What is muscular atrophy in children, including its definition, classification, etiology, pathophysiology, types, clinical features, diagnosis, management, and prognosis?

Muscular Atrophy in Children: Comprehensive Exam-Oriented Review

Definition and Classification

Muscular atrophy in children is defined as the pathological reduction in muscle mass and strength characterized by myofiber shrinkage, net loss of cytoplasm and organelles, and overall protein degradation, resulting from diverse pathophysiologic states including neurogenic, myogenic, disuse, metabolic, and genetic causes 1.

Primary Classification System

Muscle atrophy is categorized into three main pathophysiologic subtypes 2:

• Neurogenic atrophy: Results from damage to the nerve innervating muscle (e.g., spinal muscular atrophy, peripheral neuropathies) 2
• Myogenic atrophy: Primary muscle disease causing intrinsic muscle fiber degeneration (e.g., muscular dystrophies, congenital myopathies) 3
• Disuse/physiologic atrophy: Caused by underuse of skeletal muscle from immobilization or reduced physical activity 2

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Etiology and Causes

Neurogenic Causes

Anterior horn cell disease represents the most common lethal autosomal-recessive genetic disorder in infants, with progressive loss of motor neurons through apoptotic mechanisms 4:

• Spinal muscular atrophy (SMA) types 0-4 5, 4
• Poliomyelitis and post-polio syndrome 2
• Spinal cord injury with tethered cord syndrome 3

Peripheral neuropathies causing denervation atrophy 1:

• Charcot-Marie-Tooth disease (may be misdiagnosed when muscle atrophy presents with "saber shins") 3
• Guillain-Barré syndrome 2
• Hereditary motor and sensory neuropathies 2

Myogenic Causes

Muscular dystrophies with characteristic reduction or absence of dystrophin, degenerating and regenerating muscle fibers, and replacement of muscle with fat or connective tissue 3:

• Duchenne and Becker muscular dystrophy (dystrophin gene mutations) 3
• Limb-girdle muscular dystrophies (LGMD) - including sarcoglycan, calpain, dysferlin, and lamin A/C mutations 3
• Myotonic dystrophy type 1 (DM1) - CTG repeat expansion in DMPK gene 3
• Myotonic dystrophy type 2 (DM2) - CCTG repeat expansion in CNBP gene 3

Congenital myopathies with specific morphological abnormalities on muscle biopsy 3:

• Nemaline myopathy (rods) - most commonly RYR1 mutations 3
• Central core disease (cores) 3
• Centronuclear-myotubular myopathy (central nuclei) 3
• Congenital fiber type disproportion 3

Myofibrillar myopathies with myofibril disruption beginning at Z-disk 3:

• DES, MYOT, LDB3/ZASP, CRYAB, FLNC, BAG3 gene mutations 3
• Childhood-onset forms (DES, CRYAB, BAG3, FHL1) present with rapidly progressive disease and severe cardiomyopathy 3

Mitochondrial myopathies with subsarcolemmal and interfibrillar accumulation of mitochondria showing "ragged red fibers" on Gomori trichrome stain 3:

• Barth syndrome (BTHS) - X-linked TAZ gene mutation causing cardiolipin remodeling defects 3

Inflammatory myopathies (rare in children) 3:

• Juvenile dermatomyositis (JDM) - autoantibodies to p155/140 kDa protein found in 29% 3
• Juvenile polymyositis (rare, anti-SRP antibody described in African American girls) 3
• Necrotizing myopathy with anti-SRP antibody 3

Disuse and Immobilization

• Prolonged bed rest or immobilization 1, 2
• Casting or orthopedic immobilization 1
• Reduced physical activity from any chronic illness 2

Metabolic, Endocrine, and Nutritional Causes

Endocrine myopathies 3:

• Hypothyroidism 3, 6
• Hyperparathyroidism 3
• Cushing syndrome and prolonged corticosteroid use 7, 1

Metabolic causes 1, 8:

• Diabetes mellitus 1, 8
• Obesity 1
• Renal failure 8
• Hepatic dysfunction 8

Nutritional deficiencies 8:

• Severe malnutrition and cachexia 8
• Vitamin D deficiency 6

Genetic Causes

Autosomal recessive 5, 4:

• Spinal muscular atrophy (SMN1 gene mutations) 5, 4
• Limb-girdle muscular dystrophies (multiple genes) 3
• Congenital myopathies (RYR1 most common) 3

Autosomal dominant 3:

• Myotonic dystrophy type 1 and 2 3
• Myofibrillar myopathies (most forms) 3
• Some congenital myopathies 3

X-linked 3:

• Duchenne/Becker muscular dystrophy (dystrophin gene) 3
• Barth syndrome (TAZ gene) 3
• Some myofibrillar myopathies (FHL1 mutations) 3

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Pathophysiology: Cellular and Molecular Basis

Protein Degradation Pathways

Ubiquitin-proteasome system serves as the primary mechanism for protein degradation in muscle atrophy 2:

• Activated by multiple upstream signals including NF-κB pathway 2
• Results in net loss of cytoplasm, organelles, and overall protein content 1

Myofiber Changes

Structural alterations include 1:

• Shrinkage of myofibers with reduced cross-sectional area 1
• Changes in fiber types and myosin isoforms 1
• Fast-to-slow or slow-to-fast fiber-type shifts depending on the pathological state 1

Neurogenic Mechanisms

Motor neuron loss through apoptosis in spinal muscular atrophy 4:

• Progressive degeneration of anterior horn cells 4
• Loss of neurotrophic support to muscle fibers 4
• Denervation-induced muscle fiber atrophy 1, 2

Myogenic Mechanisms

Dystrophin deficiency in muscular dystrophies 3:

• Reduction or absence of dystrophin protein 3
• Degenerating and regenerating muscle fibers 3
• Progressive replacement of muscle with fat and connective tissue 3
• Possible invasion of muscle fibers by mononuclear cells 3

Mitochondrial dysfunction 3:

• Impaired cardiolipin remodeling in Barth syndrome 3
• Defective mitochondrial respiratory chain function 3
• Accumulation of abnormal mitochondria 3

Myofibril disruption in myofibrillar myopathies 3:

• Dissolution beginning at sarcomeric Z-disk 3
• Abnormal accumulation of myofibrillar degradation products 3
• Ectopic expression and aggregation of multiple proteins 3

Tethered Cord Pathophysiology

Metabolic failure from spinal cord stretching 3:

• Physical stretching leads to impaired blood flow 3
• Diminished oxidative metabolism and glucose utilization 3
• Metabolic failure at mitochondrial respiratory chain level 3
• Severity and reversibility correlate with chronicity of tethering 3

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Types of Muscular Atrophy in Children

Spinal Muscular Atrophy (SMA)

SMA is the most common autosomal-recessive genetic disorder lethal to infants, caused by mutations in SMN1 gene resulting in loss of motor neurons and progressive muscle weakness 5, 4.

