Abstract
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.
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References
Laforet P, Vianey-Saban C (2010) Disorders of muscle lipid metabolism: diagnostic and therapeutic challenges. Neuromuscul Disord 20:693–700
Bruno C, Dimauro S (2008) Lipid storage myopathies. Curr Opin Neurol 21:601–606
Gempel K, Topaloglu H, Talim B et al (2007) The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. Brain 130:2037–2044
Olsen RK, Olpin SE, Andresen BS et al (2007) ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 130:2045–2054
Nezu J, Tamai I, Oku A et al (1999) Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21:91–94
Dorfman ML, Hershko C, Eisenberg S et al (1974) Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol 110:261–266
Srebrnik A, Tur E, Perluk C et al (1987) Dorfman–Chanarin syndrome. A case report and a review. J Am Acad Dermatol 17:801–808
Lefevre C, Jobard F, Caux F et al (2001) Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin–Dorfman syndrome. Am J Hum Genet 69:1002–1012
Chanarin I, Patel A, Slavin G et al (1975) Neutral-lipid storage disease: a new disorder of lipid metabolism. Br Med J 1:553–555
Yamaguchi T, Osumi T (2009) Chanarin–Dorfman syndrome: deficiency in CGI-58, a lipid droplet-bound coactivator of lipase. Biochim Biophys Acta 1791:519–523
Fischer J, Lefevre C, Morava E et al (2007) The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 39:28–30
Jordans GH (1953) The familial occurrence of fat containing vacuoles in the leukocytes diagnosed in two brothers suffering from dystrophia musculorum progressiva (ERB.). Acta Med Scand 145:419–423
Rozenszajn L, Klajman A, Yaffe D et al (1966) Jordans’ anomaly in white blood cells. Report of case. Blood 28:258–265
Lass A, Zimmermann R, Haemmerle G et al (2006) Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin–Dorfman Syndrome. Cell Metab 3:309–319
Zimmermann R, Strauss JG, Haemmerle G et al (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306:1383–1386
Jenkins CM, Mancuso DJ, Yan W et al (2004) Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem 279:48968–48975
Schweiger M, Schreiber R, Haemmerle G et al (2006) Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem 281:40236–44024
Ohkuma A, Nonaka I, Malicdan MC et al (2008) Distal lipid storage myopathy due to PNPLA2 mutation. Neuromuscul Disord 18:671–674
Schweiger M, Lass A, Zimmermann R et al (2009) Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. Am J Physiol Endocrinol Metab 297:E289–E296
Hirano K, Ikeda Y, Zaima N et al (2008) Triglyceride deposit cardiomyovasculopathy. N Engl J Med 359:2396–2398
Schroder JM, Hoheneck M, Weis J et al (1985) Ethylene oxide polyneuropathy: clinical follow-up study with morphometric and electron microscopic findings in a sural nerve biopsy. J Neurol 232:83–90
Weis J, Schroder JM (1988) Adult polyglucosan body myopathy with subclinical peripheral neuropathy: case report and review of diseases associated with polyglucosan body accumulation. Clin Neuropathol 7:271–279
Weis J, Kaussen M, Calvo S et al (2000) Denervation induces a rapid nuclear accumulation of MRF4 in mature myofibers. Dev Dyn 218:438–451
Weis J, Schroder JM (1989) Differential effects of nerve, muscle, and fat tissue on regenerating nerve fibers in vivo. Muscle Nerve 12:723–734
Fischer JC, Ruitenbeek W, Gabreels FJ et al (1986) A mitochondrial encephalomyopathy: the first case with an established defect at the level of coenzyme Q. Eur J Pediatr 144:441–444
Goodman SI, Binard RJ, Woontner MR et al (2002) Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene. Mol Genet Metab 77:86–90
Kobayashi K, Inoguchi T, Maeda Y et al (2008) The lack of the C-terminal domain of adipose triglyceride lipase causes neutral lipid storage disease through impaired interactions with lipid droplets. J Clin Endocrinol Metab 93:2877–2884
Szczepaniak LS, Nurenberg P, Leonard D et al (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462–E468
Langin D (2006) Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol Res 53:482–491
Villena JA, Roy S, Sarkadi-Nagy E et al (2004) Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem 279:47066–47075
Akman HO, Davidzon G, Tanji K et al (2010) Neutral lipid storage disease with subclinical myopathy due to a retrotransposal insertion in the PNPLA2 gene. Neuromuscul Disord 20:397–402
Campagna F, Nanni L, Quagliarini F et al (2008) Novel mutations in the adipose triglyceride lipase gene causing neutral lipid storage disease with myopathy. Biochem Biophys Res Commun 377:843–846
Akiyama M, Sakai K, Ogawa M et al (2007) Novel duplication mutation in the patatin domain of adipose triglyceride lipase (PNPLA2) in neutral lipid storage disease with severe myopathy. Muscle Nerve 36:856–859
Ohkuma A, Noguchi S, Sugie H et al (2009) Clinical and genetic analysis of lipid storage myopathies. Muscle Nerve 39:333–342
Di Mauro S, Trevisan C, Hays A (1980) Disorders of lipid metabolism in muscle. Muscle Nerve 3:369–388
Ogasawara J, Nomura S, Rahman N et al (2010) Hormone-sensitive lipase is critical mediators of acute exercise-induced regulation of lipolysis in rat adipocytes. Biochem Biophys Res Commun 400:134–139
Lu X, Yang X, Liu J (2010) Differential control of ATGL-mediated lipid droplet degradation by CGI-58 and G0S2. Cell Cycle 9:2719–2725
Acknowledgments
This work was supported by the Medical Research Council Translational Neuromuscular Centre. R.H. was supported by the Academy of Medical Sciences, UK (BH090164) and the Medical Research Council, UK (G1000848). The Muscle Tissue Culture Collection is part of the German Network on Muscular Dystrophies (MD-NET, service structure S1, 01GM0601) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany). The Muscle Tissue Culture Collection is a partner of EuroBioBank (http://www.eurobiobank.org) and TREAT-NMD (EC, 6th FP, proposal #036825). This work was supported by a SysMBo TP11 grant (BMBF, Bonn, Germany) to B.S.
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P. Reilich, R. Horvath, and S. Krause contributed equally to this work.
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Reilich, P., Horvath, R., Krause, S. et al. The phenotypic spectrum of neutral lipid storage myopathy due to mutations in the PNPLA2 gene. J Neurol 258, 1987–1997 (2011). https://doi.org/10.1007/s00415-011-6055-4
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DOI: https://doi.org/10.1007/s00415-011-6055-4