Myotonia congenita (MC) is a hereditary skeletal muscle disorder characterized by muscle stiffness at the beginning of exercise (i.e. myotonia), alleviated by repetition of contraction (ie. warm-up effect). MC is caused by mutations in the CLCN1 gene, encoding the skeletal muscle voltage-gated chloride channel (ClC-1) and is traditionally classified as Thomsen (autosomal dominant) and Becker (autosomal recessive) diseases. We report here an Italian patient affected by diffuse muscle hypertrophy, predominant in lower limb, neck, and trapezius and difficulty in getting up from a chair after prolonged rest, suggestive of recessive MC. The combination of a specific next-generation sequencing panel for skeletal muscle channelopathies and multiplex ligation-dependent probe amplification for CLCN1, leaded to the detection of the known missense mutation p.G482R and a novel deletion of the last 3 exons of the CLCN1. This report demonstrates the importance of combining multiple genetic techniques to define recessive forms of MC.

The objective of the study is to provide age-related normative values for dorsal sural nerve (DSN) and to analyse its application during follow-up of hereditary transthyretin amyloidosis (ATTRv) pre-symptomatic subjects. We consecutively recruited ATTRv pre-symptomatic carriers in which clinical examination, cardiological evaluation, and nerve conduction studies of the sural nerve and DSN were performed. To provide normative data of DSN, neurophysiologic parameters from healthy controls referred to our service were entered into linear regression analyses to check the relative influence of age and height. A correction grid was then derived. We collected 231 healthy subjects: the mean DSN sensory nerve action potential (SNAP) amplitude was 9.99 ± 5.48 μV; the mean conduction velocity was 49.01 ± 5.31 m/s. Significant correlations were found between age and height with DSN SNAP amplitude. Fifteen ATTRv pre-symptomatic carriers were examined. Sural nerve NCS were normal in 12/15 and revealed low/borderline values in three subjects. Considering our correction grid, we found an abnormal DNS amplitude in 9/15 subjects and low/borderline values in 2/15. In ATTRv, early detection of peripheral nerve damage is crucial to start a disease-modifying treatment. DSN may be easily and reliably included in the routine neurophysiological follow-up of ATTRv pre-symptomatic subjects.

Abstract Background: Myotonia congenita (MC) is traditionally classified as Thomsen (autosomal dominant) and Becker (autosomal recessive) diseases, caused by mutations in the CLCN1, encoding the skeletal muscle voltage-gated chloride channel (ClC-1). MC is clinically characterized by muscle stiffness at the beginning of exercise (i.e. myotonia), alleviated by repetition of contraction (ie. warm-up effect). Case presentation:We report here an Italian patient affected by diffuse muscle hypertrophy, predominant in lower limb, neck, and trapezius and difficulty in getting up from a chair after prolonged rest, suggestive of recessive MC. The combination of a specific next-generation sequencing panel for skeletal muscle channelopathies and multiplex ligation-dependent probe amplification for CLCN1gene, leaded to patient’s molecular characterization with the detection of the known p.G482R mutation and a novel deletion of the last 3 exons [c.(2403+1_2404-1)_*39del]. Conclusions: This report demonstrates the importance of combining multiple genetic techniques to define recessive forms of MC.

Objective: The aim of our study was to evaluate the long-term efficacy and safety of mexiletine in 112 patients affected by genetically confirmed non-dystrophic myotonias. The study was performed at the Neurophysiologic Division of Fondazione Policlinico Universitario A. Gemelli Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome and the Children's Hospital Bambino Gesù, Rome. Methods: The treatment was accepted by 59 patients according to clinical severity, individual needs, and concerns about a chronic medication. Forty-three patients were affected by recessive congenita myotonia, 11 by sodium channel myotonia, and five by dominant congenital myotonia. They underwent clinical examination before and after starting therapy, and Electromyography (EMG). A number of recessive myotonia patients underwent a protocol of repetitive nerve stimulations, for detecting and quantifying the transitory weakness, and a modified version of the Timed Up and Go test, to document and quantify the gait impairment. Results: Treatment duration ranged from 1 month to 20 years and the daily dosages in adults ranged between 200 and 600 mg. No patient developed cardiac arrhythmias causing drug discontinuation. Mexiletine was suspended in 13 cases (22%); in three patients, affected by Sodium Channel myotonia, because flecainide showed better efficacy; in one patient because of a gastric cancer antecedent treatment; in four patients because of untreatable dyspepsia; and five patients considered the treatment not necessary. Conclusions: In our experience, mexiletine is very useful and not expensive. We did not observe any hazarding cardiac arrhythmias. Dyspepsia was the most frequent dose-limiting side effect.

