Diseases of Muscle and the Neuromuscular Junction Part 2

Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) has two genetic forms, an X-linked recessive disease mapped to Xq28 (XL-EDMD) and a less common autosomal dominant form (AD-EDMD) mapped to 1q11-q23. The two forms are clinically indistinguishable. XL-EDMD is caused by mutations in the nuclear membrane protein emerin [see Figure 1]17; the AD-EDMD is caused by mutations in the lamin A/C gene, which encodes two proteins of the nuclear lamina, lamin A and lamin C.18 Mutations in the lamin A/C gene most often cause cardiomyopathy and conduction defects.19 The integral nuclear membrane proteins interact closely with nuclear lamins, which are intermediate filament proteins found on the nucleic side (inner side) of the nuclear membrane [see Figure 1]. Emerin binds lamin A, one of the lamin A/C gene products.

Patients with EDMD present with a triad of symptoms: (1) a humeroperoneal distribution of muscle involvement with prominent wasting and weakness in the biceps, triceps, anterior tibial, and peroneal muscles that progresses slowly in a scapu-lopelviperoneal pattern to include pectoral and pelvic muscle involvement; (2) early development of contractions at the elbows, flexors, Achilles tendon, neck, and spine, which may occur before there is significant muscle weakness; and (3) cardiac involvement, which presents as conduction defects with bradycar-dia and a prolonged PR interval. Isolated atrial paralysis strongly suggests EDMD.

Female carriers of XL-EDMD generally do not have skeletal muscle weakness; however, they can develop heart block.

EDMD begins within the first two decades of life. Diagnosis is made on the basis of clinical presentation and muscle biopsy and confirmed by mutation analysis; however, a slightly elevated CK level is suggestive. Muscle biopsies reveal nonspecific myopath-ic features, but the absence of emerin as evidenced by applying antibodies to emerin on immunocytochemistry or Western blot assay on specimens derived from muscle biopsies of patients and their families may support the diagnosis. Available genetic tests identify the carriers who may have cardiac conduction defects. Prompt recognition and cardiac pacing can prevent sudden death or syncopal attacks.

No specific treatment is available, but physical therapy may slow the development of contractions.

Limb-girdle muscular dystrophies

Limb-girdle muscular dystrophies (LGMD) comprise a het-erogenous group of disorders designated as autosomal dominant (LGMD1), autosomal recessive (LGMD2), or congenital (MDC) [see Table 1]. 

Autosomal Dominant Limb-Girdle Muscular Dystrophies

The autosomal dominant forms of LGMD1 are generally uncommon disorders representing less than 10% of all LGMDs; they present with slowly progressive proximal and distal muscle weakness and elevations of serum CK levels. They tend to be milder than other LGMD presentations. The diagnosis is made by identifying the missing protein on muscle biopsy preparation and the genetic defect on mutation analysis. There is no specific treatment for this group of disorders.

LGMD1A LGMD1A results from mutations in myotilin, a protein necessary for normal assembly and maintenance of the sarcomere.21 In addition to proximal and distal muscle weakness, symptoms may include dysarthria, hypophonia, and a nasal voice. This disorder is allelic to the form of myofibrillar myopa-thy caused by myotilin mutation [see Myopathies Due to Mutations in the Intermediate Filament Proteins, below].21

LGMD1B LGMD1B is caused by mutations in lamin A/C; the phenotype for this disorder is identical to that of AD-EDMD [see Emery-Dreifuss Muscular Dystrophy, above]. In addition to having LGMD symptoms, some patients have familial partial lipodystrophy characterized by reduced subcutaneous fat, insulin resistance, increased triglyceride levels, low levels of high-density lipoproteins (HDLs), diabetes mellitus, and increased risk of atherosclerotic vascular disease.6

LGMD1C LGMD1C is caused by mutations in the caveolin-3 gene.19,22 Caveolin-3, a 21 to 24 kd internal membrane protein, may play a role in the regulation of muscle glycolysis. Patients may have different clinical phenotypes; they may present with LGMD, isolated hyperCKemia, rippling muscle disease, or distal myopathy.

