Genetic and muscular disorders

Genetic work during the past several years has led to a clearer understanding of the molecular causes of genetic-based muscle diseases. In most cases, the identification of the proteins altered in the disease states has added to our understanding of the development of muscle and the neuromuscular junction. The anesthetic management suggested for these diseases and syndromes can be better planned as a result of this knowledge. The aim of this discussion will be to review what is presently known regarding the molecular nature of diseases of the neuromuscular system and the clinical presentations of these diseases. First, a general overview of the generation of muscle contraction in a normal cell will be given ( Fig. 51.1 ). After that discussion, recent molecular and genetic studies involving the major muscle diseases will be reviewed, as they may be of use to the clinician in the care of patients.

Overview

The genetic muscle diseases can be divided into five broad categories: myasthenic syndromes, myotonias, mitochondrial myopathies, muscular dystrophies, and congenital myopathies. To these, one should add malignant hyperthermia (MH) as a separate category, though there is some overlap between MH and the other diseases. MH will be discussed fully in Chapter 52 , “Malignant Hyperthermia.” We will review each of these categories separately and relate them to the MH syndrome where possible. The general locations in the muscle cell of the molecular changes leading to these classes of disease are shown in Fig. 51.2 . The dotted circles in each panel indicate the locations of the molecular changes. It is important to note that this figure is an oversimplification, but it gives the general pattern of the molecular causes of the syndromes. As a general rule, the syndromes are caused by the following changes:

1.
The myasthenic syndromes affect transmission of the action potential from the motor neuron to the muscle cell. This generally involves a disruption of the signal carried by the neurotransmitter, acetylcholine, across the synaptic cleft (see Fig. 51.2 A).
2.
Myotonic syndromes affect transmission of the action potential along the muscle membrane and are generally caused by abnormalities in sodium, chloride, potassium, or calcium channels (see Fig. 51.2 B). These changes cause a prolonged depolarization of the muscle membrane, which leads to prolonged contraction of the muscle.
3.
Mitochondrial myopathies are caused by abnormalities in mitochondrial function. Because mitochondria are important for supplying adenosine triphosphate (ATP) in most tissues (most importantly, nerve and muscle), the symptoms often involve the nervous system in addition to muscle (see Fig. 51.2 C). The lack of ATP in muscle leads primarily to weakness and muscle wasting. Mitochondria are also important in triggering cell death, or apoptosis, so mitochondrial diseases may lead to muscle wasting via this mechanism.
4.
Muscular dystrophies result from the dissociation of contractile force from the muscle to the surrounding connective tissue. The actin-myosin filaments contract, but they are no longer connected well to the cell membrane or the surrounding tissue (see Fig. 51.2 D). As a result, the electrical signal is not translated into effective mechanical force. In addition, the defects in the membrane cause instability in the structure of the cell that may lead to deleterious responses to anesthetic agents.
5.
Congenital myopathies are primary muscle disorders that are present from birth, though their expression can be delayed until later childhood. These heterogenous genetic defects result in disruption of the general health or development of muscle cells. We will discuss some of the more important congenital myopathies; however, they are difficult to pinpoint in this figure.

Fig. 51.2, Details of Fig. 51.1 That Show the Main Areas of Defects That Lead to Muscle Disease.

Normal skeletal muscle contraction

Skeletal muscle contraction is accomplished by the generation of a neuronal action potential (AP) that terminates at the neuromuscular synapse (see Fig. 51.1 ). The neuronal AP stimulates sodium channels in the cell membrane that propagate the signal along the axon. As the AP reaches the end of the axon, voltage-gated calcium channels are activated, which allows the influx of calcium into the neuron. This influx of calcium, in turn, stimulates the release of a neurotransmitter, acetylcholine, from the nerve terminal into the synapse. The acetylcholine binds to receptors on the cell surface of the postsynaptic cell—the muscle cell in this case. Binding of the acetylcholine to its receptors allows influx of sodium into the muscle and generates a new AP (now in the muscle cell) that spreads along the membrane of the cell.

The AP is carried from the cell surface into the interior of the cell by a series of invaginations of the cell membrane known as T-tubules. These structures allow for transmembrane electrical depolarizations to be carried deeply within the cell. At the ends of the T-tubules, the sodium currents are again replaced by calcium currents, resulting from the activation of a voltage-gated calcium channel known as the dihydropyridine receptor. The resultant influx of extracellular calcium into the cell, in turn, stimulates larger calcium release from the sarcoplasmic reticulum into the sarcoplasm through a calcium-sensitive calcium channel, the ryanodine receptor. These larger fluxes of calcium stimulate movement of the actin-myosin filaments, an ATP-requiring step (and therefore dependent on functioning mitochondria). The filaments are attached to the surface of the muscle and the surrounding matrix through a variety of proteins, most notably dystrophin. Movement of the filaments is transduced into shortening of the cell (muscle contraction) by the connection to the cell surface and surrounding matrix. Muscle relaxation is accomplished by active sequestering of cytosolic calcium primarily back into the sarcoplasmic reticulum. This process relies on ATP-dependent calcium pumps and therefore mitochondrial function for ATP generation. Loss of this energy source is the cause of rigor mortis.

