Clinical and genetic analysis of lipid storage myopathies

Ohkuma, Aya; Noguchi, S.; Sugie, Hideo; Malicdan, May Christine V.; Fukuda, Tokiko; Shiota, Kunio; López, Luís C.; Hirano, Michio; Hayashi, Yukiko; Nonaka, Ikuya; Nishino, Ichizo

doi:10.1002/mus.21167

Cited by 70 publications

(48 citation statements)

References 21 publications

(25 reference statements)

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“…The subsarcolemmal distribution of the relatively large nonlysosomal and nonautophagic vacuoles in PNPLA2 deficiency differs from MADD-associated lipid storage, which shows a more diffuse pattern of lipid storage in small-sized vacuoles [3]. In contrast to recent findings, we only found a few rimmed vacuoles in our specimens, and a few scattered necrotic fibers were found [34]. In addition, any structural or histochemical alterations of mitochondria (COX-negative, SDH-hyperreactive fibers), which are typically present in MADD or carnitine transporter deficiency, are absent in NLSD-M [35].…”

Section: Discussioncontrasting

confidence: 84%

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: Discussioncontrasting

confidence: 84%

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

et al. 2011

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“…In contrast, other studies reported patients with multiple acyl-CoA dehydrogenase deficiency and ETFDH mutations who had normal CoQ 10 levels in muscle [Liang et al, 2009;Ohkuma et al, 2009].…”

Section: Isolated Myopathymentioning

confidence: 56%

Clinical Presentations of Coenzyme Q10 Deficiency Syndrome

Quinzii

Emmanuele

Hirano³

2014

Mol Syndromol

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Coenzyme Q₁₀ (CoQ₁₀) deficiency is a clinically and genetically heterogeneous syndrome which has been associated with 5 major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) nephropathy, (4) cerebellar ataxia, and (5) isolated myopathy. Of these phenotypes, cerebellar ataxia and syndromic or isolated nephrotic syndrome are the most common. CoQ₁₀ deficiency predominantly presents in childhood. To date, causative mutations have been identified in a small proportion of patients, making it difficult to identify a phenotype-genotype correlation. Identification of CoQ₁₀ deficiency is important because the disease, in particular muscle symptoms and nephropathy, frequently responds to CoQ₁₀ supplementation.

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“…Some patients may also develop severe cardiomyopathy. There is no ichthyosis, but the Jordan anomaly is present in blood smears [120,188]. Serum CK is increased and was the only consistent abnormality in a young preclinical woman with severe lipid myopathy and a retrotransposal mutation in PNPLA2 [189].…”

Section: Neutral Lipid Storage Disease With Myopathy (Nlsdm)mentioning

confidence: 94%

“…Isolated lipid storage myopathy without myoglobinuria has been described in a few patients [115][116][117][118]. The report by Gempel et al [118] implied that myopathic CoQ10 deficiency could be secondary to multiple acyl-CoA dehydrogenase deficiency (MADD) due to mutations in the gene encoding the electron-transferring-flavoprotein dehydrogenase (ETFDH), but this generalization has been contradicted [119,120].…”

Section: Coenzyme Q10 (Coq10) Deficiencymentioning

confidence: 94%

“…Late-onset MADD often causes severe lipid storage myopathy with proximal and axial weakness. Of considerable practical importance is the riboflavinresponsive form of MADD, which is predominantly associated with ETFDH deficiency [120,183]. Some of these patients had CoQ10 deficiency in muscle and responded to CoQ10 supplementation alone or together with riboflavin [118], but secondary CoQ10 deficiency is not a consistent finding [120].…”

Section: Medium-chain Acyl-coa Dehydrogenase (Mcad) Deficiencymentioning

confidence: 98%

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Metabolic Myopathies

DiMauro

Akman

Paradas

2013

Neuromuscular Disorders in Clinical Practice

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IntroductionInborn errors of glycogen and fatty acid metabolism that cause exclusively or predominantly neuromuscular disorders are characterized by dynamic or static symptoms. Dynamic symptoms are acute, recurrent, reversible muscle dysfunctions, manifesting as exercise intolerance, myalgia with or without painful cramps (contractures), and often culminating in muscle breakdown and myoglobinuria. In contrast, static symptoms are manifested by fixed, often progressive weakness, sometimes simulating dystrophic or neurogenic processes ( Fig. 63.1).To understand glycogen and lipid storage disorders, a brief review of muscle metabolism at rest and during exercise is helpful.The "fuel" utilized by muscle depends on several factors, most importantly the type, intensity, and duration of exercise but also diet and physical conditioning. At rest, muscle utilizes predominantly fatty acids. At the opposite end of the spectrum, the energy for extremely intense exercise (close to one's maximal oxygen uptake, or VO 2 max, in dynamic exercise or close to maximal force generation in isometric exercise) derives from anaerobic glycolysis, especially when there is a "burst" of activity with rapid acceleration to maximal exercise. During submaximal exercise, the type of fuel utilized by muscle depends on the relative intensity of exertion. At low intensity (below 50 % VO 2 max), blood glucose and free fatty acids (FFA) are the primary sources of energy. At higher intensities, the proportion of energy derived from carbohydrate oxidation increases, and muscle glycogen becomes an important fuel; at 70-80 % VO 2 max, aerobic metabolism of glycogen is the crucial source of energy, and fatigue appears to set in when glycogen is exhausted. The type of circulating substrate utilized during mild exercise varies with time, and there is a gradual increase in the utilization of FFA over glucose until, a few hours into

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Clinical and genetic analysis of lipid storage myopathies

Cited by 70 publications

References 21 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

Clinical Presentations of Coenzyme Q10 Deficiency Syndrome

Metabolic Myopathies

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