KCNG1-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf

Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in KCNG1 affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for KCNG1 as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible KCNG1-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.

Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients

Background:CLCN1-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. However, there is limited data of clinical and molecular spectrum of MC patients in China.Patients and Methods: Five patients with myotonia congenita due to mutations in CLCN1 gene were enrolled, which were identified through trio-whole-exome sequencing or panel-based next-generation sequencing test. The clinical presentation, laboratory data, electrophysiological tests, muscular pathology feature, and genetic results were collected and reviewed. We also searched all previously reported cases of MC patients with genetic diagnosis in Chinese populations, and their data were reviewed.Results: The median onset age of five patients was 3.0 years old, ranging from 1.0 to 5.0 years old, while the median age of admit was 5.0 years old, ranging from 3.5 to 8.8 years old. Five patients complained of muscle stiffness when rising from chairs or starting to climb stairs (5/5, 100.0%), four patients complained of delayed relaxation of their hands after forceful grip (4/5, 80.0%), all of which improved with exercise (warm-up phenomenon) (5/5, 100%). Electromyogram was conducted in five patients, which all revealed myotonic change (100%). Genetic tests revealed nine potential disease-causing variants in CLCN1 gene, including two novel variants: c.962T>A (p.V321E) and c.1250A>T (p.E417V). Literature review showed that 43 MC Chinese patients with genetic diagnosis have been reported till now (including our five patients). Forty-seven variants in CLCN1 gene were found, which consisted of 33 missense variants, 6 nonsense variants, 5 frame-shift variants, and 3 splicing variants. Variants in exon 8, 15, 12, and 16 were most prevalent, while the most common variants were c.892G>A (p.A298T) (n = 9), c.139C>T (p.R47W) (n = 3), c.1205C>T(p.A402V) (n = 3), c.1657A>T (p.I553F) (n = 3), c.1679T>C (p.M560T) (n = 3), c.350A>G (p.D117G) (n = 2), c.762C>G (p.C254W) (n = 2), c.782A>G (P.Y261C) (n = 2), and c.1277C>A (p.T426N) (n = 2).Conclusion: Our results reported five CLCN1-related MC patients, which expanded the clinical and genetic spectrum of MC patients in China. Based on literature review, 43MC Chinese patients with genetic diagnosis have been reported till now, and variants in exon eight were most prevalent in Chinese MC patients while c.892G>A (p.A298T) was probably a founder mutation.

Zur Konzeptgeschichte der Myotonia congenita: Die Beiträge von Julius Thomsen und Adolph Seeligmüller

ZusammenfassungDie Erkrankung Myotonia congenita wurde als Entität 1876 erstmals durch Julius Thomsen beschrieben. Noch im gleichen Jahr wurde diese Beschreibung von Adolph Seeligmüller kritisch betrachtet und um wesentliche Befunde ergänzt. Bereits Charles Bell, Moritz Benedict und Ernst von Leyden hatten vor 1876 die Symptomatik der Erkrankung beschrieben, ohne jedoch eine neue Entität anzunehmen. Der Vergleich der Publikationen von Thomsen und Seeligmüller von 1876 untereinander und mit Seeligmüllers Lehrbuchkapitel von 1887 sowie mit dem heute genetisch gesicherten Krankheitsbild zeigt, dass Seeligmüller zurecht zwei Aspekte an Thomsens Publikation kritisierte: (i) Die von Thomsen vermutete Pathogenese in „der einen Thätigkeitshälfte des Gehirns, des Willens“ mit „Sitz im Cerebrospinalsysteme“ und (ii) die Annahme einer Koordinationsstörung im Sinne einer Ataxie [1]. Demgegenüber diskutierte Seeligmüller eine „schwerer beweglich Muskelsubstanz“ [2] als Pathogenese mit der er gleichwohl eine angeborene Affection der Seitenstränge des Rückenmarks nicht ausschließen wollte. Es wäre deshalb durchaus gerechtfertigt gewesen, Seeligmüllers Anteil an der Konzeptgeschichte der Myotonia congenita durch die Aufnahme seines Namens in das Eponym zu würdigen [3].

The mechanism underlying transient weakness in myotonia congenita

In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to −25 to −35 mV in the genetic and pharmacologic models of Becker disease. Both Na+ and Ca2+ currents contribute to plateau potentials. Na+ persistent inward current (NaPIC) through NaV1.4 channels is the key trigger of plateau potentials and current through CaV1.1 Ca2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita.

Identification of Novel Mutations of the CLCN-1 and SCN4A Genes in Non-dystrophic Myotonia in China

Background: The aim of our study was to characterize the genetic, pathological and clinical alterations of 17 patients in China presenting with non-dystrophic myotonia (NDM). Methods: We first sequenced the CLCN-1 gene in patients having clinical features and muscle pathology indicative of NDM. If no mutations were detected, we subsequently analyzed the SCN4A, KCNE3 and CACNA1S genes. Results: As determined by needle electromyography, patients may have accompanying atypical myopathy as well as muscle hypertrophy, secondary dystonia and joint contracture All participants in this study were administered mexiletine in combination with carbamazepine and showed significant improvements in their myotonia symptoms. Routine pathological examinations showed mild abnormalities in muscle pathology. Oxidative enzyme activity was decreased in many fibers. ATPase studies of fiber subtypes demonstrated a predominance of type 2A fibers and a complete absence of type 2B muscle fibers in patients with CLCN-1 mutations. CLCN-1 gene mutations were found in 8 cases diagnosed with myotonia congenital by gene screening. The detected mutations included 5 missense, 2 nonsense, 1 deletion and 2 insertions, and these CLCN-1 mutations were concentrated in exons 8 and 12. Further gene analysis showed 4 mutations in the SCN4A gene in patients diagnosed with paramyotonia congenita. One of these mutations was consistent with a previously reported mutation, whereas 3 mutations were novel. All of these novel mutations occurred within “hot spots” of exons 22 and 24. Five patients with NDM lacked any identifiable mutations in CLCN-1, SCN4A, CACNA1S or KCNE3. Conclusions: Myotonia congenita and paramyotonia congenita are the predominant forms of NDM in China. NDM may be best diagnosed using genetic analysis in combination with clinical features. New mutations of the CLCN-1 and SCN4A genes in patients with NDM were detected, we postulate that novel pathogenic genes for NDM occur in China.