LGMD1D, 1E, 1F These three disorders represent rare mutations; linkage analysis has determined the chromosomal loci of the causative mutations, but the pertinent genes have not been identified.

Autosomal Recessive Limb-Girdle Muscular Dystrophies

At present, 10 forms of LGMD2 have been identified, and more are likely to be recognized [see Table 1].20,23

LGMD2A LGMD2A is caused by mutations in the calpain-3 gene.24 Calpain deficiency is the most frequent form of LGMD. Calpain-3 is a calcium-activated protease that plays a role in muscle differentiation.

Disease onset occurs in patients 8 to 30 years of age. Patients with calpain-3 deficiency present with weakness in the pelvic girdle muscles, especially glutei, that spares the hip abductors. Scapular winging and posterior thigh involvement are commonly seen. The serum CK level can range from 100 IU/L to more than 9,000 IU/L. Mutations in the gene encoding calpain-3, which is located on chromosome 15q15.1-q15.3, have been iden-tified.24 The diagnosis is confirmed with Western blot assay. There is no specific treatment for this disorder.

LGMD2B LGMD2B is caused by mutations in the dysferlin gene,25,26 which is a membrane-associated protein not part of the dystrophin-glycoprotein complex [see Figure 1]. Dysferlin interacts with caveolin and may be involved in membrane repair. Mutations in the dysferlin gene cause two types of myopathy: the Miyoshi myopathy, which is characterized by very high serum CK levels and early involvement of the gastrocnemius muscle, and LGMD2B, which may present as distal and proximal muscle weakness in patients in their late teens or early 20s. Identical mutations can cause either Miyoshi myopathy or LGMD2B.

Some patients with dysferlinopathy present with prominent distal weakness but do not have the phenotype of Miyoshi my-opathy. Dysferlinopathies are common disorders. The diagnosis is confirmed by finding absence of dysferlin in the sarcolemma of muscle biopsy specimens using immunohistochemistry and antidysferlin antibodies. The defect can also be seen in peripheral blood monocytes using Western blot assay. The absence of dysferlin could lead to perturbation of membrane resealing and interference with the repair of damaged muscle fibers, possibly resulting from defects in vesicular trafficking within the muscle fiber.6,20,23 There is no specific treatment for this disorder.

LGMD2C, 2D, 2E, 2F These four disorders are caused by mutations in the genes encoding the four members of the sarco-glycan complex: LGMD2C (y-sarcoglycan gene mutation mapped to chromosome 5q33), LGMD2D (a-sarcoglycan, mapped to 17q12), LGMD2E (p-sarcoglycan, mapped to 4), and LGMD2F (S-sarcoglycan, mapped to 13q12).20,23 In all four disorders, the three other components of the sarcoglycan complex are lost or partially absent, but the dystroglycan complex is normal.

Mutations in the sarcoglycan genes have been identified in various European and American families who have autosomal recessive LGMDs; these mutations include missense, nonsense, and in-frame deletions that result in an LGMD phenotype of varying clinical severity. The mutations cause an improper assembly of the sarcoglycans with the dystroglycan complex proteins, disrupting the linkage between sarcolemma and extracellular matrix [see Figure 1 ].

The transmembrane components of the sarcoglycan complex are specific to skeletal and cardiac muscle, and their integrity is critical for normal muscle physiology.

The autosomal recessive LGMDs 2D, 2E, and 2F are similar in presentation to a severe form of DMD; they affect males and females. Patients present with mild to severe weakness of the proximal muscles (especially in the legs), an elevation of the serum CK level to about 3,000 IU/L, dystrophic changes in the muscle, and frequently calf hypertrophy. The age at onset is variable. Results of immunocytochemistry and immunoblot analysis of muscle biopsy specimens for dystrophin are normal, but sarcoglycan is absent or severely deficient. Deficiency in the sarcoglycan pro-teins—easily detected using the proper antibodies—is found in 20% of patients with the presentation of LGMD. Mutations in the respective genes have been reported in as many as 60% of patients.

