Central Core Disease Research Articles

Out of a Cell into This Darkened Space

Out of a Cell into This Darkened Space

Familial RYR 1 Mutation Associated with Mild and Severe Central Core Disease

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Functional Studies of RYR1 Mutations in the Skeletal Muscle Ryanodine Receptor Using Human RYR1 Complementary DNA

Malignant hyperthermia is associated with mutations within the gene encoding the skeletal muscle ryanodine receptor, the calcium channel that releases Ca from sarcoplasmic reticulum stores triggering muscle contraction, and other metabolic activities. More than 200 variants have been identified in the ryanodine receptor, but only some of these have been shown to functionally affect the calcium channel. To implement genetic testing for malignant hyperthermia, variants must be shown to alter the function of the channel. A number of different ex vivo methods can be used to demonstrate functionality, as long as cells from human patients can be obtained and cultured from at least two unrelated families. Because malignant hyperthermia is an uncommon disorder and many variants seem to be private, including the newly identified H4833Y mutation, these approaches are limited. The authors cloned the human skeletal muscle ryanodine receptor complementary DNA and expressed both normal and mutated forms in HEK-293 cells and carried out functional analysis using ryanodine binding assays in the presence of a specific agonist, 4-chloro-m-cresol, and the antagonist Mg. Transiently expressed human ryanodine receptor proteins colocalized with an endoplasmic reticulum marker in HEK-293 cells. Ryanodine binding assays confirmed that mutations causing malignant hyperthermia resulted in a hypersensitive channel, while those causing central core disease resulted in a hyposensitive channel. The functional assays validate recombinant human skeletal muscle ryanodine receptor for analysis of variants and add an additional mutation (H4833Y) to the repertoire of mutations that can be used for the genetic diagnosis of malignant hyperthermia.

Central core myopathy with RYR1 mutation masks 5q Spinal Muscular Atrophy

We report the case of a male who presented in infancy with motor delay and muscle weakness. Typical muscle biopsy features and heterozygous RYR1 mutation confirmed a diagnosis of central core disease. Family studies showed this to be a de-novo mutation. Some years later, his two older teenage brothers presented with proximal muscle weakness. Neurophysiology, muscle biopsy and DNA studies confirmed spinal muscular atrophy. Subsequent genetic studies in the index case also confirmed homozygous deletions of exon 7 and 8 in the SMN gene. Review of the original muscle biopsy showed classical features of central core disease with no evidence to suggest denervation, such that the diagnosis of spinal muscular atrophy could not have been suspected in the absence of the family history.

Successful use of albuterol in a patient with central core disease and mitochondrial dysfunction

Albuterol, a selective beta-adrenergic agonist, has been used experimentally in combination with exercise therapy in a few inherited neuromuscular disorders to increase muscle strength and muscle volume . We report on a 9-year-old boy with central core disease and mitochondrial dysfunction due to compound heterozygous RYR1 mutations receiving albuterol treatment for 1 year. Throughout the period of albuterol administration, the patient underwent an aerobic exercise regime of training sessions three times a week that lasted 20 min each. No side effects of albuterol use were seen. Significant clinical progress, including self care, sitting up, raising arms above the shoulders, independent feeding, and better speech and writing were observed compared with minimal development of these abilities in the previous years on physiotherapy. Improved forced expiratory volume in 1 s (FEV1) score was detected and increased muscle strength was noted: progress was measured using various functional tests and assessment scales. The only complication observed was a mild progression of the joint contractures, possibly due to an unbalance between the flexor and extensor musculature. In general, in this pilot study in a complex case of metabolic myopathy our patient has shown promising results following albuterol treatment and aerobic exercise therapy.

CGRP, a Vasodilator Neuropeptide that Stimulates Neuromuscular Transmission and EC Coupling

