Next generation phenotyping in essential tremor

Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body
part. Essential tremor is the most common movement disorder in adults (1), and
is considered to be a highly heritable disorder. Estimates for the proportion
of essential tremor patients with a positive family history range from 20% to
90%. It is largely unknown, however, to what extend family members share
overlapping features like demographical (e.g. age at onset), clinical (e.g.
tremor/body distribution) and neurophysiological (e.g. tremor frequency)
characteristics.

Knowledge about familial aggregation of essential tremor features is relevant
for patient counseling. Clinicians often care for patients who have several
affected family members, as well as younger, at-risk relatives, most
importantly children and grandchildren. For these patients, it would be
informative to know whether the features in their family members can help
predict their own disease course, as essential tremor can have a serious impact
on patients* personal and professional lives.

Moreover, information on the familial aggregation of features in essential
tremor would be relevant scientifically, particularly in the field of genetics.
In recent years, the search for disease-related genes has intensified greatly,
by means of all recent technological developments (linkage analysis, whole
exome sequencing and genome-wide association studies) (2), but essential tremor
genetics still awaits a breakthrough discovery that will improve the
understanding of this disorder. A key issue is that the essential tremor
syndrome transpires to be a family of diseases rather than a single disease
entity (1). The suggested way forward is to increase focus on phenotyping and
phenotype-genotype association (2): the Internal Parkinson and Movement
Disorders Society*s tremor task force especially chose a classification scheme
that promotes detailed phenotyping in their 2018 Consensus Statement (3), to
facilitate the discovery of specific (genetic) etiologies.

We have recently written a review in which the evidence in the literature for
familial aggregation of various features in essential tremor is evaluated, and
we established that alcohol responsivity and neurophysiological features have
been studied poorly or not at all (4).
It is a well-known fact that approximately half the patients with essential
tremor report a positive effect of alcohol on their tremor. In the only
available study (5), responsiveness was either consistently present or absent
in 80% of the families, while in 20% the self-reported effect of alcohol was
heterogenic. Familial aggregation was made likely, but only descriptive
statistics were employed. Moreover, only self-reported alcohol responsivity was
assessed, while the correlation between self-reported and actual responsivity
(assessed with a validated test (6)) is known to be limited (7). Based on the
study described above, it is our hypothesis that alcohol responsivity runs in
essential tremor families.
Clinical neurophysiological tests can help a neurologist to establish a
diagnosis. Polymyography (poly-EMG), combined with accelerometry, registers the
tremor frequency and amplitude in different postures, movements and during the
performance of different tasks. Polymyography can objectify tremor
characteristics (e.g. frequency, frequency variability, etc.), making it a
valuable tool for tremor differentiation (8). Whether neurophysiological
features aggregate in essential tremor families has never been studied, but may
be helpful in defining familial phenotypes, which may ultimately prove useful
to establish genotypes.

Next, we will try to establish a familial essential tremor phenotype-subtype
within our population, based on clustering of heritable/familial disease
features including alcohol responsivity and neurophysiological features. This
information can be incorporated in our project Next Generation Sequencing in
Movement Disorders (METC-2014/119), in which patients with heritable essential
tremor are investigated genetically.
This extensive phenotyping can be used to capture the phenotype in essential
tremor families precisely. Ultimately, this will clear the path for
phenotype-genotype association and the discoveries of new genes.

Primary Objective:
To determine different familial features (demographical, clinical,
neurophysiological) in essential tremor families and subsequently clustering
these features into subtypes of familial essential tremor.

Secondary Objective(s):
To establish whether neurophysiological features run in essential tremor
families.
To establish whether alcohol responsivity is a familial feature in essential
tremor.

This is a cross-sectional study that consists of two parts: an observation and
an intervention part. In part A, participants are assessed clinically (using
history taking and neurological examination) and neurophysiologically (using
EMG, accelerometry and video-recording). In part B, participants perform a
validated test for alcohol responsivity. Both of these parts are relevant to
phenotyping of the patients.
Part A is performed during a single visit to the UMCG, or to a rented external
location. Both parts have a duration of 1-2 hours. The duration of the study is
equal to the duration of the inclusion of patients, as there is no follow-up.
We aim to include the required number of subjects within 3 years.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: There are no issues of concern applicable for
the individual patient. Regarding part A of this study, the potential risk for
the subjects is considered to be negligible because no invasive apparatuses are
used and the tasks that are included in the study are not burdensome. A
one-time visit to the UMCG has to be made, or to an external location rented by
the UMCG. There an interview, extensive neurological exam and a poly-EMG will
be conducted.
Participants of part B of this study, where alcohol responsivity in essential
tremor families is studied, takes place at the UMCG (or externally rented
location) as well. The investigator will assess whether the patient is suitable
to participate, based on a questionnaire. The risk associated with
participation in this part of the study is considered minimal, because the
reached blood alcohol concentration is low (0.6%), the majority of participants
will have experience with drinking this amount of alcohol, and because safety
instructions are in place. The burden can be considered as acceptable, it is
possible that participants experience a short-term rebound effect of their
tremor the morning after the alcohol intake.