There is a great variability in the severity of muscle weakness, which probably depends on the degree of residual sarcoglycan expression. Of note, cardiomyopathy may also be present either as an isolated manifestation of dilated cardiomyopathy or in conjunction with the skeletal myopathy. There is no specific treatment for this disorder.

LGMD2G LGMD2G is caused by mutations in the gene encoding telethonin, which is a sarcomeric protein localized to the Z disk of skeletal muscle. Mutations in the telethonin gene cause disruption of the sarcomeric structure.28 LGMD2G is a rare, relatively mild autosomal recessive disorder.

Disease onset occurs at 2 to 15 years of age, often with distal muscle involvement. Disease progression is variable. Muscle biopsy may show vacuoles within the muscle fibers. The serum CK levels are increased 10-fold to 30-fold above normal. The absence of telethonin as detected by immunocytochemistry confirms the diagnosis.

LGMD2H LGMD2H is a very rare disease identified only in the Manitoba Hutterite population. It is caused by mutations in the TRIM32 gene (the Tripartite-motif-containing gene) on chromosome 9q33.1, which is probably related to an E3-ubiqui-tin ligase.

LGMD2I LGMD2I is caused by mutations in the fukutin-re-lated protein (FKRP) gene, on chromosome 19q13.32.30 This disorder and the Fukuyama congenital muscular dystrophy (FMDC) are allelic disorders [see Fukuyama MDC, below]. Both are related to changes in the a-dystroglycan (a-DG) expression resulting from defects in glycosylation. LGMD2I is not uncommon; in some countries, such as the United Kingdom,31 it is one of the most common forms of LGMD.

Onset of LGMD2I is variable, occurring in early childhood or in adulthood. Patients present with proximal muscle weakness similar to that found in BMD; enlarged calves; an elevated serum CK level; sometimes, an enlarged tongue; and, very commonly, involvement of the respiratory and cardiac muscles. Intelligence is normal. Secondary reduction of a-DG expression on muscle biopsy or reduced molecular weight protein on immunoblot assay, accompanied by reduction of a2-laminin by immunocyto-chemistry, raises suspicion for the diagnosis of LGMD2I.

LGMD2J LGMD2J results from mutations in the titin gene, on chromosome 2q31. This disorder, which has been reported in Finland,32 is allelic with the tibial muscular dystrophy, an auto-mosmal dominant disease that has been reported in Finland.

Congenital Muscular Dystrophies

MDCs are autosomal recessive disorders characterized by muscle weakness in early infancy. Frequently, these disorders are associated with brain malformations and cognitive abnormalities.33-35 In the neonatal period, the serum CK level is highly elevated, often into the thousands. MDCs represent disorders of neuronal migration, referred to as cobblestone cortex. They result in abnormal glycosylation of a-DG that disrupts the interaction between the membrane and the extracellular matrix in muscle and brain [see Figure 1]. They are often referred to as a-dystro-glycanopathies [see Table 1].

MDC1A MDC1A is the classic form of MDC, accounting for more than 40% of cases of MDC. The disease is linked to chromosome 6q22 and is caused by a defect in merosin (a2-laminin), which represents the structural backbone of the basement membrane [see Figure 1]. In contrast to other forms of MDC, there is no brain malformation or mental retardation in MDC1A. This disease occurs in children but can also occur in young adults. The patients have a2-laminin deficiency in the skeletal muscle basal lamina.4,6,35 Some patients have partial merosin deficiency resulting either from a mild mutation or from secondary causes, most often mutations in the genes encoding fukutin or FKRP.

MDC1A may be associated with an MRI-defined leukoen-cephalopathy (without overt signs of intellectual deterioration), neonatal hypotonia, elevated serum CK levels, delayed motor milestones, axonal neuropathy, and respiratory muscle weakness. The degree of the clinical phenotype varies from moderate to severe. In patients who lack a2-laminin, the dystroglycan complex is deranged, and consequently, the muscle membrane becomes defective.4,6,35 Because a2-laminin, together with p1-laminin and Y1-laminin, are also present in Schwann cells, some MDC patients have neuropathic findings.