Calcitonin gene related peptide (CGRP) is a vasodilator; its plasma levels are altered in several human diseases, including migraine, hypertension and diabetes. CGRP is locally released by motor neurons, and is overexpressed in response to surgical or pharmacological blockage of neuromuscular transmission. Additionally to a brief discussion with regard to the clinical relevance of CGRP, this review focuses on the effects of CGRP on skeletal muscle excitation-contraction (EC) coupling, as well as the corresponding pathophysiological consequences. EC coupling involves activation of 2 different types of calcium channels: dihydropyridine receptors (DHPRs) located at the sarcolemma, and ryanodine receptors (RyR1s) located at the sarcoplasmic reticulum (SR). In response to electrical depolarization, DHPRs activate nearby and physically bound RyR1s, allowing Ca(2+) from the SR to move into the cytosol (termed voltage-gated Ca(2+) release, or VGCR). We recently found that CGRP stimulates VGCR by 350 % in as short as 1h. This effect, which lasts for at least 48 h, is due to activation of the CGRP receptor, and requires activation of the cAMP/PKA signaling pathway. CGRP also increases the amplitude of caffeine-induced Ca(2+) release (400 %); suggesting increased SR Ca(2+) content underlies stimulation of VGCR. Interestingly, in the long-term CGRP also increases the density of sarcolemmal DHPRs (up to 30%, within 24-48 h). We propose that these CGRP effects may contribute to prevent and/or restore symptoms in central core disease (CCD); a congenital myopathy that is linked to mutations in the gene encoding RyR1.

RyR1-mediated Ca2+ Leak and Ca2+ Entry Determine Resting Intracellular Ca2+ in Skeletal Myotubes

The control of resting free Ca(2+) in skeletal muscle is thought to be a balance of channels, pumps, and exchangers in both the sarcolemma and sarcoplasmic reticulum. We explored these mechanisms using pharmacologic and molecular perturbations of genetically engineered (dyspedic) muscle cells that constitutively lack expression of the skeletal muscle sarcoplasmic reticulum Ca(2+) release channels, RyR1 and RyR3. We demonstrate here that expression of RyR1 is responsible for more than half of total resting Ca(2+) concentration ([Ca(2+)](rest)) measured in wild type cells. The elevated [Ca(2+)](rest) in RyR1-expressing cells is not a result of active gating of the RyR1 channel but instead is accounted for by the RyR1 ryanodine-insensitive Ca(2+) leak conformation. In addition, we demonstrate that basal sarcolemmal Ca(2+) influx is also governed by RyR1 expression and contributes in the regulation of [Ca(2+)](rest) in skeletal myotubes.

Ryanodine receptor channelopathies.

Ryanodine receptors (RyR) are intracellular Ca2+-permeable channels that provide the sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contractions. RyR1 underlies skeletal muscle contraction, and RyR2 fulfills this role in cardiac muscle. Over the past 20 years, numerous mutations in both RyR isoforms have been identified and linked to skeletal and cardiac diseases. Malignant hyperthermia, central core disease, and catecholaminergic polymorphic ventricular tachycardia have been genetically linked to mutations in either RyR1 or RyR2. Thus, RyR channelopathies are both of interest because they cause significant human diseases and provide model systems that can be studied to elucidate important structure-function relationships of these ion channels.

Functional Properties of RYR1 Mutations Identified in Swedish Patients with Malignant Hyperthermia and Central Core Disease

A diagnosis of malignant hyperthermia susceptibility by in vitro contraction testing can often only be performed at specialized laboratories far away from where patients live. Therefore, we have designed a protocol for genetic screening of the RYR1-cDNA and for functional testing of newly identified ryanodine receptor 1 (RYR1) gene variants in B lymphocytes isolated from peripheral blood samples drawn at local primary care centers. B lymphocytes were isolated for the extraction of RYR1-mRNA and genomic DNA and for establishment of lymphoblastoid B cell lines in 5 patients carrying yet unclassified mutations in the RYR1. The B lymphoblastoid cell lines were used to study resting cytoplasmic calcium concentration, the peak calcium transient induced by the sarco(endo)plasmic reticulum Ca-ATPase inhibitor thapsigargin, and the dose-dependent calcium release induced by the ryanodine receptor agonist 4-chloro-m-cresol. It was possible to extract mRNA for cDNA synthesis and to create B lymphocyte clones from all samples. All B lymphoblastoid cell lines carrying RYR1 candidate mutations showed significantly increased resting cytoplasmic calcium levels as well as a shift to lower concentrations of 4-chloro-m-cresol inducing calcium release compared with controls. Peripheral blood samples are stable regarding RNA and DNA extraction and establishment of lymphoblastoid B cell lines after transportation at ambient temperature over large distances by ordinary mail. Functional tests on B cells harboring the newly identified amino acid substitutions indicate that they alter intracellular Ca2+ homeostasis and are most likely causative of malignant hyperthermia.

