Bentzen, Bo Hjorth

Denti, Federico

Fagerberg, Christina

Gaist, David

Schmitt, Nicole

Sloth, Christine K

Vissing, John

English

Copenhagen University Research Information System

u n i ve r s i t y  o f  co pe n h ag e n  Københavns UniversitetHomozygosity for SCN4A Arg1142Gln causes congenital myopathy with variabledisease expressionSloth, Christine K; Denti, Federico; Schmitt, Nicole; Bentzen, Bo Hjorth; Fagerberg, Christina;Vissing, John; Gaist, DavidPublished in:Neurology: GeneticsDOI:10.1212/NXG.0000000000000267Publication date:2018Document versionPublisher's PDF, also known as Version of recordDocument license:CC BY-NC-NDCitation for published version (APA):Sloth, C. K., Denti, F., Schmitt, N., Bentzen, B. H., Fagerberg, C., Vissing, J., & Gaist, D. (2018). Homozygosityfor SCN4A Arg1142Gln causes congenital myopathy with variable disease expression. Neurology: Genetics,4(5), e267. https://doi.org/10.1212/NXG.0000000000000267Download date: 03. Feb. 2020CLINICAL/SCIENTIFIC NOTES OPEN ACCESSHomozygosity for SCN4A Arg1142Gln causescongenital myopathy with variable diseaseexpressionChristine K. Sloth, MD, Federico Denti, PhD, Nicole Schmitt, PhD, Bo Hjorth Bentzen, PhD,Christina Fagerberg, MD, John Vissing, DMSci, and David Gaist, PhDNeurol Genet 2018;4:e267. doi:10.1212/NXG.0000000000000267CorrespondenceProf. Gaistdgaist@health.sdu.dkCongenital myopathy has recently been associated with biallelic pathogenic variants in theSCN4A gene that encodes the voltage-dependent sodium channel NaV1.4.1,2 In 13 previouslyreported cases,1,2 7 died in utero or shortly after birth. The 6 survivors showed features con-sistent with “classical” congenital myopathy. Here, we report 2 new familial cases with variablephenotype.Written informed consent was obtained from both patients. Permission for the study wasgranted by the Danish Data Protection Agency.The index patient, an 18-year-old woman, born as the second of 2 children to consanguineousparents, reported weakness and dyspnea from early childhood. Pregnancy and birth werenormal, but postpartum, she had dysphagia and was tube fed. Early motor milestones weredelayed, with independent ambulation achieved at age 2.25 years and inability to lift her headfrom a supine position until age 3 years. She experienced improvement in her conditionthroughout childhood, but still had reduced walking distance (2.5 km), diﬃculty lifting heavyobjects, and experienced patella luxations.On examination, the patient is 150 cm tall and has a dolichocephalic head shape and elbowhypermobility (ﬁgure 1A). Strength testing showed diﬀuse muscle force reduction at MedicalResearchCouncil (MRC) grade 4, with no distal/proximal gradient, and axial weakness. Spirometryshowed normal forced vital capacity (FVC) (88%) and forced expiratory volume (FEV1) (96%).Creatine kinase (CK) levels and neurophysiologic ﬁndings were normal. Replacement ofmuscle by fat on MRI was pronounced in gluteus maximus and hamstring muscles (ﬁgure 1B).Muscle biopsy, at age 4 years, displayed myopathic features with varying ﬁber size, increasednumber of internalized nuclei, atrophic ﬁbers, and endomysial ﬁbrosis and fat inﬁltration.Next-generation sequencing revealed homozygosity for a previously described missense variantin SCN4A (NM_000334.4: c.3425G>A(p.Arg.1142Gln)),2 conﬁrmed through Sanger se-quencing, and was deemed to be pathogenic by 6 prediction tools. Parents were heterozygousfor the variant.The 22-year-old sister of the index patient was also homozygous for Arg1142Gln. She hadmilder muscular complaints than her sister, which included diﬃculties lifting her head whenlying down, exertional shortness of breath, and poor cycling capacity since childhood. She hadelbow joint hypermobility