MDC1B This disorder is caused by mutations in the a7-inte-grin gene on chromosome 12q13. In patients with this disorder, a7-integrin is absent from thesarcolemma.36 The clinical presentation of MDC1B is identical to that of MDC1A.

MDC1C MDC1C is a rare disease caused by mutations in FKRP on chromosome 19q13.3. MDC1C and LGMD2I are allelic disorders. Onset of muscle weakness occurs in the first week after birth; affected children do not achieve independent ambulation. The disease is marked by respiratory involvement; in contrast to most other MDCs, in MDC1C intelligence may be normal. The disease is suspected by the variable reduction or absence of a-DG in the muscle or reduced a-DG size on immunoblot.

MDC1D MDC1D is caused by a mutation in the LARGE gene. This is a rare disorder resulting in severe mental retardation and dystrophy. Diagnosis is confirmed by the absence of a-DG on muscle biopsy.

Fukuyama MDC This disorder is the most common congenital muscular dystrophy in persons of Japanese descent. FMDC is caused by a mutation in the fukutin gene that results in a deficiency of fukutin and decreased glycosylation of a-DG detected by reduced a-DG staining in muscle. Patients have brain malformations, profound mental retardation, and ophthalmo-logic abnormalities. The disease starts before the age of 9 months, and the patients never learn to walk. They die by the age of 20.

Muscle-eye-brain disease Muscle-eye-brain disease (MEB) is caused by a mutation in a glycosyltransferase POMGnT gene, which results in a deficiency of a-DG, as confirmed by immuno-cytochemistry. Patients with MEB present with hypotonia, weakness, mild to moderate hydrocephalus, cortical or cerebel-lar hypoplasia, and eye abnormalities (e.g., myopia, microph-thalmia, and optic nerve hypoplasia).

Walker-Warburg syndrome This disorder results from mutations in an O-mannosyl transferase POMGnT1 gene. It is the most severe MDC, and it shares clinical features of both FMDC and MEB. Patients usually die by age 3.33,31

MDC with joint contractures Three forms of MDC are characterized by joint contractions; patients with these disorders have neither a defect in glycosylation nor mental retardation. These diseases are congenital muscular dystrophy with rigid spine syndrome (RSMD), Ullrich myopathy, and Bethlem my-opathy. No specific therapy is available.

RSMD results from mutations in selenoprotein N (SEPN1) on chromosome 1q35-36.37 Patients with this disorder present with muscle weakness; hypotonia; facial weakness; and a distinctive spinal rigidity that results in inability to flex the neck, scoliosis, and respiratory difficulties.

Ullrich myopathy is caused by mutations in one of the poly-peptide chains that form collagen VI, which is needed to interact with the extracellular matrix.38 Patients have excessive distal mobility combined with proximal contractures, rigid spine at birth, and muscle weakness. Muscle biopsy shows absence of collagen VI. Ullrich myopathy and Bethlem myopathy are allelic disorders.

Bethlem myopathy is an autosomal dominant disease caused by mutations in subunits of the extracellular matrix proteins, collagen VI a1, a2 and a3.39 Disease onset is in childhood or adolescence. Clinical manifestations include mild muscle weakness and contractures in multiple joints, which may be present even at birth.

Myopathies due to mutations in the intermediate filament proteins

Intermediate filaments play a critical role in providing mechanical integration for the myofibrils and in protecting the muscle fiber from repeated mechanical stress. The protein desmin is the chief intermediate filament of the skeletal and cardiac muscle; it maintains the structural and functional integrity of the myofibrils and functions as a cytoskeletal protein, linking Z bands to the plasma membrane [see Figure 1]. The heat shock protein ap-crys-tallin acts as a chaperone protein in protecting the desmin filaments from stress-induced damage. Desmin filaments encircle the Z bands and are fastened to them and to one another by plectin filaments. Myotilin is a Z-disc protein that interacts with a-actinin and filamin C and directly binds to F-actin [see Figure 1].