Does Central Core Disease have a Neuronal Component?

Type 1 ryanodine receptors (RyR1) are the second most common isoform found in neurons after RyR2. We have provided evidence that in nerve terminals from neurohypophysis, L-type Ca2+ channels are coupled to RyR1 in the same way found in EC coupling in skeletal muscle. In these nerve terminals (J.Neuroscience 2006, 26 −7565) L-type channels are the sensors of membrane potential for Voltage Induced Ca2+ Release (VICaR), independently of their role as Ca2+ current carriers, and RyRs of uknown type are the effectors through which Ca2+ is released into the cytosol. Here we wished to study whether RyRs of type 1 are mediators of VICaR in these nerve terminals. We employed a RyR1 mutant mouse (I4895T) with a loss of function phenotype that causes Central Core Disease in humans. We studied both, global [Ca2+] with Fura-2 and focal [Ca2+] in the form of Ca2+ syntillas with fluo3. When the nerve terminals were depolarized to 0mV, the mutant showed a 4-fold decrease in the global Ca2+ transient compared to WT. This very large decrease in the Ca2+ transient occurred in the absence of any change in the Ca2+ current. In the absence of external Ca2+, we also demonstrated the presence of VICaR in WT. Moreover, in the WT depolarization to 0mV from −80mV induced a 3 fold increase in syntilla frequency due to VICaR (i.e. in the absence of external Ca2+). VICaR was totally absent in the mutant. These data show for the first time the involvement of type 1 RyRs during depolarization of nerve terminals. This suggests that Central Core Disease has a neuronal component as well as a skeletal muscle component.( Supported by grants from NIH GM087580-01 to JW and AHA 0835580D to VD.)

Allele Specific Gene Silencing in Autosomal-Dominant Skeletal Myopathies

Central Core Disease (CCD) and Malignant Hyperthermia (MH) are linked to single amino acid substitutions in the skeletal muscle Ca2+ release channel, the type 1 ryanodine receptor (RyR1). We focus on two autosomal dominant (AD) RyR1 mutations, Y522S (YS) and I4898T (IT), which cause MH and CCD, respectively. The AD mode of inheritance and data indicating knock-out of one RyR1 allele is well-tolerated in mice led us to hypothesize that allele-specific gene silencing (ASGS) of the mutant allele would rescue RyR1 functional defects in skeletal muscle cells from YS and IT knock-in mice.We evaluated the functional consequences of allele-specific silencing in YS and IT muscle cells using short interfering RNAs (siRNAs). To screen potential siRNAs for relative knockdown efficacy and allele specificity, we generated cDNAs encoding fusion proteins derived from wild type (WT) (Venus-Exons-3XFLAG) and either YS or IT mutation-containing (Cherry-Exons-3XHA) exons. Simultaneous transfection of these cDNAs and siRNAs into HEK293 cells and subsequent evaluation of mRNA (semi-quantitative RT-PCR) and protein levels (fluorescence microscopy and western blotting) was used to determine knockdown efficacy and allele-specificity prior to functional rescue experiments. Myotubes derived from heterozygous YS mice (YS/+) exhibit ∼4-fold increase in caffeine sensitivity (EC50 values were 0.5mM and 2.3mM for YS/+ and WT, respectively). Treatment with a YS-selective siRNA, normalized caffeine sensitivity (EC50 = 2.5mM) without decreasing peak caffeine-induced release. Similarly, YS-selective siRNA treatment rescued the increased voltage sensitivity of Ca2+ release in YS/+ myotubes determined in perforated-patch clamp experiments (VF1/2: WT = −18mV, YS/+ scrambled = −35mV, YS/+ YS-selective = −18mV). These results indicate that ASGS represents a promising approach for normalization of RyR1 function in MH and CCD. Similar functional rescue experiments in adult skeletal muscle fibers are currently underway.

Calcium Influx Analysis by TIRF Microscopy on Cultured Primary Myotubes from Patients with RyR1 Mutations

Central core disease (CCD) and malignant hyperthermia (MH) have been linked to point mutations in the gene encoding the skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor), which is localized on human chromosome 19 (RYR11). Central core disease is a relatively mild, slowly progressive autosomal dominant myopathy, characterized histologically by the presence of centrally located cores running the length of the muscle fibres. MH is a pharmacogenetic induced hypermetabolic disease.