Sodium channel myotonia is a form of muscle channelopathy due to mutations that affect the Nav1.4 channel. We describe seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.Ile215Thr and p.Gly241Val, in the first domain of the Nav1.4 channel. The families described have been clinically and genetically evaluated. p.Ile215Thr and p.Gly241Val lie, respectively, on extracellular and intracellular loops of the first domain of the Nav1.4 channel. We assessed that the p.Ile215Thr mutation can be related to a founder effect in people from Southern Italy. Electrophysiological evaluation of the channel function showed that the voltage dependence of the activation for both the mutant channels was significantly shifted toward hyperpolarized potentials (Ile215Thr: −28.6 ± 1.5 mV and Gly241Val: −30.2 ± 1.3 mV vs. WT: −18.5 ± 1.3 mV). The slow inactivation was also significantly affected, whereas fast inactivation showed a different behavior in the two mutants. We characterized two novel mutations of the SCN4A gene expanding the knowledge about genetics of mild forms of myotonia, and we present, to our knowledge, the first homozygous patient with sodium channel myotonia.

Sodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses. We previously showed that two hNav1.4 mutations, p.G1306E and p.P1158L, reduce mexiletine potency in vitro, whereas another sodium channel blocker, flecainide, is less sensitive to mutation-induced gating defects. This observation was successfully translated to p.G1306E and p.P1158L carriers. Thus, the aim of this study was to perform a pharmacological characterization of myotonic Nav1.4 mutations clustered near the fast inactivation gate of the channel. We chose seven mutations (p.V1293I, p.N1297S, p.N1297K, p.F1298C, p.G1306E, p.I1310N, and p.T1313M) from the database of Italian and French networks for muscle channelopathies. Recombinant hNav1.4 mutants were expressed in HEK293T cells for functional and pharmacological characterization using the patch-clamp technique. All the studied mutations impair the kinetics and/or voltage dependence of fast inactivation, which is likely the main mechanism responsible for myotonia. The severity of myotonia is well-correlated to the enhancement of window currents generated by the intersection of the activation and fast inactivation voltage dependence. Five of the six mutants displaying a significant positive shift of fast inactivation voltage dependence reduced mexiletine inhibition in an experimental condition mimicking myotonia. In contrast, none of the mutations impairs flecainide block nor does p.T1313M impair propafenone block, indicating that class Ic antiarrhythmics may constitute a valuable alternative. Our study suggests that mutation-driven therapy would be beneficial to myotonic patients, greatly improving their quality of life.

Myotonia congenita (MC) is a skeletal-muscle hyperexcitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30 mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severities and located in the C-terminal region. The p.Val829Met, p.Thr832Ile, p.Val851Met, p.Gly859Val, and p.Leu861Pro mutations reside in the CBS2 domain, while p.Pro883Thr and p.Val947Glu are in the C-terminal peptide. We showed that the functional properties of mutant channels correlated with the clinical phenotypes of affected individuals. In addition, we defined clusters of ClC-1 mutations within CBS2 and C-terminal peptide subdomains that share the same functional defect: mutations between 829 and 835 residues and in residue 883 induced an alteration of voltage dependence, mutations between 851 and 859 residues, and in residue 947 induced a reduction of chloride currents, whereas mutations on 861 residue showed no obvious change in ClC-1 function. This study improves our understanding of the mechanisms underlying MC, sheds light on the role of the C-terminal region in ClC-1 function, and provides information to develop new antimyotonic drugs.

European Journal of NeurologyVolume 23, Issue 8 p. e55-e55 Letter to the Editor Mitochondrial neuropathy: considerations on pathogenesis M. Luigetti, Corresponding Author M. Luigetti Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalyCorrespondence: M. Luigetti, Institute of Neurology, Largo Francesco Vito 1, 00168 Rome, Italy (tel.: +39 06 30154435; fax: +39 06 35501909; e-mail: mluigetti@gmail.com).Search for more papers by this authorD. Sauchelli, D. Sauchelli Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorG. Primiano, G. Primiano Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorC. Cuccagna, C. Cuccagna Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorD. Bernardo, D. Bernardo Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorM. Lo Monaco, M. Lo Monaco Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorS. Servidei, S. Servidei Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this author M. Luigetti, Corresponding Author M. Luigetti Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalyCorrespondence: M. Luigetti, Institute of Neurology, Largo Francesco Vito 1, 00168 Rome, Italy (tel.: +39 06 30154435; fax: +39 06 35501909; e-mail: mluigetti@gmail.com).Search for more papers by this authorD. Sauchelli, D. Sauchelli Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorG. Primiano, G. Primiano Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorC. Cuccagna, C. Cuccagna Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorD. Bernardo, D. Bernardo Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorM. Lo Monaco, M. Lo Monaco Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this authorS. Servidei, S. Servidei Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, ItalySearch for more papers by this author First published: 19 July 2016 https://doi.org/10.1111/ene.13049Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue8August 2016Pages e55-e55 RelatedInformation

Objective:We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype.Methods:Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp.Results:The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition.Conclusions:Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual.