Defects in intermediate filaments cause myofibrillar my-opathies; the prototypic myopathy in this group is the desmin myopathy caused by mutations in the desmin gene.40-42 The desmin myopathy is of dominant or, rarely, sporadic inheritance; patients may present either with cardiac conduction defects or with a distal-onset skeletal myopathy that progresses to involve proximal, facial, or respiratory muscles.

Mutations in the aB-crystallin gene cause a skeletal myopathy similar to desmin myopathy.43 A case of myopathy associated with mutant plectin has also been reported.44 Mutations in the myotilin also cause myofibrillar myopathy.21 As in other myofib-rillar myopathies, patients with myotilin mutations present with distal muscle weakness; over time, they develop cardiomyopa-thy. The diagnosis is suspected when myofibrillar products are accumulated on muscle biopsy, as evidenced by enzyme histo-chemical stains; it is confirmed by mutation analysis.

There is no specific treatment for these disorders, but early recognition may lead to the identification of potential candidates for insertion of a cardiac pacemaker to prevent sudden death from arrhythmias.

Autosomal dominant dystrophies with a unique phenotype

Myotonic Dystrophy

Myotonic dystrophy (DM) is the most common adult muscular dystrophy. It has an incidence of one per 8,000 population and a prevalence of about five per 100,000 population. The disorder comprises two subsets: DM1 (the classic myotonic dystrophy, Steinert disease) and DM2 (proximal myotonic myopa-thy [PROMM]) [see Table 1]. Both are autosomal dominant mul-tiorgan syndromes; they exhibit striking similarities in clinical manifestations.

Diagnosis DM has a unique distribution: (1) ptosis of the eyelids, without extraocular muscle involvement; (2) atrophy of the masseters and the temporal muscles, which results in a unique, narrow facial configuration; (3) sternocleidomastoid muscle atrophy with relatively preserved posterior neck and shoulder girdle muscles (a clinical sign that differentiates DM from facioscapulohumeral muscular dystrophy [FSHD]); (4) distal muscle group atrophy, with slight proximal involvement in the earlier stages of disease; and (5) involvement of the palatal and pharyngeal muscles, which may produce dysarthria and dysphagia.

Myotonia, defined as the slowing of relaxation of a normal muscle contraction, is an important clinical sign. To elicit myoto-nia during examination, a patient is requested to make a firm hand grip and let it go rapidly; in myotonia, an inability to immediately release the grip is evident. Percussion of the thenar eminence or the extensor digitorum also shows the characteristic slow relaxation of myotonia. Systemic features include cardiac conduction defects, mild mental dysfunction (often with silly or inappropriate behavior and expressions), testicular atrophy, frontal baldness, cataracts, gastrointestinal tract involvement (with delayed motility and emptying), hypersomnia, and a diminished response to hypoxia, which leads to poor concentration and apathy. Clinically DM2 resembles adult DM1; however, the degree of expression of the systemic features may vary from that found in DM1. The most important factors distinguishing DM1 from DM2 are the preferential proximal muscle involvement in DM2, the lack of congenital DM2 forms, the rare incidence of anticipation (see below) in DM2 , and the rare incidence of cognitive dysfunction in DM2.

Children of affected mothers may have reduced fetal movements and early life symptoms of severe hypotonia, feeding difficulties, bilateral facial weakness, and respiratory distress (congenital myotonic dystrophy). Myotonic dystrophy must be distinguished from myotonia congenita, which follows recessive and dominant inheritance patterns. Patients with myotonia con-genita present with myotonia and often with muscle hypertrophy. In contrast to myotonic dystrophy, however, myotonia con-genita is not associated with muscle weakness, atrophy, or systemic symptoms; it results from a distinct genetic defect that affects chloride channels [see Ion Channelopathies, Periodic Paralyses, and Nondystrophic Myotonias, below].