SMA Type 0 (Prenatal/Neonatal Onset)

• Onset in utero or immediately at birth 5
• Severe generalized weakness and hypotonia 5
• Respiratory failure within first weeks of life 5
• Worst prognosis of all SMA types 5

SMA Type 1 (Werdnig-Hoffmann Disease)

• Onset before 6 months of age 5, 4
• Never achieve ability to sit independently 5
• Severe hypotonia ("floppy infant") 5, 4
• Respiratory failure typically within first months of life 5
• Progressive muscle weakness with preserved cognition 4

SMA Type 2 (Intermediate)

• Onset between 6-18 months of age 5
• Achieve sitting but never walk independently 5
• Progressive proximal muscle weakness 5
• Survival into adolescence or adulthood with supportive care 5

SMA Type 3 (Kugelberg-Welander Disease)

• Onset after 18 months of age 5
• Achieve independent ambulation initially 5
• Slow rate of progression 5
• May lose ambulation in adolescence or adulthood 5

SMA Type 4 (Adult-Onset)

• Onset in adulthood (typically after age 30) 5
• Mild, slowly progressive weakness 5
• Normal life expectancy with minimal disability 5

Muscular Dystrophies

Duchenne Muscular Dystrophy (DMD)

Dystrophin gene mutations causing absence of dystrophin protein 3:

• X-linked recessive inheritance affecting males 3
• Onset typically 2-5 years of age 3
• Progressive proximal muscle weakness starting in lower extremities 3
• Significantly elevated creatine kinase levels (10-100x normal) 9
• Loss of ambulation by age 12-13 years without treatment 3
• Cardiac and respiratory complications 3

Becker Muscular Dystrophy (BMD)

• Dystrophin gene mutations with reduced but partially functional dystrophin 3
• Later onset and slower progression than DMD 3
• Ambulation typically preserved into adulthood 3

Limb-Girdle Muscular Dystrophies (LGMD)

Heterogeneous group with variable cardiac involvement depending on genetic subtype 3:

• High cardiac risk: Lamin A/C and sarcoglycan mutations 3
• Low cardiac risk: Calpain and dysferlin mutations 3
• Atrial and ventricular arrhythmias, heart block, cardiomyopathy (dilated or hypertrophic) 3
• Onset ranges from childhood to adulthood 3
• Progressive proximal muscle weakness 3

Myotonic Dystrophy Type 1 (DM1)

CTG repeat expansion in DMPK gene with genetic anticipation 3:

• Longer repeat expansion correlates with earlier onset and increased severity 3
• Progressive facial, neck, and distal limb muscle weakness 3
• Myotonia (delayed muscle relaxation) 3
• Multisystem involvement: cataracts, neuropsychiatric deficits, endocrine abnormalities 3
• Cardiac manifestations in ~80%: progressive conduction defects, tachyarrhythmias 3
• Congenital form exists with severe neonatal presentation 3

Myotonic Dystrophy Type 2 (DM2)

CCTG repeat expansion in CNBP gene without genetic anticipation 3:

• Onset 20-70 years, no congenital form 3
• More favorable clinical course than DM1 3
• Cardiac problems less severe (10-20%): first-degree AV block, bundle-branch block 3

Congenital Myopathies

Genetic muscle disorders characterized by hypotonia and weakness from birth with static or slowly progressive course 3.

Clinical Features Common to Congenital Myopathies

• Prominent facial weakness with or without ptosis 3
• Generalized hypotonic posture with hyporeflexia 3
• Poor muscle bulk 3
• Proximal muscle weakness 3
• Respiratory and bulbar muscle dysfunction 3
• Relatively normal cognitive abilities and sensation 3

Nemaline Myopathy

• Presence of rod bodies on muscle biopsy 3
• RYR1 mutations most common (prevalence ~1 in 90,000) 3
• Severity ranges from neonatal life-threatening weakness to subtle proximal weakness 3
• Cardiac involvement rare: transient HF in neonates, occasional LV dysfunction 3

Central Core Disease

• Core structures on muscle biopsy 3
• RYR1 mutations 3
• Typically milder phenotype 3

Centronuclear-Myotubular Myopathy

• Central nuclei on muscle biopsy 3
• Variable severity 3

Congenital Fiber Type Disproportion

• Selective atrophy of type I fibers 3
• Multiple genetic causes 3

Myofibrillar Myopathies

Myofibril disruption beginning at Z-disk with abnormal protein aggregation 3:

Adult-Onset Forms (Most Common)

• Onset 30-50 years (range 7-77 years) 3
• Slowly progressive distal to proximal lower extremity weakness 3
• Eventual involvement of upper extremities, trunk, facial, respiratory muscles 3
• Peripheral neuropathy in 15-30% 3
• Cardiac conduction defects increasing sudden death risk 3

Childhood-Onset Forms

Rapidly progressive with severe cardiac involvement 3:

• DES, CRYAB, BAG3, FHL1 mutations 3
• Debilitating contractures 3
• Severe cardiomyopathy (dilated, hypertrophic, or restrictive) sometimes preceding skeletal muscle involvement 3
• Sinus node dysfunction, AV block, tachycardias, HF, sudden death 3

Mitochondrial Myopathies

Barth Syndrome (BTHS)

X-linked recessive TAZ gene mutation affecting cardiolipin remodeling 3:

• Incidence 1 in 140,000 to 1 in 670,000 births 3
• Dilated cardiomyopathy with left ventricular noncompaction 3
• Neutropenia (>66% of cases) with associated infections 3
• Nonprogressive skeletal myopathy 3
• Prepubertal growth restriction 3
• Cognitive impairments and typical facial features 3

Inflammatory Myopathies (Rare in Children)

Juvenile Dermatomyositis (JDM)

Autoantibodies less common than adults; p155/140 kDa protein in 29% 3:

• Anti-Jo-1 antibodies rare (2/99 in one study) 3
• Anti-p140 kDa protein associated with calcinosis (OR 7.0) 3
• Classic cutaneous features when anti-Mi2 present: Gottron papules, heliotrope rash, shawl sign 3
• Proximal muscle weakness with elevated muscle enzymes 3

Juvenile Polymyositis (Very Rare)

• Anti-SRP antibody described in African American girls 3
• Necrotizing myopathy, acute onset 3
• Dilated cardiomyopathy 3
• Poor response to standard immunosuppression 3

Central Causes (Upper Motor Neuron Lesions)

Tethered Cord Syndrome

Clinical deterioration from spinal cord tethering due to dysraphic malformations 3:

• Myelomeningocele (MMC) - most common open dysraphic malformation 3
• Dermal sinus tracts from failed dysjunction 3
• Persistent anatomic connection between neuroectoderm and cutaneous ectoderm 3

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Clinical Features

Age-Wise Presentation

Neonatal Period (0-1 Month)

Severe hypotonia ("floppy infant") with respiratory distress 3, 5:

• SMA type 0 and type 1 5
• Severe congenital myopathies 3
• Congenital muscular dystrophies 3
• Barth syndrome with dilated cardiomyopathy 3

Key distinguishing features 3:

• Prominent facial weakness with ptosis suggests congenital myopathy 3
• Preserved cognition and sensation in congenital myopathy vs. potential CNS involvement in other causes 3

Infancy (1-12 Months)

Progressive weakness with motor developmental delay 9, 5:

• SMA type 1 (onset <6 months, never sit) 5
• SMA type 2 (onset 6-18 months, sit but never walk) 5
• Infantile-onset muscular dystrophies 3
• Congenital myopathies with later presentation 3

Early Childhood (1-5 Years)

Proximal muscle weakness with motor regression 3, 9:

• Duchenne muscular dystrophy (onset 2-5 years) 3
• SMA type 3 (onset >18 months) 5
• Limb-girdle muscular dystrophies 3

School Age and Adolescence

Progressive weakness with loss of ambulation 3, 5:

• DMD loses ambulation by 12-13 years 3
• SMA type 3 may lose ambulation in adolescence 5
• Myotonic dystrophy manifestations 3

Adulthood

Mild, slowly progressive weakness 3, 5:

• SMA type 4 (onset after age 30) 5
• Adult-onset myofibrillar myopathies (onset 30-50 years) 3
• Myotonic dystrophy type 2 (onset 20-70 years) 3

Pattern of Muscle Involvement

Proximal Predominant Weakness

Most common pattern in childhood muscular atrophy 3, 6:

• Duchenne and Becker muscular dystrophy 3
• Limb-girdle muscular dystrophies 3
• Spinal muscular atrophy 5, 4
• Congenital myopathies 3
• Inflammatory myopathies 3

Clinical manifestations 3:

• Difficulty rising from floor (Gowers sign) 3
• Difficulty climbing stairs 3
• Waddling gait 3
• Lumbar lordosis 3

Distal Predominant Weakness

Less common in children 3:

• Myotonic dystrophy type 1 (distal limb weakness) 3
• Myofibrillar myopathies (distal to proximal progression) 3
• Some peripheral neuropathies 3, 2

Facial and Bulbar Involvement

Prominent in congenital myopathies 3:

• Facial weakness with or without ptosis 3
• Bulbar muscle dysfunction 3
• Respiratory muscle involvement 3

Also seen in 3:

• Myotonic dystrophy (facial and neck weakness) 3
• Severe SMA types 5

Gowers Sign

Classic maneuver indicating proximal lower extremity weakness 3:

• Child uses hands to "climb up" their own legs when rising from floor 3
• Pathognomonic for proximal muscle weakness 3
• Most commonly associated with Duchenne muscular dystrophy 3
• Also present in other proximal myopathies and SMA 3, 5

Hypotonia

Generalized decreased muscle tone 3, 5:

• "Floppy infant" appearance in severe cases 5
• Generalized hypotonic posture in congenital myopathies 3
• Severe hypotonia in SMA type 1 5

Distinguishing features 3:

• Hypotonia with hyporeflexia suggests congenital myopathy or SMA 3, 5
• Hypotonia with preserved reflexes less common 3

Reflex Changes

Diminished or Absent Reflexes

Characteristic of neurogenic atrophy 9, 5:

• Spinal muscular atrophy (diminished or absent reflexes) 9
• Peripheral neuropathies 2
• Congenital myopathies (hyporeflexia) 3

Preserved Reflexes

May be seen in 3:

• Some congenital myopathies 3
• Early stages of muscular dystrophies 3
• Myogenic causes before severe atrophy 3

Associated Features

Cardiac Involvement

Variable by condition 3:

• Myotonic dystrophy type 1: conduction defects, tachyarrhythmias in ~80% 3
• Limb-girdle MD: very common in lamin A/C and sarcoglycan disease 3
• Myofibrillar myopathies: conduction defects, sudden death risk 3
• Barth syndrome: dilated cardiomyopathy with LVNC 3
• Congenital myopathies: rare cardiac involvement 3

Respiratory Complications

Major cause of morbidity and mortality 3, 5:

• SMA type 1: respiratory failure within first months 5
• Congenital myopathies: respiratory muscle dysfunction 3
• Myotonic dystrophy: respiratory complications as primary cause of death 3

Skeletal Deformities

Progressive with chronic tethering or weakness 3:

• Scoliosis and exaggerated lumbosacral lordosis 3
• Orthopedic foot deformities 3
• Contractures (especially in myofibrillar myopathies) 3
• "Saber shins" mimicking Charcot-Marie-Tooth 3

Skin Changes

Diagnostic clues 3:

• Gottron papules, heliotrope rash, shawl sign in dermatomyositis 3
• Cutaneous markers overlying spinal dysraphism 3
• Thin, shiny, hairless skin with chronic denervation 3

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Differential Diagnosis with Distinguishing Points

Neurogenic vs. Myogenic Atrophy

Feature	Neurogenic	Myogenic
Reflexes	Diminished/absent [9,5]	Preserved initially [3]
CK levels	Normal or mildly elevated [9]	Significantly elevated (DMD: 10-100x) [9]
EMG pattern	Denervation potentials, fasciculations [3]	Polyphasic short-duration low-amplitude potentials [3,7]
Muscle biopsy	Grouped atrophy, fiber-type grouping [3]	Dystrophic changes, fiber degeneration [3]
Progression	Variable by type [5,4]	Progressive in dystrophies [3]

SMA vs. Congenital Myopathy

Feature	SMA	Congenital Myopathy
Reflexes	Diminished or absent [9]	Hyporeflexia or preserved [3]
Facial weakness	Variable [5]	Prominent with ptosis [3]
Cognition	Normal [4]	Normal [3]
Progression	Progressive motor neuron loss [4]	Static or slowly progressive [3]
Genetic testing	SMN1 deletion/mutation [5,4]	Multiple genes (RYR1 most common) [3]
Muscle biopsy	Denervation changes [4]	Specific structural abnormalities (rods, cores, etc.) [3]

DMD vs. SMA

Feature	Duchenne MD	Spinal Muscular Atrophy
Inheritance	X-linked recessive [3]	Autosomal recessive [5,4]
CK levels	Markedly elevated (10-100x) [9]	Normal or mildly elevated [9]
Reflexes	Preserved initially [3]	Diminished or absent [9]
Calf pseudohypertrophy	Present [3]	Absent [5]
Genetic testing	Dystrophin gene mutation [3]	SMN1 deletion/mutation [5,4]
Cardiac involvement	Common [3]	Rare [5]