like her sister. Her motor milestones were normal. Strength testingFrom the Department of Neurology (C.K.S., D.G.), Odense University Hospital; and Department of Clinical Research (C.K.S., D.G.), Faculty of Health Sciences, University of SouthernDenmark, Odense; Department of Biomedical Sciences (F.D., N.S., B.H.B.), Faculty of Health and Medical Sciences, University of Copenhagen; Department of Clinical Genetics (C.F.),Odense University Hospital; and Copenhagen Neuromuscular Center, Department of Neurology (J.V.), Rigshospitalet, University of Copenhagen, Denmark.Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article atNeurology.org/NG.The Article Processing Charge was funded by the authors.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloadingand sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1Figure 1 Clinical features in sisters with SCN4A congenital myopathyFeaturing the dococephalic head form in the indexpatient (left image) andhypermobility of the elbows inboth sisters (middle and right image) (A). T1-weightedmuscle MRI images of the index patient show severefatty infiltration and atrophy of gluteus medius(arrows, left image) and adductor magnus and, toa lesser degree, the hamstrings bilaterally (right im-age) (B).Figure 2 The mutation R1142Q causes loss-of-function of NaV1.4 current(A) Representative current traces forNaV1.4 WT and R1142Q recordedfrom transiently transfectedHEK293 cells. (B) I/V relationship forthe peak current density for NaV1.4WT (n = 9) and R1142Q (n = 8).Voltage protocol shown as inset. (C)Steady-state inactivation and acti-vation curves for NaV1.4 WT (black)and R1142Q (gray). Voltage protocolshown as inset. (D) Comparison ofactivation V50 values betweenNaV1.4 WT (black) and R1142Q(gray). *p < 0.05; **p < 0.006; ****p< 0.0001.2 Neurology: Genetics | Volume 4, Number 5 | October 2018 Neurology.org/NGshowed reduced neck ﬂexion (MRC 4+), shoulder abduction(MRC4+), and hip ﬂexion (MRC 4+). CK, lung functiontests, and MRI of thigh muscles were normal.Functional assessment of the Arg1142Gln (R1142Q) variant inhuman embryonic kidney 293 (HEK293) cells revealed partialloss-of-function eﬀects (ﬁgure 2), as previously reported inSCN4A-related congenital myopathy.1,2 NaV1.4 R1142Q peakcurrent density was signiﬁcantly lower than wild type (WT)(WT: 106.4 ± 12.4 pA/pF, R1142Q: −39.0 ± 6.4 pA/pF at5 mV, ﬁgure 2, A and B), and the voltage dependence of channelactivation was signiﬁcantly changed (ﬁgure 2, C and D).Variants in SCN4A were originally linked to congenitalmyasthenia,3,4 but recently, also to severe fetal hypokinesia andearly lethality1 and to sudden infant death syndrome.5 Astrikingly milder phenotype of “classical” congenital myopathyhas been described in 6 patients with SCN4A variants in a re-cessive pattern, only 3 of whom were adults (aged 18–35 yearsold).1,2 Our 18-year-old index patient exhibited a phenotypesimilar to that previously reported,1 while her 20-year-old sisterwas only marginally aﬀected. Our index patient’s characteristicmuscle MRI ﬁndings were similar to 4 other patients withSCN4A mutations, including 2 brothers, compound hetero-zygous for c.3425G>A(p.Arg1142Gln) and another missensevariant c.1123T>C (p.Cys375Arg).1,2 The brothers, unlike ourpatients, had elongated faces, ptosis, facial weakness, scoliosis,and elevated CK.2 We speculate whether homozygosity for thep.Arg1142Gln variant conferred the milder phenotype ob-served in our patients. The present report expands ourknowledge regarding SCN4A-related congenital myopathy inadulthood and underscores that the phenotype of this disordermay vary considerably, even within members of the samefamily, as in other recessive channelopathies aﬀectingmuscles.6Author