Anaesthesia challenges of a parturient with paramyotonia congenita and terminal filum lipoma presenting for labour and caesarean section under epidural anaesthesia - a case report.

BACKGROUND: Paramyotonia congenita is a rare autosomal dominant myopathy which presents with periodic weakness due to cold and exercise. It is caused by mutations of the SCN4 gene which encodes the sodium channel in skeletal muscles. CASE PRESENTATION: We report a full term obstetric patient with both paramyotonia congenita and terminal filum lipoma who presents for induction of labour followed by an emergency caesarean section performed under epidural anesthesia. Her recovery is subsequently complicated by a 3-day history of postpartum paraparesis attributed to hypokalemic periodic paralysis. CONCLUSION: We describe the perioperative anesthesia considerations and challenges in this case with a review of the current literature. This case report highlights the importance of early proactive and collaborative multidisciplinary approach, maintaining normal temperature and electrolytes with a heightened vigilance for muscle-related perioperative complications.

Open-label trial of ranolazine for the treatment of paramyotonia congenita.

INTRODUCTION: Paramyotonia congenita (PMC) is a nondystrophic myotonic disorder that is believed to be caused by a defect in Nav 1.4 sodium channel inactivation. Ranolazine, which acts by enhancing slow inactivation of sodium channels, has been proposed as a therapeutic option, but in vivo studies are lacking. METHODS: We conducted an open-label, single-center trial of ranolazine to evaluate efficacy and tolerability in patients with PMC. Subjective symptoms of stiffness, weakness, and pain as well as clinical and electrical myotonia were evaluated. Baseline measures were compared with those after 4 weeks of treatment with ranolazine. RESULTS: Ranolazine was tolerated well without any serious adverse events. Both subjective symptoms and clinical myotonia were significantly improved. Duration of myotonia was reduced according to electromyography, but this change was not statistically significant in all tested muscles. DISCUSSION: Our findings support the use of ranolazine as a treatment for myotonia in PMC and suggest that a randomized, placebo-controlled trial is warranted. Muscle Nerve 59:240-243, 2019.

Trouble at the junction: When myopathy and myasthenia overlap.

Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co-occurrence of myasthenia gravis or Lambert-Eaton myasthenic syndrome with an immune-mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.

Activation of the innate immune response and interferon signalling in myotonic dystrophy type 1 and type 2 cataracts.

Myotonic dystrophy (DM) is caused by a triplet repeat expansion in the non-coding region of either the DMPK (DM1) or CNBP (DM2) gene. Transcription of the expanded region causes accumulation of double-stranded RNA (dsRNA) in DM cells. We sought to determine how expression of triplet repeat RNA causes the varied phenotype typical of DM. Global transcription was measured in DM and non-DM cataract samples using Illumina Bead Arrays. DM samples were compared with non-DM samples and lists of differentially expressed genes (P≤ 0.05) were prepared. Gene set enrichment analysis and the Interferome database were used to search for significant patterns of gene expression in DM cells. Expression of individual genes was measured using quantitative real-time polymerase chain reaction. DMPK and CNBP expression was confirmed in native lens cells showing that a toxic RNA gain of function mechanism could exist in lens. A high proportion, 83% in DM1 and 75% in DM2, of the significantly disregulated genes were shared by both forms of the disease, suggesting a common mechanism. The upregulated genes in DM1 and DM2 were highly enriched in both interferon-regulated genes (IRGs) and genes associated with the response to dsRNA and the innate immune response. The characteristic fingerprint of IRGs and the signalling pathways identified in lens cells support a role for dsRNA activation of the innate immune response in the pathology of DM. This new evidence forms the basis for a novel hypothesis to explain the complex mechanism of DM.

Three family members with elevated plasma cobalamin, transcobalamin and soluble transcobalamin receptor (sCD320).

