CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: Expanding the phenotypic spectrum of caveolinopathies.
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.
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; CAPES Foundation, Ministry of Education of Brazil, Brasilia DF, Brazil. Electronic address: r.scalco@ucl.ac.uk.
Renata Siciliani
RS
Scalco
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Alice R
AR
Gardiner
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.
Robert D S
RD
Pitceathly
Department of Clinical Neurology, West Wing, John Radcliffe Hospital, Oxford, UK.
David
D
Hilton-Jones
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Anthony H
AH
Schapira
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Chris
C
Turner
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Matt
M
Parton
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Mahalekshmi
M
Desikan
NHS England HSS for Rare Neuromuscular Diseases, Muscle Immunoanalysis Unit, Dental Hospital Richardson Road, Newcastle upon Tyne, UK; The John Walton Muscular Dystrophy Research Centre and MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Rita
R
Barresi
NHS England HSS for Rare Neuromuscular Diseases, Muscle Immunoanalysis Unit, Dental Hospital Richardson Road, Newcastle upon Tyne, UK.
Julie
J
Marsh
Dubowitz Neuromuscular Centre, UCL Institute of Child Health, Great Ormond Street Hospital, London, UK.
Adnan Y
AY
Manzur
Leeds Teaching Hospitals, Leeds, UK.
Anne-Marie
AM
Childs
Dubowitz Neuromuscular Centre, UCL Institute of Child Health, Great Ormond Street Hospital, London, UK.
Lucy
L
Feng
Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Elaine
E
Murphy
Neurogenetic Unit, Dept of Neurology, Royal Perth Hospital, Australia.
Phillipa J
PJ
Lamont
Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia.
Gianina
G
Ravenscroft
Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, Australia.
William
W
Wallefeld
Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, Australia.
Mark R
MR
Davis
Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia; Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, Australia.
Nigel G
NG
Laing
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Janice L
JL
Holton
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Doreen
D
Fialho
The John Walton Muscular Dystrophy Research Centre and MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Kate
K
Bushby
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Michael G
MG
Hanna
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Dubowitz Neuromuscular Centre, UCL Institute of Child Health, Great Ormond Street Hospital, London, UK.
Rahul
R
Phadke
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK; Department of Paediatric Neurology, Evelina Children's Hospital, Guy's & St Thomas NHS Foundation Trust, London, UK; Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College London, UK.
Heinz
H
Jungbluth
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Henry
H
Houlden
MRC Centre for Neuromuscular Diseases and Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Dubowitz Neuromuscular Centre, UCL Institute of Child Health, Great Ormond Street Hospital, London, UK.
Ros
R
Quinlivan
D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D051244:Caveolin 3 / Q000235:genetics* / Q000378:metabolism; D002648:Child; D049030:Dystroglycans / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D063806:Myalgia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012206:Rhabdomyolysis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
C417736:CAV3 protein, human; D051244:Caveolin 3; C483081:DAG1 protein, human; D049030:Dystroglycans
CAV3; Caveolinopathy; Exercise Intolerance; Myalgia; Myoglobinuria; Rhabdomyolysis