contributionsC.K. Sloth: drafted the manuscript and performed adminis-trative work. F. Denti: tested the eﬀect of the SCN4A muta-tion in a cell line. N. Schmitt: tested the eﬀect of the SCN4Amutation in a cell line, interpreted data, revised the manu-script, and drafted ﬁgures. B.H. Bentzen: tested the eﬀect ofthe SCN4A mutation in a cell line. C. Fagerberg: in charge ofDNA-testing of the 2 sisters and revised the manuscript.J. Vissing and D. Gaist: design, revised the manuscript,interpreted clinical data, and drafted ﬁgures.Study fundingThis study did not receive external funding.DisclosureC.K. Sloth, F. Denti, N. Schmitt, B.H. Bentzen, andC. Fagerberg report no disclosures. J. Vissing has served onthe scientiﬁc advisory boards of Sanoﬁ Genzyme, aTyrPharma, Ultragenyx Pharmaceuticals, Santhera Pharmaceut-icals, Sarepta Therapeutics, Audentes Therapeutics, NovoNordisk, Alexion Pharmaceuticals, and Stealth BT; has re-ceived travel funding and speaker honoraria from SanoﬁGenzyme, Ultragenyx Pharmaceuticals, Santhera Pharma-ceuticals, and aTyr Pharma; serves on the editorial boards ofNeuromuscular Disorders and the Journal of NeuromuscularDiseases; has been a consultant for Sanoﬁ Genzyme, Ultra-genyx Pharmaceuticals, Santhera Pharmaceuticals, and aTyrPharma; and has received research support from the DanishMedical Research Council, the University of Copenhagen, theAugustinus Foundation, the NOVO Nordic Foundation, andthe Lundbeck Foundation. D. Gaist has received honoraria fromAstraZeneca (Sweden) for participation as a coinvestigator ina research project and has received research support from theDanish Cancer Society. Full disclosure form information pro-vided by the authors is available with the full text of this article atNeurology.org/NG.Received June 26, 2018. Accepted in ﬁnal form July 26, 2018.References1. Zaharieva IT, Thor MG, Oates EC, et al. Loss-of-function mutations in SCN4A causesevere foetal hypokinesia or “classical” congenital myopathy. Brain J Neurol 2016;139:674–691.2. Gonorazky HD, Marshall CR, Al-Murshed M, et al. Congenital myopathy with“corona” ﬁbres, selective muscle atrophy, and craniosynostosis associated with novelrecessive mutations in SCN4A. Neuromuscul Disord NMD 2017;27:574–580.3. Tsujino A, Maertens C, Ohno K, et al. Myasthenic syndrome caused by mutation ofthe SCN4A sodium channel. Proc Natl Acad Sci USA 2003;100:7377–7382.4. ArnoldWD, Feldman DH, Ramirez S, et al. Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome. Ann Neurol 2015;77:840–850.5. Ma¨nnikko¨ R, Wong L, Tester DJ, et al. Dysfunction of NaV1.4, a skeletal musclevoltage-gated sodium channel, in sudden infant death syndrome: a case-control study.Lancet 2018;391:1483–1492.6. Sahin I, Erdem HB, Tan H, Tatar A. Becker’s myotonia: novel mutations and clinicalvariability in patients born to consanguineous parents. Acta Neurol Belg Epub 2018Feb 26.Neurology.org/NG Neurology: Genetics | Volume 4, Number 5 | October 2018 3DOI 10.1212/NXG.00000000000002672018;4; Neurol Genet Christine K. Sloth, Federico Denti, Nicole Schmitt, et al. disease expression Arg1142Gln causes congenital myopathy with variableSCN4AHomozygosity for This information is current as of September 19, 2018ServicesUpdated Information & http://ng.neurology.org/content/4/5/e267.full.htmlincluding high resolution figures, can be found at:References http://ng.neurology.org/content/4/5/e267.full.html##ref-list-1This article cites 5 articles, 1 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/muscle_diseaseMuscle disease http://ng.neurology.org//cgi/collection/ion_channel_gene_defectsIon channel gene defectsfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2018 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet 

