DISORDERS OF MUSCLE

A. Properties of Muscle Fibers 1. Physiologic and histochemical properties of muscle

fibers are determined by the anterior horn cells innervating them

2. All muscle fibers innervated by the same anterior horn cell have similar properties

3. Denervation and degeneration of anterior horn cells prompts reinnervation of muscle fibers, which then assume the properties of the new reinnervating anterior horn cell

4. Muscle biopsy in neuropathic conditions (Fig. 24-1) a. Denervation atrophy with small angulated fibers and

groups of atrophied fibers b. Denervation without reinnervation: pyknotic nuclear

clumps

c. With reinnervation: grouping of muscle fibers and loss of normal “checkerboard pattern” of muscle fibers (fibertype grouping)

d. Grouped atrophy with little type grouping in amyotrophic lateral sclerosis (ALS)

e. Target fibers also appear with active denervation and reinnervation (e.g., ALS): mitochondrial stains show central clear regions

5. Type I fibers (red) a. “Slow twitch” muscle fibers: long contraction time b. High oxygen consumption: dependent on aerobic

metabolism c. More mitochondria, abundance of oxidative enzymes:

lactic dehydrogenase, succinic dehydrogenase, cytochrome oxidase (stain light with adenosine triphosphatase [ATPase] stain pH 9.4, and stain dark with pH 4.3-4.6)

d. Rich in myoglobin

e. Less predisposition to muscle fatigue with repeated activation

f. Respective motor neurons are small alpha motor neurons with low firing frequency

6. Type II fibers (white) a. “Fast twitch” muscle fibers: short contraction time b. Low oxygen consumption: dependent on anaerobic

metabolism c. Relative paucity of oxidative enzymes d. Fewer mitochondria, abundance of glycolytic enzymes

(stain dark with ATPase stain, pH 9.4, and stain light with pH 4.3-4.6)

e. Poor in myoglobin f. Greater predispostion to muscle fatigue with repeated

activation g. Respective motor neurons are large alpha motor neurons

with high firing frequency

B. Structure of Muscle Fiber (Fig. 24-2) 1. T tubules

a. Transverse hollow tubular structures formed by invagina-

tions of sarcolemma (plasma membrane of striated muscle)

b. Lies between two tubular portions of sarcoplasmic reticulum (forming a triad of membrane structures)

c. Depolarization of T-tubule membrane triggers release of calcium from sarcoplasmic reticulum, leading to muscle contraction

2. Myofibrils a. Contractile elements with banded appearance b. Composed of thick and thin filaments, constituents of

the sarcomere 3. Organelles: mitochondria, sarcoplasmic reticulum,

nuclei, others

C. Structure of a Sarcomere (Fig. 24-3) 1. Thick filaments

a. Myosin polymer admixed with nonmyosin molecules, myosin-binding proteins, which function to maintain structural integrity of thick filaments and regulate their contractile function

b. Contains a central “stem” and two globular heads

c. ATPase activity of globular myosin heads: enhanced by interaction of the head with actin

2. M line a. Situated at center of the A band b. Contains protein bridges that link thick filaments together c. Contains creatine kinase, M protein, and myomesin d. Site of attachment for intermediate filaments, acting to

connect subjacent myofibrils 3. Titin filaments

a. Extends from Z disk to M line (there is overlap of adjacent titin filaments of subjacent sarcomeres)

b. Functions 1) Maintain structural integrity of sarcomere during

both active and relaxed states 2) Serve as structural molecular template for arrange-

ment of different components of the sarcomere 3) Determinant of elastic properties of muscle and

passive length of muscle at rest c. N-terminus situated in the Z disk: binds to the titin cap

(T-cap), also termed telethonin d. C-terminus situated at the M line: binds to myosin and

myosin-binding proteins e. Examples of sarcomeric proteins implicated in limb-

girdle muscular dystrophies (LGMDs): titin (affected in LGMD 2J) and telethonin (affected in LGMD 2G)

4. Thin filaments a. Components

1) Pair of F-actin polymers arranged as a helix 2) Tropomyosin molecules

a) Arranged as α-helical coils of long filamentous proteins situated in grooves formed by double helical array of F-actin polymers

b) Likely block the myosin-binding site on actin filaments at rest

c) With activation, tropomyosin changes in configuration and exposes actin-binding sites

3) Troponin a) Troponin I: inhibitory component b) Troponin C: calcium-binding component c) Troponin T: tropomyosin-binding component;

binds to other troponin components (TnI and TnC) and to tropomyosin and actin-functional connection between different components of thin filaments

4) Nebulin a) Spans entire structure of thin filaments b) C-terminus situated at the Z disk and N-terminus

at the free end of thin filaments c) Functions: likely stabilization and length determi-

nation of thin filaments 5. A band: area of overlap of actin and myosin filaments

6. I band: area that includes only thin filaments 7. Z disk

a. Mechanical attachment between adjacent sarcomeres b. Important for maintaining structural integrity of sarco-

meres and arranging the sarcomeres to form myofibrils c. Structure: overlapping antiparallel actin and titin fila-

ments from abutting sarcomeres connected by α-actinin d. Intermediate filaments encircle myofibrils at the Z lines

and attach the subjacent sarcomeres together and to the sarcolemma: synemin is a component of the intermediate filament that binds α-actinin of the sarcomere

8. H zone: region containing only myosin filaments

D. Physiology of Muscle Contraction 1. Depolarization of muscle membrane and activation of

muscle fibers: starts at end-plate region and propagates along the length of muscle fiber

2. At the end plate region a. Release of single quantum of acetylcholine (ACh) depo-

larizes postsynaptic membrane, called miniature end plate potential (MEPP)

b. Arrival of an action potential at nerve terminal releases about 200 to 300 quanta of ACh to bind to the postsynaptic nicotinic cholinergic receptors

c. This results in an aggregate potential, end plate potential (EPP), which generally exceeds the threshold for generating an action potential by activation of voltage-dependent sodium channels on the muscle membrane

3. As action potential spreads along muscle membrane (sarcolemma), depolarization extends into sarcolemmal invaginations, the transverse tubules (T tubules)

4. Depolarization of T tubules triggers rapid release of calcium from sarcoplasmic reticulum by opening the ryanodine calcium channels (termed ryanodine receptors) located at the terminal cisternae

5. With muscle fiber activation, calcium is released from sarcoplasmic reticulum, causing an increase in intracellular calcium

6. Calcium binds to troponin C 7. This triggers a change in configuration of tropomyosin

a. At rest: tropomyosin covers the myosin-binding site of actin and inhibits this association

b. With contraction: tropomyosin moves and uncovers the myosin-binding site, allowing interaction of actin and myosin

8. Globular myosin head then binds the actin (in a crossbridge) and undergoes configurational change (bends), allowing actin filaments to slide past thick filaments

9. Detachment of myosin from actin filaments requires adenosine triphosphate (ATP); the myosin head then reverts to original configuration

A. Define Symptoms 1. Positive symptoms: myalgias, myotonia, myoglobin-

uria, cramps, contractures a. Myoglobinuria may occur in several toxic and metabolic

conditions, e.g., drugs and toxins, malignant hyperthermia associated with central core myopathy, and several inherited metabolic myopathies often cause recurrent myoglobinuria

2. Negative symptoms: weakness, atrophy, fatigue, exercise intolerance, periodic paralysis a. Proximal weakness is most common pattern: patients

usually complain of difficulty lifting objects above the head, getting up from a low chair, or walking up steps

B. Define Pattern of Weakness 1. Proximal limb-girdle distribution

a. Most common pattern b. Often symmetric weakness predominantly affecting the

proximal upper and lower limbs and neck flexors and extensors; nonspecific

2. Distal distribution (most often symmetric): diagnostic considerations include a. Late or early adult-onset distal myopathy b. Facioscapulohumeral muscular dystrophy c. Scapuloperoneal muscular dystrophy d. Desmin myopathy e. Emery-Dreifuss muscular dystrophy f. Myotonic dystrophy g. Inclusion body myositis (often affecting finger flexors) h. Metabolic myopathies: debrancher deficiency, acid malt-

ase deficiency i. Congenital myopathies (often cause diffuse myopathy):

nemaline myopathy, central core disease, centronuclear myopathy

3. Scapuloperoneal distribution (proximal arm and distal leg, often asymmetric): diagnostic considerations include a. Facioscapulohumeral muscular dystrophy b. Scapuloperoneal muscular dystrophy c. Emery-Dreifuss muscular dystrophy d. Limb-girdle dystrophies e. Congenital myopathies: nemaline myopathy, central

core disease f. Metabolic myopathies, including acid maltase deficiency

4. Distal arm and proximal leg weakness (asymmetric) a. Including finger and wrist flexors and quadriceps b. Seen with inclusion body myositis

