Contractile properties and magnetic resonance imaging-assessed fat replacement of muscles in myotonia congenita.

BACKGROUND AND PURPOSE: Myotonia congenita (MC) is a muscle channelopathy in which pathogenic variants in a key sarcolemmal chloride channel Gene (CLCN1) cause myotonia. This study used muscle magnetic resonance imaging (MRI) to quantify contractile properties and fat replacement of muscles in a Danish cohort of MC patients. METHODS: Individuals with the Thomsen (dominant) and Becker (recessive) variants of MC were studied. Isometric muscle strength, whole-body MRI, and clinical data were collected. The degree of muscle fat replacement of thigh, calf, and forearm muscles was quantitively calculated on Dixon MRI as fat fractions (FFs). Contractility was evaluated as the muscle strength per contractile muscle cross-sectional area (PT/CCSA). Muscle contractility was compared with clinical data. RESULTS: Intramuscular FF was increased and contractility reduced in calf and in forearm muscles compared with controls (FF = 7.0-14.3% vs. 5.3-9.6%, PT/CCSA = 1.1-4.9 Nm/cm2 vs. 1.9-5.8 Nm/cm2 [p < 0.05]). Becker individuals also showed increased intramuscular FF and reduced contractility of thigh muscles (FF = 11.9% vs. 9.2%, PT/CCSA = 1.9 Nm/cm2 vs. 3.2 Nm/cm2 [p < 0.05]). Individual muscle analysis showed that increased FF was limited to seven of 18 examined muscles (p < 0.05). There was a weak correlation between reduced contractility and severity of symptoms. CONCLUSIONS: Individuals with MC have increased fat replacement and reduced contractile properties of muscles. Nonetheless, changes were small and likely did not impact clinically on their myotonic symptoms.

A complex CLCN1 variant associated with hereditary myotonia in a mixed-breed dog.

Hereditary myotonia (HM) is characterized by delayed muscle relaxation after contraction as a result of a mutation in the CLCN1 gene. We describe here a complex CLCN1 variant in a mixed-breed dog with clinical and electromyographic signs of HM. Blood samples from the myotonic dog, as well as from his male littermate and parents, were analyzed via amplification of the 23 exons encoding CLCN1. After sequencing the CLCN1 gene, a complex variant was found in exon 6 c.[705T>G; 708del; 712_732del], resulting in a premature stop codon in exon 7 and a protein that was 717 amino acids shorter than the normal CLC protein. The myotonic dog was identified as homozygous recessive for the complex CLCN1 variant; its parents were heterozygous, and its male littermate was homozygous wild-type. Knowledge of the CLCN1 mutations responsible for the development of hereditary myotonia allows greater clarification of this condition.

Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report.

BACKGROUND: Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia. CASE PRESENTATION: We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described. CONCLUSIONS: Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

[Congenital myotonia. Incidence and presentation of a series of cases]. / Miotonía congénita. Incidencia y presentación de una serie de casos.

INTRODUCTION: Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration. CASES REPORT: The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker's disease and two with Thomsen's disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C). CONCLUSIONS: the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.

TITLE: Miotonía congénita. Incidencia y presentación de una serie de casos.Introducción. La miotonía congénita es la forma más común de miotonía de causa genética y se produce por mutaciones en el gen CLCN1. Puede heredarse de manera autosómica dominante o recesiva. Presentamos una serie de casos para actualizar su incidencia en nuestro medio, para describir su fenotipo en relación con el genotipo encontrado y, además, revisamos las mutaciones encontradas, entre las que aportamos una nueva alteración no descrita. Casos clínicos. Se revisaron las historias clínicas de pacientes con diagnóstico de miotonía congénita estudiados y seguidos en la consulta de neurología pediátrica en un hospital de tercer nivel entre los años 2015 y 2020. Se recogieron variables demográficas (edad y sexo), curso de la enfermedad (edad de inicio, síntomas y signos, tiempo transcurrido hasta el diagnóstico y evolución clínica), antecedentes familiares y evaluación de la respuesta al tratamiento. Se identificaron cinco casos con diagnóstico clínico de miotonía congénita (tres con enfermedad de Becker y dos con enfermedad de Thomsen). La incidencia en relación con el número de nacimientos la estimamos en 1:15.000 recién nacidos para los casos con fenotipo Becker y en 1:21.000 recién nacidos para los fenotipos Thomsen. Hallamos una mutación probablemente patogénica no descrita previamente (CLCN1: c.824T>C). Conclusiones. La incidencia aproximada en nuestro medio fue superior a la previamente conocida y describimos una nueva mutación no descrita: c.824T>C, con predictores de patogenicidad, que se comportó como un fenotipo recesivo Becker, pero con inicio más temprano.

