Insights into successful Research in
Rare Diseases
Work by the Irish Motor Neurone Disease
Research Group
Orla Hardiman BSc MD FRCPI
HRB Clinician Scientist
Trinity College & Beaumont Hospital Dublin

What is a Rare Disease?
• “Life-threatening or chronically debilitating diseases which are of such low prevalence
(fewer than 1 in 2,000) that special combined efforts are needed to address them.“
European Commission on Public Health

Problems with Studying Rare
Disease
• They are rare!
• Knowledge deficit
– Delayed diagnosis
– Low quality of care
• Limited access to new drugs.
– Cost of drug development
– Cost of post-approval drugs

Solutions
• Population based Registers
• Centralized care
• Orphan drug legislation
• Advocacy

Clinical Research in Rare Diseases
• Applied epidemiology
– Databases and Registers
• Good clinical monitoring with attention to detail
• Determination of relevant clinical questions
• Phenotype genotype correlations
• Biomarkers

Advantages of Population Based
Registers
• More accurate reflection of range of disease phenotypes
• Nobody is “lost to follow-up”
• Captures patients that might not attend specialist clinic
– Too old
– Too sick
– Too poor

Imperatives for Valid and
Clinically Relevant Study
• Prospective study of incident cases
• Adequate sources
• “Capture recapture” methodology
• Standardisation of population demography
• Large numbers over sufficiently long follow up period
• Attention to clinical detail

Motor Neuron Disease
• Commonest neurodegeneration of young and middle aged adults
• Incidence 2.6/100,000
• Prevalence: 1in 16,000
• Lifetime risk 1:400
• Unknown aetiology
• 10% familial
• Fatal within 3-5 years
• No cure
Lou Gehrig
1903 - 1941

Irish Register of Motor Neurone
Disease
• Commenced in 1993
• Ascertainment complete by 1995
• First epidemiologic data analysed for 1995-
1997; Second 2005-2007
• Data collection ongoing: >1400 patients enrolled to date

Experiences of the Irish Register over 15 years
• Basic epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other population

WORLD EPIDEMIOLOGY
OF ALS/MND

Population Based Incidence of
ALS/MND
12
10
8
6
4
2
0
Ireland Scotland Tx.,USA Wa.,USA Mn.,USA Denmark Israel Finland Sardinia On,
Canada
Sweden N.
Sweden
Traynor et al, 1999
True incidence and prevalence outside predominantly
Caucasian populations not widely known

IRISH MND

Experiences of the Irish Register over 15 years
• Basic epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other populations

Age related Incidence Rates of ALS
1997-2004
12.0
10.0
8.0
6.0
male limb male Bulbar
Female Limb female bulbar
4.0
2.0
0.0
0-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+
Age group (years)

SURVIVAL FROM MND

Survival Effect of Multidisciplinary
Clinics
.6
.4
1
.8
.2
0
0 .5
1 1.5
2 2.5
3 3.5
4 4.5
Time from diagnosis (years)
Cum. Survival (general) n = 258 pts.
Cum. Survival (multidisciplinary) n = 108 pts.

Survival
Republic of Ireland v Northern Ireland

Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparision with other populations

Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other populations

Longitudinal Follow up

Older, Aggressive
Disease
Early Executive involvement
With time they develop
Younger, Higher education and FSIQ
Slow motor progression
Small proportion develop abnormalities: mostly language or verbal fluency deficits language/memory/VP
FTD
Early memory and language difficulties
± subtle executive changes
More Benign course initially
High rate of developing executive dysfunction

Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Genetics
• Comparison with other populations

FINDING FAMILIES
Manifestation definitions :
Amyotropic Lateral Sclerosis
Fronto Temperol Demetia
Pneumonia
Stroke
Congenital Cardiac Failure (CCF)
Depression
TB

Finding Genes
16 causative genes known, accounting for ~15% of all MND

Separating the Population by
Causative Genes
Lancet Neurology 2012

Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Population Genetics
• Comparison with other populations

Looking for Susceptibility Genes
Genes of small effect that may contribute to risk

Population Structure Within Europe
(Novembre et al Nature 456 ; 6 , 2008)

IRISH POPULATION ALSO DEMONSTRATES
GENETIC SUBSTRUCTURE :
Comparison With Dutch & US populations
Simon Cronin PhD Thesis

Irish Population is Relatively
Homogeneous
• Modern Ireland is derived from a restricted founding population with a higher degree of relatedness

Angiogenin Mutations Are Associated with ALS
Nature Genetics 2006 38:4:411-12

Uses of the Irish Register of ALS
• Comparative epidemiology
• Long term follow up of population
• Accurate recording of clinical details
• Identification of defined clinical subtypes
• Complex Genetics
• Comparison with other populations

EURALS
(N= 25 million)

Lombardia
Puglia
194
130
265
Piemonte
Scotland
231
154
54
Ireland
Lancashire
N=1028

DRUG TRIALS

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
• Informs health services
• Facilitates international collaborations
• Provides well characterized populations for clinical trials

Research Team and Collaborators
•
Clinical Epidemiology & Neuropsychology
– Dr.Marwa Elamin (Beaumont & TCD)
–
Dr.Niall Pender (Beaumont &TCD)
–
Ms.Catherie Lynch (Beaumont)
– Dr.Peter Bede (Beaumont & TCD)
– Dr.Susan Byrne (Beaumont &TCD)
– Dr.Colin Doherty (St.James & TCD)
Cuban Collaborators
Dr.Tatiana Zaldivar
Dr.Joel Gutierrez
Dr. Gloria Lara
Dr.Diana Garcia del Barco
–
Dr.Giancarlo Logroscino
– EURALS Steering Group (Europe)
Previous Research Fellows
Dr.Bryan J Traynor (NIH)
Dr.Mike Alexander (LONDON /DUBLIN)
Dr.Orna O’Toole (DUBLIN / NEW YORK)
Dr.Matthew Greenway (TORONTO)
Dr.Julie Phukan (LONDON)
Genetics
, Prof.Dan Bradley (TCD)
Mr.Russell McLaughlin (TCD)
Mr.Kevin Kenna (TCD)
Prof.Leonard Van Den Berg (Utrecht)
Prof.Angnieska Slowik (Krakow)
Prof.RH Brown Jr. (MGH Boston)
Prof.Peter Andersen (Umea, Sweden)

FUNDING SOURCES
• Health Research Board
• Irish Motor Neurone
Disease Research
Foundation
• Irish Motor Neurone
Disease Association
• Irish Institute of Clinical
Neuroscience
• Muscular Dystrophy
Association USA
• American ALS Association

FURTHER INFORMATION
RESEARCH MOTOR NEURONE www.mnd.ie