5. Ptosis with or without ophthalmoplegia a. With pharyngeal involvement: oculopharyngeal

dystrophy b. Without pharyngeal involvement: a mitochondrial

cytopathy c. Facial weakness and ptosis, without ophthalmoplegia:

facioscapulohumeral muscular dystrophy and myotonic dystrophy

6. Prominent neck extensor weakness: diagnostic considerations include a. Isolated neck extensor myopathy b. Inflammatory myopathy: dermatomyositis, polymyosi-

tis, inclusion body myositis c. Congenital myopathy d. Myotonic dystrophy e. Facioscapulohumeral muscular dystrophy f. Metabolic myopathies g. Entities other than myopathies (e.g., motor neuron dis-

ease, myasthenia gravis)

C. Temporal Profile 1. Age at onset

a. Birth 1) Congenital myopathies: central core disease, centro-

nuclear, nemaline 2) Congenital muscular dystrophy 3) Congenital myotonic dystrophy 4) Lipid storage disease: carnitine palmityltransferase

deficiency 5) Glycogen storage diseases, e.g., acid maltase deficiency

b. Childhood 1) Muscular dystrophies: Duchenne’s, Becker’s,

facioscapulohumeral, Emery-Dreifuss, limb-girdle dystrophy

2) Myopathies related to endocrine disorders 3) Inflammatory myopathies, e.g., dermatomyositis 4) Congenital myopathies, e.g., nemaline myopathy 5) Mitochondrial myopathies 6) Lipid storage diseases, e.g., carnitine palmityltrans-

ferase deficiency 7) Glycogen storage diseases, e.g., acid maltase deficiency

c. Adulthood 1) Inflammatory: polymyositis, dermatomyositis, inclu-

sion body myositis 2) Infectious: viral 3) Toxic-metabolic 4) Myopathies related to endocrine disorders: thyroid,

parathyroid, adrenal, pituitary 5) Muscular dystrophies 6) Mitochondrial myopathies

7) Lipid storage diseases and glycogen storage diseases, e.g., acid maltase deficiency

8) Congenital myopathies, e.g., nemaline myopathy 2. Temporal evolution

a. Abrupt (acute or subacute) onset and progression/recurrent episodes: inflammatory myopathy, periodic paralysis, metabolic myopathy

b. Chronic, slow “dystrophic” progression: muscular dystrophy

c. Long-term, nonprogressive: congenital myopathy (some may have very slow progression later in the course)

D. Precipitating Factors That Trigger Symptoms 1. Illegal drugs, toxins, medicines (especially cortico-

steroids, statins) 2. Exercise, cold, or ingestion of carbohydrate-enriched

meals (periodic paralysis)

E. Other Organ Involvement 1. Cardiac involvement

a. Dysrhythmias: mitochondrial myopathies (Kearns-Sayre syndrome), Anderson’s syndrome

b. Congestive heart failure (CHF): nemaline myopathy, myofibrillar myopathy, Duchenne’s and Becker’s muscular dystrophies, acid maltase deficiency, carnitine palmityltransferase deficiency

c. Both dysrhythmias and CHF: polymyositis, muscular dystrophies (myotonic; Emery-Dreifuss; limb-girdle types 1A and B, 2C-G, 2I, some distal myopathies)

2. Respiratory involvement a. Inflammatory: polymyositis, anti-Jo1 antibody

syndrome b. Congenital myopathies: nemaline and centronuclear

myopathies c. Mitochondrial myopathies d. Muscular dystrophies: congenital, myotonic, Emery-

Dreifuss, and myofibrillar myopathy e. Metabolic myopathies: acid maltase deficiency, carnitine

palmityltransferase deficiency

A. General Characteristics 1. Early onset with clinical manifestations present from

birth 2. Prenatal course: fetal movements may be decreased or

absent 3. Postnatal course: hypotonia, poor respiratory effort,

complicated delivery, inability to feed, reduced muscle

bulk, diffuse or proximal weakness (nemaline myopathy may have predominantly distal weakness)

4. First year: hypotonia, weakness (may include facial weakness), flaccid speech, delayed motor milestones, failure to thrive, respiratory infections

5. Slow or nonprogressive course, but possible altered motor function and change in strength due to growth spurt, weight gain, or intercurrent illness a. Serial biopsy studies of nemaline myopathy may show

increased connective tissue, indicating progression 6. Respiratory complications may include restrictive lung

disease, sleep hypoventilation due to insidious paralysis of diaphragm

7. Orthopedic complications and skeletal deformities

B. Central Core Disease 1. Mutation in the ryanodine receptor gene (RYR1) on

chromosome 19q13.1 (allelic with malignant hyperthermia), encoding for skeletal muscle calcium release channel

2. Autosomal dominant inheritance with variable expression and incomplete penetrance (may rarely be autosomal recessive or sporadic)

3. Proximal symmetric weakness: often mild, legs more than arms

4. Delayed motor development, unable to walk until 3 or 4 years old

5. Poor muscle bulk 6. Nonprogressive or slow progressive course 7. Normal extraocular movements, and no bulbar signs 8. May have mild facial weakness 9. Orthopedic complications such as congenital disloca-

tion of hip (most common), scoliosis, foot deformities, ankle contractures, finger contractures

10. Severe infantile form with hypotonia and respiratory failure

11. Childhood or adult-onset cases may present with mild proximal weakness, exercise intolerance, or malignant hyperthermia with exposure to anesthetics

12. Creatine kinase: typically normal levels 13. Muscle histopathology (Fig. 24-4)

a. Type I fiber predominance b. Central cores

1) Single, well-circumscribed regions 2) Selectively involve type I fibers 3) Deficient in mitochondria and sarcoplasmic reticu-

lum as well as oxidative enzymes and phosphorylase activity (detected best on sections with oxidative enzyme immunohistochemistry, as poorly stained central demarcated areas)

4) Extend entire length of muscle fiber c. Increased endomysial connective tissue d. Often, increased number of internal nuclei

14. Treatment includes avoidance of anesthesia-induced malignant hypertension

C. Multicore (minicore) Disease 1. Congenital myopathy associated with multifocal degen-

eration of muscle fibers 2. Most familial cases are autosomal recessive, may also be

sporadic 3. Onset in infancy or early childhood with hypotonia

and delayed motor milestones 4. Weakness (usually nonprogressive) predominantly prox-

imal → waddling gait, frequent falls, difficulty rising from chair; neck and trunk muscle involvement

5. Facial weakness (mild), bulbar weakness with hypernasal voice

6. Ptosis and extraocular muscle weakness rare 7. Cardiac manifestations uncommon (e.g., atrial and ven-

tricular septal defects, cardiomyopathy) 8. Respiratory involvement: respiratory insufficiency or

failure, sometimes with nocturnal hypoventilation (may need nocturnal ventilation)

9. Creatine kinase: normal or slightly elevated levels 10. Electromyography (EMG): normal (early on) or

short-duration motor unit potentials (especially after age 4 years)

11. Muscle histopathology (Fig. 24-5) a. Variation in fiber size, internal nuclei, and muscle fiber

splitting

b. Type I fiber predominance c. Type I fibers may be smaller than normal; type II fibers

may be hypertrophied d. Multiple small cores in individual fibers with decreased

activity on reduced form of nicotinamide adenine dinucleotide (NADH) and oxidative stains (lack of mitochondria)

e. Small cores 1) Occur in both type I and II fibers 2) Are short and do not extend the entire length of the

muscle fiber f. Minicores: foci of reduced sarcomeric organization with

reduced mitochondrial activity g. Lesions may represent foci of myofibrillary disintegration

and collections of membraneous material and unstructured myofibrils

D. Nemaline Myopathy 1. Autosomal dominant (most families), recessive,

sporadic 2. Genetic heterogeneity

a. Mutation involving nebulin gene (NEM2) on chromosome 2q21-22 1) Nebulin contributes to formation of Z disk 2) Autosomal recessive, infantile onset

b. Mutation involving the skeletal muscle α-actin gene (ACTA1) on chromosome 1q: autosomal dominant or recessive

c. Mutation involving tropomyosin gene TPM2 on chromosome 9p13 or TPM3 on chromosome 1q: autosomal dominant or recessive 1) Encoding α-tropomyosin in thin filaments of

sarcomere 3. Phenotypic heterogeneity

a. Severe neonatal congenital form 1) Difficult delivery, cyanosis at birth, hypotonic infants

with reduced muscle bulk and severe generalized weakness (few spontaneous movements), feeding difficulties (difficulties with sucking and swallowing), gastroesophageal reflux

