Disease History

Successfully diagnosing, or ruling out, a myopathy begins with obtaining a detailed medical history. Weakness and hypotonia are common presenting concerns of parents of children with suspected muscle disease. Additionally, early feeding, respiratory difficulties, and delayed developmental milestones might prompt referral for evaluation. Although many muscle disorders have a genetic basis, clinical symptoms and physical findings may not become apparent until later in life. For some myopathies, the accumulation of muscle fiber injury may result in progressive weakness with characteristic periods of clinical disease onset. For other diseases, the limited force generation potential of the muscles becomes apparent as a child grows, causing the center of mass to elevate, and thereby increasing the force required to maintain posture and mobility. An adolescent or adult is more likely to have symptoms that include weakness, pain, muscle cramps, decreased endurance, difficulty keeping up with peers, and muscle atrophy.

For an infant or a child, a complete pregnancy and birth history are necessary. Questions should be asked to determine the quality of fetal movements, the presence of any complications during the pregnancy, and if any perinatal issues were present. Perinatal concerns, including respiratory distress, need for intubation or supported ventilation, and feeding difficulties, may raise suspicion for a myopathy. Timing of developmental milestones, including bringing hands to mouth, independent sitting, crawling, cruising, independent walking, and talking, may provide insight to disease progression.

For the adolescent and older patient, a more detailed history may be obtained, including the distribution of weakness, rate of progression, exacerbating factors, and ameliorating factors, to help narrow the differential diagnosis. In addition to functional limitations related to the suspected myopathy, a broad review of systems should be taken. Systemic information, including history of difficulty breathing, recurrent pneumonia, coughing with meals, respiratory impairment, daytime somnolence, morning headache, syncope, irregular heartbeat, exertional chest pain, rashes, weight loss, muscle atrophy, fatigue, academic performance, and previous issues with anesthesia (e.g., malignant hyperthermia), aid in determination of the breadth of the disease. Questions regarding sensation change or loss may suggest an alternative diagnosis.

Family History

Given the genetic origin of most muscle diseases, a careful family history of myopathy should be elicited. Completing a family pedigree may demonstrate a potential genetic transmission pattern of the muscle disorder. Autosomal dominant disorders may demonstrate nearly one half of siblings having the disorder without sexual predilection. By contrast, X-linked recessive disorders, such as Duchenne muscular dystrophy, will have nearly one half of males being affected on the maternal side. Increasing phenotypic severity in subsequent generations suggests genetic anticipation as may occur in myotonic muscular dystrophy.

Physical Examination

A comprehensive physical examination is the initial step in a myopathy evaluation. Information obtained from direct examination of the patient will guide the selection and interpretation of subsequent diagnostic testing, including laboratory studies, genetic testing, electrodiagnosis, and muscle biopsy.

Although it may be tempting to focus on the muscular examination, a thorough assessment of the entire body is essential to narrow the differential diagnosis of myopathic disease. The craniofacial examination may reveal a high arched palate or dental malocclusion that can be found in congenital myopathies and congenital muscular dystrophies. Macroglossia may be noted in certain limb-girdle muscular dystrophies. Temporal wasting and tenting of the upper lip are seen in myotonic muscular dystrophy. Some muscular dystrophies, such as Duchenne muscular dystrophy, sarcoglycanopathy, and Emery-Dreifuss muscular dystrophy, may have cardiac muscle involvement with resultant muscle fiber injury and endomysial fibrosis that alter conduction pathways, making cardiac evaluation imperative. Cardiac examination should include auscultation to evaluate for murmurs that may be related to a dilated cardiomyopathy. A shifted point of maximal impulse may suggest cardiac dilatation. Palpation of the distal pulse may reveal an irregular rhythm caused by a second or third degree heart block. Evaluation of the pulmonary system may demonstrate poor aeration of lung fields and restricted rib excursion from fibrosis of intercostal muscles. Accessory respiratory muscle use and nasal flaring may be markers of global weakness and compromised respiratory function. Hepatomegaly may be palpated in individuals with certain metabolic myopathies, such as acid maltase deficiency (Pompe disease, glycogen storage disease type II). In dermatomyositis, skin examination may be remarkable for a heliotrope rash around the eyes and erythema of extensor joint surfaces.

