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CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: Expanding the phenotypic spectrum of caveolinopathies

Lookup NU author(s): Dr Rita Barresi, Professor Katherine Bushby

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Abstract

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes. (C) 2016 Elsevier B.V. All rights reserved.


Publication metadata

Author(s): Scalco RS, Gardiner AR, Pitceathly RDS, Hilton-Jones D, Schapira AH, Turner C, Parton M, Desikan M, Barresi R, Marsh J, Manzur AY, Childs AM, Feng L, Murphy E, Lamont PJ, Ravenscroft G, Wallefeld W, Davis MR, Laing NG, Holton JL, Fialho D, Bushby K, Hanna MG, Phadke R, Jungbluth H, Houlden H, Quinlivan R

Publication type: Article

Publication status: Published

Journal: Neuromuscular Disorders

Year: 2016

Volume: 26

Issue: 8

Pages: 504-510

Print publication date: 01/08/2016

Online publication date: 11/05/2016

Acceptance date: 09/05/2016

ISSN (print): 0960-8966

ISSN (electronic): 1873-2364

Publisher: Pergamon Press

URL: http://dx.doi.org/10.1016/j.nmd.2016.05.006

DOI: 10.1016/j.nmd.2016.05.006


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