2) Dysmorphic features, joint contractures, foot deformities, arthrogryposis (uncommon)

3) Recurrent pulmonary infections, high early mortality due to aspiration pneumonia or respiratory insufficiency

4) Infants who survive respiratory failure continue to acquire motor development (delayed), with slow progressive or nonprogressive weakness

b. Intermediate infantile congenital form 1) Hypotonic infants with generalized weakness and

feeding difficulties, but often independent respiration at delivery

2) Proximal muscle weakness causing waddling gait and Gowers’ sign

3) Delayed and incomplete motor development; may be wheelchair-bound by age 10 years

4) Facial and masticatory muscles severely affected: appearance of long and narrow face and open mouth

5) Narrow, high-arched palate, micrognathia, chest deformities, finger contractures

6) Nonprogressive course in many cases, but slow deterioration of motor function with time

c. Mild infantile congenital form

1) Hypotonia and feeding difficulties in first year of life 2) Respiratory involvement: mild at best or subclinical 3) Bulbar weakness: hypernasal speech, swallowing

difficulties 4) Weakness usually proximal (late development of distal

involvement in some patients) d. Childhood/adolescent form

1) Motor development may be normal 2) Early distal lower extremity weakness (especially with

dorsiflexion), often presenting at onset e. Adult onset

1) Age at onset: between third and sixth decades 2) Limb-girdle proximal weakness with slow progression 3) Often no family history 4) Respiratory failure and cardiomyopathy 5) Rare adult onset of nemaline myopathy may present

as cardiomyopathy or diaphragmatic muscle involvement

4. Creatine kinase: normal or mildly elevated levels 5. Cardiac involvement: rare or uncommon in all

phenotypes

6. EMG a. Rapid recruitment of short-duration motor unit

potentials b. Changes may be normal or very mild if study is per-

formed very early c. Patients with long-standing disease or with onset at older

age may show long-duration motor unit potentials 7. Muscle histopathology (Fig. 24-6)

a. Type I fiber predominance (especially in severe cases) and atrophy

b. Marked disproportion in fiber size, with uniformly small type I fibers and normal to large type II fibers

c. Sarcoplasmic rods (nemaline bodies) 1) Short, granular-appearing 2) Subsarcolemmal and perinuclear localization in

type I fibers (especially large rods) 3) Composed of α-actinin, actin, and other Z disk

proteins, and appear to arise from, are attached to, and thicken the Z disk (small rods)

d. Intranuclear rods 1) Observed in some patients with severe congenital or

adult-onset phenotypes 2) May be associated with more severe disease and worse

prognosis

E. Myotubular (centronuclear) Myopathy 1. Inheritance: autosomal dominant, autosomal recessive,

and sporadic cases reported (rare) 2. X-linked recessive (most common): chromosome

Xq27.3-q28 (MTM1 gene) a. Missense mutation associated with mild phenotype

(variable)

b. Severe or lethal phenotype usually seen with truncating mutations

3. Gene product: tyrosine phosphatase (myotubularin) important for signal transduction and differentiation in late myogenesis (hence, in utero onset)

4. In utero onset (common): reduced fetal movements and difficult delivery, enlarged head and polyhydramnios

5. Floppy infants (diffuse weakness and severe hypotonia), facial diplegia, bilateral ptosis, nonprogressive proximal and distal symmetric weakness, respiratory insufficiency or failure (partial or complete ventilator dependency in survivors), high mortality (usually X-linked recessive)

6. Extraocular and neck axial muscles often affected 7. Macrocephaly, narrow face, long digits 8. Carriers may have mild facial weakness 9. Associated with pyloric stenosis, spherocytosis, gall-

stones, kidney stones, rapid linear skeletal bone growth, and sometimes genital abnormalities (e.g., micropenis, hypospadias)

10. Autosomal forms: milder clinical course with later age of onset

11. Creatine kinase: levels may be mildly elevated 12. Electrodiagnostic evaluation

a. Normal nerve conduction studies b. Needle EMG examination

1) May be normal in mild cases and infants 2) Rapid recruitment of short-duration polyphasic

motor unit potentials, sometimes with fibrillation potentials, complex repetitive discharge, and possibly myotonic discharges

13. Muscle histopathology (Fig. 24-7)

a. Is called “centronuclear” because of predominance of small type I fibers with central nuclei

b. Type I fiber predominance (often small, atrophied) c. Central pallor noted on ATPase staining d. Radial distribution of sarcoplasmic strands apparent on

NADH reaction e. Interstitial connective tissue: normal or mildly increased

F. Myofibrillar (desmin-related) Myopathy (now considered a muscular dystrophy)

1. Genetic and phenotypic heterogeneity (morphologically homogeneous)

2. Mostly autosomal dominant (autosomal recessive and X-linked also described)

3. Associated chromosomes: 2q, 10q, 11q, 12q a. Accumulation of desmin, αB-crystallin, dystrophin, neu-

ral cell adhesion molecule, CDC2 kinase, some other proteins

4. Age at onset: may vary between early childhood and adulthood

5. Clinical features: variable a. Distal weakness equal to or more than proximal weak-

ness and atrophy b. Peripheral neuropathy in 60% of patients (as well as

myopathy)

c. Cardiomyopathy (hypertrophic and arrhythmogenic) and respiratory involvement in some patients

d. Hearing loss, palatal weakness, cataracts reported in certain subtypes

6. Muscle histopathology (morphologically homogeneous) (Fig. 24-8) a. Subsarcolemmal accumulation of dense granular and fil-

amentous amorphous material: reacts intensely for actin; may contain desmin (some but not all) and other proteins such as lamin B, gelsolin, ubiquitin, dystrophin, and αB-crystallin

b. Variation in muscle fiber size, rimmed vacuoles, centrally located nuclei, minimal fibrosis may be present

c. Occasional perivascular or endomysial mononuclear inflammatory infiltrates in less than 10% of cases

d. Morphologic changes typically begin at Z disk e. Cardiac muscle: accumulation of the intermediate fila-

ments with disruption of myofibrils and Z disks 7. Electrophysiology

a. Nerve conduction studies: normal or show mild axonal peripheral neuropathy

b. Needle EMG: short-duration, low-amplitude motor unit potentials (sometimes long-duration, large-amplitude units given the chronicity); abnormal spontaneous activity, including increased insertional activity and fibrillation

potentials, complex repetitive discharge, and myotonic discharges

G. Congenital Fiber-Type Disproportion 1. Nonspecific histologic finding likely in congenital

myopathies and other conditions 2. Diagnosis of exclusion in patient with clinical features

of congenital myopathy and reduction of type I fiber size

3. Disproportion between size of type I and II fibers: type I fibers at least 12% smaller than type II fibers (normally, type I fibers may be up to 25% smaller than type II fibers in adults or infants younger than 2 months)

4. Hypotonia at birth, varying diffuse weakness that spares ocular muscles and improves with age

5. Weakness of face and neck: long thin face, fish mouth, high-arched palate, short stature

6. Contractures, kyphoscoliosis, foot deformities 7. Normal mental development (commonly) 8. Creatine kinase: normal to slightly elevated levels 9. EMG: normal or short-duration motor unit potentials

H. Treatment of Congenital Myopathies 1. Genetic counseling (when mutation has been identified) 2. Prenatal diagnosis (obtaining tissue via chorionic villus

biopsy or amniocentesis) 3. Early detection and treatment of medical and orthope-

dic complications 4. Prevention of complications (including surgical proce-

dures and exposure to general anesthesia)

a. Consider risk of malignant hyperthermia in patients with central core disease

b. Consider preoperative pulmonary evaluation 5. Respiratory care and physical therapy and rehabilitation

A. General Characteristics 1. Genetically determined 2. Distinguished by progressive degeneration of muscles

and production of connective tissue replacing muscle fibers

3. Systemic involvement in some patients 4. Age at onset: variable

B. Dystrophin-Associated Muscle Membrane Protein Complex (Fig. 24-9)

1. Membrane-associated proteins that span sarcolemma a. Provide mechanical support to sarcolemma and stability

between intracellular cytoskeleton and extracellular matrix

b. May participate in signal transduction 2. Cytoplasmic complex: intracellular (subsarcolemmal)

proteins associated with muscle membranes a. α-Dystrobrevin

1) Binds to dystrophin 2) Reduced or absent in subsarcolemmal space in

dystrophinopathies b. Filamin 2 c. Syncoilin d. Syntrophins

1) Bind to dystrophin and dystrophin-related proteins such as dystrobrevin

2) Reduced or absent in subsarcolemmal space in dystrophinopathies

e. Dystrophin: rod-shaped cytoskeletal protein with no transmembrane regions; consists of five different domains 1) Actin-binding domain

a) Encoded by exons 1 to 8 b) N-terminal domain c) Links dystrophin to F-actin subsarcolemmal

cytoskeleton 2) Rod domain

a) Largest domain (2,400 amino acids), encoded by exons 9 to 62

b) Consists of 24 triple-helical repeating units: a single repeat unit consists of one long and two shorter helices connected to next unit by short nonhelical spacer

