Clinical inventaristation and identification of (modifier) disease genes for movement disorders using next generation sequencing

Movement disorders (MD) are often progressive dominantly or recessively
inherited disorders that affect specific areas of the brain leading to
dysfynction of motor coordination, gait, and/or muscle contractions. This work
focuses mainly on the (spino-) cerebellar ataxias, dystonia and, hereditary
essential tremor. These diseases are clinically and genetically heterogeneous
as to date more than 30 cerebellar ataxia, 15 dystonia genes have been
identified. Despite this large number of recognized disease genes, still more
than 40% of the patients remain genetically undiagnosed leading to insecurity
in diagnosis and prognosis for doctors and patients .

The main aims of our study are 1) to make a clinical inventory of MD cases, 2)
to identify (modifier) disease genes underlying MD and 3) to link the clinical
data with the genetic data in a data-base.

Non-therapeutic study that will lead to diagnosis that can not be made in an
alternative way and may open opportunities to treat these disorders. Patients
with a familial or sporadic form of movement disorders, who visit the patient
clinic of the Neurology Department of the UMCG, will be recruited. The number
of patients that will be included depends on some variables such as 1) the
heritable compontent (dominant of recessive) of the disorder 2) the family
structure, 3) the number of available family members. This number will thus
vary per case and can not be predicted in advance, To be able to perform the
genetic analysis the familymembers will be categorized based on their disease
status (affected or non-affected). This work focusses mainly on adults,
however, in some recessive movement disorders the disease might predispose to
clinical complaints in childhood. In these families, we are limited to the
affected childhood cases and we can not do anything else than to include them
in our study in order to elucidate the disease ethiology. Making an
ethiological diagnosis will always be in the benefit of the patiënt (adult and
child) and his or her family members by 1) possibilities to treat the disorder
or 2) improves decising making in family planning.

We will make a digital clinically inventory of all collected cases with MD, and
will perform genetic analysis of the patients and their relatives by
genome-wide genotyping, shared haplotype analysis, and next generation
sequencing such as sequencing of disease gene panels using an targeted array or
exome sequencing. In special cases, a MRI will be neccessary to (re-)confirm
the clinical diagnosis and/or to validate our genetic findings.

When we are unable to set a genetic diagnosis using DNA sequencing, we will
also use RNA sequencing as well (in cases of whom RNA material is availbale and
when the case approves) to identify the genetic cause. This layer of additional
information will increase our insight in which genetic variants alter
transcript levels are are thus more likely disease causing.

The DNA material of cases and their relative in whom we are unable to set a
genetic diagnosis ourselves can be send to internal collaborations. These
samples will be used in so-called GWAS studies or will be screened for
mutations in novel disease genes. The overall aim is to enhances our genetic
diagnosis of the patients and their relatives.

Additionally, patient-derived IPs cells will be generated from fibroblast of
cases in whom the disease gene has been identified. These cells will be used
for additional molecular and transcriptome

There are no risks associated with this study.