Prof. dr. L.H. van den Berg
ZonMw
The Netherlands
Amyotrophic lateral sclerosis: disease or syndrome?
ZonMw
1,500,000
16/06/12
5.0
Motor neurone diseases
amyotrophic lateral sclerosis | motor neuron disease | genetics | neuroimaging | heterogeneity
Amyotrophic Lateral Sclerosis is usually described as a progressive disorder of upper- and lower
motor neurons leading to muscle weakness and death due to respiratory failure on average 3 years
after the onset of symptoms. In clinical practice, however, we experience a large variability in the
clinical expression of the disease. An important gap in our knowledge of ALS pathophysiology is
whether motor neurons in ALS die from a complex interaction between multiple factors or from the
manifestation of a unique cause. In other words, is ALS one disease or just a phenotype of a large
number of diseases with many causes? Filling this gap in knowledge may have important
consequences for molecular diagnostic and therapeutic strategies in ALS and possibly other
complex/neurodegenerative diseases. My working hypothesis is that ALS should be considered either
as a collection of single, unique rare diseases or a diagnostic continuum in which ALS can be subclassified
according to the relative contribution of genetic, environmental/lifestyle and phenotypic
factors. I propose to establish the largest population-based case-control study of >2500 incident ALS
patients and >5000 controls to determine phenotypic variability, genetic/environmental/lifestyle
susceptibility and disease-modifying factors. I plan to discover additional ALS associated genes by
applying (1) whole genome sequencing techniques in genetically unexplained familial ALS patients,
and (2) a novel study design that, using imputation approaches, can then take advantage of discovered
variants from whole genome sequence data from a subset of ALS patients, to infer untyped rare
variants in the in my laboratory available datasets from previous GWAS. By using sophisticated
exploratory cluster techniques, where multiple data modalities (phenotypic, neuroimaging,
environmental/lifestyle, genetic) serve as input, subgroups will be identified. The results of this VICI
research line may yield new insights in pathways underlying ALS and give leads for improved
treatment of patients suffering from ALS.