3) WW domain: overlaps rod domain and cysteine-rich domain

4) Cysteine-rich domain a) Encoded by exons 63 to 69 b) Responsible for attachment of subsarcolemmal

complex to membrane by binding directly to the intracellular portion of β-dystroglycan

5) C-terminal domain a) Encoded by exons 70 to 79 b) Binds to syntrophins and β-dystroglycan

3. Membrane proteins a. Dystroglycan complex

1) β-Dystroglycan is true membrane protein; α-dystroglycan is extracellular

2) α-and β-Dystroglycans: encoded by same gene 3) α-Dystroglycan protein contains laminin-binding

glycoprotein that binds to extracellular laminin α2 and provides structural link between sarcolemma and extracellular matrix

4) α-Dystroglycan protein also binds to agrin (see below)

5) Decrease in muscle α-dystroglycan seen in congenital muscular dystrophies

6) β-Dystroglycan is sarcolemmal protein that binds tightly to WW domain in cysteine-rich region of dystrophin

b. Sarcoglycan complex 1) Group of proteins critical for sarcolemmal stability

and for linking actin cytoskeleton to extracellular matrix

2) Transmembrane proteins containing extracellular domains and a single membrane-spanning domain

3) Types (and associated disorder) a) α-Sarcoglycan, adhalin (LGMD 2D) b) β-Sarcoglycan (LGMD 2E) c) γ-Sarcoglycan (LGMD 2C) d) δ-Sarcoglycan (LGMD 2F) e) ε-Sarcoglycan (myoclonus-dystonia syndrome) f) ζ-Sarcoglycan

c. Other membrane proteins 1) Sarcospan: binds to sarcoglycan complex 2) Caveolin

a) Integral transmembrane proteins b) Scaffolding proteins implicated in signal

transduction c) Associated with caveolae (invaginations of plasma

membrane) d) Calveolin-3 gene mutation associated with

LGMD 1C (discussed below) 3) Integrins

a) Heterodimeric membrane glycoproteins (transmembrane adhesion molecules) that mediate wide spectrum of cell-cell and cell-matrix interactions

b) α7β1-Integrin protein: primary integrin in sarcolemma i) Binds to laminin: acts as structural link between

cytoskeleton and extracellular matrix ii) Mutation of gene on chromosome 12q13 causes

a primary congenital muscular dystrophy iii) Levels of protein also decreased in other congenital

muscular dystrophies (without mutation of gene)

4. Extracellular proteins a. Laminins

1) Glycoproteins, consisting of three polypeptide chains (alpha, beta, gamma) bound to each other by disulfide bonds

2) Cross-shaped molecules 3) Location: extracellular, basement membranes 4) Bind to α-dystroglycans and integrins and interact

with other extracellular proteins 5) Important role in myogenesis 6) Implicated in congenital muscular dystrophies

b. Agrin: component of synaptic basal lamina that induces aggregation of ACh receptors and other elements of postsynaptic membrane during synaptogenesis

c. Collagen types IV and VI d. α-Dystroglycan (see above)

C. Dystrophinopathies (X-linked recessive inheritance) 1. Genetics

a. X-linked recessive; Xp21 b. Gene product is dystrophin, part of dystrophin-glyco-

protein complex: deficient dystrophin may weaken sarcolemma, with subsequent muscle fiber necrosis

c. Large deletions (65%), duplications (5%), small deletions or point mutations (30%)

d. DNA analysis: large deletions and duplications identified with polymerase chain reaction (PCR) and Southern blot analysis 1) Up to 65% of patients with Duchenne’s muscular

dystrophy have large deletions that may be identified 2) Duplications best identified with Southern blot

analysis 3) “Negative DNA test” does not exclude the diagnosis 4) Other methods that may be used if PCR fails:

mRNA analysis, immunoblotting, immunostaining e. Female carriers

1) Usually asymptomatic (adequate sarcolemmal dystrophin is produced by the X chromosome harboring the normal dystrophin gene)

2) 8% of female carriers may have mild to moderate myopathy, likely due to preferential inactivation of normal wild-type X chromosome and increased number of dystrophin-negative fibers (given the mosaic expression of dystrophin-positive and dystrophinnegative fibers)

2. Clinical features of Duchenne dystrophy a. Normal height and weight at birth, subsequent decrease

in height and weight b. Motor developmental delay; difficulty in running, climb-

ing, etc. c. Symptoms initially noted when child is observed to walk

on toes, difficulty rising from floor (age at onset: about 3-5 years)

d. Gower’s sign: patient stands up by using hands pushing on knees

e. May experience a period of apparent functional improvement due to normal increase in motor skills and strength

f. By 5 to 6 years of age: pseudohypertrophy of the calves g. By 12 years: loss of ambulation, atrophy of all muscles,

contractures h. Contracture: ankles, knees, and hips i. Progressive kyphoscoliosis and exaggerated lumbar lordo-

sis: usually after loss of ambulation, possibly due to involvement of axial muscles

j. Progression to death over 15 to 30 years (death usually due to respiratory complications)

k. Muscle weakness (proximal more than distal), upper and lower extremities involved: “scapuloperoneal distribution,” preferential involvement of proximal (more than distal) muscles and anterior tibialis and peronei muscle groups (more than gastrocnemius, soleus, and tibialis posterior muscles), neck flexors (more than neck extensors), wrist and digit extensors (more than flexors)

l. Preservation of cranial musculature m. Respiratory muscle involvement n. At risk for malignant hyperthermia-like reactions and

acute rhabdomyolysis to general anesthesia o. Cardiomyopathy: CHF and arrhythmias in late stages of

disease p. Intestinal pseudo-obstruction: due to involvement of

smooth muscles of gastrointestinal tract q. Central nervous system involvement: some with mental

retardation, average IQ about one standard deviation below normal, learning disabilities

r. Creatine kinase: markedly elevated early in the disease, but decreases with disease progression and replacement of muscle fibers with connective tissue

3. Clinical features of Becker dystrophy a. Later age of onset, less severe, and later progression com-

pared with Duchenne dystrophy b. Usual age at onset: between 5 and 15 years (range, 3-60

years) c. Most patients ambulate beyond 15 years d. Loss of ambulation usually in the fourth decade (range,

10-78 years) e. Age at death: may range from 30 to 60 years

4. Muscle histopathology of dystrophinopathies (Fig. 24-10) a. Segmental muscle necrosis and regeneration b. Hypercontracted muscle fibers c. Abnormal variation in fiber size d. Muscle fiber degeneration and regeneration e. Macrophage invasion of the necrotic fibers,

phagocytosis f. Progressive loss of muscle fibers and replacement with

connective tissue and endomysial fibrosis with reduced regenerative capacity

g. Absence of dystrophin in Duchenne dystrophy and reduction or altered staining patterns in Becker dystrophy

h. Diagnosis cannot be made without immunohistochemical staining or immunoblotting

5. Electrophysiology a. When performed in symptomatic child: increased inser-

tional activity, small myopathic motor unit potentials in affected muscle groups

b. In asymptomatic phase or in patients with minimal symptoms: insertional activity may be normal

c. With progression of disease and endomysial fibrosis: compound muscle action potential (CMAP) amplitudes may be reduced and recruitment may be reduced

6. Treatment a. Corticosteroids (prednisone and deflazacort) shown to

be beneficial temporarily (can prolong ambulation and maintain pulmonary function) 1) Should be started between ages 4 and 7 years 2) Benefit best with prednisone at a daily dose of 0.75

mg/kg 3) Benefit may be due to increased muscle mass or stabi-

lization of sarcolemma 4) Improvement in motor function by 10 days to 1

month and maximal within 2 to 3 months b. Genetic counseling, physical therapy, treatment of med-

ical and orthopedic complications

D. Emery-Dreifuss Muscular Dystrophy (EMD-1 and EMD-2)

1. Incidence 1:100,000 2. Genetics

a. EMD-1: X-linked recessive inheritance (mutations in STA gene on chromosome Xq28, which encodes nuclear membrane protein emerin)

b. EMD-2: autosomal dominant or recessive inheritance (mutations in LMNA gene on chromosome 1q21.23, which encodes nuclear envelope proteins, lamins A and C, not emerin)

