The long exercise test as a functional marker of periodic paralysis.

AIMS: The aim of this study was to evaluate the sensitivity of the long exercise test (LET) in the diagnosis of periodic paralysis (PP) and assess correlations with clinical phenotypes and genotypes. METHODS: From an unselected cohort of 335 patients who had an LET we analyzed 67 patients with genetic confirmation of PP and/or a positive LET. RESULTS: 32/45 patients with genetically confirmed PP had a significant decrement after exercise (sensitivity of 71%). Performing the short exercise test before the LET in the same hand confounded results in four patients. Sensitivity was highest in patients with frequent (daily or weekly) attacks (8/8, 100%), intermediate with up to monthly attacks (15/21, 71%) and lowest in those with rare attacks (9/16, 56%) (p = .035, Mann-Whitney U-test). Patients with a positive LET without confirmed PP mutation comprised those with typical PP phenotype and a group with atypical features. DISCUSSION: In our cohort, the LET is strongly correlated with the frequency of paralytic attacks suggesting a role as a functional marker. A negative test in the context of frequent attacks makes a diagnosis of PP unlikely but it does not rule out the condition in less severely affected patients.

In vivo assessment of muscle membrane properties in the sodium channel myotonias.

INTRODUCTION: The gain-of-function mutations that underlie sodium channel myotonia (SCM) and paramyotonia congenital (PMC) produce differing clinical phenotypes. We used muscle velocity recovery cycles (MVRCs) to investigate membrane properties. METHODS: MVRCs and responses to trains of stimuli were compared in patients with SCM (n = 9), PMC (n = 8), and normal controls (n = 26). RESULTS: The muscle relative refractory period was reduced in SCM, consistent with faster recovery of the mutant sodium channels from inactivation. Both SCM and PMC showed an increased early supernormality and increased mean supernormality following multiple conditioning stimuli, consistent with slowed sodium channel inactivation. Trains of fast impulses caused a loss of amplitude in PMC, after which only half of the muscle fibers recovered, suggesting that the remainder stayed depolarized by persistent sodium currents. DISCUSSION: The differing effects of mutations on sodium channel function can be demonstrated in human subjects in vivo using this technique. Muscle Nerve 57: 586-594, 2018.

Medullary infarction causing coexistent SUNCT and trigeminal neuralgia.

Background Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or with autonomic symptoms (SUNA) are grouped together within the trigeminal autonomic cephalalgias (TACs). However, the SUNCT and SUNA phenotype and management overlap with those of trigeminal neuralgia (TN). Additionally, a broad variety of cerebral pathologies are reportedly able to trigger either TN- or SUNCT-like pain, and emerging structural neuroimaging findings suggest the possible role of neurovascular conflict with the trigeminal nerve in SUNCT, further supporting aetiological and pathophysiological overlaps among SUNCT, SUNA and TN. Case report We present the first case of coexisting chronic SUNCT- and TN-like phenotypes caused by haemorrhagic infarct of the dorsolateral medulla. Discussion In light of our case, a perturbation of the dorsolateral medullary circuits may constitute an important pathophysiological component, supporting a unifying nosological hypothesis that considers SUNCT, SUNA and TN clinical variants of the same disorder.

In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.

Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development.

In vivo assessment of muscle membrane properties in myotonic dystrophy.

INTRODUCTION: Myotonia in myotonic dystrophy types 1 (DM1) and 2 (DM2) is generally attributed to reduced chloride-channel conductance. We used muscle velocity recovery cycles (MVRCs) to investigate muscle membrane properties in DM1 and DM2, using comparisons with myotonia congenita (MC). METHODS: MVRCs and responses to repetitive stimulation were compared between patients with DM1 (n = 18), DM2 (n = 5), MC (n = 18), and normal controls (n = 20). RESULTS: Both DM1 and DM2 showed enhanced late supernormality after multiple conditioning stimuli, indicating delayed repolarization as in MC. Contrary to MC, however, DM1 showed reduced early supernormality after multiple conditioning stimuli, and weak DM1 patients also showed abnormally slow latency recovery after repetitive stimulation. CONCLUSIONS: These findings support the presence of impaired chloride conductance in both DM1 and DM2. The early supernormality changes indicate that sodium currents were reduced in DM1, whereas the weakness-associated slow recovery after repetitive stimulation may provide an indication of reduced Na(+) /K(+) -ATPase activation. Muscle Nerve 54: 249-257, 2016.

