Bas C. Stunnenberg

Familial hemiplegic migraine is associated with febrile seizures in an FHM2 family with a novel de novo ATP1A2 mutation

combining two epilepsy genes. Nat Neurosci 10:1554–1558. Guerin AA, Feigenbaum A, Donner EJ, Yoon G. (2008) Stepwise developmental regression associated with novel CACNA1A mutation. Pediatr Neurol 39:363–364. Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG. (2001) Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358:801– 807. Kors EE, Melberg A, Vanmolkot KR, Kumlien E, Haan J, Raininko R, Flink R, Ginjaar HB, Frants RR, Ferrari MD, van den Maagdenberg AM. (2004) Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACN1A mutation. Neurology 63:1136– 1137. Ophoff RA, Terwindt GM, Vergouwe MN, van ER, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 + channel gene CACN1A4. Cell 87:543–552. Vahedi K, Denier C, Ducros A, Bousson V, Levy C, Chabriat H, Haguenau M, Tournier-Lasserve E, Bousser MG. (2000) CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 55:1040–1042.

Isolated eyelid closure myotonia in two families with sodium channel myotonia

Sodium channelopathies (NaCh), as part of the non-dystrophic myotonic syndromes (NDMs), reflect a heterogeneous group of clinical phenotypes accompanied by a generalized myotonia. Because of recent availability of diagnostic genetic testing in NDM, there is a need for identification of clear clinical genotype–phenotype correlations. This will enable clinicians to distinguish NDMs from myotonic dystrophy, thus allowing them to inform patients promptly about the disease, perform genetic counseling, and orient therapy (Vicart et al. Neurol Sci 26:194–202, 2005). We describe the first distinctive clinical genotype–phenotype correlation within NaCh: a strictly isolated eyelid closure myotonia associated with the L250P mutation in SCN4A. Using clinical assessment and needle EMG, we identified this genotype–phenotype correlation in six L250P patients from one NaCh family and confirmed this finding in another, unrelated NaCh family with three L250P patients.

CARDIAC ARRHYTHMIAS IN HYPOKALEMIC PERIODIC PARALYSIS : HYPOKALEMIA AS ONLY CAUSE?

It is unknown how often cardiac arrhythmias occur in hypokalemic periodic paralysis (HypoPP) and if they are caused by hypokalemia alone or other factors. This systematic review shows that cardiac arrhythmias were reported in 27 HypoPP patients. Cases were confirmed genetically (13 with an R528H mutation in CACNA1S, 1 an R669H mutation in SCN4A) or had a convincing clinical diagnosis of HypoPP (13 genetically undetermined) if reported prior to the availability of genetic testing. Arrhythmias occurred during severe hypokalemia (11 patients), between attacks at normokalemia (4 patients), were treatment‐dependent (2 patients), or unspecified (10 patients). Nine patients died from arrhythmia. Convincing evidence for a pro‐arrhythmogenic factor other than hypokalemia is still lacking. The role of cardiac expression of defective skeletal muscle channels in the heart of HypoPP patients remains unclear. Clinicians should be aware of and prevent treatment‐induced cardiac arrhythmia in HypoPP. Muscle Nerve 50: 327–332, 2014

Clinical experience with long-term acetazolamide treatment in children with nondystrophic myotonias: a three-case report.

BACKGROUND Today, treatment of the nondystrophic myotonias consists of mexiletine, although care has to be taken because of the proarrhythmogenic potential of this drug. In this article, we report years of experience with the carbonic anhydrase inhibitor acetazolamide. PATIENTS We present three children with nondystrophic myotonias. RESULTS During acetazolamide treatment, symptoms and signs of myotonia decreased in our children. CONCLUSIONS Based on this clinical experience and the favorable pharmacologic profile of acetazolamide, it may be a good treatment option for children with nondystrophic myotonias.

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol

BackgroundTo obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously.Methods/DesignWe will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT.DiscussionThe treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases.Trial registrationClinicalTrials.gov Identifier: NCT02045667

Myotonic discharges discriminate chloride from sodium muscle channelopathies.

