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The phenotypic spectrum of neutral lipid storage myopathy due to mutations in the PNPLA2 gene

Lookup NU author(s): Professor Rita HorvathORCiD, Emeritus Professor Doug Turnbull, Professor Mike TrenellORCiD, Dr Kieren Hollingsworth, Professor Grainne Gorman, Professor Hanns Lochmuller


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Neutral lipid storage disease is caused by mutations in the CGI-58 or the PNPLA2 genes. Lipid storage can be detected in various cell types including blood granulocytes. While CGI-58 mutations are associated with Chanarin-Dorfman syndrome, a condition characterized by lipid storage and skin involvement (ichthyosis), mutations in the patatin-like phospholipase domain-containing protein 2 gene (PNPLA2) were reported with skeletal and cardiac muscle disease only. We describe clinical, myopathological, magnetic resonance imaging (MRI), and genetic findings of six patients carrying different recessive PNPLA2 mutations. Pulse-chase labeling of control and patient cells with supplementation of clenbuterol, salmeterol, and dexamethasone was performed in vitro. The patients share a recognizable phenotype with prominent shoulder girdle weakness and mild pelvic girdle and distal muscle weakness, with highly elevated creatine kinase (CK) and cardiomyopathy developing at later stages. Muscle histology invariably reveals massive accumulation of lipid droplets. New muscle or whole-body MRI techniques may assist diagnosis and may become a useful tool to quantify intramuscular lipid storage. Four novel and two previously reported mutations were detected, affecting different parts of the PNPLA2 gene. Activation of hormone-sensitive lipase by beta-adrenergic substances such as clenbuterol appears to bypass the enzymatic block in PNPLA2-deficient patient cells in vitro. PNPLA2 deficiency is a slowly progressive myopathy with onset around the third decade. Cardiac involvement is relatively common at a later stage. Muscle MRI may detect increased lipid in a characteristic distribution, which could be used for monitoring disease progression. Beta-adrenergic agents may be beneficial in improving triacylglycerol breakdown in patients with PNPLA2 mutations.

Publication metadata

Author(s): Reilich P, Horvath R, Krause S, Schramm N, Turnbull DM, Trenell M, Hollingsworth KG, Gorman GS, Hans VH, Reimann J, MacMillan A, Turner L, Schollen A, Witte G, Czermin B, Holinski-Feder E, Walter MC, Schoser B, Lochmuller H

Publication type: Article

Publication status: Published

Journal: Journal of Neurology

Year: 2011

Volume: 258

Issue: 11

Pages: 1987-1997

Print publication date: 01/11/2011

ISSN (print): 0340-5354

ISSN (electronic): 1432-1459

Publisher: Springer Medizin


DOI: 10.1007/s00415-011-6055-4


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Funder referenceFunder name
TP11BMBF, Bonn, Germany
Medical Research Council Translational Neuromuscular Centre
01GM0601German Ministry of Education and Research (BMBF, Bonn, Germany)
BH090164Academy of Medical Sciences, UK
G1000848Medical Research Council, UK