Download Restless Legs Syndrome

The RLS (PLM) story unfolds
David Rye, MD, PhD
Professor of Neurology
Director, Emory Healthcare Program in Sleep
[Pathology] is the only basis of positive knowledge
in medicine and one should never lose sight of it in
etiological research for fear of chasing chimeras or
creating phantoms to combat…. But, I also believe
that it is dangerous to study local conditions
exclusively and to the extent that their difference
from the causes on which they depend is lost from
view…. The necessary shortcomings of a limited
outlook is often to take the effect for the cause, or
to fall into the even greater error of considering
them as identical.
• Laennec, René-Théophile-Hyacinthe. Traité de l'Auscultation Médiate,
vols. 1,2. Paris: J.A. Brosson and J.S. Chaude; 1819, pp. 413-4 (vol. 1),
pp. 233-4 (vol. 2).
RLS
PLM
An “old South” RLS/PLMs family
Proband – RLS with PLMs + lifelong unrefreshing sleep
25
20
PLMi
15
Baseline
10
*
5
Medicated
1 7
* = missed dinnertime dose
0
1
2
3
4
5
6
7
8
Asymptomatic
Sister – lifelong unrefreshing sleep
25
20
15
10
Asymptomatic
5
0
1
2
3
4
5
Night #
6
7
8
Mean Percentage of Nights with
PLMI Exceeding Threshold
Variability in PLMs within RLS is substantial
and an individual’s PLMi represents a robust
quantitative trait
100
90
80
70
60
50
40
30
20
10
0
PLMI >= 5
PLMI >= 10
PLMI >= 15
1
2
3
4
5
6
7
Number of Nights Examined
Trotti, Bliwise et al., Sleep Medicine (in press)
8
9
10
PLMs are a common ‘forme fruste’ of RLS
• 10.6% of the family members of our 514
Icelandic ‘ probands’ exhibited a maximum
PLMi > 10/hour in the absence of sensory
complaints
• Recognized by others:
•
•
•
•
•
•
Walters et al., Arch Neurol 1990;47:1219-20.
Walters et al., Sleep 1996;19:825-26.
Allen and Earley, Sleep 1996;19:205-13.
Lazzarini et al., Mov Disord 1999;14:111-6.
Santamaria et al., Sleep Med 2003;4:153-55.
Bonati et al., Brain 2003;126:1485-92.
Four gene variants account for > 80% of the
population attritubable risk for RLS
SNPs associating to RLS are intimately
related to disease biology:
• Multiple SNPs in the BTBD9 and Meis1
genes are related in a dose dependent
fashion to PLMs
• Multiple SNPs in the BTBD9 gene are
related in a dose dependent fashion to
low iron stores
• At-risk SNP frequencies in disparate
ethnic groups mirror the large range of
ethnic differences in RLS prevalence
RLS gene variants are related to PLMs
in a dose-dependent manner
H Stefansson, H Petursson and DB Rye et. al., submitted
BTBD9 genotypes predict
lower ferritin
SNPs in BTBD9, Meis1, MAP2K5
bear NO relationship to age of
onset or RLS rating scales
Age of Onset
RLS severity – IRRLSSG Rating Scale
Periodic limb movements during sleep: population prevalence,
clinical correlates, and racial differences.
Scofield H, Roth T, Drake C (Sleep. 2008 Sep 1;31(9):1221-7)
This ethnic difference in PLMi has a
parsimonious explanation
• African-American RLS
Genotype frequencies:
• Caucasian RLS
Genotype frequencies:
Meis1
rs12469063 = 0.058
0.286 (vs. controls 0.21)
BTBD9
rs3923809 = 0.777
0.762 (vs. controls 0.68)
Putting this into perspective:
• A PAR of 0.5 for BTBD9 implies that it is
causative in 50% of RLS cases – this is a level
unprecedented for a common disease.
• The genetic contribution of BTBD9 to RLS
approximates that of the ApoE4 allele
association to Alzheimer’s disease.
• The results are extremely credible – the gene
variants and their effect sizes are similar in 5
different populations in which RLS was
diagnosed by 3 different groups.
As all
mammals are
not the same:
All RLS is not
created equal
• Disease nosologies are human constructs
informed by physician experience, clinical
expediency, and regulatory agencies, but are
most often lack a complete understanding of the
biology of the disease.
• The RLS story provides the best example to date
of how discovery of sequence variants can
influence the way in which we detect a common
disease trait and subsequently monitor it.
• To disregard PLMs in favor of a clinical diagnosis
of RLS incorrectly presumes that changes in brain
function reflective of genetic variants must always
have a relevant verbal complaint.
• RLS is a complex, polygenic disease
(heterogeneity should be expected – time to forgo
lumping for splitting?)
• Multiple genes = Multiple phenotypes? (i.e., all
RLS is not created equal)
• What to split by? – Genotypes (of course)
PLMs is an endophenotype of RLS that bypasses
imprecision of clinical diagnoses
PLMs are critical to traditional epidemiological
investigations (commonly seen to predate RLS or
remain ‘asymptomatic’)
PLMi vs. periodicity vs. COV vs. diurnal
preference vs. intensity (e.g., amplitude)
Advancing RLS Science – one potential way forward:
• Genotype-phenotype correlations including individuals
who harbor copy number variants (CNVs).
• Identify putative molecular networks through which
RLS genes act by gene expression profiling of blood
harboring systematic variations of RLS risk genotypes.
• Test and refine these networks employing standard
cell biological approaches.
• Establish etiologically valid RLS models in animals
(mice, flies, zebrafish, and worms) to derive
mechanistic understanding of additional pathway
components.
• PTPRD (protein tyrosine phosphatase receptor
type delta) functions in the guidance and
termination of mammalian motor neuron axons
(Uetani, Chagnon et al. 2006), and its
expression is dampened in a dose-dependent
fashion by estradiol (Naciff, Overmann et al.
2003).
• Copy Number Variant – small deletion exon 3 –
IRLSSG rating scale
= 37 of 40
PLM index (single leg, 5 nights) = 25/hr
Acknowledgements
Emory Program in Sleep
Dr. Donald Bliwise
Dr. Michael Decker
Dr. Alex Iranzo
Dr. Jeffrey Durmer
Dr. Lynn-Marie Trotti
Dr. Lisa Billars
Dr. Reddiah Mumanenni
Dr. Glenda Keating
Dr. Amanda Freeman
Dr. Tom Genetta
J Max Beck
Dr. Gillian Hue
Daniel Miller
Kaniyika Freeman
Emory Dept. of Physiology
deCODE Genetics
Dr. Shawn Hochman
Dr. Hreinn Stefansson
Dr. KristleifurKristjansson
Emory Dept. of Genetics
Dr. Andrew Hicks
Dr. Steve Warren Dr. Larus Gudmundsson
Dr. Mark Bouzyk
Ingibjorg Eiriksdottir, RN
Dr. Jeffrey Gulcher
Dr. Kari Stefansson
Emory Dept. of Neurology
Dr. Allan Levey
Landspitali
Dr. Salina Waddy
Ami Rosen
Dr. Thordur Sigmundsson
CRIN Staff
Dr. Albert Pal Sigdursson
Emory School of Public Health
Dr. Harland Austin
Funding
RLS Foundation
Arthur L. Williams Jr.
Foundation
Woodruff Health
Sciences