Sciences InstituteTrinity College Dublin

Challenges for Service Development of Rare Disease

• Rare Diseases are heterogeneous

– Few clinical aspects in common other than the fact that they are rare

– Span all age ranges & all disciplines

– Differing needs

Challenges for Service Development of Rare Disease

• Many conditions are under-reported-

– no population based database for most conditions

– Clinical initiatives driven by strong advocates

• some groups lose out

– No built in mechanism for sustainable care

Consequences of Inadequate Services

• Knowledge deficit

– Delayed diagnosis

– Low quality of care

• Limited access to new drugs

• Poorer outcomes

Solutions

• Population based databases

• Centralized services with “hub & spoke” model using existing resources

• Embedding research into clinical care

Solutions

• Population based databases

• Centralized services with “hub & spoke” model using existing resources

• Embedding research into clinical care

Population Based Datasets

• Inclusive

• Nobody is lost to follow up

• Allows accurate mapping of disease

• Improves outcomes

• Permit inclusion in clinical trials of novel agents

Unique Advantages of Population Based Patient Registers

• Registers collect details of everybody in the country with a specific condition

• Most accurate reflection of range of disease types in a population

• Nobody is “lost to follow-up”

• Captures patients that might not attend specialist clinic

– Too old

– Too sick

– Too poor

ALS/MND Register 2015

• Longest running ALS/MND Register in the world

– >2000 cases identified over 21 years

• 110 new cases every year

• 300 living with ALS/MND

• DNA bank containing >1000 samples from patients

and >1000 controls

ALS risk map of Ireland at small area (SA) geometry

Rooney et al, Neurology, 2014

PROGNOSTIC INDICATORS

Age of

onset

Cognitive &

behavioural

status

Site of onset

Rate of

progression

Genetic

background

Elamin et al., J Neurol 2015

Solutions

• Population based databases

• Centralized services with “hub & spoke” model using existing resources

• Embedding research into clinical care

Multidisciplinary Clinics Improve Use of Hospital Services & Reduce Length of Stay

• Lower number of hospital admissions

• 50% reduction in mean length of hospital stay

• 75% Planned (non-emergency) hospitalisations

Chio et al, JNNP, 2006

Multidisciplinary Clinics are Good Value for Money

Van der Steen et al, ALS

Journal 2009

MULTIDISCIPLINARY /SPECIALIST CLINICS IMPROVE OUTCOME

PATIENT JOURNEY TO THE MDC

First Symptom to Attendance at a Multidisciplinary Clinic for Rare

Disease

Galvin el al BMC Health Serv Res 2015

Solutions

• Population based databases

• Centralized services with “hub & spoke” model using existing resources

• Embedding research into clinical care

RESEARCH INTO RARE DISEASES…..

• Permits complete population based incidence & prevalence studies

• Identifies prognostic indicators

• Identifies subpopulation that can help to find new genes/ susceptibility factors

RESEARCH INTO RARE DISEASES…..

• Informs health services

• Facilitates international collaborations

• Provides well characterized populations for clinical trials

MANY RARE NEUROLOGICAL DISEASE HAVE A GENETIC BASIS

POPULATION GENETICS

• Different populations may have different disease susceptibilities

• Finding genes help us understand biological pathways that cause /protect against diseases

• Finding and understanding pathways help develop new drugs

IRISH ALS/MND GENOMICS

• 1000 GWAS from ALS/MND patients

• 700 GWAS from matched controls

• 750 Whole Genome Sequencing ALS/MND

• 350 Whole Genome Sequencing Controls

• Access to 16000 ALS And 7000 Control WGS

GWAS CAN SEPARATE IRISH POPULATION FROM

ENGLISH

MAPPING THE POPULATION STRUCTURE OF IRELAND USING GWAS

INTERNATIONAL GWAS CONSORTIUM

NOVEL DISCOVERIES USING IRISH ALS/MND GENOMICS DATA

ALS AND SCHIZOPHRENIA SHARE COMMON SUSCEPTIBILITY GENES

McLaughlin et al, Unpublished

MAPPING THE POPULATION STRUCTURE OF IRELAND USING GWAS

RECONSTRUCTING FAMILIES:Identity-by-descent

“SUPERFAMILIES”

INTERNATIONAL GENE SEQUENCING PROJECT

• 13 countries, 22500 genomes!

INTEGRATING RESEARCH THEMES

PRECISION MEDICINE

Precision Medicine refers to the tailoring of medical treatment to the

individual characteristics of each patient…

..It relates to the ability to classify individuals into subpopulations

that differ in their susceptibility to a particular disease, in the

biology and/or prognosis of those diseases they may develop, or in

their response to a specific treatment.

POPULATION BASED DISEASE REGISTER

NEW DRUGS & BETTER TRIALS

TeamClinicalBernie Corr

Ger Foley

Deirdre Murray

Lesley Doyle

Niamh Daly

Kitty McElligott

Imaging & EEGDr.Ed Lalor

Dr.Peter Bede

Dr.Bahman Nasseroleslami

Dr.Parames Iyer

Christina Schuster

Kieran Mohr

Michael Burke

Laboratory/NeuropharmDr. Julie Kelly

Dr. Alice Vajda

Gill Slator

NeuropsychologyDr.Niall Pender

Dr.Marwa Elamin

Tom Burke

Marta Pinto

Katy Lonnergan

EpidemiologyProf.Anthony Staines (DCU)

Dr. James Rooney

Mark Heverin (Register)

Caoife Madden

Genetics Prof Dan BradleyDr.Russell McLaughlinDr. Kevin Kenna

Academic NeurologyDominique Plant

Health ServicesProf.Anthony StainesProf.Charles Normand Dr. Miriam GalvinDr.Shelagh ConnollyDr.Katy TobinDr.Padraig RyanDr.Sinead Maguire Rebecca GaffneyIain MaysBrighid Gavin

EMG & BiomarkersDr.Ger Mullins

Dr.Taha Omar

Clinical TrialsLiz FogartyDr.Sam Bouazzaoui

Dr.Sinéad Maguire

Research ManagersDr.Alice VajdaMark Heverin

International Collaborators

• European Network for the Cure of ALS– EMPOWER

– SOPHIA

– ALSCarE

– STRENGTH

• University of Utrecht

• Royal Victoria Hospital, Belfast

• Kings College London

• University of Edinburgh

• Massachusetts General Hospital

• University of Massachusetts

• Institute of Neurology, Havana

RESEARCH FUNDING