Value of short exercise and short exercise with cooling tests in diagnosis of recessive form of myotonia congenita (Becker disease) - are sex differences important?

INTRODUCTION: In myotonia congenita (MC), activation with exercise or cooling can induce transient changes in compound motor action potential (CMAP) parameters, thus providing a guide to genetic analysis. MATERIAL AND METHODS: We performed the short exercise test (SET) and the short exercise test with cooling (SETC) in 30 patients with genetically confirmed Becker disease (BMC) to estimate their utility in the diagnosis of BMC. RESULTS: Although we observed a significant decrease in CMAP amplitude immediately after maximal voluntary effort in both tests in the whole BMC group, in men this decline was significantly smaller than in women, especially in SET. Clinical implications/future directions: In men with a clinical suspicion of BMC, a small decrease in CMAP amplitude in SET together with a typical decline in SETC does not exclude the diagnosis of BMC. Our results show a sex-specific difference in chloride channel function in BMC, which needs further investigation.

[Rhabdomyolysis - the chamaeleon of the intensive care unit]. / Rhabdomyolyse ­ das Chamäleon auf der Intensivstation.

Myotonia congenita Thomsen is a rare genetic disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1). Although this channelopathy may cause disabling muscle symptoms, patient's daily routine can be almost inconspicuous. Nevertheless, during illness or acute diseases this neuromuscular disease may worsen and get clinically apparent up to severe rhabdomyolysis. Within this case report we describe and discuss the treatment of a patient with Myotonia congenita Thomsen treated at our hospital's intensive care unit. Rhabdomyolysis with acute renal failure and necessity of dialysis during the ICU stay was attributed to the initial reason for emergency hospitalization - an aortic dissection. Nevertheless, in this case the patient's myotonia caused rhabdomyolysis and initially led us on a wrong path. Diagnosis of the real cause of rhabdomyolysis is often difficult, although an early and adequate therapy may prevent complications. This case report demonstrates the importance of a thorough anamnesis with all aspects of the patient's history.

A novel mutation of the CLCN1 gene in a cat with myotonia congenita: Diagnosis and treatment.

CASE DESCRIPTION: A 10-month-old castrated male domestic longhair cat was evaluated for increasing frequency of episodic limb rigidity. CLINICAL FINDINGS: The cat presented for falling over and lying recumbent with its limbs in extension for several seconds when startled or excited. Upon examination, the cat had hypertrophied musculature, episodes of facial spasm, and a short-strided, stiff gait. DIAGNOSTICS: Electromyography (EMG) identified spontaneous discharges that waxed and waned in amplitude and frequency, consistent with myotonic discharges. A high impact 8-base pair (bp) deletion across the end of exon 3 and intron 3 of the chloride voltage-gated channel 1 (CLCN1) gene was identified using whole genome sequencing. TREATMENT AND OUTCOME: Phenytoin treatment was initiated at 3 mg/kg po q24 h and resulted in long-term improvement. CLINICAL RELEVANCE: This novel mutation within the CLCN1 gene is a cause of myotonia congenita in cats and we report for the first time its successful treatment.

Non-dystrophic myotonia: 2-year clinical and patient reported outcomes.