The clinical diagnosis of myotonic dystrophy is confirmed by EMG, which shows the myotonic discharges. In difficult cases, slit-lamp examinations may show early cataract formation. The clinical expression of myotonic dystrophy is variable, and the disorder may remain undiagnosed until patients have had children. In DM1 the age at onset is progressively earlier in successive generations (a phenomenon known as anticipation). It is not unusual to see families in which a grandmother’s only symptom was early cataracts, and yet her daughter, who did not know that she herself was affected, gave birth to a child with severe congenital myotonic dystrophy. Anticipation is common in DM1 but rare in DM2.

Genetic counseling and genetically targeted therapy DM1 is caused by an unstable CTG (cytosine, thymine, guanine) trinu-cleotide repeat sequence in the nonprotein coding region of a protein kinase gene, called DMPK, on chromosome 19.4548 In mildly affected persons, a polymorphic CTG repeat region in the protein kinase gene expands by 50 to 80 repeats; in severely affected persons, more than 2,000 repeats may be present. The size of the CTG expansion increases over generations, which accounts for the anticipation. Measurements of the CTG expansion length can be used to confirm the presence of myotonic dystrophy in family members, for prenatal diagnosis, or for effective genetic counseling of asymptomatic persons who are at risk for myotonic dystrophy.

DM2 is also caused by an expanded repeat in a nonprotein coding region involving a tetranucleotide CCTG repeat in the ZNF9 gene (zinc finger protein 9), on chromosome 3q21, which codes a transcription factor. The pathogenic factor of DM1 and DM2 is the RNA product of the mutant gene, not the protein product. This is the first disease known to be caused by harmful RNA. The mutant RNA forms inclusions in the nucleus (ri-bonuclear inclusions). It has been shown that the RNA repeat binds to proteins in the muscleblind family and interferes with the normal function of RNA processing.48 These new data suggest that therapy for DM should be aimed at eliminating the harmful RNA.

Treatment At present, therapy for DM is symptomatic. Emotional support and education regarding the precautions necessary to avoid falls and injuries are essential. Careful monitoring of the cardiac status, especially during the administration of anesthesia, is important. Drugs such as quinine, procainamide, mexiletine, phenytoin, and beta blockers may help relieve the myotonia but not the weakness. Of these agents, mexiletine appears to be the most effective. Testosterone has failed as therapy for DM. Creatine monohydrate may offer minimal relief from myalgia. Modafinil may reduce excessive daytime somnolence, improve mood, and decrease fatigue.

Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy. It usually begins during the second decade of life.

FSHD is linked to chromosome 4q. It is an autosomal dominant disease, but 25% of cases are the result of new mutations.49 There is significant heterogeneity in this disease. Some patients with the deletion mutation do not have the typical FSHD features [see Diagnosis, below]; instead they may present with distal myopathies characteristic of LGMD. In some family members, only minimal facial muscle involvement may occur. In 10% of families, germline mosaicism occurs; this means that more than one sibling is affected in a given generation without involvement of either parent.

Diagnosis Patients present with facial muscle weakness (especially of the orbicular muscle of the eye); the extraocular and masseter muscles are spared. Early weakness of the scapular muscles produces prominent scapular winging and gives the shoulders a forward, sloped appearance. Weakness in the anterior tibial muscles, which leads to footdrop, is always present. The disease progresses slowly, and there are long periods of stability. Tongue atrophy is not unusual. Progression occurs in a descending manner: involvement of the shoulder girdle muscles is followed by involvement of the biceps, triceps, and pelvic girdle muscles. A large majority of patients have retinal capillary abnormalities, retinal detachment, and impaired hearing; these findings are more frequent in the infantile form of FSHD.

The serum CK level in FSHD is slightly elevated, and cardiac muscle is spared. Muscle biopsy findings are variable and may include the presence of inflammatory cells. The diagnosis is suspected on clinical grounds and confirmed by DNA analysis. The disease is caused by a deletion within a series of 3.3 kb repeats (D4Z4) on chromosome 4. When the number of repeats falls below a critical number (approximately 10), there is clinical expression of the gene. About 95% of patients have a deletion resulting in a DNA short fragment that is less than 35 kb in length, as determined by the use of certain restriction enzymes.

