Spinal Muscular Atrophy, SMN protein and Genetics; A population based study on spinal muscular atrophy in the Netherlands to explore the prevalence of SMA type 1-4 and their severity in the Netherlands by registrating all patients in a so called SMA-database, to elucidate the genetic factors determining disease severity and to determine the value of SMN protein concentrations as a surrogate marker for clinical trials.

Spinal muscular atrophies (SMA) are a group of disorders characterized by
weakness caused by loss of motor neurons in the anterior horn cells of the
spinal cord, and are classified according to patterns of weakness and specific
genetic mutations. Proximal SMA is characterized by weakness of proximal muscle
groups and is caused by homozygous deletion of the survival motor neuron 1
(SMN1)-gene. Severity of SMA varies considerably, despite of the similar
SMN1gene defect. Treatment of these disorders is supportive. Improved insight
in the pathogenesis of SMA may help the development of new forms of treatment,
and the identification of surrogate markers for clinical trials. A significant
part of patients with SMA complains of (symptoms of) a limited mouth opening.
The underlying mechanism of the progressive reduced mouth opening is not known.
Investigating the natural history of SMA can help with intepreting the results
of different clinical trails. Furthermore, it aids in optimizing the care that
is provided for SMA patients.

The main objective of this prospective population-based study of patients with
proximal SMA in the Netherlands is to register SMA patients in the Netherlands
in a socalled SMA-database to study prevalence and severity of SMA types 1-4,
to perform genomic profiling studies to elucidate new (complex) molecular
pathways that determine disease severity in SMA, and to study the correlation
of SMN protein levels in leukocytes and fibroblasts and disability. New
insights in the pathofysiology of the reduced mouth opening will give
opportunities to prevent or cure the limited mouth opening. The objective ot
the study on the natural history of SMA is to document the natural course of
the disease.

A prospective, population based, cohort study with follow-up of patients over
time.

This research will be done in patients with SMA from all age groups. The burden
of participation consists of filling out a questionnaire to document disease
characteristics and disability, physical examination and venapuncture. We will
collect a total bloodvolume of 10ml to 12.5 ml in children and 22.5 ml in
adults. Bloodmaterial of 60 inlcuded patients will be used for genomic
profiling studies. A couple of patients will undergo a skinbiopsy. The risk of
undergoing a MRI of the temporo-mandibular joint will be minor. For the
substudy on the natural history of SMA, we will collect a total bloodvolume of
7-12 ml in patients. Also, through a surface EMG we will measure the CMAP
amplitudes of two small hand muscles. Only surface electrodes will be used.
Overall, the burden and risk associated with participation in the study will be
minor. The criteria of the Dutch Organisation for Pediatrics (Nederlandse
Vereniging voor Kindergeneeskunde (NVK) (= Dutch association of Paediatrics)
concerning research involving children will be strictly applied.