Chloride channels in myotonia congenita assessed by velocity recovery cycles.

INTRODUCTION: Myotonia congenita (MC) is caused by congenital defects in the muscle chloride channel CLC-1. This study used muscle velocity recovery cycles (MVRCs) to investigate how membrane function is affected. METHODS: MVRCs and responses to repetitive stimulation were compared between 18 patients with genetically confirmed MC (13 recessive, 7 dominant) and 30 age-matched, normal controls. RESULTS: MC patients exhibited increased early supernormality, but this was prevented by treatment with sodium channel blockers. After multiple conditioning stimuli, late supernormality was enhanced in all MC patients, indicating delayed repolarization. These abnormalities were similar between the MC subtypes, but recessive patients showed a greater drop in amplitude during repetitive stimulation. CONCLUSIONS: MVRCs indicate that chloride conductance only becomes important when muscle fibers are depolarized. The differential responses to repetitive stimulation suggest that, in dominant MC, the affected chloride channels are activated by strong depolarization, consistent with a positive shift of the CLC-1 activation curve.

Episodic ataxia type 1 without episodic ataxia: the diagnostic utility of nerve excitability studies in individuals with KCNA1 mutations.

Episodic ataxia type 1 (EA1) is caused by mutations in the KCNA1 gene encoding the fast potassium channel Kv1.1 and is characterized clinically by brief episodes of ataxia and continuous and spontaneous motor unit activity. Atypical presentations, in which the predominant manifestation is related to the peripheral nervous system, may lead to the diagnosis being missed or delayed, with the potential risk of individuals receiving inappropriate or unnecessary investigations and treatment. We present a case of a 15-year-old female with EA1 who had never had episodes of ataxia, and whose hand movements were initially thought to represent a tremor. Genetic screening for KCNA1 mutations was precipitated by the results of the nerve excitability studies (TROND protocol), which showed changes typical of reduced fast potassium channel conductance. This case highlights the utility of nerve excitability studies in identifying individuals with KCNA1 mutations.

Refined exercise testing can aid DNA-based diagnosis in muscle channelopathies.

OBJECTIVE: To improve the accuracy of genotype prediction and guide genetic testing in patients with muscle channelopathies we applied and refined specialized electrophysiological exercise test parameters. METHODS: We studied 56 genetically confirmed patients and 65 controls using needle electromyography, the long exercise test, and short exercise tests at room temperature, after cooling, and rewarming. RESULTS: Concordant amplitude-and-area decrements were more reliable than amplitude-only measurements when interpreting patterns of change during the short exercise tests. Concordant amplitude-and-area pattern I and pattern II decrements of >20% were 100% specific for paramyotonia congenita and myotonia congenita, respectively. When decrements at room temperature and after cooling were <20%, a repeat short exercise test after rewarming was useful in patients with myotonia congenita. Area measurements and rewarming distinguished true temperature sensitivity from amplitude reduction due to cold-induced slowing of muscle fiber conduction. In patients with negative short exercise tests, symptomatic eye closure myotonia predicted sodium channel myotonia over myotonia congenita. Distinctive "tornado-shaped" neuromyotonia-like discharges may be seen in patients with paramyotonia congenita. In the long exercise test, area decrements from pre-exercise baseline were more sensitive than amplitude decrements-from-maximum-compound muscle action potential (CMAP) in patients with Andersen-Tawil syndrome. Possible ethnic differences in the normative data of the long exercise test argue for the use of appropriate ethnically-matched controls. INTERPRETATION: Concordant CMAP amplitude-and-area decrements of >20% allow more reliable interpretation of the short exercise tests and aid accurate DNA-based diagnosis. In patients with negative exercise tests, specific clinical features are helpful in differentiating sodium from chloride channel myotonia. A modified algorithm is suggested.

Muscle velocity recovery cycles: effects of repetitive stimulation on two muscles.