Role of Oxidative Stress, Autophagy and Apoptosis in the I4895T RyR1 Knockin Mice

I4898T mutation in the skeletal muscle ryanodine receptor (RyR1) in humans has been suggested to underlie Central Core Disease (CCD). CCD is the congenital myopathy characterized by muscle weakness of lower extremities leading to delayed attainment of motor skill milestones. We created mice with a corresponding RyR1 I4895T mutation. Although no central cores were observed in the muscle of these mice, this uncoupling mutation dramatically reduces voluntary running. The soleus muscle from the I4895T mice displays decreased ability to generate force, increased oxidative stress, decreased antioxidant capacity and decreased cytochrome c oxidase activity (suggesting mitochondrial damage). We also find evidence of both autophagy and apoptosis in the mutant muscle since Atg5, Atg6 (Beclin1), Atg9, Atg12, Bcl2, caspase family members, C/EBP homologous protein (CHOP) are all upregulated in the soleus. Upregulation of several ER stress related proteins (BiP, IRE1α, and PDI) was also observed. We propose that the I4895 mutation is associated with the oxidative stress, an unfolded protein response (UPR), autophagy and apoptosis, all of which may contribute to mitochondrial destruction associated with this disease.

Effects of a Y522S-RyR1 Mutation on Cerebellar Purkinje Cell Function

The devastating consequences of calcium dysregulation are exemplified by the skeletal muscle diseases malignant hyperthermia (MH) and central core disease (CCD). These diseases result from mutations in the ‘skeletal muscle-isoform’ of the ryanodine receptor calcium release channel (RyR1). To investigate the etiology of MH and CCD, mouse models have recently been generated (Chelu et al. 2005). Skeletal muscle harboring the Y522S-RyR1 knock-in mutation exhibit Ca2+ leak from internal stores, basal cellular stress, and ultimately progressive mitochondrial and cellular damage (Durham et al. 2008). Although the effects of this MH-causing mutation have been characterized in skeletal muscle, the effects in the nervous system have not been documented. RyR1 is expressed highly in cerebellar Purkinje neurons. Y522S-RyR1 mice do not exhibit gross neurological defects suggesting that the defects may be subtle or that neuronal function is spared due to compensatory changes.We have initiated studies investigating 3 main aspects of Y522S-RyR1 mouse Purkinje cells: intracellular calcium release, cellular organization/morphology, and cellular stress. In preliminary studies using imaging techniques with the calcium indicator dye Fura2-AM, RyR-mediated calcium release in Y522S-RyR1 Purkinje neurons exhibited a negative shift in the apparent EC50 for the agonist caffeine. In addition, the sensitivity of RyR to other activators (temperature, voltage, ryanodine) and intracellular calcium store content were investigated. Since calcium signaling is important during neuronal development and maturation, the morphology of Y522S-RyR1 Purkinje cells was examined using immunohistochemistry and confocal microscopy. Moreover, we have initiated studies to determine if altered RyR1 function results in basal cellular stress using Western blot and immunohistochemical analyses. Y522S-RyR1 mutant mice provide an excellent tool to address calcium dysregulation, its pathological consequences, and potential approaches for compensation of altered calcium signaling in the central nervous system.

Rational Design and Structrual Analysis of Ca2+ Biosensor and Application in Skeletal Muscle Cells

Quantitative and real-time detection of Ca2+ signaling in internal Ca2+ store sarcoplasmic reticulum (SR) of skeletal muscle cells is essential to explore the mechanism of various diseases such as malignant hyperthermia, central core diseases, brody diseases and so on highly related with SR calcium abnormal handling. To overcome the limitation of reported genetically encoded Ca2+ sensors based on natural Ca2+ binding proteins of perturbing Ca2+ signaling, we report a novel design of calcium biosensor for the first time by rational de novo engineering a non-natural Ca2+ binding site into a single enhanced green fluorescent protein (EGFP), which can successfully quantitatively reveal the subcellular calcium signaling by fluorescence change. These developed Ca2+ sensors exhibit Kd values measured inside the mammalian cells in situ optimal for the measurement of Ca2+ in the SR. Metal selectivity of the sensors for Ca2+ in competition to excessive biological metal ions such as Mg2+, K+, Na+ has been examined. In addition, these developed sensors can be targeted to the SR of muscle cells, and detected the Ca2+ signaling induced by various agonists and antagonists interacting with SR membrane Ca2+ pumps or receptors. Moreover, they exhibit fast response to Ca2+. Further, their optical and conformational properties have been investigated using various spectroscopic methods, including high resonance resolution NMR. Moreover, more than 70% of the amino acids of the EGFP-based designed sensor have been successfully assigned using heteronuclear-labeled proteins. Our studies further reveal the key factors that contribute to the molecular mechanisms of the fluorescence change upon calcium binding and dynamic properties of our designed Ca2+ sensors.

