Novel N‐terminal truncating <i>CLCN1</i> mutation in severe becker disease

Hoche, Franziska; Seidel, Kay; Barbosa-Sicard, Eduardo; Heidegger, Tonio; Kang, Jun-Suk; Koenig, Rainer; Kieslich, Matthias

doi:10.1002/mus.24312

Cited by 4 publications

(5 citation statements)

References 8 publications

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“…Similarly to clinical reports of Hereditary Myotonia affecting humans 7–13 and other animals 16–22 , myotonic pigs exhibited muscle hypertrophy and stiffness, startle response, and warm-up phenomenon. Observed phenotypic variation was similar to that on buffalos 20 , cats 21 , goats 36 , and humans 9,10 affected by mutations in the CLCN1 gene.…”

Section: Discussionsupporting

confidence: 58%

“…The leading causes of the former (i.e., Myotonia Congenita or Hereditary Myotonia) are mutations in the CLCN1 gene inherited in either an autosomal dominant or recessive mode 4–6 . Hereditary Myotonia has extensively been reported in humans 7–13 , and it has been associated with more than 200 different mutations affecting the CLCN1 gene 14 . This disease has also been associated with mutations in the CLCN1 gene in rats 15 , goats 16 , dogs 17,18 , horses 19 , buffalo 20 , cats 21 , and sheep 22 .…”

Section: Introductionmentioning

confidence: 99%

“…This disease has also been associated with mutations in the CLCN1 gene in rats 15 , goats 16 , dogs 17,18 , horses 19 , buffalo 20 , cats 21 , and sheep 22 . It is clinically characterized by muscle stiffness after stimuli, muscle hypertrophy (mainly observed in the epaxial and appendicular muscles), and warm-up effect 7–13,15–21 . Humans and animals affected with Hereditary Myotonia, even with the same causative mutation, can present variable intensity of the clinical signs 17,18,20,21,23–25 .…”

Section: Introductionmentioning

confidence: 99%

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A large intragenic deletion in the CLCN1 gene causes Hereditary Myotonia in pigs

Araújo

Oliveira

Barbosa

et al. 2019

Sci Rep

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Mutations in the CLCN1 gene are the primary cause of non-dystrophic Hereditary Myotonia in several animal species. However, there are no reports of Hereditary Myotonia in pigs to date. Therefore, the objective of the present study was to characterize the clinical and molecular findings of Hereditary Myotonia in an inbred pedigree. The clinical, electromyographic, histopathological, and molecular findings were evaluated. Clinically affected pigs presented non-dystrophic recessive Hereditary Myotonia. Nucleotide sequence analysis of the entire coding region of the CLCN1 gene revealed the absence of the exons 15 and 16 in myotonic animals. Analysis of the genomic region flanking the deletion unveiled a large intragenic deletion of 4,165 nucleotides. Interestingly, non-related, non-myotonic pigs expressed transcriptional levels of an alternate transcript (i.e., X2) that was identical to the deleted X1 transcript of myotonic pigs. All myotonic pigs and their progenitors were homozygous recessive and heterozygous, respectively, for the 4,165-nucleotide deletion. This is the first study reporting Hereditary Myotonia in pigs and characterizing its clinical and molecular findings. Moreover, to the best of our knowledge, Hereditary Myotonia has never been associated with a genomic deletion in the CLCN1 gene in any other species.

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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A large intragenic deletion in the CLCN1 gene causes Hereditary Myotonia in pigs

Araújo

Oliveira

Barbosa

et al. 2019

Sci Rep

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“…Clinical signs related to the presence of the p.Met485Val were reported by Mazon et al (12) in a homozygous case sharing with our patient myotonia, and weakness after intense exercise. A clinical description of this mutation in heterozygous compound with p.Ser18Thrfs * 55 was also done by Hoche et al (13) in a boy of German/Indian origin presenting with symptoms of severe MC, including stiffness, myotonia after rapid initiation of movements, post-myotonic weakness, muscle pain, lid, percussion, and handgrip myotonia. Functional studies by protein expression in Xenopus oocytes had shown that this mutation led to a severe reduction of the single channel conductance becoming strongly inwardly rectifying, compared to wild type, thus the channel was incompletely deactivated at negative voltages (7).…”

Section: Discussionmentioning

confidence: 89%

Case report: Sodium and chloride muscle channelopathy coexistence: A complicated phenotype and a challenging diagnosis

Pagliarani

Meola²,

Filareti³

et al. 2022

Front. Neurol.

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Non-dystrophic myotonias (NDM) encompass chloride and sodium channelopathy. Mutations in CLCN1 lead to either the autosomal dominant form or the recessive form of myotonia congenita (MC). The main symptom is stiffness worsening after rest and improving by physical exercise. Patients with recessive mutations often show muscle hypertrophy, and transient weakness mostly in their lower limbs. Mutations in SCN4A can lead to Hyper-, Hypo- or Normo-kalemic Periodic Paralysis or to different forms of myotonia (Paramyotonia Congenita-PMC and Sodium Channel Myotonia-SCM and severe neonatal episodic laryngospasm-SNEL). SCM often presents facial muscle stiffness, cold sensitivity, and muscle pain, whereas myotonia worsens in PMC patients with the repetition of the muscle activity and cold. Patients affected by chloride or sodium channelopathies may show similar phenotypes and symptoms, making the diagnosis more difficult to reach. Herein we present a woman in whom sodium and chloride channelopathies coexist yielding a complex phenotype with features typical of both MC and PMC. Disease onset was in the second decade with asthenia, weakness, warm up and limb stiffness, and her symptoms had been worsening through the years leading to frequent heavy retrosternal compression, tachycardia, stiffness, and symmetrical pain in her lower limbs. She presented severe lid lag myotonia, a hypertrophic appearance at four limbs and myotonic discharges at EMG. Her symptoms have been triggered by exposure to cold and her daily life was impaired. All together, clinical signs and instrumental data led to the hypothesis of PMC and to the administration of mexiletine, then replaced by acetazolamide because of gastrointestinal side effects. Analysis of SCN4A revealed a new variant, p.Glu1607del. Nonetheless the severity of myotonia in the lower limbs and her general stiffness led to hypothesize that the impairment of sodium channel, Nav1.4, alone could not satisfactorily explain the phenotype and a second genetic “factor” was hypothesized. CLCN1 was targeted, and p.Met485Val was detected in homozygosity. This case highlights that proper identification of signs and symptoms by an expert neurologist is crucial to target a successful genetic diagnosis and appropriate therapy.

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“…28 A myotonic-associated mutation involving the adjacent codon (G230E/A/V) has been reported previously and mutation of glycine 230 to glutamate or alanine has been shown to yield functional channels. [29][30][31][32][33] Both residue V229 and G230 were in the E-F linker of CLC-1 7 .…”

Section: Discussionmentioning

confidence: 97%