Late Adult-onset of X-linked Myopathy with Excessive Autophagy

Overview

Journal Muscle Nerve

Date 2014 Feb 4

PMID 24488655

Citations 10

Authors

Cameron D Crockett

Alessandra Ruggieri

Meena Gujrati

Christopher M Zallek

Nivetha Ramachandran

Berge A Minassian

Steven A Moore

Affiliations

Soon will be listed here.

Abstract

Introduction: X-linked myopathy with excessive autophagy (XMEA) is characterized by autophagic vacuoles with sarcolemmal features. Mutations in VMA21 result in insufficient lysosome acidification, causing progressive proximal weakness with onset before age 20 years and loss of ambulation by middle age.

Methods: We describe a patient with onset of slowly progressive proximal weakness of the lower limbs after age 50, who maintains ambulation with the assistance of a cane at age 71.

Results: Muscle biopsy at age 66 showed complex muscle fiber splitting, internalized capillaries, and vacuolar changes characteristic of autophagic vacuolar myopathy. Vacuoles stained positive for sarcolemmal proteins, LAMP2, and complement C5b-9. Ultrastructural evaluation further revealed basal lamina reduplication and extensive autophagosome extrusion. Sanger sequencing identified a known pathologic splice site mutation in VMA21 (c.164-7T>G).

Conclusions: This case expands the clinical phenotype of XMEA and suggests VMA21 sequencing be considered in evaluating men with LAMP2-positive autophagic vacuolar myopathy.

Citing Articles

X-linked myopathy with excessive autophagy: characterization and therapy testing in a zebrafish model.

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Identification of a Novel Intronic Mutation in Associated with a Classical Form of X-Linked Myopathy with Autophagy.

Bardhan M, Polavarapu K, Baskar D, Preethish-Kumar V, Vengalil S, Nashi S Glob Med Genet. 2024; 11(2):167-174.

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Phenotype variability and natural history of X-linked myopathy with excessive autophagy.

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Novel Intronic Mutation in Causing Severe Phenotype of X-Linked Myopathy with Excessive Autophagy-Case Report.

Pegat A, Streichenberger N, Lacoste N, Hermier M, Menassa R, Coudert L Genes (Basel). 2022; 13(12).

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References

Malicdan M, Nishino I . Autophagy in lysosomal myopathies. Brain Pathol. 2011; 22(1):82-8. PMC: 8029060. DOI: 10.1111/j.1750-3639.2011.00543.x. View

Echaniz-Laguna A, Mohr M, Epailly E, Nishino I, Charron P, Richard P . Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease. Muscle Nerve. 2005; 33(3):393-7. DOI: 10.1002/mus.20471. View

Maron B, Roberts W, Arad M, Haas T, Spirito P, Wright G . Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA. 2009; 301(12):1253-9. PMC: 4106257. DOI: 10.1001/jama.2009.371. View

Malicdan M, Noguchi S, Nonaka I, Saftig P, Nishino I . Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscul Disord. 2008; 18(7):521-9. DOI: 10.1016/j.nmd.2008.04.010. View

Chabrol B, Figarella-Branger D, Coquet M, Mancini J, Fontan D, Pedespan J . X-linked myopathy with excessive autophagy: a clinicopathological study of five new families. Neuromuscul Disord. 2001; 11(4):376-88. DOI: 10.1016/s0960-8966(00)00209-1. View

Kurashige T, Takahashi T, Yamazaki Y, Nagano Y, Kondo K, Nakamura T . Elevated urinary β2 microglobulin in the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. Neuromuscul Disord. 2013; 23(11):911-6. DOI: 10.1016/j.nmd.2013.06.003. View

Nishino I . Autophagic vacuolar myopathy. Semin Pediatr Neurol. 2006; 13(2):90-5. DOI: 10.1016/j.spen.2006.06.004. View

Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y . In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2003; 15(3):1101-11. PMC: 363084. DOI: 10.1091/mbc.e03-09-0704. View

Tanaka Y, Guhde G, Suter A, Eskelinen E, Hartmann D, Lullmann-Rauch R . Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature. 2000; 406(6798):902-6. DOI: 10.1038/35022595. View

10.

Kalimo H, Savontaus M, Lang H, Paljarvi L, SONNINEN V, Dean P . X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol. 1988; 23(3):258-65. DOI: 10.1002/ana.410230308. View

11.

Murrow L, Debnath J . Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Annu Rev Pathol. 2012; 8:105-37. PMC: 3971121. DOI: 10.1146/annurev-pathol-020712-163918. View

12.

Sugimoto S, Shiomi K, Yamamoto A, Nishino I, Nonaka I, Ohi T . LAMP-2 positive vacuolar myopathy with dilated cardiomyopathy. Intern Med. 2007; 46(11):757-60. DOI: 10.2169/internalmedicine.46.6265. View

13.

Saviranta P, Lindlof M, Lehesjoki A, Kalimo H, Lang H, SONNINEN V . Linkage studies in a new X-linked myopathy, suggesting exclusion of DMD locus and tentative assignment to distal Xq. Am J Hum Genet. 1988; 42(1):84-8. PMC: 1715330. View

14.

Auranen M, Villanova M, Muntoni F, Fardeau M, Scherer S, Kalino H . X-linked vacuolar myopathies: two separate loci and refined genetic mapping. Ann Neurol. 2000; 47(5):666-9. View

15.

Kaneda D, Sugie K, Yamamoto A, Matsumoto H, Kato T, Nonaka I . A novel form of autophagic vacuolar myopathy with late-onset and multiorgan involvement. Neurology. 2003; 61(1):128-31. DOI: 10.1212/01.wnl.0000069605.00498.bd. View

16.

Sugie K, Noguchi S, Kozuka Y, Arikawa-Hirasawa E, Tanaka M, Yan C . Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies. J Neuropathol Exp Neurol. 2005; 64(6):513-22. DOI: 10.1093/jnen/64.6.513. View

17.

Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T . Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000; 406(6798):906-10. DOI: 10.1038/35022604. View

18.

Louboutin J, Villanova M, Fardeau M . X-linked vacuolated myopathy: membrane attack complex deposition on muscle fiber membranes with calcium accumulation on sarcolemma. Ann Neurol. 1997; 41(1):117-20. DOI: 10.1002/ana.410410121. View

19.

Sugie K, Yamamoto A, Murayama K, Oh S, Takahashi M, Mora M . Clinicopathological features of genetically confirmed Danon disease. Neurology. 2002; 58(12):1773-8. DOI: 10.1212/wnl.58.12.1773. View

20.

Villard L, Portes V, Levy N, Louboutin J, Recan D, Coquet M . Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28. Eur J Hum Genet. 2000; 8(2):125-9. DOI: 10.1038/sj.ejhg.5200432. View