INTRODUCTION: We sought to characterize the excitability properties of tibialis anterior (TA) and brachioradialis (BR) muscles at rest and during electrically induced muscle activation in normal subjects. METHODS: Two centers recruited 10 subjects each. Multi-fiber velocity recovery cycles (VRCs) were recorded from TA (both centers) and BR (one center). VRCs were assessed at rest and during repetitive stimulation (intermittent 20 Hz for 6 min). Changes in latency and peak amplitude of the muscle action potential induced by a frequency ramp to 30 Hz were also characterized. RESULTS: Excitability properties recorded from TA were very similar between centers. Repetitive stimulation generated marked excitability changes, which were similar between TA and BR. CONCLUSIONS: Standardized tests of muscle VRCs and responses to repetitive stimulation can provide consistent measures of membrane function and may encourage their wider use in clinical neurophysiology to investigate the pathophysiology of neuromuscular disorders.

Hand-held nerve conduction device in carpal tunnel syndrome: a prospective study.

INTRODUCTION: We assessed the clinical impact of replacing standard neurophysiologic testing with a hand-held device (Mediracer) for diagnosis of carpal tunnel syndrome (CTS). METHODS: One hundred patients (200 hands) with suspected CTS were studied by blinded assessors [Hand-therapist (HT)1 and Consultant Neurophysiologist] using the Mediracer, followed by standard neurophysiologic testing. To simulate testing by personnel without neurological training, Mediracer recordings were analyzed separately by an assessor who had not seen the patients (HT2). RESULTS: Correlation of the CTS grades was 0.94 for the results obtained by HT1, and 0.87 for HT2. The sensitivity and specificity of the Mediracer was 0.85 and 0.9, respectively, by HT1, and 0.84 and 0.89 for HT2. Nine patients had conditions other than CTS, and 35 patients were judged to require further investigation. CONCLUSIONS: The Mediracer should only be used in patients with typical CTS symptoms and signs and no muscle wasting who have had careful neurological assessment.

Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles.

INTRODUCTION: Andersen-Tawil syndrome (ATS) due to Kir2.1mutations typically manifests as periodic paralysis, cardiac arrhythmias and developmental abnormalities but is often difficult to diagnose clinically. This study was undertaken to determine whether sarcolemmal dysfunction could be identified with muscle velocity recovery cycles (MVRCs). METHODS: Eleven genetically confirmed ATS patients and 20 normal controls were studied. MVRCs were recorded with 1, 2, and 5 conditioning stimuli and with single conditioning stimuli during intermittent repetitive stimulation at 20 Hz, in addition to the long exercise test. RESULTS: ATS patients had longer relative refractory periods (P < 0.0001) and less early supernormality, consistent with membrane depolarization. Patients had reduced enhancement of late supernormality with 5 conditioning stimuli (P < 0.0001), and less latency reduction during repetitive stimulation (P < 0.001). Patients were separated completely from controls by combining MVRC and repetitive stimulation. CONCLUSIONS: MVRCs combined with repetitive stimulation differentiated ATS patients from controls more effectively than the conventional long-exercise test.

Development and early diagnosis of critical illness myopathy in COVID-19 associated acute respiratory distress syndrome.

