NEUROMUSCULAR DISORDERS Noninflammatory As genetic diagnosis increases, noninflammatory myopathies are being seen more in clinical practice. By Yessar Hussain, MD; Krishna Pokala, MD; and Nancy Kuo, MS, MD

Noninflammatory myopathies ing results that show a CTG trinucleotide repeat expansion are heterogeneous mostly (> 50 repeats) of DMPK on chromosome 19q13.2.1,2,3-11 The hereditary rare disorders. size of the unstable CTG repeat expansion is directly related Prevalence is increasing because to the severity of clinical weakness. Genetic anticipation is of genetic testing advances. seen, with children of affected parents having a higher num- Individuals with noninflamma- ber of repeats and more severe clinical phenotype. Typical tory may present with proximal facial features and examination findings should prompt a weakness, myalgia, and, sometimes, systemic focused genetic workup for these individuals. involvement (eg, cardiac, endocrine, audio- logic, and ocular symptoms). Onset can occur Type 2 at any age and presentation varies with age. Type 2 (DM2) also affects many organ systems causing This article summarizes epidemiology, clini- weakness, cardiac conduction defects, cataracts, hypogamma- cal features, and diagnostic approach to the most common globulinemia, and testicular atrophy. Onset is typically in early noninflammatory myopathies seen in general to middle adulthood. Individuals with DM2 typically present practice. Dystrophinopathies (Becker’s and Duchenne’s with intermittent stiffness and proximal leg muscle pain that ), nutritional myopathies, and endocrine may be described as debilitating or burning. Proximal and dis- myopathies are outside the scope of this review. tal weakness progresses slowly and clinical myotonia may not be as prevalent as in DM1. Symptoms and severity of clinical Myotonic Dystrophy weakness are heterogeneous, even within a family. Intellectual Type 1 Myotonic Dystrophy disability is less common in adults with DM2 compared with Individuals with type 1 myotonic dystrophy (DM1) typi- DM1 (Table 1). Diagnostic test results show mildly elevated cally present as youth with distal extremity weakness that may CK, normal motor and sensory nerve conduction studies, and progress proximally. Specific neck flexor involvement may be needle EMG myotonic discharges even in patients without apparent early, and typical facial features include temporalis clinical myotonia. Muscle biopsy shows nonspecific myopathic atrophy and a tent-shape mouth caused by facial muscle features (eg, increased internal nuclei, fiber size variability with atrophy. Delayed relaxation (action myotonia) of hand-grip or type 2 fiber atrophy, small angulated fibers, and atrophic fibers eyelid closure is seen. Percussing bellies of affected muscles (eg, with pyknotic nuclear clumps).12-14 Genetic test results show abductor pollicis brevis) results in prolonged muscle contrac- CCTG repeat expansion NF9 intron 1 on chromosome 3.12,15 tion with delayed relaxation (percussion myotonia). A systemic disorder, DM1 affects the heart, eyes, muscles of respiration, TABLE 1. KEY CLINICAL AND GENETIC DIFFERENCES and gastrointestinal tract. Cardiac conduction defects may lead OF MYOTONIC DYSTROPHY TYPES 1 AND 2 to sudden cardiac death, and all persons with DM1 should be Type 1 (DM1) Type 2 (DM2) followed by a cardiologist; some benefit from a pacemaker. Inheritance Autosomal dominant Autosomal dominant Cataracts, gastrointestinal motility issues, sleep apnea, testicu- Genetic CTG trinucleotide CCTG tetranuculeotide lar atrophy, and high rates of fetal loss to mothers with DM1 mutation repeat expansion expansion on ZNF9 are common. Individuals with adult-onset DM1 may have mild on DMPK gene on gene on chromosome 3 intellectual disability and those with congenital DM1 born to chromosome19q13 mothers with DM1 may have severe intellectual disability. Diagnostic test results usually show normal to mildly Main clinical Facial and distal Proximal weakness elevated creatine kinase (CK) levels, normal sensory and findings weakness motor nerve conduction studies, and myotonic discharges on Myotonia Grip myotonia, Variable mild grip needle EMG of several muscles. Diagnosis is with genetic test- no fluctuation myotonia