3. Clinical features a. Age at onset: early to middle childhood b. Scapulohumeroperoneal or limb-girdle distribution,

slowly progressive weakness c. EMD-1: early onset of joint contractures, often before

notable weakness d. EMD-2: contractures often follow onset of notable mus-

cle weakness e. Loss of ambulation more common with EMD-2 f. Contractures: predominantly ankle, elbows, cervical

spine g. Cardiomyopathy with conduction abnormalities: usual-

ly after second or third decades h. Muscle pseudohypertrophy absent i. Creatine kinase: normal or mildly elevated levels

4. Muscle histopathology a. Pattern consistent with a slowly progressive muscular

dystrophy: variation in muscle fiber size, minimal necrosis with regeneration, and increase in connective tissue

b. Reduced or absent emerin immunostaining in muscle or skin biopsy specimens

5. Electrophysiology a. Chronic myopathic changes: small myopathic motor

unit potentials with minimal abnormal spontaneous activity or fibrillation potentials

b. Large motor unit potentials may be present, indicative of the chronicity of the myopathic process

6. Treatment a. Physical therapy with stretching exercises b. Prevention and screening for medical complications,

including early detection of cardiac conduction abnormalities and pacemaker insertion when needed

E. Barth’s Syndrome (X-linked) 1. X-linked recessive: linked to chromosome Xp28, gene

encoding Tafazzin protein 2. Onset usually in infancy 3. Mild limb-girdle myopathic weakness 4. Cardiomyopathy, short stature, neutropenia

F. Autosomal Dominant Dystrophies 1. Facioscapulohumeral muscular dystrophy

a. Incidence 1:20,000 b. Genetics

1) Autosomal dominant inheritance, with high penetrance and variable expression

2) Chromosome 4q35 (deletion and reduced number of D4Z4 tandem repeat segments)

c. Clinical features 1) Usually symptomatic after age 18 (usually between

second and fourth decades) 2) Severe infantile form exists 3) Slowly progressive (insidious onset) asymmetric weak-

ness of facial, scapular, and proximal upper extremity muscles as well as peroneal muscles

4) Biceps, triceps, trapezius, serratus anterior, pectoral, and scapular muscles affected; deltoid muscles spared

5) Facial weakness causes incomplete eye closure, asymmetric defect in puckering, and flattened smile; initial symptoms often involve facial muscles

6) Forearm muscles less involved: wrist extensors affected more than wrist flexors

7) Ankle dorsiflexors involved early 8) Hip flexors and quadriceps may be affected 9) Involvement of abdominal muscles usually early and

may cause protruding abdomen and Beevor’s sign 10) Symptoms often patchy and asymmetric

11) 20% of patients may eventually lose ability to ambulate

12) Slow progression over years 13) Life expectation unchanged

d. Creatine kinase: level elevated less than 5 times normal e. Muscle histopathology

1) Dystrophic pattern: mild necrosis with regeneration, variation in muscle fiber size, increased amount of connective tissue

2) Moth-eaten appearance on oxidative enzyme stains (NADH)

2. Oculopharyngeal dystrophy a. Genetics

1) Inheritance: mostly autosomal dominant (autosomal recessive also reported)

2) Expanded GCG repeat in PABN1 gene on chromosome 14q11.2-q13: gene product PABPN1 (polyadenylate-binding protein nuclear 1 [previously known as PABP2]) is nuclear protein involved in polyadenylation of all mRNAs

b. Clinical features 1) Typically begins in fifth to sixth decades with progres-

sive ptosis (bilateral and sometimes asymmetric) and dysphagia

2) Extraocular muscle involvement can occur later 3) Facial weakness in some patients 4) Weakness of proximal upper and lower extremities in

some patients 5) Dysphonia from laryngeal involvement 6) Slowly progressive course

c. Creatine kinase: often normal levels d. Electrophysiology

1) Normal nerve conduction studies (sometimes lengthdependent axonal peripheral neuropathy)

2) Needle examination showing rapid recruitment of short-duration motor unit potentials, sometimes with long-duration motor unit potentials given chronicity of disorder

e. Muscle histopathology 1) Dystrophic changes: abnormal variation in fiber size,

loss of muscle fibers, and increase in interstitial connective tissue and internal nuclei

2) Small angulated fibers (may be attributed to concurrent denervation or aging)

3) Autophagic (rimmed) vacuoles and intranuclear inclusions

f. Treatment 1) Prevention and treatment of medical complications

(swallowing evaluation, gastrostomy as needed) 2) Lid crutches and blepharoplasty for ptosis as needed

3. Classic myotonic dystrophy type 1 (DM1): most prevalent inherited neuromuscular disease in adults a. Genetics

1) Autosomal dominant inheritance 2) Expanded unstable CTG repeat in gene encoding

myotonin protein kinase (DMPK, serine threonine protein kinase) on chromosome 19q13.3: expansion not in the coding region, not translated

3) Anticipation: average age at onset, 29 years; younger in child than in parent

4) Length of repeats correlates inversely with age at onset b. Clinical presentation

1) Myotonia, most often affects hand grip and evoked by percussion; not seen in congenital form

2) Slowly progressive weakness and atrophy of facial muscles and distal limbs (preferentially affecting forearm and peroneal muscles)

3) With progression, proximal muscle groups may be involved

4) Frontal balding and temporal wasting 5) Cranial musculature involved (other than muscles of

facial expression): tongue, palate, masseter, temporalis, neck flexors, and sternocleidomastoid muscles may be affected

6) Symmetric ptosis and reduced facial expression → characteristic facies

7) Mild and late extraocular weakness and extraocular myotonia

8) Tendon reflexes may be reduced or absent 9) Mild length-dependent peripheral neuropathy

10) Cardiac involvement a) Conduction defects, arrhythmias, dilated

cardiomyopathy b) Sudden death may be first manifestation

11) Alimentary tract involvement due to smooth muscle involvement a) Gastrointestinal tract dysmotility b) Megacolon c) Gallbladder disease (history of cholecystitis

common) d) Constipation and diarrhea

12) Cataracts, polychromatic lens opacities 13) Endocrine abnormalities

a) Testicular atrophy and secondary increase in pituitary gonadotrophic hormones (e.g., follicle-stimulating hormone)

b) Women: high rate of miscarriages; complications during pregnancy; complicated, prolonged labor and delivery

c) Hyperinsulinism and insulin resistance, abnormal

glucose tolerance test 14) Mental deficiency

a) Abnormal verbal and nonverbal IQ scores b) Mental retardation in congenital myotonic

dystrophy 15) Frequent miscarriages or important gestational com-

plications in affected females who become pregnant 16) Sleep difficulties: hypoventilation, uncontrollable

urge to sleep, hypercarbia due to abnormal central ventilatory response

c. Electrophysiology 1) Nerve conduction studies: normal or length-depend-

ent sensorimotor peripheral neuropathy 2) Needle examination

a) Myotonic discharges: widespread, may range from 2 to 30 seconds in duration (shorter duration of myotonic discharges in myotonia congenita, mostly <2 seconds)

b) No myotonic discharges in congenital form c) Short-duration, rapidly recruiting motor unit

potentials with fibrillation potentials and abnormal spontaneous activity, face and distal limbs more than proximal limbs

d. Muscle histopathology 1) Increased internal (central) nuclei with pyknotic

nuclear clumps 2) Variation in muscle fiber size 3) Ring fibers 4) Small, angulated fibers 5) Type I fiber atrophy, hypertrophy of type II fibers 6) Occasional necrotic muscle fibers 7) Sarcoplasmic masses

e. Ancillary testing 1) Creatine kinase: normal to mildly elevated levels 2) Magnetic resonance imaging (MRI): may show sub-

cortical white matter changes f. Diagnosis

1) Molecular testing required to confirm the diagnosis: combination of PCR and Southern blot analysis to detect CTG expansions

2) Prenatal testing: amniocentesis or chorionic villus sampling may identify cases of congenital myotonic dystrophy

4. Congenital myotonic dystrophy a. Poor fetal movements and polyhydramnios due to diffi-

culty swallowing b. Usually apparent at birth c. Severe weakness (including facial weakness) and

hypotonia d. Respiratory insufficiency due to intercostal and diaphrag-

matic weakness and hypoplasia e. Feeding difficulties due to weakness of muscles of masti-

cation and facial expression and weakness of palatal and pharyngeal muscles

f. Muscle histopathology: hypoplastic muscles with decreased muscle fiber size and number, absence of fiber type differentiation, presence of central nuclei, satellite cells

g. Delayed motor development h. Mental retardation i. Clinical or electrophysiologic myotonia absent in first

few years of life 5. Proximal myotonic myopathy (PROMM): type 2

myotonic dystrophy (DM2) a. Genetics

1) Autosomal dominant inheritance 2) Normal size DM1 gene 3) Most families show linkage to DM2 markers on chro-

mosome 3q 4) CCTG expansion producing long repeat RNA and

abnormal splicing of muscle chloride channel RNA 5) DM2 is due to a CCTG expansion in intron 1 of the

ZNF9 gene on chromosome 3, encoding ZNF9 protein (zinc finger protein 9)

6) Anticipation: mild, less prominent than DM1 b. Age at onset: varies widely between 8 and 60 years c. Weakness: primarily proximal, severity variable d. Facial weakness: minimal or absent e. Myalgias: frequent f. Myotonia: clinically minimal or absent, usually detected

with EMG (diagnosis is not excluded by absence of myotonia)

g. Cataracts: eventually occur in all patients h. Other systemic manifestations present to lesser degree

than in DM1: cardiac arrhythmias, diabetes mellitus, hearing loss

i. No congenital form j. High level follicle-stimulating hormone k. Reduced IgG l. Creatine kinase: normal or mildly elevated levels

m. Muscle histopathology: nonspecific, similar to that of DM1

G. Limb-Girdle Muscular Dystrophies (Table 24-1) 1. Clinical manifestation

a. Clinically and genetically heterogeneous b. Progressive proximal muscle weakness and atrophy c. Face and neck muscles generally spared d. Distal muscles could be affected in later stages of disease e. Congenital and infantile onset may have hypotonia and

generalized weakness f. Other features in older children and adults: ankle con-

tractures, calf hypertrophy, exertional myalgias, lumbar lordosis

2. Muscle histopathology a. Nonspecific: degeneration of muscle fibers with regener-

ation and variable necrosis and fiber splitting, variable muscle fiber size, central nuclei

b. Immunostaining and Western blot analysis helpful in detecting known protein deficiencies

c. Deficiency of one sarcoglycan protein affects others → specific diagnosis of sarcoglycanopathies is difficult

3. Electrophysiology a. Findings correlate with severity of myopathy and timing

of the study b. More severe forms associated with fibrillation potentials

and highly polyphasic myopathic motor unit potentials c. Decreased insertional activity and large motor unit

potentials may be seen late in disease course 4. LGMD 1: autosomal dominant inheritance

a. Usually presents in adulthood with slowly progressive proximal weakness and atrophy, including scapular winging, calf hypertrophy, nearly normal or mildly elevated

creatine kinase levels, less severe clinical course and less common than the recessive form

b. LGMD 1A: myotilinopathy 1) Mutation in MYOT gene on chromosme 5q31-q34

encoding myotilin 2) Myotilin mutations may also cause phenotype of

myofibrillar myopathy 3) Myotilin interacts with components of Z disk, includ-

ing α-actinin 4) Young adult onset with anticipation 5) Proximal upper and lower extremity weakness, with

later progression to distal muscles 6) Dysarthria with hypernasal speech 7) Joint contractures at ankles 8) Slow progression with late loss of ambulation 9) Creatine kinase: elevated levels

10) Muscle histopathology: rimmed autophagic vacuoles, sarcomeric disorganization, rod-like inclusions (Zband streaming noted on electron microscopy)

c. LGMD 1B: laminopathy 1) Mutation in LMNA gene encoding lamin A/C, asso-

ciated with the nuclear envelope 2) Allelic with autosomal dominant Emery-Dreifuss

Table 24-1. Classification of the Limb-Girdle Dystrophies (LGMD)

Type Chromosome (gene product) Distinguishing clinical features

muscular dystrophy (EMD-2) 3) Age at onset: late teens, early adulthood 4) Most common symptom at onset: difficulty with

running, followed by more obvious pelvic girdle weakness

5) Slow progression to involve arms in next 10 to 20 years 6) Creatine kinase: normal or mildly elevated levels 7) Muscle contractures may develop late; are usually

milder than those of Emery-Dreifuss muscular dystrophy

8) Cardiac manifestations (up to 60% of patients): conduction blocks, arrhythmias (may present with syncope or sudden death), or dilated cardiomyopathy

d. LGMD 1C: caveolinopathy 1) CAV3 mutations on chromosome 3p25 encoding

caveolin-3; cause severe depletion of caveolin-3 from sarcolemma a) Caveolin-3: transmembrane protein of skeletal

muscle; associated with invaginations of plasma membrane involved in vesicle trafficking and signal transduction (Fig. 24-9)

b) Variants: mutations in caveolin-3 may cause asymptomatic elevation of creatine kinase (hyper CK-emia), a distal myopathy, or rippling muscle disease

2) Typical phenotype a) Early childhood onset b) Mild to moderate proximal weakness and calf

hypertrophy c) Cramps (often experienced after exercise) d) Calf hypertrophy

3) Intrafamilial variability 4) Creatine kinase: levels elevated 4-to 25-fold 5) Rippling muscle disease variant

a) Autosomal dominant inhieritance: linked to chromosome 1q41

b) Muscle pain and stiffness c) Myoedema d) Wave of involuntary contraction of muscle (electri-

cally silent) spreading from one region to another, precipitated by percussion

6) Muscle histopathology: characterized by decreased caveolin-3 staining of muscle fiber sarcolemma

e. LGMD 1D 1) Linked to chromosome 6q 2) Mild, predominantly proximal and slowly progressive

weakness 3) Cardiac manifestations: arrhythmias are common;

later, cardiomyopathy f. Bethlem myopathy

1) Autosomal dominant inheritance: many mutations identified (linked to chromosomes 21q and 2q); affected protein is collagen type VI

2) Age at onset: variable, usually congenital or childhood onset (adult onset reported)

3) Congenital onset: hypotonia (floppy infant), arthrogryposis, fetal movements may be decreased

4) Childhood onset: delayed motor milestones, “clumsy” gait, difficulty with running or other sports activities, difficulty rising from squatting position

5) Slow progression, some wheelchair use may be needed by 2/3 of patients older than 50 (range, 12-82 years)

6) Weakness: limb-girdle, later affecting anterior compartment (more than posterior compartment) muscles and extensors (more than flexors)

7) Flexion contractures at lateral four fingers, elbows, and ankles eventually present in all patients; usually apparent by end of first or second decade (there may be congenital contractures that resolve early)

8) Skeletal deformities: pectus excavatum, scoliosis, hypermobility of wrists and fingers evolving into contractures

9) Normal life expectancy 5. LGMD 2: autosomal recessive inheritance

a. LGMD 2A: calpainopathy 1) Mutation of calpain-3 protein (CAPN3 gene on chro-

mosome 15q15.1-q21.1): calcium-activated intracellular protease that may be involved in regulation of transcription and expression of genes involved in cell survival a) Mutation may cause apoptosis, with altered activi-

ty of the transcription factor NF-κB (nuclear factor κB) involved in cell survival

2) Age at onset: usually between ages 8 and 15 years (range, 2-40 years)

3) Delayed walking, “toe-walking” may be noted early on in disease

4) Slow progression, some wheelchair use usually needed 5) Symmetric weakness of proximal limb-girdle and

trunk muscles, including rectus abdominis, periscapular muscles, proximal arm and leg muscles; later involvement of ankle dorsiflexion and wrist extension

6) Selective atrophy of hip extensors and adductors 7) Quadriceps may be relatively spared until more

advanced disease stage 8) Facial and bulbar muscles spared 9) Minimal neck involvement

10) Cardiac function normal 11) Calf hypertrophy

12) Contractures around ankles, hips, knees, elbows mild and usually more prominent later with disease progression

13) Creatine kinase: levels may be elevated 10 to 100 times normal

14) Muscle histopathology: necrosis and regeneration, muscle fiber size variability, internal nuclei, type I muscle fiber predominance, lobulation of type I muscle fibers

b. LGMD 2B: dysferlinopathy 1) Mutations in dysferlin gene (DYSF) lead to either

LGMD 2B or Miyoshi myopathy 2) Age at onset: usually second to third decade of life 3) Mild phenotype, but phenotypic heterogeneity: typi-

cally pelvic-girdle weakness in legs (waddling gait), followed by involvement of arm

4) Relatively early involvement of distal muscles (relatively early involvement of gastrocnemius and soleus before tibialis anterior muscles)

5) Upper extremity muscles primarily affected include biceps brachii, with relative preservation of shouldergirdle muscle groups and periscapular muscles

6) With progression, most leg muscles may be affected 7) Loss of ambulation in the fourth decade 8) Creatine kinase: typically very high levels 9) Muscle histopathology: dystrophic changes (muscle

fiber size variation, degeneration, necrosis with fiber splitting, increased endomysial connective tissue) and dysferlin staining absent or reduced

c. Sarcoglycanopathies (LGMD 2C-2F) 1) Phenotype similar to Duchenne’s and Becker’s muscu-

lar dystrophies: similar pattern of weakness, associated with calf hypertrophy

2) Age at onset: generally earlier in life than other forms of LGMD; median age, 6 to 8 years (milder course of disease with adult onset)

3) Weakness initially detectable in pelvic girdle, proximal leg, followed by shoulder muscle groups (particularly deltoid, biceps, and infraspinatus muscles)

4) Progression to involve distal muscle groups (preferentially anterior compartment muscles such as tibialis anterior muscle) and trunk

5) Calf hypertrophy common 6) Early lordosis common because of early axial and

trunk muscle involvement 7) Macroglossia 8) Creatine kinase: severely elevated levels early in dis-

ease course, later levels decrease 9) Cardiac involvement common (often subclinical) in β-and δ-sarcoglycanopathies, rare in γ-and α-sarco-

glycanopathies d. LGMD 2G: telethoninopathy

1) Phenotypic heterogeneity 2) Atrophic myopathy: proximal and distal (predomi-

nantly anterior compartment) muscle groups 3) Childhood onset with progression noticed in the sec-

ond or third decade and wheelchair-bound by 30s or 40s

4) Creatine kinase: mildly elevated levels 5) Rimmed vacuoles seen on muscle biopsy and

telethonin absent from muscle e. LGMD 2I: fukutin-related proteinopathy

1) Mutation of the FKRP gene on chromosome 19q13.3, encoding fukutin-related protein

2) Phenotypic heterogeneity 3) Mutation of FKRP gene also causes congenital mus-

cular dystrophy with muscle hypertrophy and congenital merosin-deficient muscular dystrophy

4) Age at onset: may be infantile (with hypotonia and delayed motor milestones), childhood, or young adulthood (normal early motor milestones)

5) Weakness: predominantly pelvic girdle (also proximal upper extremities)

6) Facial weakness: rare 7) Macroglossia (most apparent in early-onset disease),

calf hypertrophy 8) Normal intelligence 9) Dilated cardiomyopathy

10) Respiratory insufficiency due to diaphragmatic weakness

11) Creatine kinase: high f. LGMD 2J: titinopathy

1) Genetics: mutation of gene coding for titin, on chromosome 2q31

2) Clinical phenotype of proximal limb-girdle weakness 3) Onset: usually in childhood, wheelchair-bound by

second decade 4) Creatine kinase: high levels

H. Distal Myopathies 1. Late adult-onset hereditary distal myopathies

a. Welander’s (late onset type I) distal myopathy 1) Late-onset distal myopathy 2) Autosomal dominant inheritance, linked to chromo-

some 2p13 (same locus for Miyoshi distal myopathy and LGMD 2B)

3) Mean age at onset: 47 years (range, 20-77 years) 4) Distal weakness: upper extremities more than lower

extremities 5) Intrinsic hand muscles and finger extensors affected

first; initial symptoms at onset include clumsiness of fine-finger movements

6) Distal lower extremity weakness affecting mainly anterior compartment; toe and ankle extensors (develops with progression)

7) Slow progression with normal life span 8) Mild sensory neuropathy, may be subclinical 9) Creatine kinase: normal or mildly elevated levels

10) Muscle histopathology: dystrophic changes consisting of increased variation in muscle fiber size, increased endomysial connective tissue, central nuclei, fiber splitting, rimmed vacuoles

b. Tibial (Finnish) muscular dystrophy (Udd myopathy, late adult-onset IIa) 1) Late-onset distal myopathy 2) Autosomal dominant inheritance, linked to chromo-

some 2q31 3) Age at onset: fourth decade or later (childhood onset

in homozygotes) 4) Selective involvement of distal lower extremity anteri-

or compartment (anterior tibialis); later, proximal lower extremity

5) Slow progression: footdrop becomes more prominent 6) Creatine kinase: normal or mildly elevated levels 7) Muscle histopathology: dystrophic changes with

rimmed vacuoles c. Markesbery-Griggs (late adult-onset type IIb) distal

myopathy 1) Late-onset distal myopathy 2) Autosomal dominant inheritance, linked to chromo-

some 10q 3) Affected protein: ZASP protein (Z band alternatively

spliced PDZ motif-containing protein) 4) With progression: proximal arm and leg weakness 5) Age at onset: after age 40 6) Distal weakness beginning in anterior compartment

of legs 7) Cardiomyopathy in some patients 8) Creatine kinase: normal or mildly elevated levels 9) Muscle histopathology: dystrophic changes with

rimmed vacuoles 10) Allelic variant: ZASP-related myofibrillar myopathy

2. Early adult-onset hereditary distal myopathies a. Nonaka distal myopathy (hereditary inclusion body

myopathy) 1) Early adult-onset distal myopathy 2) Autosomal recessive inheritance, due to mutation of

gene GNE on chromosome 9p (to date, 40 different mutations identified, most of which are missense mutations)

3) Original descriptions in Japan and Iranian Jewish families

4) Age at onset: usually second or third decade 5) Initial symptoms: gait disturbance and footdrop 6) Weakness with early and preferential involvement of

distal anterior compartment muscles (ankle dorsiflexors and toe extensors), followed by proximal limbgirdle muscles with sparing of quadriceps muscles (even with advanced disease)

7) Weakness in upper extremities: shoulder-girdle muscles, wrist extensors, and intrinsic hand muscles; relative sparing of deltoid muscles

8) Sparing of bulbar muscles 9) Neck flexor weakness

10) Usually wheelchair-bound about 20 years after onset 11) Creatine kinase: mildly elevated levels 12) Muscle histopathology: rimmed autophagic vacuoles

b. Distal dysferlinopathy (Miyoshi myopathy) 1) Early adult-onset distal myopathy (type II) 2) Autosomal recessive inheritance, due to mutation of

gene DYSF on chromosome 2p13 (coding for dysferlin)

3) Allelic with LGMD 2B 4) Asymptomatic patients may have mild muscular

wasting 5) Age at onset: usually early adulthood (ages 15-30);

mean age, 19 years 6) Slowly progressive weakness and atrophy of distal

lower extremities, preferentially affecting posterior compartment muscle groups, with prominent involvement of gastrocnemius muscles (may be asymmetric)

7) Anterior compartment muscles, forearm muscles, proximal upper and lower extremities may be affected as disease progresses; relative sparing of intrinsic hand muscles

8) Variable progression 9) 1/3 of patients may require wheelchair after 10 years

10) Proximal pelvic girdle weakness at onset is suggestive of allelic condition LGMD 2B

11) Creatine kinase: markedly elevated levels (20-150 times normal)

12) Muscle histopathology: dystrophic changes with evidence of necrosis and degeneration, regeneration, increased endomysial connective tissue, abnormal variation in size, and perimysial and perivascular inflammatory infiltrates observed in some

c. Laing distal myopathy 1) Early adult-onset distal myopathy (type III) 2) Autosomal dominant inheritance; due to mutation of

MHC7 gene encoding protein myosin heavy chain 7, linked to chromosome 14q

3) Other mutations of MHC7 can cause isolated hypertrophic cardiomyopathy

4) Age at onset: between 4 and 35 years 5) Distal weakness at onset, preferentially affecting distal

anterior compartment muscles (tibialis anterior), sternocleidomastoid muscle, and neck flexors

6) With progression: finger extensor weakness; later, hip and shoulder-girdle weakness; relative preservation of intrinsic hand muscles

7) Some patients have dilated cardiomyopathy 8) Muscle histopathology: nonspecific changes

3. Distal myopathy with vocal cord and pharyngeal weakness a. Autosomal dominant inheritance, linked to chromosome

5q31, same locus as LGMD 1A b. Age at onset: fourth to sixth decades c. Distal upper and lower extremities (asymmetric early

on), vocal cord, and pharyngeal weakness d. Lower extremity weakness usually starts in anterior

compartment e. Onset of vocal cord weakness (hypophonic, hypernasal

speech) usually after limb weakness f. Creatine kinase: normal or mildly elevated levels g. Muscle histopathology: rimmed vacuoles