BACKGROUND: The COVID-19 pandemic has greatly increased the incidence and clinical importance of critical illness myopathy (CIM), because it is one of the most common complications of modern intensive care medicine. Current diagnostic criteria only allow diagnosis of CIM at an advanced stage, so that patients are at risk of being overlooked, especially in early stages. To determine the frequency of CIM and to assess a recently proposed tool for early diagnosis, we have followed a cohort of COVID-19 patients with acute respiratory distress syndrome and compared the time course of muscle excitability measurements with the definite diagnosis of CIM. METHODS: Adult COVID-19 patients admitted to the Intensive Care Unit of the University Hospital Bern, Switzerland requiring mechanical ventilation were recruited and examined on Days 1, 2, 5, and 10 post-intubation. Clinical examination, muscle excitability measurements, medication record, and laboratory analyses were performed on all study visits, and additionally nerve conduction studies, electromyography and muscle biopsy on Day 10. Muscle excitability data were compared with a cohort of 31 age-matched healthy subjects. Diagnosis of definite CIM was made according to the current guidelines and was based on patient history, results of clinical and electrophysiological examinations as well as muscle biopsy. RESULTS: Complete data were available in 31 out of 44 recruited patients (mean [SD] age, 62.4 [9.8] years). Of these, 17 (55%) developed CIM. Muscle excitability measurements on Day 10 discriminated between patients who developed CIM and those who did not, with a diagnostic precision of 90% (AUC 0.908; 95% CI 0.799-1.000; sensitivity 1.000; specificity 0.714). On Days 1 and 2, muscle excitability parameters also discriminated between the two groups with 73% (AUC 0.734; 95% CI 0.550-0.919; sensitivity 0.562; specificity 0.857) and 82% (AUC 0.820; CI 0.652-0.903; sensitivity 0.750; specificity 0.923) diagnostic precision, respectively. All critically ill COVID-19 patients showed signs of muscle membrane depolarization compared with healthy subjects, but in patients who developed CIM muscle membrane depolarization on Days 1, 2 and 10 was more pronounced than in patients who did not develop CIM. CONCLUSIONS: This study reports a 55% prevalence of definite CIM in critically ill COVID-19 patients. Furthermore, the results confirm that muscle excitability measurements may serve as an alternative method for CIM diagnosis and support its use as a tool for early diagnosis and monitoring the development of CIM.

Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1.

Episodic ataxia type 1 is a neuronal channelopathy caused by mutations in the KCNA1 gene encoding the fast K(+) channel subunit K(v)1.1. Episodic ataxia type 1 presents with brief episodes of cerebellar dysfunction and persistent neuromyotonia and is associated with an increased incidence of epilepsy. In myelinated peripheral nerve, K(v)1.1 is highly expressed in the juxtaparanodal axon, where potassium channels limit the depolarizing afterpotential and the effects of depolarizing currents. Axonal excitability studies were performed on patients with genetically confirmed episodic ataxia type 1 to characterize the effects of K(v)1.1 dysfunction on motor axons in vivo. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from abductor pollicis brevis. Threshold tracking techniques were used to record strength-duration time constant, threshold electrotonus, current/threshold relationship and the recovery cycle. Recordings from 20 patients from eight kindreds with different KCNA1 point mutations were compared with those from 30 normal controls. All 20 patients had a history of episodic ataxia and 19 had neuromyotonia. All patients had similar, distinctive abnormalities: superexcitability was on average 100% higher in the patients than in controls (P < 0.00001) and, in threshold electrotonus, the increase in excitability due to a depolarizing current (20% of threshold) was 31% higher (P < 0.00001). Using these two parameters, the patients with episodic ataxia type 1 and controls could be clearly separated into two non-overlapping groups. Differences between the different KCNA1 mutations were not statistically significant. Studies of nerve excitability can identify K(v)1.1 dysfunction in patients with episodic ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with episodic ataxia type 1 from normal controls with high sensitivity and specificity.

Alpha coma EEG pattern in patients with severe COVID-19 related encephalopathy.

OBJECTIVE: Encephalopathy is a major neurological complication of severe Coronavirus Disease 2019 (COVID-19), but has not been fully defined yet. Further, it remains unclear whether neurological manifestations are primarily due to neurotropism of the virus, or indirect effects, like cerebral hypoxia. METHODS: We analysed the electroencephalograms (EEGs) of 19 consecutive patients with laboratory-confirmed COVID-19, performed at peak disease severity as part of their clinical management. Disease severity, respiratory failure, immune and metabolic dysfunction, sedation status, and neurological examination on the day of the EEG were noted. RESULTS: Severe encephalopathy was confirmed in 13 patients, all with severe COVID-19; 10 remained comatose off sedation, and five of them had alpha coma (AC). Disease severity, sedation, immune and metabolic dysfunction were not different between those with AC and those without. CONCLUSIONS: Severe COVID-19 encephalopathy is a principal cause of persisting coma after sedation withdrawal. The relatively high incidence of the rare AC pattern may reflect direct SARS-CoV-2 neurotropism with a predilection for the brainstem ascending reticular system. SIGNIFICANCE: Systematic early EEG detection of encephalopathy related to severe COVID-19 is important for the acute care and the management of long-term neurological and cognitive sequelae, and may help our better understanding of its pathophysiology.

The role of potassium in muscle membrane dysfunction in end-stage renal disease.