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Nondystrophic Myotonias and Periodic Periodic Paralyses Marked by episodic attacks of flaccid muscle weakness, peri- Inherited in autosomal dominant (Thomsen’s disease) or odic paralyses are typically associated with fluctuating serum autosomal recessive patterns (Becker’s disease), myotonia potassium levels—high or low. Between exacerbations, serum congenita is a chloride that causes slowly potassium levels and sensory and motor nerve conductions progressing limb stiffness, usually first in the lower extremi- are normal. After long exercise there is an initial increase in ties and progressing to the upper extremities. Muscle stiff- CMAP followed by gradual drop, then recovery to baseline. ness typically improves with activity, termed the warm-up Exercise testing shows a drop in CMAP amplitude after sus- phenomena. Individuals with myotonia congenita usually do tained contraction of the abductor digiti minimi, maximally not complain of muscle pain. Cold temperatures or preg- approximately 25 minutes after exercise. Treatment for peri- nancy may worsen clinical myotonia. Anesthesia may cause odic paralyses includes or other carbonic anhy- malignant hyperthermia. drase inhibitors and avoidance of triggers. People with myotonia congenita often have a muscular Hyperkalemic Periodic Paralysis. Typically presenting before build, even without regular exercise, action myotonia and age 10 years, attacks of flaccid paralysis in hyperkalemic peri- percussion myotonia, and mild proximal weakness on manual odic paralysis last minutes to hours. Triggers include fasting, strength testing. Thomsen’s disease usually presents in rest after exercise, and intake of potassium-rich foods. Ictal infancy; whereas, Becker’s disease typically presents after age areflexia with preserved sensation is typical. Some people 5 years and has worse muscle weakness. with hyperkalemic periodic paralysis progress to fixed proxi- Laboratory test results include normal CK levels, normal mal weakness. During attacks, serum potassium may be less sensory and motor nerve conduction studies, and predomi- than 5 mmol per L or increased by more than 1.5 mmol per L nant myotonic discharges on needle EMG. On short exer- above baseline. Genetic test results show mutations in SCN4A cise tests, individuals with Becker’s disease have decreased on chromosome 17q23. Preventative measures, including compound muscle action potential (CMAP) amplitude a low-potassium/high carbohydrate diet and avoiding fast- immediately after exercise that returns to normal after 30 to ing, intense exercise, and cold temperatures may be useful. 40 seconds. In contrast, people with Thomsen’s disease have Acetazolamide may be used preventatively. decreased CMAP amplitude after the limb muscle cools Hypokalemic Periodic Paralysis. Presenting in young adult- down. However, short exercise tests have been rendered hood, hypokalemic periodic paralysis has the highest frequen- obsolete by genetic testing for causative CLCN1 mutations cy of attacks before age 35. The severity of weakness may vary on chromosome 7q35in both forms.16-18 Mutations in the from mild weakness to frank flaccid paralysis. Exacerbations chloride result in decreased chloride conductance last hours to days, significantly longer than with hyperkalemic and decreased rate of muscle membrane repolarization. periodic paralysis. Triggers include alcohol, carbohydrate- rich foods, stress, and rest after exercise. Serum potassium levels may drop to less than 3.0 mmol per L during an attack. Paramyotonia congenita is an autosomal dominant disorder Genetic test results show CACNA1S mutations on chromo- that typically presents before age 10 years, with eyelid open- some 1q32 or SCN4A mutations on chromosome 17q23.20-22 ing weakness after crying or eyelid closure. Cold temperatures Treatment with acetazolamide or potassium-sparing or potassium intake may trigger myotonia and weakness. In can be tried and trigger avoidance is useful. paramyotonia congenita there is worse muscle stiffness with Andersen-Tawil Syndrome. Marked by episodes of flaccid exercise or prolonged activity. Muscle pain is less prominent muscle weakness, Andersen-Tawil syndrome occurs in the set- than in DM2, and muscle weakness may progress. ting of any potassium, ventricular arrhythmia, and prolonged Results of laboratory testing show mildly elevated CK, nor- QT interval. Individuals with Anderson-Tawil syndrome have mal to elevated potassium levels during exacerbations, and dysmorphic features, including short stature, fifth digit clino- normal sensory and motor nerve conduction studies in the dactyly, and of the second and third toes. Genetic absence of exacerbations. After brief exercise, repetitive after- test results show KCNJ2 mutation, Kir 2.1 on chromosome discharges occur with a single supramaximal stimulus, termed 17q23 in the majority of patients.23 postexercise myotonic potentials (PEMPs). There may be a dec- rement with repetitive stimulation at 5 Hz. Short exercise test Congenital Myopathies results are normal or show small increments in a warm muscle; Although some present in later childhood or early adult- in a cooled muscle there will be a marked drop in CMAP hood, most congenital myopathies present in infancy with amplitude and very slow recovery over 1 hour. On needle and generalized weakness, and motor develop- EMG, there are prominent myotonic discharges. Genetic test- ment is often delayed. Even within the same family with ing shows SCN4A mutations.19 the same known genotype, clinical phenotype varies.