Characterization and temporal development of cores in a mouse model of malignant hyperthermia

Malignant hyperthermia (MH) and central core disease are related skeletal muscle diseases often linked to mutations in the type 1 ryanodine receptor (RYR1) gene, encoding for the Ca(2+) release channel of the sarcoplasmic reticulum (SR). In humans, the Y522S RYR1 mutation is associated with malignant hyperthermia susceptibility (MHS) and the presence in skeletal muscle fibers of core regions that lack mitochondria. In heterozygous Y522S knock-in mice (RYR1(Y522S/WT)), the mutation causes SR Ca(2+) leak and MHS. Here, we identified mitochondrial-deficient core regions in skeletal muscle fibers from RYR1(Y522S/WT) knock-in mice and characterized the structural and temporal aspects involved in their formation. Mitochondrial swelling/disruption, the initial detectable structural change observed in young-adult RYR1(Y522S/WT) mice (2 months), does not occur randomly but rather is confined to discrete areas termed presumptive cores. This localized mitochondrial damage is followed by local disruption/loss of nearby SR and transverse tubules, resulting in early cores (2-4 months) and small contracture cores characterized by extreme sarcomere shortening and lack of mitochondria. At later stages (1 year), contracture cores are extended, frequent, and accompanied by areas in which contractile elements are also severely compromised (unstructured cores). Based on these observations, we propose a possible series of events leading to core formation in skeletal muscle fibers of RYR1(Y522S/WT) mice: Initial mitochondrial/SR disruption in confined areas causes significant loss of local Ca(2+) sequestration that eventually results in the formation of contractures and progressive degradation of the contractile elements.

Ca 2+ dysregulation in Ryr1 I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Ryr1(I4895T/wt) (IT/+) mice express a knockin mutation corresponding to the human I4898T EC-uncoupling mutation in the type 1 ryanodine receptor/Ca(2+) release channel (RyR1), which causes a severe form of central core disease (CCD). IT/+ mice exhibit a slowly progressive congenital myopathy, with neonatal respiratory stress, skeletal muscle weakness, impaired mobility, dorsal kyphosis, and hind limb paralysis. Lesions observed in myofibers from diseased mice undergo age-dependent transformation from minicores to cores and nemaline rods. Early ultrastructural abnormalities include sarcomeric misalignment, Z-line streaming, focal loss of cross-striations, and myofibrillar splitting and intermingling that may arise from defective myofibrillogenesis. However, manifestation of the disease phenotype is highly variable on a Sv129 genomic background. Quantitative RT-PCR shows an equimolar ratio of WT and mutant Ryr1 transcripts within IT/+ myofibers and total RyR1 protein expression levels are normal. We propose a unifying theory in which the cause of core formation lies in functional heterogeneity among RyR1 tetramers. Random combinations of normal and either leaky or EC-uncoupled RyR subunits would lead to spatial differences in Ca(2+) transients; the resulting heterogeneity of contraction among myofibrils would lead to focal, irreversible tearing and shearing, which would, over time, enlarge to form minicores, cores, and nemaline rods. The IT/+ mouse line is proposed to be a valid model of RyR1-related congenital myopathy, offering high potential for elucidation of the pathogenesis of skeletal muscle disorders arising from impaired EC coupling.

Histochemical and immunohistological approach to comparative neuromuscular diseases.

