Predominantly myalgic phenotype caused by the c.3466G>A p.A1156T mutation inSCN4Agene.
OBJECTIVE
To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation.


METHODS
Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in theSCN4Agene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp.


RESULTS
The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise- and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation.


CONCLUSIONS
The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milderSCN4Amutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.
From the Neuromuscular Research Center (J.P., S.P., B.U.), Department of Neurology, Tampere University and University Hospital, Neurology; Seinäjoki Central Hospital (S.S.), Department of Neurology, Finland; MRC Centre for Neuromuscular Disease (M.G.H., R.M.), UCL Institute of Neurology, Queen Square, London, UK; Folkhälsan Institute of Genetics and the Department of Medical Genetics (B.U.), Haartman Institute, University of Helsinki; and Vaasa Central Hospital (B.U.), Department of Neurology, Finland. johanna.palmio@uta.fi.
Johanna
J
Palmio
From the Neuromuscular Research Center (J.P., S.P., B.U.), Department of Neurology, Tampere University and University Hospital, Neurology; Seinäjoki Central Hospital (S.S.), Department of Neurology, Finland; MRC Centre for Neuromuscular Disease (M.G.H., R.M.), UCL Institute of Neurology, Queen Square, London, UK; Folkhälsan Institute of Genetics and the Department of Medical Genetics (B.U.), Haartman Institute, University of Helsinki; and Vaasa Central Hospital (B.U.), Department of Neurology, Finland.
Satu
S
Sandell
From the Neuromuscular Research Center (J.P., S.P., B.U.), Department of Neurology, Tampere University and University Hospital, Neurology; Seinäjoki Central Hospital (S.S.), Department of Neurology, Finland; MRC Centre for Neuromuscular Disease (M.G.H., R.M.), UCL Institute of Neurology, Queen Square, London, UK; Folkhälsan Institute of Genetics and the Department of Medical Genetics (B.U.), Haartman Institute, University of Helsinki; and Vaasa Central Hospital (B.U.), Department of Neurology, Finland.
Michael G
MG
Hanna
From the Neuromuscular Research Center (J.P., S.P., B.U.), Department of Neurology, Tampere University and University Hospital, Neurology; Seinäjoki Central Hospital (S.S.), Department of Neurology, Finland; MRC Centre for Neuromuscular Disease (M.G.H., R.M.), UCL Institute of Neurology, Queen Square, London, UK; Folkhälsan Institute of Genetics and the Department of Medical Genetics (B.U.), Haartman Institute, University of Helsinki; and Vaasa Central Hospital (B.U.), Department of Neurology, Finland.
Roope
R
Männikkö
From the Neuromuscular Research Center (J.P., S.P., B.U.), Department of Neurology, Tampere University and University Hospital, Neurology; Seinäjoki Central Hospital (S.S.), Department of Neurology, Finland; MRC Centre for Neuromuscular Disease (M.G.H., R.M.), UCL Institute of Neurology, Queen Square, London, UK; Folkhälsan Institute of Genetics and the Department of Medical Genetics (B.U.), Haartman Institute, University of Helsinki; and Vaasa Central Hospital (B.U.), Department of Neurology, Finland.
Sini
S
Penttilä
From the Neuromuscular Research Center (J.P., S.P., B.U.), Department of Neurology, Tampere University and University Hospital, Neurology; Seinäjoki Central Hospital (S.S.), Department of Neurology, Finland; MRC Centre for Neuromuscular Disease (M.G.H., R.M.), UCL Institute of Neurology, Queen Square, London, UK; Folkhälsan Institute of Genetics and the Department of Medical Genetics (B.U.), Haartman Institute, University of Helsinki; and Vaasa Central Hospital (B.U.), Department of Neurology, Finland.
Bjarne
B
Udd
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005356:Fibromyalgia / Q000235:genetics / Q000503:physiopathology; D005387:Finland; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063806:Myalgia / Q000235:genetics* / Q000503:physiopathology*; D009223:Myotonic Dystrophy / Q000235:genetics / Q000503:physiopathology; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D044465:White People / Q000235:genetics; D055815:Young Adult
D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human