Evaluation of the musculoskeletal system may start with assessment of muscle bulk. Identifying muscles with atrophy, persevered size, and pseudohypertrophy may suggest a pattern common to a specific disease. For example, individuals with Duchenne muscular dystrophy may have pseudohypertrophy of the deltoid and infraspinatus causing a posterior axillary depression sign on examination. Pseudohypertrophy of the calves may be seen in Duchenne muscular dystrophy and sarcoglycanopathy ( Figure 42-1 ). Preferential atrophy of the biceps and triceps is noted in individuals with facioscapulohumeral muscular dystrophy and Emery-Dreifuss muscular dystrophy. Scapular winging may be observed in cases of calpainopathy and sarcoglycanopathy ( Figure 42-2 ). The presence, distribution, and timing of contractures are other important examination points. Congenital myopathies and congenital muscular dystrophies may have such profound weakness that the joints do not develop normally in utero resulting in arthrogryposis noted at birth. Some myopathies have characteristic contractures, such as early elbow flexion contractures in Emery-Dreifuss muscular dystrophy. Ullrich congenital muscular dystrophy has a unique combination of proximal joint contractures (i.e., knees, elbows) with distal joint hypermobility (i.e., wrists, ankles). Progressive muscle fiber injury and fibrosis, as occurs in several muscular dystrophies, may result in increasing contractures as strength declines. Evaluation of the spine may demonstrate scoliosis that may be observed in patients with central core myopathy, nemaline myopathy, multiminicore myopathy, and Duchenne muscular dystrophy.

Calf pseudohypertrophy in a patient with limb-girdle muscular dystrophy 2C.

Scapular winging in a patient with limb-girdle muscular dystrophy 2C.

The neurologic examination in patients with suspected myopathy should include cognitive assessment. Cognitive impairment may be present in individuals with Du­­chenne muscular dystrophy, congenital muscular dystrophy, congenital myotonic muscular dystrophy, and mitochondrial myopathies. Evaluation of strength will aid in differentiating myopathic disorders. After 5 years of age, most cognitively intact children will be able to fully participate in manual muscle testing. For patients unable to comprehend the instructions for strength testing, attempting to have them reach for an object, kick an object, or mirror the examiner’s movements can provide insight to which muscle groups have at least antigravity strength. Facial weakness is not universally seen with myopathies and may suggest specific disorders, such as facioscapulohumeral muscular dystrophy, congenital fiber-type disproportion, and myotonic muscular dystrophy. Similarly, ophthalmoparesis may help narrow potential disorders to centronuclear myopathy, multiminicore myopathy, congenital fiber-type disproportion, and mitochondrial myopathy. Most myopathies have proximal greater than distal weakness; however, exceptions with greater distal weakness, including inclusion body myositis, myotonic muscular dystrophy, and some variants of multiminicore myopathy, may stand out. Depending on the severity of weakness, muscle stretch reflexes may be normal or diminished. Percussion myotonia may be elicited in individuals with myotonic muscular dystrophy. Functional assessment, including transitions from supine to sit and sit to stand, may demonstrate neck flexion weakness, core weakness, and limb-girdle weakness. Myopathies associated with pelvic girdle weakness may demonstrate a Gower sign, in which the upper limbs are used to generate hip extension moments by “walking” up the lower limbs.

