Phenotyping and Exploring biomarkers in Asymptomatic Relatives of aLS variants

Genotype-specific therapies for Amyotrophic Lateral Sclerosis (ALS) are
approaching quick, with Tofersen for SOD1-ALS already being in use. However,
there is often a delay from symptom onset till diagnosis of one year and these
compounds take up to another year before therapeutic effect becomes visible,
while survival from symptom onset is in certain genotypes only 2 years (e.g.
FUS-ALS). As such, early detection of disease onset, is crucial in order to
reduce invalidity and mortality.

The primary objective is to identify early signs of disease onset in
asymptomatic carriers of ALS-related mutations. This will allow them to
initiate treatment or partake in clinical trials in an early stage of
morbidity.

Secondary Objectives are:
- To test the validity and utility of promising biomarkers that predict the
onset of the disease process, that carry prognostic value and/or facilitate the
diagnosis.
- To map the natural course of disease from asymptomatic stage till further in
the disease.
- To identify phenotypical differences related to carriership.
The biobank objectives is to collect urine and CSF of 200 individuals of
aforementioned population in a recurrent longitudinal manner.

Combined multimodal longitudinal cohort study (WMO) and Biobank

The benefit for the pre-symptomatic participants is that they are regularly
seen by a physician and symptoms or (biochemical) signs of disease onset are
detected early in the disease course. This allows these so called
phenoconverters to either receive treatment early on or take part in trials
with investigational medical compounds.
Visits are scheduled to take place once a year, whereby most participants are
expected to also take part in other ALS-related studies where they are seen by
a physician. If not, then according to participant preference, more frequent
visits aretwo visits per year are possible.
Ultrasound is a procedure that generally does not cause discomfort. Lumbar
punction is a safe procedure to collect CSF, although for some patients an
unpleasant experience, hence this is also optional and will only be performed
once a year. All genotype-specific treatments for ALS, both proven and under
investigation, are being dosed intrathecal, i.e. by performing lumbar punction.
Both in clinic and in clinical trials our experience is that patients cope with
this procedure well. Eye movement tracking happens with a device placed on the
head of the subject for a couple of minutes and causes no discomfort. VR-tasks
are in general being regarded quite entertaining by subjects.