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Classification is based on clinical presentation and electron most common metabolic myopathy, occurring in 1 in microscopic muscle biopsy structural findings (Table 2). 100,000 people. Many individuals may have a second-wind phenomenon, unique to McArdle’s disease, in which pain Metabolic Myopathies may resolve after onset of exertional myalgias or cramps, The metabolic myopathies are genetic disorders that allowing the individual to resume exercising. impair intermediary metabolism in ; most fall In glycogen storage diseases, CK can be—but is not into 1 of 3 categories, including the glycogen storage diseas- always—elevated, and EMG and nerve conduction studies are es, fatty acid oxidation defects, and mitochondrial myopa- often normal and not of diagnostic value with the exception of thies. Metabolic myopathy typically presents with exercise Pompe’s disease. An autosomal recessive disease, Pompe’s dis- intolerance and weakness.24 ease has a classic infantile form presenting with hypertrophic Glycogen Storage Diseases. Presenting during brief periods of cardiomyopathy and a late-onset juvenile/adult form without high-intensity exercise, glycogen storage diseases cause muscle cardiomyopathy. The late-onset form should be suspected in cramps within seconds to minutes of exercise. Many people people with progressive proximal weakness in a limb-girdle dis- with glycogen storage disease also have pigmenturia (ie, dark tribution with or without respiratory involvement. In Pompe’s or red urine from myoglobin caused by rhabdomyolysis dur- disease, EMG and nerve conduction study results show char- ing exercise). Most glycogen storage diseases are autosomal acteristic myotonic and complex repetitive discharges. Gene recessive with a negative family history. Neurologic examina- sequencing is the preferred test for diagnosis.25 tion findings are typically normal between episodes. The classic diagnostic test for glycogen storage myopathies McArdle’s disease, a disorder of glycolysis, is the is the forearm exercise test in which a blood pressure cuff is

TABLE 2 CLINICAL AND GENETIC CHARACTERISTICS OF CONGENITAL MYOPATHIES Late onset Late onset nemaline Multi/minicore myopathy Central core myopathy Inheritance AD AD/AR/Sporadic AR/Spontaneous/AD AD Clinical Variable pattern of weak- Onset after age 40 with Onset in infancy or adult- Proximal weakness and findings ness; sometimes proximal proximal, distal, and general- hood with generalized weak- mild face and neck only or distal only ized weakness; dysphagia and ness and atrophy greater extensor weakness cardiomyopathy; isolated neck proximally than distally; some extensor weakness possible have distal hand weakness Facial/EOM May be present None or mild Rare Spares EOM involvement Progression Mild, slowly progressive Fast onset with slow progression Stable/slowly progressive Contractures None None Common Rare Creatine Normal/mild elevation Normal Normal/mild elevation Normal/mild elevation kinase Gene DNM2 on 19p13 Sporadic SEPN1 1p36 (classic form) RYR1 on 19q13 Histopath- Central nuclei often form- Nemaline rods best seen on Disorganized myofibrils Cores in type 1 muscle ology ing chains/clusters, no electron microscopy form minicores (lack of fibers only (lack of ATPase staining around NADH staining) in type 1 NADH-TR staining) nuclei; type 1 fiber pre- and type 2 muscles; type 1 extend longitudinally dominance and atrophy predominance, atrophy, and throughout the muscle and normal type 2 fibers fiber size variation fiber; fiber size variation, internalized nuclei Other DNM2 mutation associ- Respiratory weakness, dyspha- High arched palate, club Risk of malignant ated with some forms gia, and cardiomyopathy; may feet, cardiomyopathy, respi- hyperthermia of CMT; NCS may be be associated with MGUS ratory weakness particularly abnormal during sleep Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CMT, Charcot–Marie–Tooth disease; EOM, extraocular muscles, NCS, nerve conduction study; MGUS, monoclonal gammopathy of unknown significance.

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inflated beyond arterial pressure while isometric rhythmic of 1 in 15,000. The classic distribution of muscle weakness exercises are performed for 1 minute, followed by release of involves the facial, scapular, upper arm, lower leg, and abdomi- the cuff. Lactate and ammonia values collected before inflating nal muscles, with asymmetric involvement (Figure). and immediately after deflation are collected and compared. The most frequent initial symptoms are inability to lift In glycolytic and glycogenolytic diseases, ammonia is elevated arms over shoulder height or weakness of the facial muscles. threefold, but lactate shows no significant rise.26 Genetic test- Characteristic facial and upper torso appearance is seen on ing can be done with next generation sequencing or targeted physical examination with decreased brow furrow, inability to analysis of a known genetic mutation. Muscle biopsy is not close eyes, flattened smile, scapular winging, trapezius hump, necessary after these steps but can show high glycogen, absent and significant weakness and atrophy of the biceps brachii and phosphorylase, or absent phosphofructokinase. triceps. The forearm muscles are relatively spared, producing Fatty Acid Oxidation Defects. Fatty acid oxidation defects “Popeye arms.” A positive Beevor’s sign may be elicited (umbili- present during long duration or short intensity activities, fast- cus will move up or down a few centimeters when the patient ing, or stressful events (eg, surgery, fever, or flu). In fatty acid is supine and attempts to flex the head).27 Extramuscular oxidation defects, CK levels may be elevated during acute involvement including retinal vasculopathy, hearing loss, cardi- rhabdomyolysis, and EMG and nerve conduction study results ac arrhythmia, cognitive impairment, and epilepsy may occur. are often normal. The most sensitive and specific diagnostic Diagnosis is usually based on clinical history, exam, and test is a serum acylcarnitine profile, performed under fasting family history. Molecular genetic testing confirms the diag- conditions.26 Next generation sequencing panels or target nosis. Individuals with type 1 FSHD have reduced D4Z4 analysis of the known genetic mutation based on the serum repeats in chromosome 4q, and those with type 2 have acylcarnitine profile can be done afterwards. Muscle biopsy SMCHD1 mutations on chromosome 18. Both types cause is not necessary after genetic testing; when done it may show reduced methylation in the D4Z4 region, resulting in the nonspecific increase in neutral lipid. expression of toxic DUX4 protein. Mitochondrial Myopathies. A heterogeneous group of disor- ders with a range of phenotypes and genotypes, mitochondrial myopathies also present during long duration or short inten- sity exercise, fasting, or stressful events. Rhabdomyolysis and pigmenturia are uncommon and findings on the neurologic examination are variable owing to the multisystem involve- ment of the disease (eg, ptosis, ophthalmoplegia, or deafness). The serum lactate level is elevated in 65% of patients with mitochondrial myopathies, and EMG and nerve conduction study results are often normal and not of diagnostic value.25 Muscle biopsy is more helpful than in the glycogen storage diseases and fatty acid oxidation defects with characteristic his- tologic features of ragged red fibers on the modified-Gomori trichrome stain. As with the other myopathies, next generation sequencing or target analysis of the known genetic mutation is available for diagnosis.