Inflammatory Myopathy vs. Muscular Dystrophy

Feature	Inflammatory Myopathy	Muscular Dystrophy
Onset	Acute to subacute [3]	Gradual, progressive [3]
CK elevation	Variable, can be very high [3,7]	Consistently elevated [3,9]
Skin findings	Gottron papules, heliotrope rash [3]	Absent [3]
Autoantibodies	Present (though rare in children) [3]	Absent [3]
Muscle biopsy	Mononuclear cell infiltration [3,7]	Dystrophic changes, absent dystrophin [3]
Response to immunosuppression	Responsive (except anti-SRP) [3]	No response [3]
EMG	Myopathic with fibrillations [3,7]	Myopathic pattern [3]

Steroid Myopathy vs. Inflammatory Myopathy

Feature	Steroid Myopathy	Inflammatory Myopathy
CK levels	Low-normal [7]	Elevated [3,7]
EMG	Normal [7]	Polyphasic potentials with fibrillations [3,7]
Muscle biopsy	Type 2 fiber atrophy [7]	Mononuclear infiltration [3,7]
Autoantibodies	Negative [7]	May be positive [3]
Steroid history	Prolonged use [7,1]	Variable [3]

Mitochondrial Myopathy vs. Muscular Dystrophy

Feature	Mitochondrial Myopathy	Muscular Dystrophy
Muscle biopsy	Ragged red fibers on Gomori trichrome [3]	Dystrophic changes, absent dystrophin [3]
Systemic involvement	Multisystem (CNS, cardiac, endocrine) [3]	Primarily neuromuscular [3]
Inheritance	Maternal or nuclear [3]	X-linked, autosomal [3,5]
Lactate	Elevated [3]	Normal [3]

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Investigations

Creatine Kinase (CK) Levels

Primary screening test for muscle disease 7, 6:

Markedly Elevated (>10x Upper Limit Normal)

• Duchenne muscular dystrophy (10-100x normal) 9
• Acute inflammatory myopathy 3, 7
• Necrotizing myopathy with anti-SRP antibody 3
• Some limb-girdle muscular dystrophies 3

Action: If symptomatic with CK >10x ULN, discontinue statins or potentially offending medications immediately 6

Mildly Elevated (1-10x Upper Limit Normal)

• Spinal muscular atrophy 9
• Some congenital myopathies 3
• Becker muscular dystrophy 3
• Chronic inflammatory myopathies 3

Normal or Low-Normal

• Steroid myopathy 7
• Neurogenic atrophy 9
• Some congenital myopathies 3
• Advanced muscular dystrophy with muscle replacement by fat 3

Pitfall: Normal CK does not exclude muscle disease, particularly neurogenic causes or steroid myopathy 7, 9

Additional Muscle Enzymes

Comprehensive muscle enzyme panel 6:

• Aldolase 6
• Aspartate aminotransferase (AST) 6
• Alanine aminotransferase (ALT) 6
• Lactate dehydrogenase (LDH) 6

Serial measurements off steroids: Rising levels suggest inflammatory or dystrophic process rather than steroid myopathy 7

Electromyography (EMG) and Nerve Conduction Studies (NCS)

Two major indications 3, 7:

1. Confirm myopathic vs. neuropathic process 3, 7, 6
2. Target muscle for biopsy 3, 7

Myopathic Pattern

Polyphasic motor unit action potentials of short duration and low amplitude 3, 7:

• Increased insertional and spontaneous activity 3, 7
• Fibrillation potentials 3, 7
• Sharp waves 3, 7
• Repetitive discharges 3, 7

Seen in: Muscular dystrophies, inflammatory myopathies, congenital myopathies 3, 7

Neurogenic Pattern

Denervation potentials and fasciculations 3:

• Large amplitude, long duration motor units 3
• Reduced recruitment 3

Seen in: Spinal muscular atrophy, peripheral neuropathies 3, 2

Normal EMG/NCS

Strongly argues against active inflammatory myopathy 7:

• Suggests steroid myopathy 7
• May be seen in very early or mild disease 3

Pitfall: Normal EMG does not exclude muscle disease; muscle biopsy may still be needed 3, 7

Muscle Biopsy

Gold standard for confirming diagnosis and subclassification 3, 7, 6:

Technique

• Choose weak muscle demonstrated by EMG abnormalities 3, 7
• Biopsy opposite side muscle to avoid EMG artifact 3, 7
• Maximize diagnostic yield and reduce sampling error 3, 7

Muscular Dystrophy Findings

Reduction or absence of dystrophin 3:

• Degenerating and regenerating muscle fibers 3
• Replacement of muscle with fat or connective tissue 3
• May have mononuclear cell invasion 3

Genetic testing for dystrophin gene should accompany biopsy 3

Mitochondrial Myopathy Findings

Subsarcolemmal and interfibrillar accumulation of mitochondria 3:

• "Ragged red fibers" on Gomori trichrome stain 3
• Glycogen and neutral lipids against blue background 3
• Reduction or absence of cytochrome c oxidase 3

Inflammatory Myopathy Findings

Mononuclear cell infiltration 3, 7:

• Perivascular and endomysial inflammation 3
• Muscle fiber invasion by inflammatory cells 3, 7
• Perifascicular atrophy in dermatomyositis 3

Congenital Myopathy Findings

Specific morphological abnormalities 3:

• Rods (nemaline myopathy) 3
• Cores (central core disease) 3
• Central nuclei (centronuclear myopathy) 3
• Type I fiber atrophy (congenital fiber type disproportion) 3

Neurogenic Atrophy Findings

Grouped atrophy and fiber-type grouping 3:

• Denervation and reinnervation changes 4
• Angular atrophic fibers 4

Myofibrillar Myopathy Findings

Myofibril disruption beginning at Z-disk 3:

• Abnormal accumulation of myofibrillar degradation products 3
• Ectopic protein aggregation 3

Pitfall: No morphological feature consistently predicts specific gene mutation 3

Genetic Testing

Spinal Muscular Atrophy

SMN1 gene deletion or mutation 5, 4:

• Noninvasive diagnostic approach 4
• Confirms diagnosis without need for invasive testing 5, 4
• Enables newborn screening 5

Pitfall: Genetic testing has limitations; some cases may be missed 4

Muscular Dystrophies

Dystrophin gene testing 3:

• Essential for Duchenne and Becker MD diagnosis 3
• Deletion, duplication, or point mutation analysis 3

Limb-girdle MD gene panels 3:

• Multiple genes depending on clinical phenotype 3
• Guides cardiac screening and prognosis 3

Congenital Myopathies

RYR1 gene most common 3:

• Multiple other genes possible 3
• Genotype-phenotype correlations not straightforward 3

Myotonic Dystrophy

Repeat expansion testing 3:

• DM1: CTG repeat in DMPK gene 3
• DM2: CCTG repeat in CNBP gene 3
• Longer repeats correlate with severity in DM1 3

Myofibrillar Myopathies

Six traditional genes account for ~50% of cases 3:

• DES, MYOT, LDB3/ZASP, CRYAB, FLNC, BAG3 3
• Additional genes: FHL1, DNAJB6, TTN 3

Mitochondrial Myopathies

TAZ gene for Barth syndrome 3:

• X-linked inheritance 3
• Genotype does not predict phenotypic course 3

Autoantibody Testing

Myositis-specific antibodies (MSAs) 3, 6:

Anti-Synthetase Antibodies

• Anti-Jo-1 (most common in adults, rare in children) 3
• Anti-PL-7, PL-12, OJ, EJ, KS, Ha, Zo 3
• Associated with antisynthetase syndrome 3

Frequency in children: Only 2/52 children tested positive in one study 3

Anti-Mi2 Antibody

• Classic dermatomyositis skin features 3
• Gottron papules, heliotrope rash, shawl sign 3

Anti-SRP Antibody

• Necrotizing myopathy, acute onset 3
• Dilated cardiomyopathy 3
• Poor response to immunosuppression 3
• Rarely seen in children (described in African American girls) 3

Anti-p155/140 kDa Protein

• Found in 29% of JDM patients 3
• Anti-p140 associated with calcinosis (OR 7.0) 3
• Not associated with cancer in children (unlike adults) 3

Pitfall: Autoantibodies absent in 20-30% of inflammatory myopathy cases 7

Imaging

MRI of Proximal Muscles

STIR sequences to detect muscle edema and inflammation 7, 6:

• Active inflammatory myositis shows T2 hyperintensity and edema 7, 6
• Helps target muscle for biopsy 6
• Distinguishes active inflammation from chronic fatty replacement 7

Repeat MRI off steroids if initial diagnosis uncertain 7

Cardiac Imaging

Echocardiogram 3, 6:

• Screen for cardiomyopathy (dilated, hypertrophic, restrictive, LVNC) 3
• Assess ventricular function 3
• Particularly important in: myotonic dystrophy, LGMD, myofibrillar myopathies, Barth syndrome 3

Cardiac MRI for detailed assessment when indicated 3

Spinal Imaging

MRI spine for suspected tethered cord 3:

• Conus medullaris ending below middle third of L2 is radiographically tethered 3
• Identify dysraphic malformations 3
• Evaluate for dermal sinus tracts 3

Screening for Complications

Pulmonary Function Tests

Negative inspiratory force and vital capacity 7, 6:

• Screen for respiratory muscle weakness 7
• CO diffusion capacity for interstitial lung disease 6
• Particularly important with anti-synthetase antibodies 6

Cardiac Evaluation

Troponin, ECG, echocardiogram 7, 6:

• Exclude cardiac involvement in inflammatory myopathies 7, 6
• Screen for conduction defects and arrhythmias 3
• Required before anesthesia in NMD patients 3

Cardiac monitoring by experienced anesthesiologist for NMD patients at increased cardiac risk during surgery 3

Malignancy Screening

Adult dermatomyositis patients 6:

• Particularly with anti-TIF1-γ or anti-NXP2 antibodies 6
• Not applicable to children (p155/140 not associated with cancer in JDM) 3

Metabolic and Endocrine Screening

Screen for secondary causes 6:

• Thyroid function tests 3, 6
• Diabetes screening 6, 1
• Celiac disease screening 6
• Electrolyte panel 6
• Parathyroid hormone if indicated 3

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Management Approach

Supportive Care (Universal)

Respiratory Support

Proactive monitoring and intervention 3, 5:

• Serial pulmonary function testing 3, 7
• Non-invasive ventilation (BiPAP) for nocturnal hypoventilation 5
• Mechanical ventilation for respiratory failure 5
• Cough assist devices 5
• Aggressive treatment of respiratory infections 5

Critical for: SMA type 1, severe congenital myopathies, advanced muscular dystrophies 3, 5

Cardiac Management

Condition-specific monitoring and treatment 3:

• Regular ECG and echocardiogram surveillance 3
• Pacemaker for conduction defects 3
• Implantable cardioverter-defibrillator (ICD) for arrhythmia risk 3
• Heart failure management (ACE inhibitors, beta-blockers) 3
• Cardiac transplantation in severe cases 3

High-risk conditions: Myotonic dystrophy type 1, lamin A/C LGMD, myofibrillar myopathies, Barth syndrome 3

Nutritional Support

Optimize nutrition and prevent complications 5, 8:

• Gastrostomy tube for dysphagia or inadequate oral intake 5
• High-calorie supplementation for growth 5
• Prevent aspiration pneumonia 5
• Address malnutrition and cachexia 8

Orthopedic Management

Prevent and treat skeletal deformities 3, 5:

• Scoliosis monitoring and bracing 3, 5
• Surgical correction for severe scoliosis 3
• Contracture prevention with stretching and splinting 3, 5
• Orthotic devices for foot deformities 3

Multidisciplinary Care Team

Coordinate comprehensive care 3:

• Neurology/neuromuscular specialist 3
• Cardiology (HF specialist or electrophysiologist) 3
• Pulmonology 3
• Physical and occupational therapy 5
• Orthopedics 3
• Nutrition 5
• Genetics 5
• Palliative care when appropriate 5

Disease-Specific Treatment

Spinal Muscular Atrophy

Three FDA-approved disease-modifying therapies 5:

Nusinersen (Spinraza)

• Antisense oligonucleotide for SMN2 splicing modulation 5
• Intrathecal administration 5
• Significantly modifies natural course when initiated early 5

Onasemnogene abeparvovec (Zolgensma)

• SMN1 gene replacement by AAV9 gene therapy 5
• One-time intravenous infusion 5
• Approved for children <2 years 5

Risdiplam (Evrysdi)

• Oral SMN2 splicing modifier 5
• Daily oral administration 5

Newborn screening: Increasingly implemented to enable presymptomatic treatment 5

Limitation: Evidence often limited to specific age ranges and disease stages 5

Real-world data collection: Essential with standardized outcome measures 5

Duchenne Muscular Dystrophy

Corticosteroids 3:

• Prednisone or deflazacort 3
• Prolongs ambulation by 2-3 years 3
• Delays respiratory and cardiac complications 3

Exon-skipping therapies 3:

• Eteplirsen, golodirsen, viltolarsen, casimersen 3
• Mutation-specific (only for amenable deletions) 3

Gene therapy 3:

• Investigational micro-dystrophin gene therapy 3

Cardiac protection 3:

• ACE inhibitors or ARBs starting by age 10 3
• Beta-blockers for cardiomyopathy 3

Inflammatory Myopathies

Corticosteroids as first-line 3:

• High-dose prednisone or methylprednisolone 3
• Taper based on clinical response and CK levels 3

Steroid-sparing agents 3:

• Methotrexate 3
• Azathioprine 3
• Mycophenolate mofetil 3

Intravenous immunoglobulin (IVIG) 3:

• For refractory cases 3
• Particularly effective in JDM 3

Biologic agents 3:

• Rituximab for refractory disease 3

Exception: Anti-SRP myopathy has poor response to standard immunosuppression 3

Tethered Cord Syndrome

Surgical detethering 3:

• Release anatomic connection between neuroectoderm and cutaneous ectoderm 3
• Prevents progressive neurological deterioration 3
• Reversibility of metabolic disturbances correlates with chronicity 3

Timing: Early intervention before irreversible changes 3

Barth Syndrome

Supportive cardiac management 3:

• Heart failure therapy 3
• Arrhythmia management 3
• Cardiac transplantation in severe cases 3

Infection prevention 3:

• Prophylactic antibiotics for neutropenia 3
• G-CSF for severe neutropenia 3

Myotonic Dystrophy

Symptomatic management 3:

• Mexiletine or other sodium channel blockers for myotonia 3
• Cardiac pacemaker for conduction defects 3
• ICD for arrhythmia risk 3

No disease-modifying therapy available 3

Congenital Myopathies

Primarily supportive care 3:

• Respiratory support 3
• Nutritional support 3
• Orthopedic management 3

Rare cardiac complications require monitoring 3

Steroid Myopathy

Discontinue or reduce corticosteroids 7, 1:

• Taper steroids if clinically feasible 7
• Switch to alternate-day dosing 1
• Use lowest effective dose 1

Recovery expected with steroid reduction 7

Physiotherapy and Rehabilitation

Essential component of comprehensive care 5:

Physical Therapy

• Maintain range of motion 5
• Prevent contractures 5
• Strengthen unaffected muscles 5
• Gait training and mobility aids 5

Caution: Avoid overwork in some conditions 5

Occupational Therapy

• Activities of daily living training 5
• Adaptive equipment 5
• Energy conservation techniques 5

Respiratory Therapy

• Breathing exercises 5
• Cough assistance techniques 5
• Airway clearance 5

Aquatic Therapy

• Low-impact exercise 5
• Maintains strength without overwork 5

Gene Therapy (Where Applicable)

Emerging treatment modality 5:

Currently Available

• Onasemnogene abeparvovec (Zolgensma) for SMA 5
• One-time AAV9-mediated SMN1 gene replacement 5

Investigational

• Micro-dystrophin gene therapy for DMD 3
• Other gene replacement strategies in development 5

Limitation: Age restrictions and limited long-term data 5

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Prognosis (Condition-Wise)

Spinal Muscular Atrophy

Without Treatment

• Type 0: Death within weeks 5
• Type 1: Death or ventilator dependence by age 2 years 5, 4
• Type 2: Survival into adolescence or adulthood with supportive care 5
• Type 3: Near-normal life expectancy with variable disability 5
• Type 4: Normal life expectancy with minimal disability 5

With Disease-Modifying Therapy

Significantly improved outcomes when initiated early 5:

• Presymptomatic treatment can prevent motor neuron loss 5
• Symptomatic treatment slows progression 5
• Long-term outcomes still being defined 5

Duchenne Muscular Dystrophy

Without Treatment

• Loss of ambulation by age 10-12 years 3
• Death from cardiorespiratory failure in late teens to early 20s 3

With Comprehensive Care

• Ambulation prolonged to age 12-15 years with corticosteroids 3
• Survival into 30s-40s with respiratory and cardiac support 3
• Quality of life significantly improved 3

Becker Muscular Dystrophy

• Later onset and slower progression than DMD 3
• Ambulation typically preserved into adulthood 3
• Near-normal life expectancy with cardiac monitoring 3

Limb-Girdle Muscular Dystrophies

Variable by genetic subtype 3:

• Lamin A/C and sarcoglycan: High cardiac risk, sudden death possible 3
• Calpain and dysferlin: Lower cardiac risk, slower progression 3
• Wheelchair dependence variable (10-30 years after onset) 3

Myotonic Dystrophy

Type 1

• Respiratory complications and cardiac arrhythmias are primary causes of death 3
• Congenital form has severe prognosis 3
• Adult-onset form has variable progression 3

Type 2

• More favorable clinical course than DM1 3
• Cardiac problems less severe (10-20%) 3
• Near-normal life expectancy 3

Congenital Myopathies

• Static or slowly progressive course 3
• Severity ranges from neonatal life-threatening to subtle weakness 3
• Cardiac involvement rare but can be life-threatening when present 3
• Cognitive abilities typically preserved 3

Myofibrillar Myopathies

Adult-Onset

• Slowly progressive over decades 3
• Cardiac conduction defects increase sudden death risk 3
• Wheelchair dependence in later life 3

Childhood-Onset

• Rapidly progressive 3
• Severe cardiomyopathy often preceding skeletal muscle involvement 3
• Cardiorespiratory failure 3
• Poor prognosis 3

Barth Syndrome

• Nonprogressive skeletal myopathy 3
• Cardiac complications determine prognosis 3
• Neutropenia-related infections (pneumonia 28%, sepsis 10%) 3
• Cardiac transplantation may be required 3

Inflammatory Myopathies

Juvenile Dermatomyositis

• Generally good response to immunosuppression 3
• Calcinosis in ~30% (associated with anti-p140) 3
• Not associated with malignancy in children 3

Anti-SRP Myopathy

• Poor response to standard immunosuppression 3
• Dilated cardiomyopathy 3
• Guarded prognosis 3

Tethered Cord Syndrome

• Progressive neurological deterioration if untreated 3
• Surgical detethering can prevent progression 3
• Reversibility depends on chronicity of tethering 3
• Early intervention improves outcomes 3

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Complications

Respiratory Complications

Leading cause of morbidity and mortality 3, 5:

• Respiratory failure requiring ventilation 5
• Recurrent pneumonia and aspiration 5
• Nocturnal hypoventilation 5
• Restrictive lung disease 3, 5

High-risk conditions: SMA type 1, severe congenital myopathies, advanced DMD, myotonic dystrophy 3, 5

Cardiac Complications

Variable by condition 3:

• Dilated cardiomyopathy 3
• Hypertrophic cardiomyopathy 3
• Restrictive cardiomyopathy 3
• Left ventricular noncompaction 3
• Progressive conduction defects (AV block, bundle-branch block) 3
• Atrial and ventricular arrhythmias 3
• Sudden cardiac death 3

Highest risk: Myotonic dystrophy type 1 (~80%), lamin A/C LGMD, myofibrillar myopathies, Barth syndrome 3

Skeletal Complications

Progressive deformities 3, 5:

• Scoliosis (may require surgical correction) 3, 5
• Contractures (especially in myofibrillar myopathies) 3, 5
• Foot deformities 3
• Hip dislocation 5
• Pathologic fractures 5

Nutritional and Gastrointestinal

• Dysphagia with aspiration risk 5
• Failure to thrive 5
• Gastroesophageal reflux 5
• Constipation 3, 5

Neurological Complications

Tethered cord syndrome 3:

• Progressive sensorimotor deficits 3
• Bladder and bowel dysfunction 3
• Pain (back, leg, groin, genitals, perianal) 3
• Gait disturbances 3

Myotonic dystrophy 3:

• Neuropsychiatric deficits 3
• Cognitive impairment 3

Infectious Complications

Barth syndrome 3:

• Mouth ulcers (60%) 3
• Pneumonia (28%) 3
• Bacteremia/sepsis (10%) 3

General 5:

• Recurrent respiratory infections 5
• Urinary tract infections (with neurogenic bladder) 3

Endocrine and Metabolic

Myotonic dystrophy 3:

• Endocrine/metabolic abnormalities 3
• Diabetes mellitus 3

Barth syndrome 3:

• Prepubertal growth restriction 3

Ophthalmologic

• Cataracts (myotonic dystrophy) 3
• Ptosis (congenital myopathies) 3

Psychosocial

• Depression and anxiety 5
• Social isolation 5
• Educational challenges 5
• Reduced quality of life 8

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Red Flags and Important Exam Pearls

Red Flags Requiring Urgent Evaluation

Respiratory Distress

• Neonatal hypotonia with respiratory failure: Consider SMA type 0/1, severe congenital myopathy 3, 5
• Progressive respiratory decline: Urgent pulmonary function testing and ventilatory support 5
• Recurrent aspiration pneumonia: Evaluate for dysphagia, consider gastrostomy 5

Cardiac Red Flags

• Syncope or palpitations: Urgent ECG and cardiac monitoring for arrhythmias 3
• New-onset heart failure symptoms: Echocardiogram and cardiology consultation 3
• Family history of sudden death: High-risk cardiac screening 3

Conditions requiring cardiac evaluation before anesthesia: All NMDs at risk for cardiac involvement 3

Neurological Red Flags

• Acute weakness after back trauma: Consider tethered cord syndrome 3
• Bladder/bowel dysfunction with weakness: Urgent spinal imaging 3
• Progressive scoliosis with neurological symptoms: Evaluate for tethered cord 3

Infectious Red Flags

• Recurrent severe infections with myopathy: Consider Barth syndrome (neutropenia) 3
• Fever with muscle weakness: Rule out infection, consider inflammatory myopathy 3

Key Exam Pearls

Clinical Examination Pearls

• Gowers sign: Pathognomonic for proximal muscle weakness, most commonly DMD 3
• Calf pseudohypertrophy: Highly suggestive of Duchenne muscular dystrophy 3
• "Saber shins" with muscle atrophy: May mimic Charcot-Marie-Tooth but consider tethered cord 3
• Prominent facial weakness with ptosis: Think congenital myopathy 3
• Gottron papules and heliotrope rash: Diagnostic of dermatomyositis 3
• Myotonia (delayed muscle relaxation): Pathognomonic for myotonic dystrophy 3

Laboratory Pearls

• CK 10-100x normal in young boy: Duchenne muscular dystrophy until proven otherwise 9
• Normal or mildly elevated CK with weakness: Consider SMA, neurogenic causes, or steroid myopathy 7, 9
• Low-normal CK with proximal weakness on steroids: Steroid myopathy, not inflammatory myopathy 7
• Normal EMG with proximal weakness: Strongly argues against active inflammatory myopathy 7

Genetic Pearls

• X-linked inheritance with progressive weakness: Consider DMD/BMD or X-linked myofibrillar myopathy 3
• Autosomal recessive with motor neuron loss: Spinal muscular atrophy 5, 4
• Genetic anticipation (worsening in successive generations): Myotonic dystrophy type 1 3
• No genetic anticipation: Myotonic dystrophy type 2 3

Cardiac Pearls

• ~80% cardiac involvement: Myotonic dystrophy type 1 3
• Cardiac involvement may precede skeletal myopathy: Childhood-onset myofibrillar myopathies 3
• Dilated cardiomyopathy with LVNC: Consider Barth syndrome 3
• Very common cardiac involvement: Lamin A/C and sarcoglycan LGMD 3
• Infrequent cardiac involvement: Calpain and dysferlin LGMD 3

Biopsy Pearls

• Ragged red fibers on Gomori trichrome: Mitochondrial myopathy 3
• Absent dystrophin: Duchenne muscular dystrophy 3
• Rods, cores, or central nuclei: Congenital myopathy 3
• Mononuclear cell infiltration: Inflammatory myopathy 3, 7
• Myofibril disruption at Z-disk: Myofibrillar myopathy 3

Autoantibody Pearls

• Anti-Jo-1 in child: Rare but associated with arthritis and ILD 3
• Anti-p155/140 in child: Not associated with cancer (unlike adults) 3
• Anti-p140 in JDM: Associated with calcinosis (OR 7.0) 3
• Anti-SRP: Necrotizing myopathy with poor prognosis and treatment response 3
• Negative autoantibodies: Does not exclude inflammatory myopathy (20-30% seronegative) 7

Prognosis Pearls

• SMA type 1 without treatment: Death or ventilator dependence by age 2 5, 4
• DMD without treatment: Loss of ambulation by age 10-12, death in late teens to early 20s 3
• Early treatment in SMA: Can prevent motor neuron loss and significantly modify course 5
• Corticosteroids in DMD: Prolong ambulation by 2-3 years 3

Common Pitfalls to Avoid

Diagnostic Pitfalls

• Assuming normal CK excludes muscle disease: Neurogenic causes and steroid myopathy have normal CK 7, 9
• Assuming normal EMG excludes myopathy: Steroid myopathy and early disease may have normal EMG 7
• Missing cardiac involvement: Many NMDs have significant cardiac complications requiring screening 3
• Attributing weakness to "just being out of shape": May delay diagnosis of progressive NMD 5
• Misdiagnosing tethered cord as Charcot-Marie-Tooth: Look for "saber shins" and spinal cutaneous markers 3

Treatment Pitfalls

• Delaying respiratory support: Proactive approach improves outcomes 5
• Not screening for cardiac complications: Sudden death preventable with monitoring and intervention 3
• Assuming all myopathies respond to steroids: Anti-SRP myopathy has poor response 3
• Continuing steroids in steroid myopathy: Taper or discontinue to allow recovery 7, 1
• Missing treatment window in SMA: Early/presymptomatic treatment most effective 5