Homozygosity for SCN4A Arg1142Gln causes congenital myopathy with variable disease expression

University of Southern Denmark Research Output

Syddansk UniversitetHomozygosity for SCN4A Arg1142Gln causes congenital myopathy with variabledisease expressionSloth, Christine K; Denti, Federico; Schmitt, Nicole; Bentzen, Bo Hjorth; Fagerberg, ChristinaRingmann; Vissing, John; Gaist, DavidPublished in:Neurology: GeneticsDOI:10.1212/NXG.0000000000000267Publication date:2018Document versionPublisher's PDF, also known as Version of recordDocument licenseCC BY-NC-NDCitation for pulished version (APA):Sloth, C. K., Denti, F., Schmitt, N., Bentzen, B. H., Fagerberg, C., Vissing, J., & Gaist, D. (2018). Homozygosityfor SCN4A Arg1142Gln causes congenital myopathy with variable disease expression. Neurology: Genetics,4(5), [e267]. DOI: 10.1212/NXG.0000000000000267General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 15. Nov. 2018CLINICAL/SCIENTIFIC NOTES OPEN ACCESSHomozygosity for SCN4A Arg1142Gln causescongenital myopathy with variable diseaseexpressionChristine K. Sloth, MD, Federico Denti, PhD, Nicole Schmitt, PhD, Bo Hjorth Bentzen, PhD,Christina Fagerberg, MD, John Vissing, DMSci, and David Gaist, PhDNeurol Genet 2018;4:e267. doi:10.1212/NXG.0000000000000267CorrespondenceProf. Gaistdgaist@health.sdu.dkCongenital myopathy has recently been associated with biallelic pathogenic variants in theSCN4A gene that encodes the voltage-dependent sodium channel NaV1.4.1,2 In 13 previouslyreported cases,1,2 7 died in utero or shortly after birth. The 6 survivors showed features con-sistent with “classical” congenital myopathy. Here, we report 2 new familial cases with variablephenotype.Written informed consent was obtained from both patients. Permission for the study wasgranted by the Danish Data Protection Agency.The index patient, an 18-year-old woman, born as the second of 2 children to consanguineousparents, reported weakness and dyspnea from early childhood. Pregnancy and birth werenormal, but postpartum, she had dysphagia and was tube fed. Early motor milestones weredelayed, with independent ambulation achieved at age 2.25 years and inability to lift her headfrom a supine position until age 3 years. She experienced improvement in her conditionthroughout childhood, but still had reduced walking distance (2.5 km), diﬃculty lifting heavyobjects, and experienced patella luxations.On examination, the patient is 150 cm tall and has a dolichocephalic head shape and elbowhypermobility (ﬁgure 1A). Strength testing showed diﬀuse muscle force reduction at MedicalResearchCouncil (MRC) grade 4, with no distal/proximal gradient, and axial weakness. Spirometryshowed normal forced vital capacity (FVC) (88%) and forced expiratory volume (FEV1) (96%).Creatine kinase (CK) levels and neurophysiologic ﬁndings were normal. Replacement ofmuscle by fat on MRI was pronounced in gluteus maximus and hamstring muscles (ﬁgure 1B).Muscle biopsy, at age 4 years, displayed myopathic features with varying ﬁber size, increasednumber of internalized nuclei, atrophic ﬁbers, and endomysial ﬁbrosis and fat inﬁltration.Next-generation sequencing revealed homozygosity for a previously described missense variantin SCN4A (NM_000334.4: c.3425G>A(p.Arg.1142Gln)),2 conﬁrmed through Sanger se-quencing, and was deemed to be pathogenic by 6 prediction tools. Parents were heterozygousfor the variant.The 22-year-old sister of the index patient was also homozygous for Arg1142Gln. She hadmilder muscular complaints than her sister, which included diﬃculties lifting her head whenlying down, exertional shortness of breath, and poor cycling capacity since childhood. She hadelbow joint hypermobility like her sister. Her motor milestones were normal. Strength testingFrom the Department of Neurology (C.K.S., D.G.), Odense University Hospital; and Department of Clinical Research (C.K.S., D.G.), Faculty of Health Sciences, University of SouthernDenmark, Odense; Department of Biomedical Sciences (F.D., N.S., B.H.B.), Faculty of Health and Medical Sciences, University of Copenhagen; Department of Clinical Genetics (C.F.),Odense University Hospital; and Copenhagen Neuromuscular Center, Department of Neurology (J.V.), Rigshospitalet, University of Copenhagen, Denmark.Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article atNeurology.org/NG.The Article Processing Charge was funded by the authors.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloadingand sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1Figure 1 Clinical features in sisters with SCN4A congenital myopathyFeaturing the dococephalic head form in the indexpatient (left image) andhypermobility of the elbows inboth sisters (middle and right image) (A). T1-weightedmuscle MRI images of the index patient show severefatty infiltration and atrophy of gluteus medius(arrows, left image) and adductor magnus and, toa lesser degree, the hamstrings bilaterally (right im-age) (B).Figure 2 The mutation R1142Q causes loss-of-function of NaV1.4 current(A) Representative current traces forNaV1.4 WT and R1142Q recordedfrom transiently transfectedHEK293 cells. (B) I/V relationship forthe peak current density for NaV1.4WT (n = 9) and R1142Q (n = 8).Voltage protocol shown as inset. (C)Steady-state inactivation and acti-vation curves for NaV1.4 WT (black)and R1142Q (gray). Voltage protocolshown as inset. (D) Comparison ofactivation V50 values betweenNaV1.4 WT (black) and R1142Q(gray). *p < 0.05; **p < 0.006; ****p< 0.0001.2 Neurology: Genetics | Volume 4, Number 5 | October 2018 Neurology.org/NGshowed reduced neck ﬂexion (MRC 4+), shoulder abduction(MRC4+), and hip ﬂexion (MRC 4+). CK, lung functiontests, and MRI of thigh muscles were normal.Functional assessment of the Arg1142Gln (R1142Q) variant inhuman embryonic kidney 293 (HEK293) cells revealed partialloss-of-function eﬀects (ﬁgure 2), as previously reported inSCN4A-related congenital myopathy.1,2 NaV1.4 R1142Q peakcurrent density was signiﬁcantly lower than wild type (WT)(WT: 106.4 ± 12.4 pA/pF, R1142Q: −39.0 ± 6.4 pA/pF at5 mV, ﬁgure 2, A and B), and the voltage dependence of channelactivation was signiﬁcantly changed (ﬁgure 2, C and D).Variants in SCN4A were originally linked to congenitalmyasthenia,3,4 but recently, also to severe fetal hypokinesia andearly lethality1 and to sudden infant death syndrome.5 Astrikingly milder phenotype of “classical” congenital myopathyhas been described in 6 patients with SCN4A variants in a re-cessive pattern, only 3 of whom were adults (aged 18–35 yearsold).1,2 Our 18-year-old index patient exhibited a phenotypesimilar to that previously reported,1 while her 20-year-old sisterwas only marginally aﬀected. Our index patient’s characteristicmuscle MRI ﬁndings were similar to 4 other patients withSCN4A mutations, including 2 brothers, compound hetero-zygous for c.3425G>A(p.Arg1142Gln) and another missensevariant c.1123T>C (p.Cys375Arg).1,2 The brothers, unlike ourpatients, had elongated faces, ptosis, facial weakness, scoliosis,and elevated CK.2 We speculate whether homozygosity for thep.Arg1142Gln variant conferred the milder phenotype ob-served in our patients. The present report expands ourknowledge regarding SCN4A-related congenital myopathy inadulthood and underscores that the phenotype of this disordermay vary considerably, even within members of the samefamily, as in other recessive channelopathies aﬀectingmuscles.6Author contributionsC.K. Sloth: drafted the manuscript and performed adminis-trative work. F. Denti: tested the eﬀect of the SCN4A muta-tion in a cell line. N. Schmitt: tested