Gait may be altered for many reasons in myopathic diseases. Hip extension weakness may result in increased lumbar lordosis that shifts the weight line posterior to the hip. In this situation, the extension of the femurs will be limited by the Y ligaments of Bigelow and will require minimal hip extension strength to maintain. As knee extension becomes weaker, individuals may develop an equinus gait pattern that causes an extension moment at the knee and moves the weight line anterior to the knee. Both of these biomechanical changes help stabilize the knee in extension preventing knee buckling. Hip abductor weakness, involving gluteus medius in particular, may contribute to a drop of the pelvis such that the lower limb in swing phase will be lower as the contralateral hip abductors have insufficient strength to maintain a level pelvis. Compensation for gluteus medius weakness includes lateral bending of the torso toward the weak side (compensated Trendelenburg gait pattern) to functionally limit the pelvic drop.

Laboratory Workup

Initial laboratory screening tests typically include serum creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and aldolase. CK reversibly catalyzes creatine and adenosine triphosphate (ATP) to phosphocreatine and adenosine diphosphate (ADP) with energy release. Although CK is found predominantly in muscle, the liver contains high amounts of ALT, AST, and aldolase. In myopathies where muscle fibers are injured, these enzymes are released into the serum. Gamma-glutamyl transferase (GGT) is found mainly in the liver and can be evaluated to help differentiate muscle and liver disease. An elevated CK level may suggest a muscle disease but lacks sensitivity and specificity. In Duchenne and Becker muscular dystrophies, a marked elevation in CK (up to 100 times the upper limit of normal for Du­­chenne and up to 20,000 for Becker) is typical, with a normal CK level excluding these diagnoses. Inflammatory myopathies, limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, and Emery-Dreifuss muscular dystrophy may also demonstrate elevated CK levels. CK levels, however, may be elevated after strenuous exercise in normal individuals. Myopathic disorders with structural abnormalities that affect contractility without causing fiber breakdown may have normal to slightly elevated CK values. Congenital myopathies such as central core myopathy, nemaline myopathy, and centronuclear myopathy represent such conditions. Additionally, CK level does not correlate with disease severity because chronic myopathies with significant atrophy may have a normal or even a low value. Because needle electromyography causes a transient increase in CK, testing should occur before electrodiagnostic evaluation or at least 72 hours afterward.

Clinical scenarios suggestive of metabolic myopathies may benefit from further testing. The respiratory chain abnormalities seen in mitochondrial myopathies may cause elevated lactate and pyruvate levels. Ischemic forearm exercise testing without at least a 3-fold increase in lactate level from baseline may support further evaluation for a glycogen storage disease. Serum uric acid may be elevated in acid maltase deficiency (Pompe disease, glycogen storage disease type II), whereas myoglobinuria may be noted in myophosphorylase deficiency (McArdle disease, glycogen storage disease type V). Quantification of urine amino and organic acids in addition to plasma amino acids further aids in the differentiation of some metabolic myopathic disorders.

Molecular Genetics

Progress in molecular genetics has tremendously improved the understanding of many myopathies, especially muscular dystrophies. Because the phenotypic presentation of familial myopathies can vary, understanding of the pathophysiologic etiology has allowed clarification of inheritance patterns and refined classification schemata. Additionally, identification of specific genetic mutations and deletions has fundamentally changed the diagnostic approach in some areas. For example, dystrophin gene sequencing may detect nearly 100% of mutations causing Duchenne and Becker muscular dystrophies, eliminating the need for electrodiagnostic studies and muscle biopsy for these cases. Genetic heterogeneity seen with certain myopathic disorders necessitates multimodal diagnostic evaluations, when such diseases are being evaluated. Nemaline myopathy, multiminicore myopathy, and congenital fiber-type disproportion are a few examples of muscles diseases with multiple gene loci and inheritance patterns. A challenge to molecular genetic testing includes cost, notably in situations where multiple genes may underlie the disorder. A further limitation of genetic studies is that allelic variation may result in different clinical diseases being associated with the same gene. Lamin A/C mutations may result in autosomal dominant limb-girdle muscular dystrophy 1B, autosomal dominant Emery-Dreifuss muscular dystrophy 2, and autosomal recessive Emery-Dreifuss muscular dystrophy 2.