Anesthetic impact on neuromuscular physiology

Normal transduction of electrical signals into mechanical force can be disrupted at many places. As anesthesiologists, we often inhibit the transmission of the signal across the neuromuscular junction with the use of neuromuscular blockers such as rocuronium. Such an effect is conceptually similar to a myasthenic syndrome. Local anesthetics applied to the motor neuron inhibit the propagation of an AP along the neuron, resulting in decreased release of neurotransmitters. The use of local anesthetics directly on muscle blocks voltage-gated sodium channels in the muscle membrane, with the resulting inhibition of AP propagation, acting distally to the synapse (distal to the myasthenic mechanism) and in a mechanism conceptually opposite to that causing myotonias. Volatile anesthetics are also inhibitors of the voltage-gated membrane channels (sodium, potassium, and calcium). Their inhibitory activity at post-synaptic sodium channels is a mechanism opposite that of myotonias. Additionally, these drugs inhibit mitochondria and are capable of causing a relaxation effect in a manner similar to a mitochondrial myopathy. These examples are given only to further acquaint the anesthesiologist with the underlying interaction of drugs with the myopathies, and these similar effects largely explain the interaction of the medications with the disease states.

Myasthenic syndromes

Myasthenic syndromes result from failure of transmission of the signal from the terminal of a motor neuron to the muscle innervated by the neuron. Most myasthenic syndromes are the result of immune responses against components of the neuromuscular junction (primarily the postsynaptic acetylcholine receptors) and are not classic genetic diseases. The symptoms result from decreased neurotransmission across the neuromuscular junction, and task-specific fatigue is the hallmark of these diseases (see Fig. 51.2 A). The well-known disease of myasthenia gravis (MG) is an example of such a disorder, though it is primarily a disease of adulthood. MG can occur neonatally because of placental transfer of maternal antibodies ( ; ; ).

Rarely, inherited disorders of neuromuscular transmission known as congenital myasthenic syndromes (CMSs) can result from acetylcholine receptor mutations or other mutations inhibiting the release of acetylcholine ( ; ). Included in this group are familial infantile myasthenia, familial limb-girdle myasthenia, end-plate acetylcholinesterase deficiency, and syndromes with altered or deficient acetylcholine receptors. One form of congenital myasthenia is a genetic defect resulting from defects in the dok-7 gene, which is important in the formation or maintenance of synaptic structure ( ). A second form is associated with a defect in the rapsn gene, which codes for a protein interacting with the acetylcholine receptor ( ). In fact, congenital myasthenia syndrome was diagnosed after prolonged muscle weakness after an anesthetic in a patient with a rapsn mutation ( ). These genetic diseases mimic MG in their presentation and implications for anesthesia, and they present in children ( ). In addition, juvenile-onset MG is seen in association with thymoma, and the anesthetic implications have been discussed ( ).

Anesthetic considerations

The considerations for congenital myasthenias are similar to those of the better-known autoimmune-caused myasthenias. The primary concern during the perioperative period for patients with myasthenic syndromes is to avoid respiratory compromise from weakened respiratory muscles or upper airway muscles ( ; ). For this reason, muscle relaxants are used sparingly, if at all, in these patients. In addition, patients with MG or myasthenic syndromes are often resistant to succinylcholine ( ). It is important to remember that patients can appear strong upon awakening only to become fatigued later in the recovery period. In fact, seronegativity for the antiacetylcholine receptor antibody does not necessarily predict a normal response to muscle relaxants ( ). In particular, MG patients “cured” by thymectomy may also retain a high sensitivity to muscle relaxants. The conclusion of these reports is that the anesthesiologist must presume a high sensitivity to nondepolarizing muscle relaxants in all patients with myasthenic syndromes, even if they are functioning well after medical or surgical treatment. However, the use of rocuronium with successful reversal by sugammadex has been reported ( ; ; ; ). For cases in which muscle relaxation is necessary, this approach appears to often work well, although caution is still advised, as even small amounts of residual block can be problematic in these patients ( ). One report of incomplete reversal of rocuronium with sugammadex in the setting of MG illustrates the importance of neuromuscular blockade (NMB) monitoring in these patients ( ).

Techniques using a variety of short-acting anesthetics without the addition of muscle relaxants have been very successful ( ; ; ). Others have reported encouraging results after use of regional anesthesia in these patients ( ; ). However, one report cautions that even with a stable anesthetic, tourniquet release may trigger an exacerbation of myasthenic symptoms ( ).

Myotonias

Myotonia is a temporary, involuntary contraction of muscle fibers caused by transient hyperexcitability of the surface membrane ( ). The persistent contracture of the skeletal muscle generally occurs after muscle stimulation (either voluntary or involuntary) but may be triggered by other stimuli such as cold, pain, stress, or drugs such as succinylcholine. A classic finding in patients with myotonia is the inability to easily relax after a firm handshake. Myotonias can be subdivided into two general groups: dystrophic and nondystrophic. The dystrophic group (represented by myotonic dystrophy) shows a progressive wasting of muscle strength; the nondystrophic group does not show such progressive changes.