Treatment In controlled trials, use of prednisone or the beta2-adrenergic agonist albuterol has shown no benefit in the treatment of FSHD, although the latter may increase muscle mass.

Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a rare auto-somal dominant disease that manifests from the fourth to the sixth decades of life. It is characterized by ptosis and dysphagia, both of which can be severe. Mild distal muscle weakness may occur. The mutation responsible for OPMD is caused by a trinu-cleotide GCG expansion repeat in the first exon of the poly(A) binding protein 2 gene (PABP2), on chromosome 14q11.2. PABP2 is localized to the intramuscular aggregates of muscle fibers and is causally related to these inclusions.

Malignant Hyperthermia

Malignant hyperthermia (MH) occurs in one in 50,000 to one in 100,000 adults during general anesthesia, especially when halothane is used alone or in conjunction with succinylcholine and other depolarizing muscle relaxants. MH is characterized by a rapid increase of aerobic and anaerobic metabolism, during which the body temperature may exceed 43° C (109.4° F). In addition, the concentrations of carbon dioxide and lactate increase (the arterial carbon dioxide tension [PaCO2] may exceed 100 mm Hg), and the blood pH may fall below 7.


Triggers for MH include potent volatile anesthetics, such as halothane, enflurane, desflurane, cyclopropane, ether, and suc-cinylcholine. Although MH occurs in some patients without a known muscle disease, patients at risk include those who have multiple congenital musculoskeletal abnormalities, isolated congenital hip dislocation, or central core disease; it has also been known to occur in some patients with DMD or BMD.


Susceptibility to MH is inherited as an autosomal dominant trait; in up to 50% of the pedigrees, mutant alleles have been found on the ryonidine receptor (RyR),52 on chromosome 19q13, or on the CACNA1S gene on chromosome 1q, which encodes the a1 subunit of the dihydropyridine-sensitive L-type voltage-dependent calcium channel.52 Some other loci have been found on a second dihydropyridine receptor locus (CACNLA2) on chromosome 7q. MH appears to be precipitated by an inability to control calcium concentrations within the muscle fibers because of a malfunctioning sarcoplasmic reticulum (SR) and mutations in the RyR gene. The RyR is the calcium release channel of the SR and bridges the gap between the SR and the transverse tubule. Mutations in the receptor affect communication between the SR and the transverse tubule such that accelerated calcium release from the SR occurs when depolarization of the transverse tubule takes place.


MH presents with tachycardia, muscle rigidity (caused by muscle contracture that may progress to rigor or death), increased muscle permeability (resulting in increased serum levels of K+, Ca+, and Na+ and muscle edema), excessive release of myo-globulin from the muscle, and myoglobinuria. Trismus or mas-seter muscle spasm that occurs during induction of anesthesia may be indicative of MH. MH must be distinguished from (1) postanesthetic rhabdomyolysis after muscular stress; (2) toxic reaction to drugs; (3) porphyria; (4) thyroid storm precipitated by surgery and anesthesia; and (5) the neuroleptic malignant syndrome precipitated by psychoactive drugs (e.g., haloperiodol and phenothiazines) that block central dopaminergic pathways.

The in vitro caffeine-halothane contraction test, which is performed on muscle biopsy specimens, is used to screen patients for MH. The sensitivity and specificity of this test, if performed properly, may be as high as 97% and 80%, respectively.53


Dantrolene is an effective treatment for MH. It decreases calcium release from the SR without altering calcium reuptake. Dantrolene use has reduced the mortality of this condition to 7%. The acute episode of MH is treated symptomatically. Intravenous dantrolene (2 to 10 mg/kg every 5 minutes) must be given early in the episode, while there is still adequate muscle perfusion. For patients who are known to be susceptible to MH, dantrolene can be administered at a dosage of 2 mg/kg 10 to 15 minutes before anesthesia administration. The best way to prevent MH episodes in susceptible persons is to use safe anesthetic agents (e.g., nitrous oxide and thiopental) and nondepolarizing muscle relaxants.

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