the eﬀect of the SCN4Amutation in a cell line, interpreted data, revised the manu-script, and drafted ﬁgures. B.H. Bentzen: tested the eﬀect ofthe SCN4A mutation in a cell line. C. Fagerberg: in charge ofDNA-testing of the 2 sisters and revised the manuscript.J. Vissing and D. Gaist: design, revised the manuscript,interpreted clinical data, and drafted ﬁgures.Study fundingThis study did not receive external funding.DisclosureC.K. Sloth, F. Denti, N. Schmitt, B.H. Bentzen, andC. Fagerberg report no disclosures. J. Vissing has served onthe scientiﬁc advisory boards of Sanoﬁ Genzyme, aTyrPharma, Ultragenyx Pharmaceuticals, Santhera Pharmaceut-icals, Sarepta Therapeutics, Audentes Therapeutics, NovoNordisk, Alexion Pharmaceuticals, and Stealth BT; has re-ceived travel funding and speaker honoraria from SanoﬁGenzyme, Ultragenyx Pharmaceuticals, Santhera Pharma-ceuticals, and aTyr Pharma; serves on the editorial boards ofNeuromuscular Disorders and the Journal of NeuromuscularDiseases; has been a consultant for Sanoﬁ Genzyme, Ultra-genyx Pharmaceuticals, Santhera Pharmaceuticals, and aTyrPharma; and has received research support from the DanishMedical Research Council, the University of Copenhagen, theAugustinus Foundation, the NOVO Nordic Foundation, andthe Lundbeck Foundation. D. Gaist has received honoraria fromAstraZeneca (Sweden) for participation as a coinvestigator ina research project and has received research support from theDanish Cancer Society. Full disclosure form information pro-vided by the authors is available with the full text of this article atNeurology.org/NG.Received June 26, 2018. Accepted in ﬁnal form July 26, 2018.References1. Zaharieva IT, Thor MG, Oates EC, et al. Loss-of-function mutations in SCN4A causesevere foetal hypokinesia or “classical” congenital myopathy. Brain J Neurol 2016;139:674–691.2. Gonorazky HD, Marshall CR, Al-Murshed M, et al. Congenital myopathy with“corona” ﬁbres, selective muscle atrophy, and craniosynostosis associated with novelrecessive mutations in SCN4A. Neuromuscul Disord NMD 2017;27:574–580.3. Tsujino A, Maertens C, Ohno K, et al. Myasthenic syndrome caused by mutation ofthe SCN4A sodium channel. Proc Natl Acad Sci USA 2003;100:7377–7382.4. ArnoldWD, Feldman DH, Ramirez S, et al. Defective fast inactivation recovery of Nav1.4 in congenital myasthenic syndrome. Ann Neurol 2015;77:840–850.5. Ma¨nnikko¨ R, Wong L, Tester DJ, et al. Dysfunction of NaV1.4, a skeletal musclevoltage-gated sodium channel, in sudden infant death syndrome: a case-control study.Lancet 2018;391:1483–1492.6. Sahin I, Erdem HB, Tan H, Tatar A. Becker’s myotonia: novel mutations and clinicalvariability in patients born to consanguineous parents. Acta Neurol Belg Epub 2018Feb 26.Neurology.org/NG Neurology: Genetics | Volume 4, Number 5 | October 2018 3DOI 10.1212/NXG.00000000000002672018;4; Neurol Genet Christine K. Sloth, Federico Denti, Nicole Schmitt, et al. disease expression Arg1142Gln causes congenital myopathy with variableSCN4AHomozygosity for This information is current as of September 19, 2018ServicesUpdated Information & http://ng.neurology.org/content/4/5/e267.full.htmlincluding high resolution figures, can be found at:References http://ng.neurology.org/content/4/5/e267.full.html##ref-list-1This article cites 5 articles, 1 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/muscle_diseaseMuscle disease http://ng.neurology.org//cgi/collection/ion_channel_gene_defectsIon channel gene defectsfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2018 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet 

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Homozygosity for SCN4A Arg1142Gln causes congenital myopathy with variable disease expression

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