In general, the nondystrophic myotonias may be thought of as a family of channelopathies mostly affecting muscle ( ; ). Two forms of nondystrophic myotonia (myotonia congenita and Becker disease) result from defects in the same skeletal muscle chloride channel (termed ClC-1 ) ( ; ; ). Myotonia congenita (Thomsen disease) is an autosomal dominant disease that presents in childhood and is associated with a normal life expectancy and minimal symptoms ( ). Becker disease, not to be confused with Becker muscular dystrophy (discussed later), is an autosomal recessive form of this channelopathy, also appearing in childhood ( ). In addition, some mutations in this chloride channel cause a variant of dominant myotonia with a milder phenotype: myotonia levior ( ; ). These myotonic diseases are nonprogressive and do not have a dystrophic component; that is, there is no deterioration of the muscle over time. Other, milder myotonias result from abnormalities in sodium or potassium channels on the muscle cell membrane. These include paramyotonia congenita (sodium channel), hyperkalemic periodic paralysis (sodium channel), and hypokalemic periodic paralysis (calcium, sodium, or potassium channels) ( ).

Anesthetic considerations

As noted earlier, myotonic contractions may be precipitated by cold, pain, and stress. Thus these triggering factors must be aggressively avoided during the perioperative period for these patients. Regional anesthesia and NMB do not reverse the contractions because the treatments act upstream from the molecular causes of the syndrome (compare Fig. 51.2 A and B). Succinylcholine may precipitate masseter spasm in addition to contractions in other muscle groups that can lead to extreme difficulty with positive pressure ventilation and intubation ( ). For these reasons, the use of succinylcholine is discouraged in patients with myotonia. If an episode of myotonia occurs during anesthesia, volatile anesthetics, quinine, or procainamide can be used for relaxation. If a myotonic episode occurs in patients with periodic paralysis, use of the carbonic anhydrase inhibitor dichlorphenamide has been shown to be useful ( ). Because the myotonias occur as the result of abnormal ion channels, great care must be taken to keep electrolytes normal at all times. Although myotonic syndromes may have symptoms in common with MH (hyperkalemia, elevated creatine phosphokinase [CPK] levels, muscle spasm), they are not associated with true MH.

Myotonic dystrophy

Myotonic dystrophy is the most common form of myotonia ( ). This disease is a form of muscular dystrophy and includes congenital myotonic dystrophy. Myotonic dystrophy is discussed here instead of with other muscular dystrophies because its presentation resembles that of the myotonias.

Myotonic dystrophy actually includes two different molecular diseases, myotonic dystrophy type 1 (DM1, Steinert disease) ( ) and myotonic dystrophy type 2 (DM2, previously called proximal myotonic dystrophy) ( ). The congenital form of DM1 presents in utero with reduced fetal movement and polyhydramnios. It shares features with the childhood-onset DM1, including facial, neck, and distal muscle weakness; myotonia; developmental delay; and cardiac arrhythmias that often begin to present in the second decade of life ( ). DM1 results from alterations in the human dystrophica myotonica-protein kinase gene (DMPK) ( ), leading to an increase in unstable CTG DNA repeats in the 3′ untranslated region of the DMPK gene ( ; ). The DMPK gene codes for a serine-threonine protein kinase. The CTG changes in the DMPK gene lead to abnormal splicing of many genes (estimated at over 200), most notably the muscleblind-like proteins ( ; ; ). However, the changes also alter the messages for the calcium channel protein, CLCN1, and the NR1 subunit of the N-methyl- d -aspartic acid (NMDA) receptor, with resulting defects in functions of both channels ( ; ; ). The precise mechanisms by which this mutation causes the changes in muscle function are not entirely clear but appear to involve several pathways ( ; ; ; ). The involvement of many pathways explains that the disease not only has muscle defects but also affects multiple other systems, including the central nervous system (CNS) ( ). However, the myotonia is probably the result of defects of calcium channels, resulting in altered transmembrane potentials and calcium-dependent relaxation of actin-myosin filaments in muscle ( ).

As noted earlier, the changes in the protein kinase gene are in the promoter or starting region of the gene and are the result of duplications in short repetitive sequences (CTG triplets) ( ; ). The number of repetitive sequences is often increased in the offspring compared with an affected parent. As a result, each successive generation tends to exhibit a more severe form of the disease.

In contrast to DM1, DM2 has a more clinically diverse presentation, including myotonia, proximal muscle wasting, endocrine, and cardiac and cerebral abnormalities. DM2 also results from expansion of a similar sequence (CCTG) in an intron of a gene, but the gene is separate from that causing DM1 and codes for a probable transcription factor, ZFN9 ( ; , ). The precise physiologic changes leading to myotonic or dystrophic changes are not known; however, the final changes are probably similar to DM1: a decrease in muscleblind-like proteins. In both disease states, the abnormalities result from abnormal RNA species that disrupt normal cell development ( ).

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