Myopathic disorders encompass a large heterogenous group of neuromuscular disease, hallmarked by weakness due to primary dysfunction of muscle fibers. The weakness pattern is often progressive resulting in a diverse spectrum of disease morbidity and mortality. Some of the most common neuromuscular diseases fall into this category including Duchenne muscular dystrophy (DMD), myotonic muscular dystrophy, limb girdle muscular dystrophy (LGMD), and fascioscapulohumeral muscular dystrophy (FSHD). Myopathic disorders are most commonly inherited; however, acquired forms (including toxic myopathies) and inflammatory myopathies (such as inclusion body myositis, polymyositis, and dermatomyositis) comprise a large portion of myopathies.Neuromuscular disease management has historically been limited to supportive care and symptom management. Medication treatments have been limited to immunosuppressive therapies targeting secondary muscle inflammation. Recent advancements in molecular cellular research, however, have led to the discovery of new disease-specific therapeutic targets.These advancements have made neuromuscular medicine an exciting and emerging field of medicine for which the physiatrist plays a crucial role. Comprehensive rehabilitative management is essential in optimizing physical function, supporting longevity, and promoting improved quality of life. Additionally, management of chronic disease–related sequalae including respiratory and cardiac dysfunction, endocrine dysfunction, speech and swallow dysfunction, and cognitive and behavioral disorders are the key focus of the neuromuscular rehabilitation multidisciplinary team.

Many elements combine to validate the hypothesis that tempus and prolatio definitions, as found in 15th-century dance treatises, were also used to indicate the ratios between the four misure: bassadanza, quadernaria, saltarello and piva. Domenico da Piacenza placed them in a ratio of 6:5:4:3/6, with the piva worth half of the bassadanza. It follows that, by subtracting or adding sixths of the bassadanza to each misura, it should be possible to transition from one misura to another. However, this is not the case, unless there is a change to the duration of a minim. On studying the treatises by Guglielmo Ebreo, Antonio Cornazano and M-o Giorgio, it is revealed that their definitions of the misure suggest a ratio of 9:8:6:4/9, with a piva misura worth half of that of the quadernaria and not that of the bassadanza, as stated by Domenico. This ratio means that bassadanza misura must be divisible in ninths (and for this reason it is defined as in tempus perfectum) while keeping its rhythmical structure of four irregular botte, or beats (defined as being in tempus imperfectum cum prolatio maior). Coupling the beats (which express the rhythmical structure of the four misure) with the notation of the dance tunes, it is possible to shift from the bassadanza to any other misura by changing the value of the semibrevis from perfect (3/9 of that of the bassadanza) to imperfect (2/9 of that of the bassadanza) and to shift through the other three misure by adding or subtracting a semibrevis, the value of which remains constant. The piva, saltarello and quadernaria appear, then, to be related by minim and semibrevis equivalence, while the notes in bassadanza are to be considered augmented by half of their value again.

Myoclonus consists of sudden, brief, involuntary jerky muscular contractions. Central and peripheral nervous system lesions are involved in the pathogenesis of this movement disorder. Symptomatic or secondary spinal myoclonus is the most common form. A 68-year-old woman was diagnosed with hemiabdominal spinal myoclonus. Occasional and very mild involuntary repetitive movements of the hemiabdomen began immediately after surgery for uterine cancer. After surgery for laparocele, secondary to the uterine cancer surgery, performed under spinal anesthesia, there was severe worsening of movements. Neuroradiological investigations failed to demonstrate spinal injury, while neurophysiological studies showed impairment of the right central somatosensory pathway. Considering the low resolution of magnetic resonance imaging in the evaluation of thoracic level, we suggest an extensive neurophysiological evaluation in patients with spinal myoclonus.