The broad category of neuromuscular diseases covers conditions that involve the weakness or wasting of the body muscles. These problems may occur in the spinal cord, the peripheral nerves or the muscle fibers. Some may be hereditary, while others are acquired. Commonly recognized conditions fall into the categories of myopathies, which are diseases of the muscle like muscular dystrophy, disorders of the junction where the nerve impulses are transmitted to the muscle like myasthenia gravis, and neuropathies, which are diseases of the peripheral nervous system. The diagnosis of most neuromuscular diseases rest on careful clinical evaluation of the patient, electromyography, the muscle biopsy, and in some instances, molecular genetic studies. Muscle biopsy, associated to histochemical and immunohistological techniques, plays a key role in diagnosis of many neuromuscular disorders. A number of morphological abnormalities of muscle can be recognized on histological stains such as haematoxylin and eosin and Engel trichrome. Histochemical techniques are essential for the study of muscle biopsies for four main reasons. First, they demonstrate the non-uniform nature of the muscle highlighting the different biochemical properties of specific fibre type and their selective involvement in certain disease processes. Second, they may show an absences of a particular enzyme. Third, an excess of a particular substrate can be demonstrated. Fourth, they may show structural changes in the muscle which would not be apparent with routine histological stains, such as the enzyme-deficient cores in central core disease "mouth-eaten" fibers, and abnormalities in the distribution of mitochondria. In some neuromuscular disorders there could be only non-specific myopathological features. However, a number of proteins, including sarcolemmal, sarcomeric, and nuclear proteins as well as enzymes with defects responsible for neuromuscular disorders, have been identified during the past two decades, allowing a more specific and firm diagnosis of muscle diseases. Identification of protein defects relies predominantly on immunohistochemical preparations and on Western blot analysis. While immunohistochemistry is very useful in identifying abnormal expression of primary protein abnormalities in recessive conditions, it is less helpful in detecting primary defects in dominantly inherited disorders. Abnormal immunohistochemical expression patterns can be confirmed by Western blot analysis which may also be informative in dominant disorders. Besides identification of specific protein defects, immunohistochemistry is also helpful in the differentiation of inflammatory myopathies by subtyping cellular infiltrates and demonstrating up-regulation of subtle immunological parameters. This review will summarize and describe the impact that histochemistry and immunohistochemistry has had and the possibilities it has opened up in the diagnosis of neuromuscular disorders in human as well as in veterinary myology.

CORE-ROD MYOPATHY CAUSED BY MUTATIONS IN THE NEBULIN GENE

Nemaline myopathy (NM) and central core disease (CCD), 2 of the most frequent congenital myopathies, are clinically and genetically heterogeneous disorders of skeletal muscle. NM (OMIM 161800) is caused by mutations in at least 6 different genes encoding thin filament proteins of the striated muscle sarcomere: skeletal alpha-actin ( ACTA1 ), nebulin ( NEB ), beta-tropomyosin ( TPM2 ), slow alpha-tropomyosin ( TPM3 ), slow skeletal muscle troponin-T ( TNNT1 ), and cofilin-2 ( CFL2 ). CCD (OMIM 117000) is mainly caused by mutations in the gene encoding the skeletal muscle ryanodine receptor ( RYR1 ), a Ca2+ channel involved in excitation-contraction coupling. Congenital myopathies with the combination of distinct “cores” and “rods” in the same muscle fibers have been described in a small number of cases. In 2 families mutations have been identified in RYR1 1,2 and in others, linkage has been found to a locus on chromosome 15.3 Here we report a patient with recessively inherited core-rod myopathy caused by compound heterozygous mutations in NEB . This observation broadens the spectrum of genes involved in core-rod myopathies. ### Case report. The patient is a 27-year-old white man. He presented at birth with generalized hypotonia and required immediate intubation and resuscitation. Spontaneous movements were very poor and he had seizures from the first week. Restrictive respiratory insufficiency led to continuous mechanical ventilation via tracheotomy at the age of 2 years. The patient did not acquire independent walking but was able to take a few steps with orthosis at the age of 4; diffuse muscle weakness with axial predominance was observed. Electromyography showed myopathic patterns and normal motor and sensory responses. Serum creatine kinase levels were normal. The patient developed …

Core Myopathies and Risk of Malignant Hyperthermia

In this article, we analyze myopathies with cores, for which an association to malignant hyperthermia (MH) has been suggested. We discuss the clinical features, the underlying genetic defects, subsequent effects on cellular calcium metabolism, and in vitro muscle responses to MH triggers. We describe in detail central core disease, multiminicore disease, and nemaline rod myopathy. We categorize the diseases according to the affected proteins and discuss the risk for MH, which is high or theoretically possible when the calcium-conducting proteins are affected.