Electrodiagnostic Studies

Because an electrodiagnostic study is considered an extension of the physical examination, in clinical cases in which a myopathy is strongly suspected, an electrodiagnostic evaluation may not be indicated because the study will rarely provide a specific diagnosis. In these situations, pursuing genetic studies and muscle biopsy are more likely to yield the myopathic diagnosis. Electrodiagnosis may be of utility when the underlying pathologic process is unclear. Neuromuscular junction disorders, motor neuropathies, and motor neuron diseases may be excluded from the differential diagnosis based on electrodiagnostic findings. Electromyography may provide information regarding the distribution of muscle involvement that can aid in the selection of muscle biopsy sites.

Sensory nerve conduction studies should have normal peak latencies and normal amplitudes in myopathic diseases. Motor nerve conduction studies of individuals with a myopathy are typically normal; however, with increasing muscle injury and atrophy the compound motor action potential amplitude may be reduced. Repetitive nerve stimulation studies are usually normal in myopathic disease, but could be included if a neuromuscular junction disorder, such as myasthenia gravis, is clinically suggested.

Of the components that comprise an electrodiagnostic study, needle electromyography will provide the greatest information about a muscle disorder. Insertional activity is variable depending on the underlying disease process. Although many myopathies will have normal insertional activity, disorders that lead to muscle fibrosis, such as Duchenne muscular dystrophy, may have decreased insertional activity. Acid maltase deficiency (Pompe disease) may have increased insertional activity. The motor unit morphology may demonstrate the characteristic short duration, low amplitude, polyphasic motor unit action potentials with increased or “early” recruitment. These findings are not absolute because myopathic disorders can have normal-appearing motor units. Steroid myopathy, which predominantly affects type II fibers, may appear normal on electromyography because type I fibers are the first recruited muscle. An electrodiagnostic evaluation may also reveal unique features of the myopathy. Spontaneous electrical activity, such as fibrillation potentials, positive sharp waves, complex repetitive discharges, and myotonic discharges, may be present depending on the underlying myopathy ( Box 42-2 ). Muscle fiber necrosis may result in effectively denervating some fibers through the loss of the motor end plate. Similarly, muscle fiber splitting may denervate muscle, as the fibers will not be in continuity, thereby blocking fiber-to-fiber depolarization. Fibrillation potentials and positive sharp waves may be generated from these denervated fibers. Myotonic muscular dystrophies will often have the characteristic “dive bomber” sound of waxing and waning motor unit frequency and amplitude from myotonic discharges.

Muscle Biopsy

Muscle biopsy allows for direct examination of structural changes caused by a myopathic process. A tissue specimen may be obtained via open or needle biopsy. Although a needle muscle biopsy is less invasive, this technique yields smaller tissue samples and does not allow direct inspection of the tissue before a sample is taken. In suspected myopathies that will require histochemistry studies or may have focal involvement, open biopsy would be a preferred procurement method. For any muscle biopsy, close coordination between the individual obtaining the tissue specimen, the processing laboratory, and the pathologist will maximize the utility of the endeavor. Selection of the biopsy site will often be guided by clinical and electrodiagnostic examination. A weak muscle is typically selected; however, one with marked atrophy or profound weakness is best avoided because fibrotic and fatty replacement may limit diagnostic information that can be obtained. Electromyography should only be performed on one side, with the biopsy obtained from the contralateral side, to minimize needle injury of the muscle, confounding histologic findings. Because most myopathies involve proximal musculature, biopsies are commonly obtained from the biceps, triceps, deltoid, and quadriceps.

The histology and histochemistry evaluations of the muscle identify structural alterations, including fiber size change, fiber splitting, fiber necrosis, inflammatory infiltration, and fibrosis ( Figure 42-3 ). Congenital myopathies, including central core myopathy, nemaline myopathy, and multiminicore myopathy, are classified based on structural characteristics. Mitochondrial myopathies with defective oxidative phosphorylation may demonstrate accumulations of abnormal mitochondria resulting in the ragged-red fibers. The presence of rimmed vacuoles may suggest the diagnosis of inclusion body myositis. Immunohistochemical staining and quantification of proteins may further elucidate the etiology of the myopathic disorder ( Table 42-1 ).