OBJECTIVE: Uremic myopathy is a condition seen in end-stage renal disease (ESRD), characterized by muscle weakness and muscle fatigue, in which the pathophysiology is uncertain. The aim of this study was to assess the role of abnormal serum constituents in ESRD patients by relating them to the excitability properties of the tibialis anterior muscle, at rest and during electrically induced muscle activation, by recording muscle velocity recovery cycles (MVRC) and frequency ramp responses. METHODS: Eighteen ESRD patients undergoing hemodialysis were evaluated by blood sample, MVRC, and frequency ramp (before and near the end of dialysis treatment), quantitative electromyography, and nerve conduction studies. Patients were compared to 24 control subjects. RESULTS: In patients, muscle relative refractory period, early supernormality, late supernormality after 5 conditioning stimuli, and latency of the last of 15 and 30 frequency ramp pulses were strongly associated with potassium levels (p < 0.01), showing depolarization before and normalization in the end of hemodialysis. CONCLUSIONS: In ESRD patients, the muscle membrane is depolarized, mainly due to hyperkalemia. SIGNIFICANCE: Since normal muscle fatigue has been attributed to potassium-induced depolarization, it seems likely that this mechanism is also a major cause of the exaggerated muscle fatigue and weakness in ESRD patients.

Ageing contributes to phenotype transition in a mouse model of periodic paralysis.

BACKGROUND: Periodic paralysis (PP) is a rare genetic disorder in which ion channel mutation causes episodic paralysis in association with hyper- or hypokalaemia. An unexplained but consistent feature of PP is that a phenotype transition occurs around the age of 40, in which the severity of potassium-induced muscle weakness declines but onset of fixed, progressive weakness is reported. This phenotype transition coincides with the age at which muscle mass and optimal motor function start to decline in healthy individuals. We sought to determine if the phenotype transition in PP is linked to the normal ageing phenotype transition and to explore the mechanisms involved. METHODS: A mouse model of hyperkalaemic PP was compared with wild-type littermates across a range of ages (13-104 weeks). Only male mice were used as penetrance is incomplete in females. We adapted the muscle velocity recovery cycle technique from humans to examine murine muscle excitability in vivo. We then examined changes in potassium-induced weakness or caffeine contracture force with age using ex vivo muscle tension testing. Muscles were further characterized by either Western blot, histology or energy charge measurement. For normally distributed data, a student's t-test (± Welch correction) or one- or two-way analysis of variance (ANOVA) was performed to determine significance. For data that were not normally distributed, Welch rank test, Mann Whitney U test or Kruskal-Wallis ANOVA was performed. When an ANOVA was significant (P < 0.05), post hoc Tukey testing was used. RESULTS: Both WT (P = 0.009) and PP (P = 0.007) muscles exhibit increased resistance to potassium-induced weakness with age. Our data suggest that healthy-old muscle develops mechanisms to maintain force despite sarcolemmal depolarization and sodium channel inactivation. In contrast, reduced caffeine contracture force (P = 0.00005), skeletal muscle energy charge (P = 0.004) and structural core pathology (P = 0.005) were specific to Draggen muscle, indicating that they are caused, or at least accelerated by, chronic genetic ion channel dysfunction. CONCLUSIONS: The phenotype transition with age is replicated in a mouse model of PP. Intrinsic muscle ageing protects against potassium-induced weakness in HyperPP mice. However, it also appears to accelerate impairment of sarcoplasmic reticulum calcium release, mitochondrial impairment and the development of core-like regions, suggesting acquired RyR1 dysfunction as the potential aetiology. This work provides a first description of mechanisms involved in phenotype transition with age in PP. It also demonstrates how studying phenotype transition with age in monogenic disease can yield novel insights into both disease physiology and the ageing process itself.

In vivo assessment of interictal sarcolemmal membrane properties in hypokalaemic and hyperkalaemic periodic paralysis.