Non-dystrophic myotonic syndromes represent a heterogeneous group of clinically quite similar diseases sharing the feature of myotonia. These syndromes can be separated into chloride and sodium channelopathies, with gene-defects in chloride or sodium channel proteins of the sarcolemmal membrane. Myotonia has its basis in an electrical instability of the sarcolemmal membrane. In the present study we examine the discriminative power of the resulting myotonic discharges for these disorders. Needle electromyography was performed by an electromyographer blinded for genetic diagnosis in 66 non-dystrophic myotonia patients (32 chloride and 34 sodium channelopathy). Five muscles in each patient were examined. Individual trains of myotonic discharges were extracted and analyzed with respect to firing characteristics. Myotonic discharge characteristics in the rectus femoris muscle almost perfectly discriminated chloride from sodium channelopathy patients. The first interdischarge interval as a single variable was longer than 30 ms in all but one of the chloride channelopathy patients and shorter than 30 ms in all of the sodium channelopathy patients. This resulted in a detection rate of over 95%. Myotonic discharges of a single muscle can be used to better guide toward a molecular diagnosis in non-dystrophic myotonic syndromes.

Teaching Video NeuroImages: Lid lag sign and diplopia in paramyotonia congenita

Clinical bedside tests to provoke myotonia, such as eyelid closure, handgrip, and percussion myotonia, help to diagnose and differentiate myotonic disorders and prevent delayed genetic confirmation. Sodium channelopathies present with predominantly myotonia of the ocular muscles.1 In these cases, testing for myotonia of the upper eyelid and extraocular muscles could be of decisive diagnostic value. We present additional clinical bedside tests: the lid lag sign2 and provocation of short-term diplopia (video on the Neurology® Web site at Neurology.org and the figure). In our experience, these symptoms are especially present in paramyotonia congenita. Therefore, we advise to test for lid lag sign and short-term diplopia every time a myotonic disorder is suspected.

A novel Ile1455Thr variant in the skeletal muscle sodium channel alpha-subunit in a patient with a severe adult-onset proximal myopathy with electrical myotonia and a patient with mild paramyotonia phenotype

In sodium channelopathies, a severe fixed myopathy caused by a dominant mutation is rare. We describe two unrelated patients with a novel variant, p.Ile1455Thr, with phenotypes of paramyotonia in one case and fixed proximal myopathy with latent myotonia in another. In-vitro whole cell patch-clamp studies show that the mutation slows inactivation and accelerates recovery, in line with other paramyotonia variants with destabilized fast inactivation as pathomechanism. Additionally, p.IleI1455 causes a loss-of-function by reduced membrane insertion, right-shift of activation, and slowed kinetics. Molecular dynamics simulations comparing wild type and mutant Nav1.4 showed that threonine substitution hindered D4S4 mobility in response to membrane depolarization, consistent with effects of the mutation on channel inactivation. The fixed myopathy is likely to be associated to gain-of-function leading to sodium accumulation, regional edema, T-tubular swelling and mitochondrial stress. A possible contribution of the loss-of-function features towards myotonia and myopathy is discussed.

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands

Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non-dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically-defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies.

Prolonged attacks of weakness with hypokalemia in SCN4A-related paramyotonia congenita: R1448H Mutation

Autosomal dominant mutations in the SCN4A-gene cause dysfunction of the skeletal muscle voltage-gated sodium channel (Nav1.4). Skeletal muscle sodium (natrium) channelopathies (NaChs) are typically characterized by myotonia (paramyotonia congenita, PMC), episodic weakness attacks (hypoand hyperkalemic periodic paralysis, HypoPP and HyperPP, respectively) or a combination of both. In clinical practice, the co-occurrence of episodic weakness with paramyotonia helps to guide the clinician toward the diagnosis of HyperPP. The R1448C SCN4A-mutation has been associated with a “pure” PMC or HyperPP phenotype. We report a Dutch patient in whom the R1448C mutation was associated with prolonged, severe attacks of weakness associated with hypokalemia and paramyotonia.