Muscle biopsy from a patient with Duchenne muscular dystrophy, demonstrating increased fiber size variability (including fiber atrophy and hypertrophy) and a small cluster of basophilic regenerating fibers (just left of center).

Classification of Myopathies

The term myopathy encompasses a large heterogeneous collection of diseases defined by muscle abnormality. Myopathic diseases may be separated into two large categories: acquired and hereditary. Acquired myopathies include inflammatory myopathies, toxic myopathies, and systemic disease associated myopathies. The pathology of an acquired myopathy involves alteration of normal muscle fibers by extrinsic factors. Inflammatory cells, toxins, endocrinopathies, and infections are examples of external mediators that may impact the function and survival of muscle fibers.

Hereditary myopathies are inherited disorders with genetic mutations that compromise the muscle fiber structure, physiology, or both. Myopathies with muscle fiber destruction are classified as muscular dystrophies. Phenotypic characteristics, electromyographic findings, and genetic variations have been utilized to further group subtypes of muscular dystrophies. Although the genetic basis for hereditary myopathies is present at birth, individuals with these diseases may not clinically manifest weakness or functional change initially. Myopathic disorders that are clinically symptomatic at birth or during the perinatal period are referred to as congenital. Metabolic and mitochondrial myopathies represent hereditary myopathies classified by the mechanism underlying the muscle fiber physiologic dysfunction.

Muscular Dystrophies

Dystrophinopathies.

Dystrophinopathies are X-linked recessive muscular dystrophies caused by mutation of the dystrophin gene found at locus Xp21.2. The 427-kDa dystrophin protein functions as a plasma membrane stabilizer, preventing fiber damage from the mechanical stress associated with muscle contraction. Without the dystrophin protein to link the intracellular cytoskeleton with transmembrane glycoproteins, the skeletal muscle may have membrane rupture, cellular damage, and fiber necrosis. Dystrophin is also expressed in the central nervous system, peripheral nerves, cardiac muscle, and smooth muscle. The 2.4-megabase dystrophin gene comprises 79 exons and is the largest identified human gene. Up to 70% of dystrophinopathy mutations are deletions that may change the reading frame of the gene. Frame-shift mutations will prevent dystrophin protein expression, resulting in the more severe Duchenne phenotype. Mutations with a persevered reading frame will yield a truncated dystrophin protein and the milder Becker phenotype.

Duchenne muscular dystrophy has an incidence of 1 in 3600 to 6000 live male births and a prevalence of nearly 2.5 per 100,000. Duchenne muscular dystrophy may be suspected in males with hypotonia, delayed developmental milestones, limb-girdle weakness, difficult climbing stairs and running, and frequent falls. Examination of individuals with Duchenne muscular dystrophy typically reveals calf pseudohypertrophy, compensatory toe walking, and the use of a Gower maneuver to facilitate transition to standing. Most children with Duchenne muscular dystrophy are diagnosed by 5 years of age.

Becker muscular dystrophy is much less common compared with Duchenne muscular dystrophy, with an incidence of 1 in 18,000 live male births and a prevalence of approximately 0.5 per 100,000. Becker muscular dystrophy shares a similar limb-girdle weakness pattern with the allelic Duchenne muscular dystrophy but with less severity and often presenting after 7 years of age. Individuals with Becker muscular dystrophy may have muscle atrophy and pseudohypertrophy similar to Duchenne muscular dystrophy; however, joint contractures occur less frequently in cases of Becker muscular dystrophy.

