Relevance of pathogenicity prediction tools in human RYR1 variants of unknown significance.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, hyperkalemia and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca release from myotubes via the ryanodine receptor type 1 (RYR1) and the voltage-dependent L-type calcium channel (CACNA1S). As more than 300 variants of unknown significance have been detected to date, we examined whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants.

Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation.

Reduced Cl conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca- and voltage-activated K channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia.

Correction to: Preclinical pharmacological in vitro investigations on low chloride conductance myotonia: effects of potassium regulation.

The original article contains an error during online publication. Table 2 was included during production round and now deleted. The Original article has been corrected.

Preclinical pharmacological in vitro investigations on low chloride conductance myotonia: effects of potassium regulation.

In myotonia, reduced Cl conductance of the mutated ClC-1 channels causes hindered muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. Repetitive contraction temporarily decreases myotonia, a phenomena called "warm up." The underlying mechanism for the reduction of hyperexcitability in warm-up is currently unknown.

Strength and muscle structure preserved during long-term therapy in a patient with hypokalemic periodic paralysis (Cav1.1-R1239G).

We report a young wheelchair-dependent patient with an unclear proximal myopathy and a heterozygous, de-novo Cav1.1-R1239G mutation suggesting hypokalemic periodic paralysis (HypoPP). Sonography showed a loss of the pennate pattern indicative of an edema, whereas fatty degeneration was excluded.

Kir2.2 p.Thr140Met: a genetic susceptibility to sporadic periodic paralysis.

Introduction: Periodic paralyses (PP) are recurrent episodes of flaccid limb muscle weakness. Next to autosomal dominant forms, sporadic PP (SPP) cases are known but their genetics are unclear.

Methods: In a patient with hypokalemic SPP, we performed exome sequencing to identify a candidate gene.

Elevation of extracellular osmolarity improves signs of myotonia congenita in vitro: a preclinical animal study.

Key Points: During myotonia congenita, reduced chloride (Cl ) conductance results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction. Repetitive contraction of myotonic muscle decreases or even abolishes myotonic muscle stiffness, a phenomenon called 'warm up'. Pharmacological inhibition of low Cl channels by anthracene-9-carboxylic acid in muscle from mice and ADR ('arrested development of righting response') muscle from mice showed a relaxation deficit under physiological conditions compared to wild-type muscle.

Fascial tissue research in sports medicine: from molecules to tissue adaptation, injury and diagnostics: consensus statement.

The fascial system builds a three-dimensional continuum of soft, collagen-containing, loose and dense fibrous connective tissue that permeates the body and enables all body systems to operate in an integrated manner. Injuries to the fascial system cause a significant loss of performance in recreational exercise as well as high-performance sports, and could have a potential role in the development and perpetuation of musculoskeletal disorders, including lower back pain. Fascial tissues deserve more detailed attention in the field of sports medicine.

Na1.4 DI-S4 periodic paralysis mutation R222W enhances inactivation and promotes leak current to attenuate action potentials and depolarize muscle fibers.

Hypokalemic periodic paralysis is a skeletal muscle disease characterized by episodic weakness associated with low serum potassium. We compared clinical and biophysical effects of R222W, the first hNa1.4 domain I mutation linked to this disease.

Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life.

Introduction: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life.

Two novel families with hemiplegic migraine caused by recurrent SCN1A mutation p.F1499L.

Background Familial hemiplegic migraine type 3 is a monogenic subtype of migraine caused by missense mutations in the neuronal voltage-gated sodium channel gene SCN1A, with 10 different mutations reported so far. In two familial hemiplegic migraine type 3 families, partial cosegregation with a rare eye phenotype (elicited repetitive daily blindness) was previously reported. Methods Two novel familial hemiplegic migraine pedigrees were subjected to genetic analysis and detailed work-up of associated clinical features.

High prevalence of rare ryanodine receptor type 1 variants in patients suffering from aneurysmatic subarachnoid hemorrhage: A pilot study.

Subarachnoid hemorrhage (SAH) remains a challenging neurosurgical disease. The ryanodine receptor type 1 Ca2+ channel (RyR1) plays a crucial role in vasoconstriction and hemostasis. Mutations of the encoding gene, RYR1, are known to cause susceptibility to malignant hyperthermia (MH).

Na MRI and myometry to compare eplerenone vs. glucocorticoid treatment in Duchenne dystrophy.