Muscular Dystrophy The primary symptom of muscular dystrophy, an inherit- ed disorder, is muscle weakness. Dystrophinopathies (Becker and Duchenne muscular dystrophy) are outside the scope of this review. Here we focus on facioscapulohumeral and limb girdle muscular dystrophies (FSHD and LGMD).

Facioscapulohumeral Muscular Dystrophy There are 2 types of genetically distinct FSHD with similar clinical features; 95% of cases are type 1 and 5% are type 2. Both are autosomal dominant, thought to be secondary to abnormal expression of toxic DUX4 protein. Among the most common muscular dystrophies, FSHD has prevalence Figure. Facioscapulohumeral Muscular Dystrophy Clinical Features.

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1. Meola G. Clinical and genetic heterogeneity in myotonic dystrophies. Muscle Nerve. 2000;23(12);1789-1799. Limb Girdle Muscular Dystrophy 2. Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of myotonic dystrophy; expansion of a trinucleotide (CTG) repeat The LGMDs are heterogeneous, progressive, genetic dis- at the 3’ end of transcript encoding protein kinase family member. Cell. 1992;68(4);799-808. 3. Fischbeck KH. The mechanism of myotonic dystrophy. Ann Neurol. 1994;35(3);255-256. orders, characterized by shoulder and pelvic girdle muscle 4. Fu Y-H, Friedman DL, Richards S, et al. Decreased expression of myotonin protein kinase messenger RNA and protein in weakness, with incidence of 1 to 6 out of 100,000. Inheritance adult for of myotonic dystrophy. Science. 1993;2(5102):60:235-238. 5. Fu Y-H, Pizzuti A, Fenwick R Jr, et al. An unstable triplet repeat in a gene related to myotonic dystrophy. Science. can be autosomal dominant (type 1), or recessive (type 2), or 1992;255(5049);1256-1258. X-linked. Diagnosis is based on phenotype and genetic testing 6. Harper PS, Harley HG, Reardon W, Shaw DJ. Anticipation in myotonic dystrophy: new light on an old problem. Am J Hum 6 Genet. 1992;51(1):10-16. (Table 3), which should be done before ancillary testing (eg, 7. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3 prime untrans- biopsy, imaging, or electrodiagnostics). n lated region of the gene. Science. 1992;255:1253-1255. 8. Ptacek LJ, Johnson KJ, Griggs RC. Genetics and physiology of the myotonic disorders. New Engl J Med. 1993;328(7):482-489. 9. Shelbourne P, Davies J, Buxton J, et al. Direct diagnosis of myotonic dystrophy with a disease specific DNA marker. New TABLE 3. LIMB-GIRDLE MUSCULAR DYSTROPHIES Engl J Med. 1993;328(7):471-475. 10. Tian B, White RJ, Xia T, et al. Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent Type Gene Common clinical feature protein kinase PKR. RNA. 2000;6(1):79-87. 11. Mankodi A, Takahashi MP, Jiang H, et al. Expanded CUG repeats trigger aberrant splicing of CIC-1 chloride channel pre- Autosomal Dominant mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10(1):35-44. LGMD1A MYOT Upper extremity distal weakness and 12. Day JW, Ricker K, Jacobsen JF, et al. Myotonic dystrophy type 2: molecular, diagnostic, and clinical spectrum. Neurology. 2003;60(4):657-664. contractures, dysarthria, palatal hypo- 13. Schoser BG, Schneider-Gold C, Kress W, et al. Muscle pathology in 57 patients with myotonic dystrophy type 2. Muscle phonia, footdrop, areflexia Nerve. 2004a;29(2):275-281. 14. Vihola A, Bassez G, Meola G, et al. Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. LGMD1B LMNA Contractures, cardiac conduction Neurology. 2003;60(11):1854-1857. 