The initial workup for dystrophinopathies usually starts with CK that is elevated up to 100 times the normal level in both individuals with Duchenne muscular dystrophy and Becker muscular dystrophy. AST and ALT are expressed in liver and muscle cells. Both AST and ALT may be elevated in dystrophinopathies and further workup for Duchenne muscular dystrophy and Becker muscular dystrophy should be considered in young males being evaluated for increased transaminases to prevent unnecessary liver biopsy. Dystrophin gene mutation testing of a blood sample is the next step in the evaluation for a dystrophinopathy. Current testing techniques include multiplex polymerase chain reaction, multiplex amplifiable probe hybridization, multiplex ligation-dependent probe amplification, and single-condition amplification/internal primer. Open muscle biopsy may be considered in cases in which no genetic mutation has been genetically identified but the clinical findings strongly suggest a dystrophinopathy. Immunocytochemistry and immunoblotting may be used to determine the presence, quantity, and molecular size of dystrophin. Electromyography has been supplanted by genetic testing for Duchenne muscular dystrophy and Becker muscular dystrophy and generally is not indicated.

The natural history of Duchenne muscular dystrophy is progressive weakness resulting in loss of ambulation between 7 and 12 years of age and death at the start of the third decade. Becker muscular dystrophy progresses slower, with ambulation preserved until after 16 years of age or later. Scoliosis and limb contractures typically progress around the time ambulation is lost in patients with Duchenne muscular dystrophy resulting from overall weakness. Bracing does not slow scoliosis progression and timing for spinal fusion must take into consideration the individual’s respiratory function. Monitoring of respiratory function is critical in patients with Duchenne muscular dystrophy. Although ambulatory, individuals with Becker muscular dystrophy usually do not have the rapid changes in scoliosis and decline in respiratory muscle strength noted in Duchenne muscular dystrophy. Du­­chenne muscular dystrophy and Becker muscular dystrophy have cardiac involvement in up to 90% of cases that range from conduction abnormalities to severe systolic and diastolic dysfunction. Because up to 50% of carriers have cardiac involvement, cardiology evaluation and monitoring is necessary for patients with Duchenne muscular dystrophy and Becker muscular dystrophy and mutation carriers.

Corticosteroid therapy has been shown to improve strength and slow functional decline in Duchenne muscular dystrophy. Preservation of ambulation for up to 3 years may occur with prednisone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day. Steroid therapy is usually initiated when motor function plateaus; however, the timing of initiation and duration of treatment has not been universally established. Studies continue to explore alternative dosing regimens. Chronic steroid use increases the risk of obesity, behavior changes, immune suppression, cataracts, and bone demineralization requiring regular monitoring. Investigational treatments are exploring mechanisms to induce exon skipping to change a Du­­chenne muscular dystrophy genotype into a Becker muscular dystrophy phenotype. Gene transfer studies have been attempted to utilize adeno-associated virus to deliver microdystrophin constructs into muscle cells.

Limb-Girdle Muscular Dystrophies.

Limb-girdle muscular dystrophies are a large group of myopathic diseases with predominantly proximal limb-girdle weakness. This genetically diverse collection of myopathies is classified into dominant (LGMD1) and recessive (LGMD2) types ( Table 42-2 ). Each type is further divided based on gene discovery, approximately following subtype frequency. Most limb-girdle muscular dystrophies are slowly progressive, presenting from early childhood for LGMD2 to the start of the third decade of life for LGMD1. Outside of founder effects, limb-girdle muscular dystrophy is rare, and other myopathies should be considered and excluded first. Family history with passage of limb-girdle muscular dystrophy from parent to child may suggest LGMD1-dominant inheritance; however, spontaneous mutations may confuse interpretation of inheritance. One clinical phenotype of LGMD2 that deserves special attention is severe childhood autosomal recessive muscular dystrophy (SCARMD). Mutations of any of the four muscle sarcoglycans can result in SCARMD that may mimic Duchenne muscular dystrophy, but has an autosomal rather than X-linked inheritance pattern and spares cognitive function.

Table 42-2

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