OBJECTIVE: Hypokalaemic periodic paralysis (HypoPP) is caused by mutations of Cav1.1, and Nav1.4 which result in an aberrant gating pore current. Hyperkalaemic periodic paralysis (HyperPP) is due to a gain-of-function mutation of the main alpha pore of Nav1.4. This study used muscle velocity recovery cycles (MVRCs) to investigate changes in interictal muscle membrane properties in vivo. METHODS: MVRCs and responses to trains of stimuli were recorded in tibialis anterior and compared in patients with HyperPP(n = 7), HypoPP (n = 10), and normal controls (n = 26). RESULTS: Muscle relative refractory period was increased, and early supernormality reduced in HypoPP, consistent with depolarisation of the interictal resting membrane potential. In HyperPP the mean supernormality and residual supernormality to multiple conditioning stimuli were increased, consistent with increased inward sodium current and delayed repolarisation, predisposing to spontaneous myotonic discharges. CONCLUSIONS: The in vivo findings suggest the interictal resting membrane potential is depolarized in HypoPP, and mostly normal in HyperPP. The MVRC findings in HyperPP are consistent with presence of a window current, previously proposed on the basis of in vitro expression studies. Although clinically similar, HyperPP was electrophysiologically distinct from paramyotonia congenita. SIGNIFICANCE: MVRCs provide important in vivo data that complements expression studies of ion channel mutations.

Muscle Velocity Recovery Cycles to Examine Muscle Membrane Properties.

Although conventional nerve conduction studies (NCS) and electromyography (EMG) are suitable for the diagnosis of neuromuscular disorders, they provide limited information about muscle fiber membrane properties and underlying disease mechanisms. Muscle velocity recovery cycles (MVRCs) illustrate how the velocity of a muscle action potential depends on the time after a preceding action potential. MVRCs are closely related to changes in membrane potential that follow an action potential, thereby providing information about muscle fiber membrane properties. MVRCs may be recorded quickly and easily by direct stimulation and recording from multi-fiber bundles in vivo. MVRCs have been helpful in understanding disease mechanisms in several neuromuscular disorders. Studies in patients with channelopathies have demonstrated the different effects of specific ion channel mutations on muscle excitability. MVRCs have been previously tested in patients with neurogenic muscles. In this prior study, muscle relative refraction period (MRRP) was prolonged, and early supernormality (ESN) and late supernormality (LSN) were reduced in patients compared to healthy controls. Thereby, MVRCs can provide in vivo evidence of membrane depolarization in intact human muscle fibers that underlie their reduced excitability. The protocol presented here describes how to record MVRCs and analyze the recordings. MVRCs can serve as a fast, simple, and useful method for revealing disease mechanisms across a broad range of neuromuscular disorders.

Myotonia in a patient with a mutation in an S4 arginine residue associated with hypokalaemic periodic paralysis and a concomitant synonymous CLCN1 mutation.

The sarcolemmal voltage gated sodium channel NaV1.4 conducts the key depolarizing current that drives the upstroke of the skeletal muscle action potential. It contains four voltage-sensing domains (VSDs) that regulate the opening of the pore domain and ensuing permeation of sodium ions. Mutations that lead to increased NaV1.4 currents are found in patients with myotonia or hyperkalaemic periodic paralysis (HyperPP). Myotonia is also caused by mutations in the CLCN1gene that result in loss-of-function of the skeletal muscle chloride channel ClC-1. Mutations affecting arginine residues in the fourth transmembrane helix (S4) of the NaV1.4 VSDs can result in a leak current through the VSD and hypokalemic periodic paralysis (HypoPP), but these have hitherto not been associated with myotonia. We report a patient with an Nav1.4 S4 arginine mutation, R222Q, presenting with severe myotonia without fulminant paralytic episodes. Other mutations affecting the same residue, R222W and R222G, have been found in patients with HypoPP. We show that R222Q channels have enhanced activation, consistent with myotonia, but also conduct a leak current. The patient carries a concomitant synonymous CLCN1 variant that likely worsens the myotonia and potentially contributes to the amelioration of muscle paralysis. Our data show phenotypic variability for different mutations affecting the same S4 arginine that have implications for clinical therapy.

Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia.

OBJECTIVE: To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability. METHODS: CPEO patients (n=13) with large size deletion of mitochondrial DNA and matching healthy controls (n=22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model. RESULTS: Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the 'Barrett-Barrett' conductance across the myelin sheath. CONCLUSION: CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement. SIGNIFICANCE: This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients.