Muscular Dystrophies and Other Muscle Diseases¶
Chapter 460 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 460
Key Clinical Points¶
- Myopathies are characterized by structural changes or functional impairment of muscle, distinguished from motor unit pathologies (e.g., lower motor neuron or neuromuscular junction disorders) by preserved reflexes and sensation in most cases.
- Limb-girdle weakness (proximal, symmetric limb weakness with preserved reflexes/sensation) is the hallmark of most myopathies.
- The Gower sign (using arms to 'climb' up legs to stand) indicates combined trunk and hip weakness.
- Duchenne Muscular Dystrophy (DMD) incidence is 1 in 3000 male births; Becker Muscular Dystrophy (BMD) incidence is ~5 per 100,000.
- Serum Creatine Kinase (CK) is the most sensitive measure of muscle damage; it may be normal in cases of chronic fibrofatty replacement.
- Glucocorticoids slow progression in DMD, but their use in BMD has not been adequately studied.
- Genetic testing is the gold standard for diagnosing hereditary myopathies; muscle biopsy is less frequently required but remains useful for differentiating specific disorders.
- Forearm exercise tests are used to detect glycol1ic defects (absent lactic acid rise) or lipid metabolism disorders (reduced lactic acid rise).
- DMD and BMD are X-linked recessive dystrophinopathies; DMD results from out-of-frame mutations, while BMD typically involves in-frame mutations (~95% of cases).
- The LGMD classification has shifted from a lineage-based system (LGMD1/2) to a genotype-based system (LGMDR/LGMDD).
- Cardiac involvement is common in both DMD and BMD and is a leading cause of mortality.
1. DEFINITION & OVERVIEW¶
• Definition: Myopathies are disorders with structural changes or functional impairment of muscle. They are differentiated from other motor unit diseases (e.g., lower motor neuron or neuromuscular junction pathologies) by characteristic clinical and laboratory findings.
• Clinical Presentation: ◦ Most myopathies cause persistent weakness. ◦ Limb-Girdle Weakness: Characterized by proximal muscles being weaker than distal, symmetric involvement, and spared facial muscles.
• Fatigue vs. Asthenia: ◦ Asthenia: Fatigue caused by excess tiredness or lack of energy; associated with sleepiness, difficulty concentrating, and feelings of stress. ◦ Pathologic Fatigability: Occurs in disorders of neuromuscular transmission or altered energy production (e.g., defects in glycolysis, lipid metabolism, or mitochondrial production). ◦ Clinical Rule: Fatigue without the supporting features of asthenia almost never indicates a primary muscle disease.
• Patterns of Weakness (Section 1.1): ◦ Proximal > Distal: Hallmark of most myopathies; includes muscular dystrophies, inflammatory myopathies, and metabolic/mitochondrial myopathies. ◦ Ptosis & EOM Involvement: Suggests Oculopharyngeal muscular dystrophy (OPMD), mitochondrial myopathy, or neuromuscular junction disorders. ◦ Facial, Neck, & Scapular Winging: Characteristic of facioscapulohumeral dystrophy (FSHD). ◦ Distal Weakness: Seen in distal myopathies and some metabolic/mitochondrial conditions. ◦ Axial/Dropped Head: Suggests SLONM, RyR1 myopathies, hyperparathyroidism, or myasthenia gravis.
2. EPIDEMIOLOGY¶
• Duchenne Muscular Dystrophy (DMD): Most common mutational disease affecting boys; incidence 1 in 3000 male births.
• Becker Muscular Dystrophy (BMD): Incidence ~5 per 100,000; most cases survive into the fourth or fifth decade.
• Limb-Girdle Muscular Dystrophies (LGMD): Prevalence of 1.63 per 100,000 (range 0.56–5.75 per 100,000).
3. ETIOLOGY & PATHOPHYYSOLOGY¶
3.1 Dystrophinopathies¶
• Genetics: X-linked recessive; mutations in the dystrophin gene. ◦ DMD vs. BMD: → DMD: Out-of-frame mutations (approx. 5% of cases) resulting in absent/truncated dystrophin. → BMD: In-frame mutations (~95% of cases) allowing for some dystrophin production; typically milder phenotype. ◦ Clinical Impact: → Cardiac and ventilatory muscle involvement are common in both and are the leading causes of mortality. → Intellectual disability may occur in both but is less common in BMD. ◦ Other presentations: Asymptomatic hyper-CK-emia, myalgias without weakness, or myoglobinuria.
3.2 Limb-Girdle Muscular Dystrophies (LGMD)¶
• Clinical Features: Genetically heterogeneous; affects males and females equally; typically presents with proximal pelvic and shoulder girdle weakness. ◦ Laboratory/Imaging: Serum CK is elevated; EMG is myopathic; biopsy shows dystrophic features (not specific for subtype differentiation unless immunohistochemistry is used).
• Classification System Evolution: ◦ Old System: Based on inheritance (LGMD1 = Autosomal Dominant; LGMD2 = Autosomal Recessive). ◦ New System (ENMC): Based on genotype. → Autosomal dominant cases are termed LGMD D. → Autosomal recessive cases are termed LGMDR. ◦ Exclusions from LGMD Classification: → Myotilin mutations (formerly LGMD1A) are now classified as Myofibrillar Myopathy (MFM3). → Desmin mutations (formerly LGMD1E/2R) are now MFM1. → Lamin A and C mutations (formerly LG1B) are now EDMD. → Sarcoglycan mutations (e.g., γ-Sarcoglycan, α-Sarcoglycan) are excluded from the new LGMD classification if they present with specific phenotypes.
4. CLINICAL FEATURES¶
4.1 Myotonia and Stiffness¶
• Myotonia: Prolonged muscle contraction followed by slow relaxation. ◦ Action Myotonia: Follows voluntary activation. ◦ Percussion Myotonia: Triggered by mechanical stimulation.
• Muscle Stiffness: ◦ Stiff-person syndrome: Spontaneous motor neuron discharges; involves axial/proximal muscles; associated with anti-GAD antibodies. ◦ Neuromyotonia (Isaacs' syndrome): Hyperexcitability of peripheral nerves; continuous muscle fiber activity; increased sweating.
4.2 Muscle Enlargement and Atrophy¶
• Pseudohypertrophy: Seen in DMD/BMD; enlargement is due to fat/connective tissue replacement. ◦ True Hypertrophy: In many LGMDs, enlarged calf muscles represent true muscle hypertrophy (muscles remain strong).
• Specific Atrophy Patterns: ◦ Miyoshi myopathy: Early atrophy of the gastrocnemius (especially medial aspect). ◦ FSHD and EDMD: Characterized by atrophy of the humeral muscles.
• Gait & Posture Indicators: ◦ Gower sign: Indicates proximal/hip weakness. ◦ Hyperlordotic posture: Result of trunk/hip weakness; exacerbated by standing on toes. ◦ Waddling gait: Caused by inability of weak hip muscles to prevent hip drop. ◦ Genu recurvatum (back-kneeing): Indicates quadriceps muscle weakness. ◦ Steppage gait: Due to foot drop, indicating distal weakness.
5. DIFFERENTIAL DIAGNOSIS¶
• Assessment Strategy: Use history, progression, family history, serum CK, and EMG to localize the lesion (muscle vs. nerve/junction) and identify patterns.
• Pattern-Based Differentiation (Table 460-1): ◦ Proximal (Limb-Girdle) Weakness: → Dystrophies (DMD, BMD, LGMD, MFM, Myotonic Dystrophy Type 2). → Congenital myopathies (Central core, multiminicore, centronuclear, nemaline rod). → Metabolic/Mitochondrial myopathies (Glycogen/lipid storage, mitochondrial). → Inflammatory myopathies (DM, PM, IMNM, anti-synthetase syndrome). ◦ Eye Muscle Weakness: → Ptosis without ophthalmoparesis: Myotonic dystrophy. → Ptosis with ophthalmoparesis: Oculopharyngeal dystrophy, Oculopharygeal distal myopathy, Mitochondrial myopathy. ◦ Distal Weakness: → Distal muscular dystrophies/myofibrillar myopathy (Table 460-5). → Congenital myopathies (late-onset centronuclear and nemaline rod). → Metabolic: Glycogen storage disease, Lipid storage disease. ◦ Proximal Arm / Distal Leg Weakness: → FSHD, Scapuloperoneal myopathy/neuropathy, Myofibrillar myopathies, EDMD, Bethlem myopathy. ◦ Distal Arm / Proximal Leg Weakness: → Inclusion body myositis (IBM), Myotonic dystrophy. ◦ Axial Muscle Weakness: → Inflammatory (cervicobrachial myositis), sIBM, hIBM, Myotonic dystrophy 2, Isolated neck extensor myopathy, FSHD.
6. INVESTIGATIONS & DIAGNOSIS¶
• Diagnostic Evaluation of Persistent Weakness (Flowchart 1): 1. Identify Clinical Pattern: ◦ Proximal > distal → IMNM, PM, DM, anti-synthetase, muscular dystrophies, metabolic/mitochondrial myopathies, toxic/endocrine myopathies. ◦ Ptosis, EOMs → OPMD, mitochondrial myopathy, myotubular myopathy. ◦ Facial, neck, scapular winging → FSHD. ◦ Facial, distal, quadriceps; handgrip no myotonia → Myotonic myositis/myotonic muscular dystrophy. ◦ Proximal & distal (hand grip), and quadriceps → IBM. ◦ Distal → Distal myopathy (Table 460-1). ◦ Dropped head/Axial → MG, PM, ALS, hyperparathyroidism, axial myopathy. 2. Electromyography (EMG) & Nerve Stimulation: ◦ Myopathic EMG: Confirms muscle disease and excludes ALS. ◦ Repetitive nerve stimulation: Identifies neuromuscular junction disorders (MG, LEMS, botulism). 3. Laboratory Evaluation: ◦ Serum CK: Elevated levels support a diagnosis of myopathy. 4. Genetic Testing: ◦ DNA analysis: Used to distinguish inherited myopathies and identify specific genotypes. 5. Histopathology: ◦ Muscle biopsy: Final step to differentiate many disorders when genetics are inconclusive.
7. MANAGEMENT & TREATMENT¶
- Duchenne Muscular Dystrophy (DMD): ◦ Glucocorticoids: Used to slow the progression of muscle weakness.
- Becker Muscular Dystrophy (BMD): ◦ Management: Standard care; glucocorticoid efficacy not well-established.
- General Monitoring: ◦ Cardiac and respiratory function must be monitored in all dystrophinopathies due to high risk of heart failure and respiratory insufficiency.
8. PROGNOSIS & COMPLICATIONS¶
• Dystrophinopathies: ◦ Primary causes of mortality: Cardiac involvement (heart failure) and respiratory insufficiency. ◦ Progression: Slow, progressive weakness; severity varies by subtype.
9. SPECIAL CONSIDERATIONS¶
• Drug-Induced Myopathies (Table 460-8): ◦ Lipid-lowering agents (HMG-CoA reductase inhibitors, Fibric acid derivatives, Niacin) can cause myalgias and rhabdomyolysis. ◦ Amphophilic drugs (Amiodarone, Chloroquine, Hydroxychloroquine) may cause painless, proximal weakness associated with necrosis and autophagic vacuoles. ◦ Drugs of abuse (Alcohol, Amphetamines, Cocaine, Heroin, Phencyclidine, Meperidine) can lead to widespread muscle breakdown, rhabdomyolysis, and myoglobinuria.
10. KEY PEARLS & CLINICAL TRAPS¶
• Gower Sign: Use of arms to 'climb' up legs; indicates proximal/hip weakness. ◦ Associated with: DMD, BMD, and other myopathies. • Hyperlordosis: A curved spine (exaggerated by toe-walking) indicates trunk and hip muscle weakness. • Sarcoglycan Mutations: Lead to congenital muscular dystrophy with severe brain/eye abnormalities or milder LGMD phenotypes. • Myofibrillar Myopathy (MFM): Distinct from LGMD; includes conditions like MFM1 (Desmin) and MFM3 (Myotilin). • Forearm Exercise Test: Used to differentiate metabolic myopathies (e.g., Glycolytic vs. Lipid metabolism defects).