BACKGROUND: Plasma cobalamin is requested in order to diagnose cobalamin deficiency and low levels confirm a deficient state. Here, we present three family members with unexpected high levels of cobalamin. METHODS: We included a patient referred for cobalamin measurement due to neurological symptoms, her son and her daughter. Mother and son both suffered from myotonic dystrophy type II, while the daughter tested negative for this disease. Blood samples were analyzed for cobalamin, haptocorrin, transcobalamin, holoTC, and sCD320. We employed gel filtration and antibody precipitation for further characterization. The protein coding region of the TCN2 gene, encoding transcobalamin, was sequenced. RESULTS: The patient, her {son} and [daughter] all had cobalamin levels above the measurement range of the routine method employed (>1476 pmol/L). Total transcobalamin and (holoTC) were 5980 (1500), {5260 (2410)} and [5630 (1340)] pmol/L, which is well above the upper reference limits of 1500 (160) pmol/L. The sCD320 concentration was also well above the upper reference limit of 97 arb.u.: 1340, {1510} and [1090] arb.u. Haptocorrin levels were within the reference range and no signs of cobalamin deficiency were found. DNA sequencing of the TCN2 gene revealed several known polymorphisms not associated with highly elevated transcobalamin levels. Upon gel filtration, sCD320 eluted as a larger molecule than previously reported. By incubation with anti-transcobalamin antibodies, we precipitated both transcobalamin and part of sCD320. CONCLUSIONS: The high cobalamin levels were mainly explained by high levels of holoTC, possibly caused by complex formation with its soluble receptor, sCD320. The family occurrence points to a genetic explanation.

Pain in patients with myotonic dystrophy type 2: a postal survey in Finland.

INTRODUCTION: Widespread musculoskeletal pain is a well-known symptom of myotonic dystrophy type 2 (DM2), but so far it has been addressed in only a few studies. METHODS: A postal survey for all traceable DM2 patients (n = 132) was conducted. A specific questionnaire, and severity and interference subscales of the Brief Pain Inventory, quality of life (RAND-36), and modified Beck Depression Inventory were completed. RESULTS: The response rate was 70%. The mean age of respondents was 53 years, 59% of whom were women. Current pain was reported by 54%. Lifetime prevalence of pain was 76%. The mean intensity of pain at its highest in the last week was 5.9, and 2.3 at its lowest (on a numerical rating scale of 0-10). Quality of life was lower in DM2 patients who reported pain. In 18%, the depression score was noticeably different. CONCLUSIONS: Pain of moderate severity and unpleasant muscular symptoms are common in DM2. DM2 should be taken into consideration in the differential diagnosis of musculoskeletal pain.

Sleep disturbances in myotonic dystrophy type 2.

Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep-disordered breathing, hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) data. Eight patients (5 women, 3 men) with DM2 were identified. Excessive daytime sleepiness was seen in 6 patients (75%), insomnia in 5 (62.5%), and excessive fatigue in 4 (50%). Obstructive sleep apnea was diagnosed in 3 of 5 patients (60%) studied with PSG. Respiratory muscle weakness was present in all 6 patients (100%) who received pulmonary function testing. Four of 8 (50%) met criteria for diagnosis of restless legs syndrome. The clinical spectrum of DM2 may include a wide range of sleep disturbances. Although respiratory muscle weakness was frequent, sustained sleep-related hypoxia suggestive of hypoventilation was not seen in our patients. Further prospective studies are needed to examine the frequency and scope of sleep disturbances in DM2.

Relief from episodic weakness with pyridostigmine in paramyotonia congenita: a family study.

Pyridostigmine relieved episodic weakness in a family with paramyotonia congenita resulting from the R1448C mutation in the sodium channel gene. The transmission was autosomal dominant and the patients had paradoxical myotonia and exercise-induced weakness. On electrophysiological studies there were myotonic potentials, and there was progressive reduction of compound muscle action potential (CMAP) amplitudes after short exercise associated with clinical weakness. Pyridostigmine in doses of 60 mg three times daily abolished the drop in the postexercise CMAP amplitude and reduced the amplitude decrement to slow rate repetitive stimulation, but there continued to be a drop in amplitude on exposure to cold. The decline of the CMAP amplitude on exposure to cold was controlled by treatment with phenytoin. The clinical and electrophysiological features are discussed in relation to therapy with pyridostigmine and phenytoin.

Paramyotonia Congenita with Persistent Distal and Facial Muscle Weakness: A Case Report with Literature Review.

BACKGROUND: Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon. CASE REPORT: We report a family with a history of PC accompanied by persistent hand muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. The PC causative mutation T1313M in the SCN4A gene was prevalent in the family. Administration of acetazolamide chloride improved clinical symptoms and the results of cold and short exercise tests. Phenotypic variation within the family was remarkable, as the two younger affected patients did not present with persistent weakness or muscle atrophy. CONCLUSIONS: PC associated with the T1313M mutation is a possible cause of persistent distal hand weakness.

The myotonias and susceptibility to malignant hyperthermia.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle in which volatile anesthetics trigger a sustained increase in intramyoplasmic Ca(2+) via release from sarcoplasmic reticulum and, possibly, entry from the extracellular milieu that leads to hypermetabolism, muscle rigidity, rhabdomyolysis, and death. Myotonias are a class of myopathies that result from gene mutations in various channels involved in skeletal muscle excitation-contraction coupling and sarcolemmal excitability, and unusual DNA sequence repeats that result in the inability of many proteins, including skeletal muscle channels that affect excitability, to undergo proper splicing. The suggestion has often been made that myotonic patients have an increased risk of developing MH. In this article, we review the physiology of muscle excitability and excitation-contraction coupling, the pathophysiology of MH and the myotonias, and review the clinical literature upon which the claims of MH susceptibility are based. We conclude that patients with these myopathies have a risk of developing MH that is equivalent to that of the general population with one potential exception, hypokalemic periodic paralysis. Despite the fact that there are no clinical reports of MH developing in patients with hypokalemic periodic paralysis, for theoretical reasons we cannot be as certain in estimating their risk of developing MH, even though we believe it is low.

Clinico-Genotypic Correlation: Recurrent Attacks of Paralysis and Skeletal Muscle SCN4A Mutation (p.Ile693Thr).

Skeletal sodium channel mutations have been known to demonstrate a multitude of clinical manifestations of which one such commonly known entity is paramyotonia congenita. We describe the clinical features of proband in our case report and the various phenotypic manifestations described with the mentioned mutation from different centres. Our case serves to highlight the heterogeneity that exists in SCN4A mutations and the possible effect of other genetic/environmental factors in determining the final phenotype.

A unique presentation and etiology of neonatal paradoxical vocal fold motion.

We present a unique case of intermittent paradoxical vocal fold motion (PVFM) as the presenting symptom of a rare underlying neuromuscular disorder in a neonate. Paramyotonia congenita (PC) is an autosomal dominant condition that typically presents in infancy with myotonic episodes affecting the skeletal muscles. Our patient developed intermittent episodes of stridor quickly progressing to apnea shortly after birth that were marked by PVFM on laryngoscopy, ultimately leading to the diagnosis of a previously unrecognized mutation in SCN4A, the gene responsible for PC.

Left ventricular non-compaction in a patient with myotonic dystrophy type 2.

Cardiac involvement is frequent in myotonic dystrophy type 2 (DM2) with dilated cardiomyopathy and severe arrhythmias having been reported. Left ventricular non-compaction is a cardiomyopathy often associated with neuromuscular disorders. We report the case of a 61-year-old man with DM2 treated for 5 years for a suspected dilated cardiomyopathy. Echocardiography showed left ventricular non-compaction typical pattern, with prominent apical trabeculations and intertrabecular spaces perfused from ventricular cavity. MRI confirmed the diagnosis. Physicians should be aware of the risk of severe cardiac complications in DM2 patients. Left ventricular non-compaction diagnosis is often overlooked. Neurological examination should be performed in all patients with left ventricular non-compaction.

Proximal myotonic dystrophy associated with parkinsonism.

Although mental changes and cognitive disorders are seen frequently in myotonic dystrophy (MD) there are only three cases of MD associated with parkinsonism reported in the literature. We report another case of this extremely rare combination.