15. Udd B, Meola G, Krake R, et al. Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies. defects Neuromusc Disord. 2003;13;589-596. 16. George AL, Crackover MA, Abdulla JA, Hudson JA, Ebers GC. Molecular basis of Thomsen’s disease (autosomal dominant LGMD1C CAV3 Rippling muscles, muscle hypertrophy myotonia congenital). Nat Genet. 1993;3:305-310. 17. Lorenz C, Meyer-Kleine C, Steinmeyer K, Koch MC, Jentsch TJ. Genomic organization of the human muscle chloride channel LGMD1D DNAJB6 Cardiomyopathy CIC-1 and analysis of novel mutations leading to Becker-type myotonia. Hum Mol Genet. 1994;3:941-946. 18. Wu FF, Ryan A, Devaney J, et al. Novel CLCN1 mutations with unique clinical and electrophysiological consequences. Brain. LGMD1E DES Facial weakness, cardiac conduction 2002;125:2392-2407. defect 19. Streib EW, Sun SF, Hanson M. Paramyotonia congenita: clinical and electrophysiologic studies. Electromyogr Clinical Neurophysiol. 1983;23(4):315-325. LGMD1F TNPO3 Early respiratory muscle involvement 20. Ricker K, Moxley RT 3rd, Heine R, Lehmann-Horn F. Myotonia fluctuans. A third type of muscle sodium channel disease. Arch Neurol. 1994;51(11):1095-1102.. LGMD1G HNRNPDL Finger and toe flexion limitation 21. Rüdel R, Ruppersberg JP, Spittelmeister W. Abnormalities of the fast sodium current in myotonic dystrophy, recessive generalized myotonia, and adynamia episodica. Muscle Nerve. 1989;12(4):281-287. Autosomal Recessive 22. Bradley WG, Taylor R, Rice DR, et al. Progressive myopathy in hyperkalemic periodic paralysis. Arch Neurol. 1990;47:1013-1017. 23. Plaster NM, Tawil R, Trisani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical pheno- LGMD2A CAPN3 Contractures and atrophy of shoulder types of Andersen’s Syndrome. Cell. 2001;105(4):511-519. 24. Haller RG. Treatment of McArdle disease. Arch Neurol. 2000;57(7):923-924. and pelvic girdle muscles 25. Hobson-Webb DD, Dearmey S, Kishnani PS. The clinical and electrodiagnostic characeristics of Pompe disease with post- enzyme replacement therapy findings. Clin Neurophysiol. 2011 Nov;122(11):2312-2317. LGMD2B DYSF Medial gastrocnemius atrophy 26. Tanopolsky MA. Metabolic myopathies. Continuum (Minneap Minn). 2016;22(6):1829-1851. LGMD2C SGCG Tongue hypertrophy 27. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum (Minneap Minn). 2016;22(6):1916-1931. LGMD2D SGCA Tongue hypertrophy Yessar Hussain, MD LGMD2F SGCD Tongue hypertrophy Director, Austin Neuromuscular Center Board Certified in Neurology, Neuromuscular Medicine, LGMD2G TCAP Weakness of quadriceps and anterior & Pathology tibial muscles Assistant Professor UT Austin Dell Medical School LGMD2H TRIM32 Scapular winging, calf hypertrophy Austin, TX LGMD2I FKRP Tongue and calf hypertrophy, cardiac and respiratory muscle involvement Krishna Pokala MD Assistant Professor of Neurology LGMD2J TTN Anterior tibial muscle weakness University of Texas at Austin Dell Medical School LGMD2L ANO5 Asymmetric atrophy of muscles, Austin, TX mandibular dysplasia LGMD2R DES Facial weakness, respiratory muscle Nancy Kuo, MS, MD Neurology Chief Resident involvement, high-arched palate Department of Neurology LGMD2S TRAPPC11 Scapular winging, hyperkinesis The University of Texas at Austin Dell Medical School LGMD2V GAA Proximal weakness, respiratory Austin, TX insufficiency Disclosures LGMD2W LIMS2 Calf and tongue hypertrophy, YH, KP, and NK report no disclosures. triangular tongue

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