The Effect of Fibrate Therapy in Two Patients With Neutral Lipid Storage Disease With Myopathy (NLSDM) (NLSDM)

Neutral Lipid Storage Disease With Myopath (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. Therefore, the investigators 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 treatment. Cardiac and muscular lipid accumulation, cardiac function, mitochondrial function and insulin sensitivity will be assessed during these baseline measurements.

Study Overview

• Status: Completed
• Conditions: Neutral Lipid Storage Disease
• Intervention / Treatment: Drug: Fibrate treatment

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6200MD
      • Maastricht University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• suffering from NLSDM

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fibrate Treatment; Patients will be treated during 28 weeks with a fibrate to assess the effects of PPAR activation on the NLSDM disease.	Drug: Fibrate treatment; Patients will receive a dosage of 400mg Bezafibrate every day during 28 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mitochondrial function	mitochondrial function will be measured in vivo with 1H-MRS by pCr-recovery and ex vivo by high resolution respirometry.	28 weeks
lipid accumulation	Lipid accumulation will be measured both by 1H-MRS as CH/H2O ratio's in the Tibialis anterior muscle, as well as quantified from skeletal muscle biopsy with ORO from the vastus lateralis muscle.	28 weeks
Cardiac function	Cardiac function will be measured with ultrasound and be assessed by 2 blinded cardiologists.	28 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity	This will be assessed by an euglycemic hyperinsulenemic clamp and whole body isulin sensitivity will be expressed with the M-value.	28 weeks

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center

Publications and helpful links

General Publications

• Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A, van de Weijer T, Hesselink M, Jaeger D, Kienesberger PC, Zierler K, Schreiber R, Eichmann T, Kolb D, Kotzbeck P, Schweiger M, Kumari M, Eder S, Schoiswohl G, Wongsiriroj N, Pollak NM, Radner FP, Preiss-Landl K, Kolbe T, Rulicke T, Pieske B, Trauner M, Lass A, Zimmermann R, Hoefler G, Cinti S, Kershaw EE, Schrauwen P, Madeo F, Mayer B, Zechner R. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med. 2011 Aug 21;17(9):1076-85. doi: 10.1038/nm.2439.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: February 6, 2012
• First Posted (Estimate): February 7, 2012

Study Record Updates

• Last Update Posted (Estimate): May 14, 2013
• Last Update Submitted That Met QC Criteria: May 13, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: NLSDM; Lipid accumulation
• Additional Relevant MeSH Terms: Nervous System Diseases; Skin Diseases; Congenital Abnormalities; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Neuromuscular Diseases; Skin Diseases, Genetic; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Skin Abnormalities; Keratosis; Ichthyosis; Muscular Diseases; Metabolic Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Ichthyosiform Erythroderma, Congenital; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Clofibric Acid
• Other Study ID Numbers: MEC 11-3-013