The effect of fibrate therapy in two patients with neutral lipid storage disease with myopathy (NLSDM).

NLSDM is a disease caused by a defect in the PNPLA2 gene encoding ATGL.
Patients with NLSDM accumulate triglycerides and exhibit muscle weakness,
cardiac failure and hepatosteatosis. Most of these patients die at young age
due to cardiac failure. Not much is known about the underlying mechanisms,
though recently it was discovered that PPAR activation in ATGL-/- mice was
impaired leading to decreased mitochondrial function, lipid accumulation and
cardiac failure resulting in death at young age. Activation of PPARs, by
treatment with fibrates rescued the phenotype and reduced mortality rates in
these mice. These findings may have a major impact for patients with NLSDM if
these results can be translated to humans.

We would like to evaluate the beneficial effects of fibrate treatment on muscle
mitochondrial and cardiac function in patients with NLSDM.

Patients will be treated with fibrates during a period of 28 weeks. Baseline
measurements will be performed prior to the study and after 12 and 28 weeks of
treatment. Cardiac and muscular lipid accumulation, cardiac function,
mitochondrial function and insulin sensitivity will be assessed during these
baseline measurements.
Besides these patients, also healthy control subjects will be included in this
study. They will not recieve treatment but will only perform the baseline
measurements in order to estimate the size of the effect of the treatment of
the NLSDM patients.

Patients will receive a dosage of 400mg Bezafibrate every day during 28 weeks.
Control subjects will not be treated.

For all subjects:
They will come to Maastricht for baseline measurements such as a Bodpod
measurement, a series of MRI/MRS scans, a clamp and a biopsy.

For the NLSDM patients:
After baseline measurements, patients will receive treatment by an
endocrinologist at the Azm (dr. B. Havekes) and after 12 and 24 weeks of
treatment the measurements will be repeated. The patients will eventually visit
the department 15 times (day 1 screening, day 7 Bodpod, muscle strength/grip
test, ultrasound and MRS; day 8 and MRS, clamp and biopsy; 9x check-up during
intervention period, and after 12 and 28 weeks the measurements of day 7 and 8
will be repeated) during the 28 week study period. During these visits 3
hyperinsulinemic-euglycemic clamps, including 3 muscle biopsies, will be
performed and 6 MRS-sessions will take place.

Control subjects will only visit the MUMC for baseline measurements and thus
will undergo the clamp, biopsy and 2 MRI sessions only once.