INTRODUCTION/AIMS: Consistency of differences between non-dystrophic myotonias over time measured by standardized clinical/patient-reported outcomes is lacking. Evaluation of longitudinal data could establish clinically relevant endpoints for future research. METHODS: Data from prospective observational study of 95 definite/clinically suspected non-dystrophic myotonia participants (six sites in the United States, United Kingdom, and Canada) between March 2006 and March 2009 were analyzed. Outcomes included: standardized symptom interview/exam, Short Form-36, Individualized Neuromuscular Quality of Life (INQoL), electrophysiological short/prolonged exercise tests, manual muscle testing, quantitative grip strength, modified get-up-and-go test. Patterns were assigned as described by Fournier et al. Comparisons were restricted to confirmed sodium channelopathies (SCN4A, baseline, year 1, year 2: n = 34, 19, 13), chloride channelopathies (CLCN1, n = 32, 26, 18), and myotonic dystrophy type 2 (DM2, n = 9, 6, 2). RESULTS: Muscle stiffness was the most frequent symptom over time (54.7%-64.7%). Eyelid myotonia and paradoxical handgrip/eyelid myotonia were more frequent in SCN4A. Grip strength and combined manual muscle testing remained stable. Modified get-up-and-go showed less warm up in SCN4A but remained stable. Median post short exercise decrement was stable, except for SCN4A (baseline to year 2 decrement difference 16.6% [Q1, Q3: 9.5, 39.2]). Fournier patterns type 2 (CLCN1) and 1 (SCN4A) were most specific; 40.4% of participants had a change in pattern over time. INQoL showed higher impact for SCN4A and DM2 with scores stable over time. DISCUSSION: Symptom frequency and clinical outcome assessments were stable with defined variability in myotonia measures supporting trial designs like cross over or combined n-of-1 as important for rare disorders.

Clinical and molecular characteristics of myotonia congenita in China: Case series and a literature review.

Myotonia congenita (MC) is a rare genetic disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1), encoding the voltage-gated chloride channel ClC-1 in skeletal muscle. Our study reported the clinical and molecular characteristics of six patients with MC and systematically review the literature on Chinese people. We retrospectively analyzed demographics, clinical features, family history, creatine kinase (CK), electromyography (EMG), treatment, and genotype data of our patients and reviewed the clinical data and CLCN1 mutations in literature. The median ages at examination and onset were 26.5 years (range 11-50 years) and 6.5 years (range 1.5-11 years), respectively, in our patients, and 21 years (range 3.5-65 years, n = 45) and 9 years (range 0.5-26 years, n = 50), respectively, in literature. Similar to previous reports, myotonia involved limb, lids, masticatory, and trunk muscles to varying degrees. Warm-up phenomenon (5/6), percussion myotonia (3/5), and grip myotonia (6/6) were common. Menstruation triggered myotonia in females, not observed in Chinese patients before. The proportion of abnormal CK levels (4/5) was higher than data from literature. Electromyography performed in six patients revealed myotonic changes (100%). Five novel CLCN1 mutations, including a splicing mutation (c.853 + 4A>G), a deletion mutation (c.2010_2014del), and three missense mutations (c.2527C>T, c.1727C>T, c.2017 G > C), were identified. The c.892 G > A (p.A298T) mutation was the most frequent mutation in the Chinese population. Our study expanded the clinical and genetic spectrum of patients with MC in the China. The MC phenotype in Chinese people is not different from that found in the West, while the genotype is different.

[On the Conceptual History of Myotonia Congenita: The Contributions of Julius Thomsen and Adolph Seeligmüller]. / Zur Konzeptgeschichte der Myotonia congenita: Die Beiträge von Julius Thomsen und Adolph Seeligmüller.