Reference Tables¶
TABLE 460-1 Myopathies by Pattern of Weakness/Muscle Involvement Proximal (Limb-Girdle) Weakness Most dystrophies…¶
Harrison's 22e, p.3635
| Proximal (Limb-Girdle) Weakness | Late-onset central core (RYR1 mutations) SLONM Metabolic (late-onset Pompe, McArdle disease, lipid storage, mitochondrial) Hyperparathyroidism/osteomalacia/vitamin D deficiency Myasthenia gravis Eye Muscle Weakness (Ptosis/Ophthalmoparesis) Ptosis without ophthalmoparesis Myotonic dystrophy Congenital myopathies Neuromuscular junction disorders Ptosis with ophthalmoparesis Oculopharyngeal dystrophy Oculopharygeal distal myopathy Mitochondrial myopathy hIBM type 3 Neuromuscular junction disorders Episodic Weakness or Myoglobinuria Related to exercise Glycogenoses (e.g., McArdle disease, etc.) Lipid disorders (e.g., CPT2 deficiency) Mitochondrial myopathies (e.g., cytochrome B deficiency) Not related to exercise RYR1 mutations can cause malignant hyperthermia, episodic rhabdomyolysis/ myoglobinuria, and atypical periodic paralysis Other causes of malignant hyperthermia Drugs/toxins (e.g., statins) Prolonged/intensive eccentric exercise Inflammatory (e.g., PM/DM—rare, viral/bacterial infections) Delayed or unrelated to exercise Periodic paralysis (e.g., hereditary hyper- or hypokalemic, thyrotoxic, associated renal tubular acidosis, acquired electrolyte imbalance) NMJ disorders Muscle Stiffness/Decreased Ability to Relax Myotonic dystrophy 1 and 2 Myotonia congenita Paramyotonia congenita Hyperkalemic periodic paralysis with myotonia Potassium aggravated myotonia Schwartz-Jampel syndrome Other: rippling muscle disease (acquired and hereditary), acquired neuromyotonia (Isaacs’ syndrome), stiff-person syndrome, Brody’s disease |
|
|---|---|---|
| Most dystrophies (e.g., dystrophinophies, limb-girdle, myofibrillar myopathy, myotonic dystrophy type 2, rare FSHD) Congenital myopathies (e.g., central core, multiminicore, centronuclear, nemaline rod) Metabolic myopathies (e.g., glycogen and lipid storage diseases) Mitochondrial myopathies Inflammatory myopathies (DM, PM, IMNM, anti-synthetase syndrome) Toxic myopathies (see Table 460-6) Endocrine myopathies Neuromuscular junction disorders (myasthenia gravis, LEMS, congenital myasthenia, botulism, see Chap. 459) SLONM |
||
| Distal Weakness | ||
| Distal muscular dystrophies/myofibrillar myopathy (see Table 460-5) Congenital myopathies (e.g., late-onset centronuclear and nemaline rod myopathies) Oculopharyngeal distal myopathy Metabolic Glycogen storage disease (e.g., brancher and debrancher deficiency, rarely McArdle disease) Lipid storage disease (e.g., neutral lipid storage myopathy, multiacyldehydrogenase deficiency) NMJ disorders (e.g., rare myasthenia gravis and congenital myasthenia) |
||
| Proximal Arm/Distal Leg Weakness (Scapuloperoneal or Humeroperonal) Weakness |
||
