Distal lipid storage myopathy due to PNPLA2 mutation

Ohkuma, Aya; Nonaka, Ikuya; Malicdan, May Christine V.; Noguchi, S.; Ohji, Satoru; Nomura, Kyoichi; Sugie, Hideo; Hayashi, Yukiko; Nishino, Ichizo

doi:10.1016/j.nmd.2008.06.382

Cited by 49 publications

(32 citation statements)

References 8 publications

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“…The posterior compartment was similarly more impaired in the lower legs (gastrocnemius) with relatively well-preserved tibial muscles. This is consistent with previously reported computed tomography (CT) findings in other PNPLA2 patients [18,32,33]. The predisposition of the muscle involvement suggests that muscle MRI may be a useful tool in the follow-up of PNPLA2 deficiency.…”

Section: Discussionsupporting

confidence: 92%

“…Most patients with PNPLA2 mutations show muscle symptoms and involvement of other organs, but not skin [11]. Myopathy may lead to proximal weakness of the upper and lower limbs, but predominant distal involvement was also observed [18]. Cardiomyopathy, hepatomegaly, and diabetes may be associated symptoms [19], and an isolated cardiomyopathy [20] has been also described.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…5,11,12,14,15 One might question whether the disorder is not more common than previously thought, and the diagnosis is missed in some of these milder patients owing to missing the diagnostic sign of Jordans' bodies (due to variable percentage of droplets in blood smear or the use of automated blood cell analysis) without specifically looking for the vacuoles by electron microscopy.…”

Section: Discussionmentioning

confidence: 99%

Symptomatic lipid storage in carriers for the PNPLA2 gene

et al. 2012

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Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with associated cardiac disease, myopathy and frequent infections, but without ichthyosis. Here we describe the clinical and biochemical characteristics of a long surviving patient and report on four carrier family members with diverse clinical involvement. Interestingly, heterozygous patients show neutral lipid storage in muscle and in the keratocytes of the skin, Jordans' bodies, mild myopathy and frequent infections. Biochemical analysis of fibroblasts obtained from patients revealed increased triglyceride storage and reduced lipid droplet-associated triglyceride hydrolase activity. Together, our data implicate that the wild-type allele cannot fully compensate for the mutated dysfunctional allele of PNPLA2 leading to triglyceride accumulation in muscle and mild myopathy in PNPLA2 mutation carriers. The presence of neutral lipid droplets in the skin in PNPLA2 mutation carriers strengthens the link between NLSD and other neutral lipid storage diseases with ichthyosis.

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“…Interestingly, rimmed vacuoles are shown in the muscle fibers in a significant number of patients with NLSDM, unlike PCD and MADD [11,34]. In addition, fiber size variation seems to be more significant than PCD and MADD.…”

Section: Neutral Lipid Storage Diseases With Ichthyosis and Myopathymentioning

confidence: 93%

Lipid Storage Myopathy

Liang

Nishino

2010

Curr Neurol Neurosci Rep

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Lipid storage myopathy (LSM) is pathologically characterized by prominent lipid accumulation in muscle fibers due to lipid dysmetabolism. Although extensive molecular studies have been performed, there are only four types of genetically diagnosable LSMs: primary carnitine deficiency (PCD), multiple acyl-coenzyme A dehydrogenase deficiency (MADD), neutral lipid storage disease with ichthyosis, and neutral lipid storage disease with myopathy. Making an accurate diagnosis, by specific laboratory tests including genetic analyses, is important for LSM as some of the patients are treatable: individuals with PCD show dramatic improvement with high-dose oral L-carnitine supplementation and increasing evidence indicates that MADD due to ETFDH mutations is riboflavin responsive.

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Distal lipid storage myopathy due to PNPLA2 mutation

Cited by 49 publications

References 8 publications

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

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

Symptomatic lipid storage in carriers for the PNPLA2 gene

Lipid Storage Myopathy

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