In this pilot study we tested whether a low dose application of a mild diuretic substance such as eplerenone is beneficial in early stages of Duchenne muscular dystrophy using Na und H imaging, myometry, and clinical testing versus the glucocorticoid gold standard. Two 7-years old patients with DMD were examined on a 3T MRI system. H MRI and Na density-adapted 3-dimensional radial MRI sequences were performed both before and 1, 3 and 6 months after therapy with eplerenone respectively cortisone.

Successful treatment of periodic paralysis with coenzyme Q10: two case reports.

Primary periodic paralyses (PPs) are autosomal dominant ion channel disorders characterized by episodic flaccid weakness associated with variations in serum potassium level. The main prophylactic therapy of choice for PPsis carbonic anhydrase inhibitors that are not always effective. In this report, we described two PP patients who were successfully treated with coenzyme Q10.

Eplerenone repolarizes muscle membrane through Na,K-ATPase activation by Tyr10 dephosphorylation.

Eplerenone, an aldosterone antagonist, repolarizes muscle membrane in-vitro and increases strength in-vivo in channelopathies. In Duchenne dystrophy, it is administered for cardiomyopathy. We studied its mechanism of action on skeletal muscle to test its suitability for increasing strength in Duchenne dystrophy.

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.

Hypermetabolism in B-lymphocytes from malignant hyperthermia susceptible individuals.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism which is characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca(2+) release in myotubes via the ryanodine receptor type 1 (RyR1). As RyR1 is also expressed in B-lymphocytes, this study investigated whether cellular metabolism of native B-lymphocytes was also altered in MH susceptible (MHS) individuals.

7-T (35)Cl and (23)Na MR Imaging for Detection of Mutation-dependent Alterations in Muscular Edema and Fat Fraction with Sodium and Chloride Concentrations in Muscular Periodic Paralyses.

Purpose To determine whether altered sodium (Na(+)) and chloride (Cl(-)) homeostasis can be visualized in periodic paralyses by using 7-T sodium 23 ((23)Na) and chlorine 35 ((35)Cl) magnetic resonance (MR) imaging. Materials and Methods Institutional review board approval and informed consent of all participants were obtained. (23)Na (repetition time msec/echo time msec, 160/0.

Early-onset familial hemiplegic migraine due to a novel SCN1A mutation.

Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na channel Na1.1.

Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy.

We report a patient with paramyotonia congenita/hyperkalemic periodic paralysis due to Nav1.4 I693T mutation who had worsening of myotonia and muscle weakness in the setting of hypomagnesemia and hypocalcemia with marked recovery after magnesium administration. Computer simulations of the effects of the I693T mutation were introduced in the muscle fiber model by both hyperpolarizing shifts in the Nav1.

SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy.

Essential tremor (ET) is the most prevalent movement disorder, affecting millions of people in the USA. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In an attempt to identify genetic causes for ET, we performed whole-exome sequencing analyses in a large Spanish family with ET, in which two patients also developed epilepsy.

Painful cramps and giant myotonic discharges in a family with the Nav1.4-G1306A mutation.

Introduction: Two previously reported Norwegian patients with painful muscle cramps and giant myotonic discharges were genotyped and compared with those of members of 21 families harboring the same mutation.

Methods: Using primers specific for SCN4A and CLCN1, the DNA of the Norwegian family members was amplified and bidirectionally sequenced. Clinical and neurophysiological features of other families harboring the same mutation were studied.

Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients.

Objective: To examine rare KCNJ18 variations recently reported to cause sporadic and thyrotoxic hypokalaemic periodic paralysis (TPP).

Methods: We sequenced KCNJ18 in 474 controls (400 Caucasians, 74 male Asians) and 263 unrelated patients with periodic paralysis (PP), including 30 patients with TPP without mutations in established PP genes.

Results: In 10 patients without TPP, we identified 9 heterozygous, novel variations (c.

Domain III S4 in closed-state fast inactivation: insights from a periodic paralysis mutation.

Heterologous expression of sodium channel mutations in hypokalemic periodic paralysis reveals 2 variants on channel dysfunction. Charge-reducing mutations of voltage sensing S4 arginine residues alter channel gating as typically studied with expression in mammalian cells. These mutations also produce leak currents through the voltage sensor module, as typically studied with expression in Xenopus oocytes.