| Facioscapulohumeral muscular dystrophy (FSHD) Scapuloperoneal myopathy and neuropathy Myofibrillar myopathies Emery-Dreifuss muscular dystrophy (EDMD) Bethlem myopathy |
||
| Distal Arm/Proximal Leg Weakness | ||
| Inclusion body myositis (usually wrist and finger flexors in arms, hip flexors and knee extensors in legs, and asymmetric) Myotonic dystrophy (uncommon presentation) |
||
| Axial Muscle Weakness | ||
| Inflammatory (cervicobrachial myositis) sIBM and hIBM Myotonic dystrophy 2 Isolated neck extensor myopathy/bent spine syndrome FSHD |
TABLE 460-2 Observations on Examination That Disclose Muscle Weakness¶
Harrison's 22e, p.3637
| FUNCTIONAL IMPAIRMENT | MUSCLE WEAKNESS |
|---|---|
| Inability to forcibly close eyes | Upper facial muscles |
| Inability to raise head from prone position | Neck extensor muscles |
| Inability to raise arms above head | Proximal arm muscles (may be only scapular stabilizing muscles) |
| Inability to walk with heels touching the floor (toe walking) |
Shortening of the Achilles tendon |
| Inability to walk without a waddling gait | Hip muscles |
| Inability to get up from a chair without using arms |
Hip muscles |
TABLE 460-3 Autosomal Dominant (AD) Limb-Girdle Muscular Dystrophies (LGMDs) OLD¶
Harrison's 22e, p.3639
| OLD / NEW NOMENCLATURE | INHERITANCE | GENE | AFFECTED PROTEIN |
|---|---|---|---|
| LGMD1A / MFM3 | AD | MYOT | Myotilin |
| AD | LMNA | ||
| LGMD1C / Rippling muscle disease | AD | CAV3 | Caveolin-3 |
| AD | DNAJB6 | ||
| LGMD1E / MFM1 | AD | DES | Desmin |
| AD | TNPO3 | ||
| LGMD1G / LGMDD3 | AD | HNRNPDL | Heterogeneous nuclear ribonucleoprotein D like protein |
| LGMD1I / LGMDD4 | AD | CAPN3 | Calpain 3 |
| AD | COL6A1/2/3 |
TABLE 460-4 Autosomal Recessive (AR) Limb-Girdle Muscular Dystrophies (LGMDs) OLD¶
Harrison's 22e, p.3639
| OLD / NEW NOMENCLATURE | INHERITANCE | GENE | AFFECTED PROTEIN |
|---|---|---|---|
| LGMD2A / LGMDR1 | AR | CAPN3 | Calpain 3 |
| AR | DYSF | ||
| LGMD2C / LGMDR5 | AR | SGCG | γ-Sarcoglycan |
| AR | SGCA | ||
| LGMD2E / LGMDR4 | AR | SCGB | β-Sarcoglycan |
| AR | SCGD | ||
| LGMD2G / LGMDR7 | AR | TCAP | Telethonin |
| AR | TRIM32 | ||
| LGMD2I / LGMDR9 | AR | FKRP | Fukutin-related protein |
| AR | TTN | ||
| LGMD2K / LGMDR11 | AR | POMT1 | Protein O-mannosyltransferase 1 |
| AR | ANO5 | ||
| LGMD2M / LGMDR13 | AR | FKTN | Fukutin |
| AR | POMT2 | ||
| LGMD2O / LGMDR15 | AR | POMGnT1 | Protein O-linked mannose Beta-1,2-N-acetyl glucosaminyltranferase-1 |
| AR | DAG1 | ||
| LGMD2Q / LGMDR17 | AR | PLEC1 | Plectin 1 |
| AR | DES | ||
| LGMD2S / LGMDR18 | AR | TRAPPC11 | Trafficking protein particle complex 11 |
| AR | GMPPB | ||
| LGMD2U / LGMDR20 | AR | CRPPA | CDP-L-ribitol pyrophosphorylase A (also known as ISPD) |
| AR | GAA | ||
| LGMD2W / PINCH-2-related myopathy | AR | LIMS2 | PINCH-2 |
| AR | BVES | ||
| LGMD2Y / TOR1AIP1-related myopathy | AR | TOR1AIP1 | Torsin A interacting protein 1 |