Myotonia congenita was first described as an entity in 1876 by Julius Thomsen. Shortly later in the same year it was criticized by Adolph Seeligmüller who extended the clinical findings. Charles Bell, Moritz Benedict and Ernst von Leyden had already partly described the symptoms of the disease before 1876, but did not recognize this as a new entity. A comparison of the publications of Thomsen and Seeligmüller in 1876 and of Seeligmüller's textbook published in 1887, as well as the today's genetically proven disease shows that Seeligmüller correctly criticized two aspects of Thomsen's publication: (i) Thomsen suspected the pathogenesis to be in "one half of the brain's activity, the will" with "seat in the cerebrospinal system" and (ii) he made the assumption of a coordination disorder in the sense of an ataxia [1]. Due to a better understanding of the pathogenesis enabled by Seeligmüller's postulate of a "more difficult mobile muscle substance" [2] without excluding an inborn affection of the lateral cords of the spinal cord, it would have been entirely justified to recognize Seeligmüller's contribution to the conceptual history of Myotonia congenita by including his name in the eponym [3].

Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d-transposition of the great arteries.

BACKGROUND: Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1-related myopathies (RYR1-RM); the most common subgroup of congenital myopathies. METHODS: Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole-exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole-genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis. RESULTS: WGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1-RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries. CONCLUSION: While there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1-RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.

Diagnostic yield of muscle biopsy in infants: Retrospective analysis of clinical and histopathologic findings.

The aim was to define the clinical and histopathologic findings of infants who underwent muscle biopsy and identify the diagnostic yield of muscle biopsy in this cohort. Infants who underwent muscle biopsy from January 2010 to March 2017 at a tertiary hospital were included in the study (N = 87; 64 boys (73.6%), 23 girls (26.4%); age range 0 - 2 years; mean age 9.73 ± 7.04 months). Clinical and histopathologic data were obtained from medical records. Developmental delay (64.4%) and hypotonia (59.8%) were the most frequent clinical findings, and mitochondrial disease (61%) was the most frequent clinical diagnosis, followed by muscular dystrophy (15.9%) and congenital myopathy (11.5%). Creatine kinase level was normal in 65.9% and > 1,000 U/L in 17.1%. Specific pathologic findings were identified from 38 biopsies (43.7%). The most frequent pathologic findings were features compatible with mitochondrial/metabolic myopathy (14 patients, 16.1%) and muscular dystrophy (12 patients, 13.8%). Myopathic changes were present in 7 biopsy samples (8.0%) and neurogenic changes in 5 (5.7%). The clinical and pathologic diagnoses were compatible in 24 patients (63.2%). The diagnostic yield of muscle biopsy remains significant, especially in this age group. Mitochondrial disease is a major diagnostic challenge, and muscle biopsy helps to support the clinical diagnosis and guide further studies.

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.

Myotonia is a neuromuscular condition that causes problems with the relaxation of muscles following voluntary movements. One type of myotonia is Becker disease, also called recessive myotonia congenita. This is a genetic condition that causes muscle stiffness as a result of involuntary muscle activity. Patients may also suffer transient weakness for a few seconds or as long as several minutes after initiating a movement. The cause of these bouts of temporary weakness is still unclear, but there are hints that it could be linked to the muscle losing its excitability, the ability to respond to the stimuli that make it contract. However, this is at odds with findings that show that muscles in Becker disease are hyperexcitable. Muscle excitability depends on the presence of different concentrations of charged ions (positively charged sodium, calcium and potassium ions and negatively charged chloride ions) inside and outside of each muscle cells. These different concentrations of ions create an electric potential across the cell membrane, also called the 'membrane potential'. When a muscle cell gets stimulated, proteins on the cell membrane known as ion channels open. This allows the flow of ions between the inside and the outside of the cell, which causes an electrical current that triggers muscle contraction. To better understand the causes behind this muscle weakness, Myers et al. used mice that had either been genetically manipulated or given drugs to mimic Becker disease. By measuring both muscle force and the electrical currents that drive contraction, Myers et al. found that the mechanism underlying post-movement weakness involved a transient change in the concentrations of positively charged ions inside and outside the cells. Further experiments showed that proteins that regulate the passage of both sodium and calcium in and out of the cell ­ called sodium and calcium channels ­ contributed to this change in concentration. In addition, Myers et al. discovered that using a drug called ranolazine to stop sodium ions from entering the cell eliminated transient weakness in live mice. These findings suggest that in Becker disease, muscles cycle rapidly between being hyperexcited or not able to be excited, and that targeting the flow of sodium ions into the cell could be an effective treatment to prevent transient weakness in myotonia congenita. This study paves the way towards the development of new therapies to treat Becker disease as well as other muscle ion channel diseases with transient weakness such as periodic paralysis.

