Determination of presymptomatic disease features in Spinocerebellar Ataxia type 6 (SCA6) patients

Spinocerebellar Ataxia type 6 (SCA6) is one of the dominant hereditary ataxias.
In this disease onset is defined as the moment permanent ataxia manifests
itself. However, early features in this disease, named the pre-symptomatic
features, are often present prior to the onset of permanent ataxia and question
whether the criteria used for onset of the disease are correct.
SCA6 is a hereditary disease that manifests during aging, averaging at 50 years
of age. The genetical defect however, is already present at birth. The cause of
this delay in onset is still unclear. SCA6 is caused by a polyglutamine repeat
in a subunit of a voltage gated calciumchannel that is located in the
Purkinjecells. This faulty subunit causes the channels to disfunction and this
eventually leads to cell loss in the cerebellum. In later stages of the disease
there is marked atrophy of the cerebellum on MRI.
During motor performance, motor learning and motor control the cerebellum is
heavily involved in adjusting movements. In cerebellar ataxia patients these
performances are disturbed and we use behavioral tests to detect cerebellar
dysfunction.

SCA6 patients, who carry the disease mutation, but do not express any permanent
symptoms yet, are called presymptomatic patients. These individuals offer an
opportunity to study presymptomatic manifestations of cerebellar disease that
might not be clinically apparent, but could be measurable before permanent
symptoms of ataxia appear.
We already examine the motor performance and motor learning behaviors in
symptomatic SCA6 patients. In this study we will yearly examine pre-symptomatic
patients to detect the transition from the pre-symptomatic stage towards SCA6.
It is important to detect early signs if disease modulating compounds become
available. Treatment may be most efficient when introduced in the earliest
stage of disease but is not recommended before disease onset considering the
side effects. Therefore, recognition of pre-symptomatic features is valuable
and can be a promising approach.

We aim to determine onset of SCA6 disease more accurate then with the clinical
scores and questionnaires that are currently used.
We will study motor performance, motor learning behavior, PPI and MRI scans in
pre-symptomatic SCA6 patients and compare these results to controls. The main
objective is to find early pre-symptomatic disease features that can predict
onset of disease more accurately than clinical assessment.
By following the presymptomatic patients in their transition towards
symptomatic disease we also hope to elucidate SCA6 performance.
Last, we will examine correlations between CAG repeat length and early
symptoms, impaired delay eyeblink conditioning and PPI. This will be done by
making a comparison between results in presymptomatic patients and in healthy
controls.

All patients and control subjects will be examined yearly during a ten years
follow-up case-control study.

There are no risks associated with participation.
Subjects will not have a direct benefit of joining this study. This is why we
strive to make the burden as low as possible. They will only be asked to come
in for testing once a year and will undergo an MRI once every 3 years. If
necessary we can visit people at their homes with our mobile testing unit (the
NeurasBus) to ensure proper follow-up.