| AR | POGLUT1 | ||
| Bethlem myopathy /LGMDR22 | AR | COL6A1/2/3 | Collagen VI subunits A1, A2, or A3 |
| AR | LAMA2 | ||
| POMGNT2-related dystrophy/ LGMDR24 | AR | POMGNT2 | Protein O-linked mannose beta 1,4-N-acetyl- glucosaminyltransferase 2 |
| AR | POPDC3 | ||
| NA / LGMDR27 | AR | JAG2 | Jagged2 |
TABLE 460-5 Hereditary Distal Myopathies/Dystrophies DISORDER Welander Udd Markesbery-Griggs GNE myopathy (Nonaka…¶
Harrison's 22e, p.3640
| DISORDER | INHERITANCE | GENE | AFFECTED PROTEIN |
|---|---|---|---|
| Welander | AD | TIA1 | T-cell restricted intracellular antigen |
| AD | TTN | ||
| Markesbery-Griggs | AD | LDB3 | ZASP |
| AR | GNE | ||
| Miyoshi 1 | AR | DYSF | Dysferlin |
| AR | ANO5 | ||
| Laing | AD | MYH7 | Myosin heavy chain 7 |
| AD | FLNC | ||
| Distal myopathy with vocal cord and pharyngeal weakness (VCPDM) |
AD | MTR3 | Matrin 3 |
| AD | KLH9 | ||
| ADSSL myopathy | AR | ADSSL | Adenylosuccinate synthase |
| AD | PLIN4 |
TABLE 460-6 Myofibrillary Myopathies¶
Harrison's 22e, p.3640
| MYOFIBRILLAR MYOPATHY | INHERITANCE | GENE | AFFECTED PROTEIN |
|---|---|---|---|
| MFM1 | AD/AR | DES | Desmin |
| AD | CRYAB | ||
| MFM3 | AD | MYOT | Myotolin |
| AD | LDP3 | ||
| MFM5 | AD | FLNC | Filamin C |
| AD | BAG3 | ||
| MFM7 | AD | KY | Kyphoscoliosis peptidase |
| AD | PYROXD1 | ||
| MFM9 | AD | TTN | Titin |
| AD | SVIL | ||
| MFM11 | AD | UNC45B | UNC45 myosin chaperone B |
| AD | MYL2 |
TABLE 460-7 Multisystem Proteinopathies¶
Harrison's 22e, p.3644
| MULTISYSTEM PROTEINOPATHY |
INHERITANCE | GENE | AFFECTED PROTEIN |
|---|---|---|---|
| MSP1 / IBMPFD1 | AD | VCP | Valosin-containing protein |
| AD | HNRPA2B1 | ||
| MSP3 / IBMPFD3 | AD | HNRNPA1 | HNRNPA1 |
| AD | SQTM1 | ||
| MSP5 | AD | MTR3 | Matrin 3 |
TABLE 460-8 Drug-Induced Myopathies DRUGS Lipid-lowering agents¶
Harrison's 22e, p.3648
| DRUGS | MAJOR TOXIC REACTION |
|---|---|
| Lipid-lowering agents HMG-CoA reductase inhibitors Fibric acid derivatives Niacin (nicotinic acid) |
Drugs belonging to all three of the major classes of lipid-lowering agents can produce a spectrum of toxicity: asymptomatic serum creatine kinase elevation, myalgias, exercise-induced pain, rhabdomyolysis, and myoglobinuria. |
| Nondepolarizing neuromuscular blocking agents |
Acute quadriplegic myopathy can occur with or without concomitant glucocorticoids. |
| Drugs of abuse Alcohol Amphetamines Cocaine Heroin Phencyclidine Meperidine |
All drugs in this group can lead to widespread muscle breakdown, rhabdomyolysis, and myoglobinuria. Local injections cause muscle necrosis, skin induration, and limb contractures. |
| Amphophilic cationic drugs Amiodarone Chloroquine Hydroxychloroquine |
All amphophilic drugs have the potential to produce painless, proximal weakness associated with necrosis and autophagic vacuoles in the muscle biopsy. |