Prognostic Pitfalls

• Assuming all congenital myopathies are progressive: Most are static or slowly progressive 3
• Assuming all muscular dystrophies have poor prognosis: Becker MD has near-normal life expectancy 3
• Underestimating impact of supportive care: Comprehensive care significantly improves survival and quality of life 3, 5

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Comparison Tables

SMA Types Comparison

Feature	Type 0	Type 1	Type 2	Type 3	Type 4
Onset	Prenatal/birth [5]	<6 months [5]	6-18 months [5]	>18 months [5]	Adulthood [5]
Motor milestones	None [5]	Never sit [5]	Sit, never walk [5]	Walk initially [5]	Walk [5]
Respiratory	Failure in weeks [5]	Failure in months [5]	Variable support [5]	Late involvement [5]	Minimal [5]
Prognosis (untreated)	Death in weeks [5]	Death by age 2 [5,4]	Survive to adulthood [5]	Near-normal lifespan [5]	Normal lifespan [5]
Treatment response	Limited [5]	Significant if early [5]	Good [5]	Good [5]	Good [5]

Muscular Dystrophy Comparison

Feature	Duchenne	Becker	LGMD	Myotonic DM1
Inheritance	X-linked [3]	X-linked [3]	Variable [3]	Autosomal dominant [3]
Gene	Dystrophin [3]	Dystrophin [3]	Multiple [3]	DMPK [3]
Onset	2-5 years [3]	5-15 years [3]	Variable [3]	Variable [3]
CK	10-100x normal [9]	5-50x normal [3]	Variable [3]	Mildly elevated [3]
Cardiac	Common [3]	Common [3]	Variable by type [3]	~80% [3]
Ambulation loss	Age 10-12 [3]	Adulthood [3]	Variable [3]	Variable [3]
Prognosis	Death 20s-30s [3]	Near-normal [3]	Variable [3]	Variable [3]

Congenital Myopathy vs. SMA vs. DMD

Feature	Congenital Myopathy	SMA	DMD
Onset	Birth [3]	<6 months (type 1) [5]	2-5 years [3]
Facial weakness	Prominent [3]	Variable [5]	Minimal [3]
Reflexes	Hyporeflexia [3]	Diminished/absent [9]	Preserved initially [3]
CK	Normal/mild elevation [3]	Normal/mild elevation [9]	10-100x normal [9]
Progression	Static/slow [3]	Progressive [4]	Progressive [3]
Cognition	Normal [3]	Normal [4]	Normal [3]
Cardiac	Rare [3]	Rare [5]	Common [3]
Biopsy	Structural abnormalities [3]	Denervation [4]	Absent dystrophin [3]

Inflammatory vs. Non-Inflammatory Myopathy

Feature	Inflammatory	Muscular Dystrophy	Steroid Myopathy
Onset	Acute/subacute [3]	Gradual [3]	Gradual [7]
CK	Variable, can be high [3,7]	Consistently elevated [3,9]	Low-normal [7]
EMG	Myopathic with fibrillations [3,7]	Myopathic [3]	Normal [7]
Autoantibodies	May be positive [3]	Negative [3]	Negative [7]
Skin findings	Gottron, heliotrope [3]	None [3]	None [7]
Biopsy	Inflammation [3,7]	Dystrophic changes [3]	Type 2 fiber atrophy [7]
Treatment	Immunosuppression [3]	Supportive [3]	Reduce steroids [7,1]

Cardiac Involvement by Condition

Condition	Frequency	Type	Risk
Myotonic DM1	~80% [3]	Conduction defects, arrhythmias [3]	High [3]
Lamin A/C LGMD	Very common [3]	Dilated CM, arrhythmias, heart block [3]	High [3]
Sarcoglycan LGMD	Very common [3]	Dilated/hypertrophic CM [3]	High [3]
Myofibrillar (childhood)	Common [3]	Dilated/hypertrophic/restrictive CM [3]	High [3]
Barth syndrome	Universal [3]	Dilated CM with LVNC [3]	High [3]
DMD	Common [3]	Dilated CM [3]	Moderate [3]
Calpain/Dysferlin LGMD	Infrequent [3]	Variable [3]	Low [3]
Congenital myopathy	Rare [3]	Variable [3]	Low [3]
SMA	Rare [5]	Minimal [5]	Low [5]

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Recent Advances and Newer Therapies

Spinal Muscular Atrophy

Three disease-modifying therapies approved in past decade 5:

• Nusinersen (2016): First approved therapy, antisense oligonucleotide 5
• Onasemnogene abeparvovec (2019): One-time gene therapy 5
• Risdiplam (2020): Oral SMN2 splicing modifier 5

Newborn screening: Increasingly implemented worldwide to enable presymptomatic treatment 5

Emerging phenotypes: Treatment creating new clinical presentations requiring adapted care strategies 5

Real-world data collection: Essential to understand treatment effects across all SMA subtypes 5

Duchenne Muscular Dystrophy

Exon-skipping therapies 3:

• Multiple FDA-approved antisense oligonucleotides for specific mutations 3
• Mutation-specific approach 3

Gene therapy 3:

• Micro-dystrophin gene therapy in clinical trials 3
• Potential for one-time treatment 3

Improved cardiac management 3:

• Earlier initiation of ACE inhibitors/ARBs 3
• Prolonged survival into 30s-40s 3

Inflammatory Myopathies

Improved understanding of myositis-specific antibodies 3:

• Better phenotype-genotype correlations 3
• Targeted therapy based on antibody profile 3

Biologic agents 3:

• Rituximab for refractory disease 3
• Other biologics in development 3

Diagnostic Advances

Genetic testing 5, 4:

• Noninvasive diagnosis for many conditions 5, 4
• Enables newborn screening 5
• Guides prognosis and treatment 5

MRI muscle imaging 7, 6:

• STIR sequences detect active inflammation 7, 6
• Guides biopsy site selection 6
• Monitors treatment response 7

Comprehensive gene panels 3:

• Simultaneous testing of multiple genes 3
• Improved diagnostic yield 3

Multidisciplinary Care Models

Coordinated comprehensive care 3:

• Neuromuscular specialist as care coordinator 3
• Proactive cardiac and respiratory monitoring 3
• Improved survival and quality of life 3, 5

Standardized outcome measures 5:

• Enable comparison across studies 5
• Track real-world treatment effects 5

Future Directions

Gene therapy expansion 5:

• Development for additional conditions 5
• Improved vectors and delivery methods 5

Precision medicine 3:

• Antibody-guided treatment in inflammatory myopathies 3
• Genotype-specific therapies 3, 5

Biomarker development 5:

• Improved monitoring of disease activity 5
• Earlier detection of complications 5