Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita
Myotonia congenita, both in a dominant (Thomsen disease) and recessive form (Becker disease), is caused by molecular defects in CLCN1 that encodes the major skeletal muscle chloride channel, ClC-1. This channel is important for the normal repolarization of muscle action potentials and consequent rel...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2024.1486977/full |
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| author | Sabrina Lucchiari Francesco Fortunato Giovanni Meola Andrea Mignarri Serena Pagliarani Stefania Corti Stefania Corti Giacomo P. Comi Giacomo P. Comi Dario Ronchi Dario Ronchi |
| author_facet | Sabrina Lucchiari Francesco Fortunato Giovanni Meola Andrea Mignarri Serena Pagliarani Stefania Corti Stefania Corti Giacomo P. Comi Giacomo P. Comi Dario Ronchi Dario Ronchi |
| author_sort | Sabrina Lucchiari |
| collection | DOAJ |
| description | Myotonia congenita, both in a dominant (Thomsen disease) and recessive form (Becker disease), is caused by molecular defects in CLCN1 that encodes the major skeletal muscle chloride channel, ClC-1. This channel is important for the normal repolarization of muscle action potentials and consequent relaxation of the muscle, and its dysfunction leads to impaired muscle relaxation after voluntary or evoked contraction and muscle stiffness. More than 300 CLCN1 pathogenic variants have been found in association with congenital myotonia, inherited as recessive or dominant traits (with complete or incomplete penetrance). In this study, we describe the case of a 44-year-old woman complaining of “leg stiffness” since the age of 20 years and presenting with transient muscle weakness, especially after sitting for several minutes, with grip myotonia and feet myotonia, cold-sensitive and warm-up. The strength was normal, but muscle hypertrophy in the lower limbs was evident. EMG myotonia was detected in all explored muscles. The patient’s father had precocious cataract correction but did not show myotonic discharges at EMG. Examination of the patient’s sons (aged 18 years and 12 years) was unremarkable. The patient started treatment with mexiletine, with improvement in grip myotonia and limb stiffness, but it was soon interrupted due to gastrointestinal disturbances. Direct sequencing of CLCN1 identified the previously described heterozygous intronic variant c.1471 + 1G > A, which resulted in the skipping of exon 13 in the CLCN1 muscle transcript. In addition, the rare heterozygous synonymous nucleotide change c.762C > T p.Cys254Cys was identified and predicted to alter physiological splicing. The detection of multiple splicing abnormalities leading to premature termination codons supported the in silico prediction. We developed a Western blot assay to assess the ClC-1 protein in muscle biopsy, and we observed that ClC-1 levels were consistently reduced in the patient’s muscle, supporting the pathogenic behavior of the variants disclosed. Overall, we report a novel case of Becker myotonia and highlight the importance of multiple levels of analysis to achieve a firm molecular diagnosis. |
| format | Article |
| id | doaj-art-3f4c069e461a4546a1bbd4c61a7a6bbc |
| institution | Kabale University |
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| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj-art-3f4c069e461a4546a1bbd4c61a7a6bbc2024-12-06T06:50:44ZengFrontiers Media S.A.Frontiers in Genetics1664-80212024-12-011510.3389/fgene.2024.14869771486977Case report: Multiple approach analysis in a case of clinically assessed myotonia congenitaSabrina Lucchiari0Francesco Fortunato1Giovanni Meola2Andrea Mignarri3Serena Pagliarani4Stefania Corti5Stefania Corti6Giacomo P. Comi7Giacomo P. Comi8Dario Ronchi9Dario Ronchi10Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyDepartment of Neurorehabilitation Sciences, Casa di Cura Igea, Department of Biomedical Sciences for Health, Fondazione Malattie Miotoniche ETS, University of Milan, Milan, ItalyUnit of Neurology and Neurometabolic Diseases, Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyNeuromuscular and Rare Disease Unit, Department of Neuroscience, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, ItalyMyotonia congenita, both in a dominant (Thomsen disease) and recessive form (Becker disease), is caused by molecular defects in CLCN1 that encodes the major skeletal muscle chloride channel, ClC-1. This channel is important for the normal repolarization of muscle action potentials and consequent relaxation of the muscle, and its dysfunction leads to impaired muscle relaxation after voluntary or evoked contraction and muscle stiffness. More than 300 CLCN1 pathogenic variants have been found in association with congenital myotonia, inherited as recessive or dominant traits (with complete or incomplete penetrance). In this study, we describe the case of a 44-year-old woman complaining of “leg stiffness” since the age of 20 years and presenting with transient muscle weakness, especially after sitting for several minutes, with grip myotonia and feet myotonia, cold-sensitive and warm-up. The strength was normal, but muscle hypertrophy in the lower limbs was evident. EMG myotonia was detected in all explored muscles. The patient’s father had precocious cataract correction but did not show myotonic discharges at EMG. Examination of the patient’s sons (aged 18 years and 12 years) was unremarkable. The patient started treatment with mexiletine, with improvement in grip myotonia and limb stiffness, but it was soon interrupted due to gastrointestinal disturbances. Direct sequencing of CLCN1 identified the previously described heterozygous intronic variant c.1471 + 1G > A, which resulted in the skipping of exon 13 in the CLCN1 muscle transcript. In addition, the rare heterozygous synonymous nucleotide change c.762C > T p.Cys254Cys was identified and predicted to alter physiological splicing. The detection of multiple splicing abnormalities leading to premature termination codons supported the in silico prediction. We developed a Western blot assay to assess the ClC-1 protein in muscle biopsy, and we observed that ClC-1 levels were consistently reduced in the patient’s muscle, supporting the pathogenic behavior of the variants disclosed. Overall, we report a novel case of Becker myotonia and highlight the importance of multiple levels of analysis to achieve a firm molecular diagnosis.https://www.frontiersin.org/articles/10.3389/fgene.2024.1486977/fullmyotonia congenitaCLCN1Western blotsplicingexonic splicing silencer |
| spellingShingle | Sabrina Lucchiari Francesco Fortunato Giovanni Meola Andrea Mignarri Serena Pagliarani Stefania Corti Stefania Corti Giacomo P. Comi Giacomo P. Comi Dario Ronchi Dario Ronchi Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita Frontiers in Genetics myotonia congenita CLCN1 Western blot splicing exonic splicing silencer |
| title | Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita |
| title_full | Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita |
| title_fullStr | Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita |
| title_full_unstemmed | Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita |
| title_short | Case report: Multiple approach analysis in a case of clinically assessed myotonia congenita |
| title_sort | case report multiple approach analysis in a case of clinically assessed myotonia congenita |
| topic | myotonia congenita CLCN1 Western blot splicing exonic splicing silencer |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2024.1486977/full |
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