Objective: We aim to demonstrate the effect of mexiletine on the compound muscle action potential (CMAP) amplitude transitory depression (TD) in a cohort of patients with recessive myotonia congenita.Methods: We evaluated 21 patients with recessive myotonia congenita referred to our institute from 1990 to 2013 and treated with mexiletine chlorhydrate. All patients underwent prolonged 3 Hz repetitive nerve stimulation (3 Hz-PLRS) before and after the beginning of treatment.Results: We observed in all subjects a reduction of CMAP amplitude TD after the beginning of treatment. The mean value of the TD nadir before starting mexiletine treatment was -62.0% and reduced to -28.8% after the therapy was started (51.6% reduction, p < 0.001).Conclusions: The 3 Hz-PLRS is configured as a neurophysiological test able to indirectly detect and quantify, through the measurement of TD, the clinical phenomenon of the transitory weakness that occurs in myotonic syndromes due to CLCN1 mutations.Significance: This neurophysiological test might be considered a helpful tool to assess the effect of antimyotonic drugs, as mexiletine, in recessive myotonia congenita. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Background: Classic clinical manifestations of HNPP are characterized by recurrent painless mononeuropathies, but a minority of patients present with an atypical clinical pattern, including CMT-like neuropathy, acute or chronic inflammatory demyelinating neuropathy-like polyneuropathy, and carpal tunnel syndrome. Electrophysiological examination plays a central role in the diagnosis of HNPP, disclosing a non-uniform conduction slowing, more pronounced at entrapment sites.Patients and methods: We report clinical, electrophysiological and pathological findings from 73 patients with HNPP, coming from 53 unrelated families, followed at our Institute of Neurology over a 20-year period.Results: Typical presentation with recurrent multiple mononeuropathies was observed in 28/64 (44%) patients. In the remaining 36/64 (56%), we observed an atypical clinical presentation, characterized by generalized weakness and cramps, chronic ulnar neuropathy, carpal tunnel syndrome, chronic sensory polyneuropathy, Guillain-Barre-like presentation, and CMT-like presentation. Nine patients were asymptomatic for neuropathic symptoms. Nerve conduction studies showed in all cases a sensori-motor demyelinating polyneuropathy with conduction abnormalities preferentially localized at common entrapment sites. When performed, sural nerve biopsy disclosed the focal thickening of the myelin sheath in all patients.Conclusions: About half of the patients with HNPP from our cohort showed an atypical clinical presentation. Neurophysiological examination represents the main tool for a proper diagnosis. (C) 2014 Elsevier B.V. All rights reserved.

Practitioners may refer to experienced hand surgeons to differentiate a recurrence in carpal tunnel syndrome (CTS) from a failed carpal tunnel release. The patient may complain about the reappearance of symptoms, whatever is the cause. Nerve conduction studies (NCS) are often required by the practitioner to assist the final diagnosis. We observed abnormal values in NCS in patients who were clinically healed from CTS. We evaluated the changes preoperatively and, then, at 1, 3, 6, 9, and 12 month postoperatively. At the same time, we performed a retrospective study on a group of 37 clinically healed patients. Follow-up ranged from 2 to 20 years. Surgical treatment let the electrophysiological parameters to improve toward physiological values; however, normality is hardly ever reached. This sort of ''electrophysiological scar'' is true for all the parameters measured. In presence of CTS, the latency difference between the radial and median sensory nerve action potentials, recorded following thumb stimulation, produces a double peak shift. The ''double peak shift'' best described this ''electrophysiological scar,'' being a parameter that should measure about zero in the normal population. In conclusion, abnormal postoperative electrophysiological findings cannot substantiate the diagnosis of a poor outcome of a carpal tunnel release nor a recurrence of CTS.

Objective Idiopathic brachial plexopathy is a non-progressive disorder characterized by the sudden onset of shoulder pain associated with weakness and sometimes paraesthesia of the arm. Clinical and electrophysiological examinations are the primary diagnostic tools and allow physicians to localize the site of damage. MRI neurography is rarely performed in this setting. Methods We herein describe the cases of eight consecutive patients suffering from idiopathic brachial plexopathy. All patients underwent clinical visits, neurophysiological evaluations and MRI neurography. Results We confirmed the primary role of clinical and neurophysiological evaluations in the diagnosis of idiopathic brachial plexopathy and demonstrate the usefulness of brachial plexus MRI neurography for confirming the presence of inflammatory changes. Conclusion In patients with idiopathic brachial plexopathy, MR neurography is a helpful tool for excluding different aetiologies, such as compression or tumour formation, and/or confirming inflammatory changes.

Familial amyloid polyneuropathy (FAP) is a rare condition caused by mutations of the transthyretin (TTR) gene and it is generally characterized by a length-dependent polyneuropathy affecting prevalently the small fibers. We reviewed clinical, electrophysiological and pathological findings of 15 unrelated patients with genetically confirmed TTR-FAP. All patients presented a progressive sensory-motor polyneuropathy. Pathological findings were negative for amyloid deposits in about half of the cases. Sequence analysis of TTR gene revealed the presence of three different mutations (p.Val30Met, p.Phe64Leu, and p.Ala120Ser). The p.Val30Met was the most frequently identified mutation and it often occurred in apparently sporadic cases. Conversely, the p.Phe64Leu generally presented in a high percentage of familial cases in patients coming from Southern Italy. Clinicians should consider, to avoid misdiagnosis, the screening for TTR mutations in patients presenting with progressive axonal polyneuropathy of undetermined etiology, including apparently sporadic cases with pathological examinations negative for amyloid deposition.