Making sense of missense variants in TTN-related congenital myopathies.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Recessive myotonia congenita caused by a homozygous splice site variant in CLCN1 gene: a case report.

BACKGROUND: Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state. CASE PRESENTATION: We report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities. CONCLUSIONS: Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.

Chronic inflammatory demyelinating polyradiculoneuropathy relapse after mexiletine withdrawal in a patient with concomitant myotonia congenita: A case report on a potential treatment option.

INTRODUCTION: we report on the first case of a woman affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and recessive myotonia congenita (MC), treated with mexiletine. We aimed at describing the possible role of mexiletine in CIDP management. PATIENT CONCERNS: A 44-year-old female affected by CIDP and MC, gained beneficial effects for CIDP symptoms (muscle weakness, cramps, and fatigue) and relapses, after mexiletine intake (200 mg twice a day). The patient presented with detrimental effects after mexiletine drop out, with a worsening of CIDP symptoms. INTERVENTIONS: The patient reported a nearly complete remission of muscle stiffness and weakness up to 3 years since mexiletine intake. Then, she developed an allergic reaction with glottis edema, maybe related to mexiletine intake, as per emergency room doctors' evaluation, who suggested withdrawing the drug. OUTCOMES: The patient significantly worsened after the medication drop out concerning both CIDP and MC symptoms. CONCLUSION: This is the first report on the association of CIDP and MC in the same patient. Such diseases may share some clinical symptoms related to a persistent sodium currents increase, which maybe due either to the over-expression of sodium channels following axonal damage due to demyelination or to the chloride channel genes mutations. This is the possible reason why mexiletine maybe promising to treat CIDP symptoms.

Brody myopathy demonstrates a pseudo-increment on repetitive nerve stimulation.

INTRODUCTION: Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM. METHODS: We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM. RESULTS: All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001). DISCUSSION: Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype.

Congenital Myotonic Dystrophy and Brugada Syndrome: A Report of Two Cases.

BACKGROUND Congenital myotonic dystrophy is a subtype of type 1 myotonic dystrophy presenting in the neonatal period. Cardiac involvement is commonly seen in patients with type 1 myotonic dystrophy beyond the neonatal period. Brugada syndrome is a conduction abnormality associated with a mutation in the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene and has been described in adult patients with type 1 myotonic dystrophy. Two cases are presented of type 1 myotonic dystrophy in neonates, one who had family members with a confirmed diagnosis of Brugada syndrome. CASE REPORT Case 1: A female infant at 40 weeks gestational age, birth weight of 3,395 grams was born to a 40-year-old gravida 4, para 3 (G4P3) mother. The mother had previously been diagnosed with Brugada syndrome. Multiple family members were identified and diagnosed with type 1 myotonic dystrophy and Brugada syndrome. The infant is being monitored closely with a plan to perform genetic testing for Brugada syndrome if she develops cardiac conduction abnormalities. Case 2: A male infant at 37 weeks gestational age, with a birth weight of 2,900 grams, was born to a 24-year-old gravida 2, para 1 (G2P1) mother. He was admitted to the neonatal intensive care unit (NICU) secondary to poor respiratory effort and generalized hypotonia. Severe polyhydramnios was diagnosed during pregnancy. The mother had previously been diagnosed with type 1 myotonic dystrophy. CONCLUSIONS Infants with congenital myotonic dystrophy should be carefully monitored for both structural and conduction abnormalities of the heart, supported by genetic testing.