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

Renata Siciliani Scalco; Alice R. Gardiner; Robert D.S. Pitceathly; David Hilton-Jones; Anthony H Schapira; Chris Turner; Matt Parton; Mahalekshmi Desikan; Rita Barresi; Julie Marsh; Adnan Y Manzur; Anne-Marie Childs; Lucy Feng; Elaine Murphy; Phillipa J Lamont; Gianina Ravenscroft; William Wallefeld; Mark R Davis; Nigel G Laing; Janice L. Holton; Doreen Fialho; Kate Bushby; Michael G Hanna; Rahul Phadke; Heinz Jungbluth; Henry Houlden; Ros Quinlivan

doi:10.1016/j.nmd.2016.05.006

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

Renata Siciliani Scalco, Alice R. Gardiner, Robert D.S. Pitceathly, David Hilton-Jones, Anthony H Schapira, Chris Turner, Matt Parton, Mahalekshmi Desikan, Rita Barresi, Julie Marsh, Adnan Y Manzur, Anne-Marie Childs, Lucy Feng, Elaine Murphy, Phillipa J Lamont, Gianina Ravenscroft, William Wallefeld, Mark R Davis, Nigel G Laing, Janice L. HoltonDoreen Fialho, Kate Bushby, Michael G Hanna, Rahul Phadke, Heinz Jungbluth, Henry Houlden, Ros Quinlivan

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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=6) 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.

Original language	English
Pages (from-to)	504-510
Number of pages	7
Journal	Neuromuscular Disorders
Volume	26
Issue number	8
Early online date	11 May 2016
DOIs	https://doi.org/10.1016/j.nmd.2016.05.006
Publication status	Published - 1 Aug 2016

Keywords

CAV3
Rhabdomyolysis
Myoglobinuria
Caveolinopathy
Exercise Intolerance
Myalgia

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CAV3 mutations causing exercise_SCALCO_Publishedonline11May2016_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 961 KBLicence: CC BY-NC-ND

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Scalco, R. S., Gardiner, A. R., Pitceathly, R. D. S., Hilton-Jones, D., Schapira, A. H., Turner, C., Parton, M., Desikan, M., Barresi, R., Marsh, J., Manzur, A. Y., Childs, A.-M., Feng, L., Murphy, E., Lamont, P. J., Ravenscroft, G., Wallefeld, W., Davis, M. R., Laing, N. G., ... Quinlivan, R. (2016). CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies. Neuromuscular Disorders, 26(8), 504-510. https://doi.org/10.1016/j.nmd.2016.05.006

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title = "CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies",

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=6) 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.",

keywords = "CAV3, Rhabdomyolysis, Myoglobinuria, Caveolinopathy, Exercise Intolerance, Myalgia",

author = "Scalco, {Renata Siciliani} and Gardiner, {Alice R.} and Pitceathly, {Robert D.S.} and David Hilton-Jones and Schapira, {Anthony H} and Chris Turner and Matt Parton and Mahalekshmi Desikan and Rita Barresi and Julie Marsh and Manzur, {Adnan Y} and Anne-Marie Childs and Lucy Feng and Elaine Murphy and Lamont, {Phillipa J} and Gianina Ravenscroft and William Wallefeld and Davis, {Mark R} and Laing, {Nigel G} and Holton, {Janice L.} and Doreen Fialho and Kate Bushby and Hanna, {Michael G} and Rahul Phadke and Heinz Jungbluth and Henry Houlden and Ros Quinlivan",

year = "2016",

month = aug,

day = "1",

doi = "10.1016/j.nmd.2016.05.006",

language = "English",

volume = "26",

pages = "504--510",

journal = "Neuromuscular Disorders",

issn = "0960-8966",

publisher = "Elsevier Ltd",

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Scalco, RS, Gardiner, AR, Pitceathly, RDS, Hilton-Jones, D, Schapira, AH, Turner, C, Parton, M, Desikan, M, Barresi, R, Marsh, J, Manzur, AY, Childs, A-M, 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 2016, 'CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies', Neuromuscular Disorders, vol. 26, no. 8, pp. 504-510. https://doi.org/10.1016/j.nmd.2016.05.006

TY - JOUR

T1 - CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies

AU - Scalco, Renata Siciliani

AU - Gardiner, Alice R.

AU - Pitceathly, Robert D.S.

AU - Hilton-Jones, David

AU - Schapira, Anthony H

AU - Turner, Chris

AU - Parton, Matt

AU - Desikan, Mahalekshmi

AU - Barresi, Rita

AU - Marsh, Julie

AU - Manzur, Adnan Y

AU - Childs, Anne-Marie

AU - Feng, Lucy

AU - Murphy, Elaine

AU - Lamont, Phillipa J

AU - Ravenscroft, Gianina

AU - Wallefeld, William

AU - Davis, Mark R

AU - Laing, Nigel G

AU - Holton, Janice L.

AU - Fialho, Doreen

AU - Bushby, Kate

AU - Hanna, Michael G

AU - Phadke, Rahul

AU - Jungbluth, Heinz

AU - Houlden, Henry

AU - Quinlivan, Ros

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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=6) 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.

AB - 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=6) 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.

KW - CAV3

KW - Rhabdomyolysis

KW - Myoglobinuria

KW - Caveolinopathy

KW - Exercise Intolerance

KW - Myalgia

U2 - 10.1016/j.nmd.2016.05.006

DO - 10.1016/j.nmd.2016.05.006

M3 - Article

SN - 0960-8966

VL - 26

SP - 504

EP - 510

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

IS - 8

ER -

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

Abstract

Keywords

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