I. Congenital Muscular Dystrophies 1. Autosomal recessive inheritance 2. Usually discovered at birth 3. Clinical course: variable (benign to death within first

decade) 4. Diffuse weakness and hypotonia on presentation at

birth 5. Associated with dysgenesis of brain and eye, especially

type II lissencephaly (neuronal overmigration into leptomeninges)

6. Fukuyama congenital muscular dystrophy (FMDC) a. Autosomal recessive inheritance; caused by mutation of

fukutin gene on chromosome 9q31 b. Gene product (fukutin) expressed in brain, skeletal and

cardiac muscle, pancreas, fetal Cajal-Retzius cells, and fetal cerebellum

c. Clinical course: marked by diffuse weakness, ocular manifestations, and central nervous system (CNS) involvement (mental retardation and seizures)

d. In utero: fetal movements may be poor e. Usually normal at birth, some have hypotonia, lack of

head control with “myopathic facies” (with open, inverted V-shaped mouth) due to facial diplegia

f. Presentation: typically in infancy, with severe weakness

and delayed development; never learn to walk, bedridden before age 10 (some may be able only to sit with support)

g. Mean life expectancy: 15 years h. Joint contractures develop during first year, initially

affecting ankles and knees i. Macroglossia by age 5 to 6 years j. Ocular manifestations: cataracts, strabismus, severe

myopia, abnormal extraocular movements, optic pallor and atrophy, retinal detachment

k. CNS manifestations 1) Mental retardation (usually severe) 2) Progressive hydrocephalus 3) Microcephaly 4) Seizures before age 3 years

l. CNS anatomic changes 1) Type II lissencephaly: pachygyria-agyria (overmigra-

tion of neuroblasts into leptomeninges, with occasional absence of gray matter lamination)

2) Ventriculomegaly 3) White matter: hypomyelination, diffuse lucencies 4) Hypoplasia of corticospinal tracts

m. Cardiac manifestations: dialted cardimyopathy, myocardial fibrosis, CHF may develop (usually in second decade)

n. Creatine kinase: usually markedly elevated levels o. Muscle histopathology: dystrophic changes (internal

nuclei, variability in fiber size, and fibrosis), with reduced expression of laminin α2, and severely reduced or absent glycosylated α-dystroglycan

7. Congenital muscular dystrophy with laminin α2 (merosin) deficiency (MDC 1A) a. Autosomal recessive inheritance; mutation of LAMA2

gene on chromosome 6q2, encoding laminin α2 protein b. Laminins

1) Extracellular proteins that bind to α-dystroglycans and integrins and interact with other extracellular proteins

2) Responsible for anchoring dystroglycan complex to extracellular matrix (discussed above)

c. In utero: fetal movements may be reduced d. At birth or infancy: hypotonia, poor feeding (poor swal-

lowing, difficulty chewing, gastroesophageal reflux); persists to some degree, leading to poor nutrition

e. Delayed motor development and contractures of feet and hips

f. Diffuse, symmetric, nonprogressive weakness affecting both proximal and distal limb muscle groups and facial muscles (distributed evenly)

g. Severity: variable (delayed onset and mild weakness in

mild forms, floppy infants with respiratory insufficiency in severe forms)

h. Normal mentation in most patients (some with learning disabilities, some with mental retardation)

i. MRI of head 1) Diffuse abnormal white matter signal, most severe in

frontal U fibers and periventricular area 2) Migration defects: cortical dysplasia, agyria,

polymicrogyria j. Creatine kinase: usually elevated levels k. Deficiency of laminin α2 demonstrated on immuno-

histochemical staining of muscle or skin punch biopsy specimens

8. Santavuori congenital muscular dystrophy (muscle-eyebrain disease) a. Autosomal recessive inheritance; mutation of

POMGnT1 gene on chromosome 1p32-p34 b. Gene product is glycosyltransferase O-mannose β1,2-N-

acetylglucosaminyltransferase 1, enzyme responsible for O-mannosyl glycosylation (mannosylation) of α-dystroglycan, required for binding between α-dystroglycan and laminin

c. Pathophysiology: related to deficient glycosylated αdystroglycan and deficient laminin α2 binding

d. Affected protein may also have role in neuronal migration, accounting for migration defects observed in this disorder

e. Phenotypic heterogeneity f. Neonatal hypotonia, visual dysfunction, moderate to

severe mental retardation g. Ocular manifestations and visual dysfunction causing

poor visual contact and recognition of relatives: severe myopia, cataracts, glaucoma, retinal dysplasia or detachment, optic colobomas

h. CNS structural malformations 1) Polymicrogyria and pachygyria-agyria 2) Features of dysmyelination: absent or partially absent

corpus callosum and septum pellucidum 3) Ventriculomegaly 4) Hypoplastic corticospinal tracts

9. Walker-Warburg syndrome (WWS) a. Autosomal recessive inheritance; often due to mutation

of POMT1 gene on chromosome 9q34 b. Mutation of POMT2 gene on chromosome 14q24.3 has

also been identified, with similar phenotype c. Gene product is an O-mannosyltransferase, important

for mannosylation of α-dystroglycan, together with Omannose β1,2-N-acetylglucosaminyltransferase noted above (the latter is deficient in muscle-eye-brain disease)

d. Pathophysiology: related to deficient glycosylated α-

dystroglycan and deficient laminin α2 binding, as in muscle-eye-brain disease

e. Syndrome of brain malformations, cerebellar malformations, retinal malformations, and congenital muscular dystrophy

f. Severe mental retardation and seizures g. Ocular malformations: unilateral or bilateral microph-

thalmia, cataracts, glaucoma, retinal detachment, ocular coloboma, hypoplastic or absent optic nerve

h. Muscular dystrophy usually present at birth: poor feeding and hypotonia

i. Creatine kinase: severely elevated levels j. CNS structural malformations: similar to those of other

congenital muscular dystrophies but more severe 1) Severe hydrocephalus 2) Encephaloceles (not reported in muscle-eye-brain dis-

ease or Fukuyama congenital muscular dystrophy) 3) Complete type II lissencephaly (overmigration into

leptomeninges) with pontocerebellar hypoplasia

A. General Characteristics of Periodic Paralysis (Table 24-2)

1. Autosomal dominant inheritance, with complete penetrance in men (about 50% in women)

2. Clinical manifestation: mainly periodic paralysis (intermittent weakness), muscle stiffness, and paramyotonia

3. Respiratory and cranial musculature relatively spared (exception: some hyperkalemic patients have facial muscle myotonia)

4. Clinical heterogeneity depends on a. The ion involved b. Properties of the ion channel (Table 24-3) c. Increased (myotonia) or decreased muscle excitability

5. In patients with sporadic periodic paralysis but no family history, other causes must be excluded (Table 24-4)

6. Serum potassium level during an attack may be normal, serial measurements may be needed

B. Periodic Paralysis Without Myotonia 1. Familial hypokalemic periodic paralysis (HypoPP)

a. HypoPP type I 1) Mutation of CACNL1AS gene on chromosome

1q31-32, encoding α1 subunit of dihydropyridinesensitive L-type calcium channel (substitution of positively charged arginine residues in voltage-sensitive S4 segment of domains II and IV)

2) Autosomal dominant inheritance

b. Possible mechanism of action 1) Reduced extracellular potassium concentration causes

prolonged depolarization in affected muscle (instead of normal hyperpolarization), triggering inactivation of sodium channels

2) Reduction of calcium influx into muscle, decreased activation of ryanodine receptors, decreased calcium release from sarcoplasmic reticulum stores, muscle hypoexcitability, and reduced muscle contraction

c. HypoPP type II: mutation of SCN4A gene on chromosome 17q13, encoding α subunit of sodium channel, mutation causes enhancement of sodium channel slow inactivation and delay of recovery after repolarization

d. HypoPP type III: mutation of KCNE3 gene on chromo-

some 11q13-14, encoding voltage-gated potassium channel β subunit

e. Similar phenotype observed with different genetic mutations

f. Age at onset 1) Usually adolescence or young adulthood (usually

fewer attacks after third decade) 2) Severe cases have onset in childhood; mild cases, later

age at onset (as late as third decade) g. Precipitating factors for attacks: heavy carbohydrate meal,

heavy exercise followed by period of rest, local anesthetic, fasting, dehydration, exposure to cold, administration of insulin, or other causes of increased insulin secretion

h. Characteristics of attacks

Table 24-2. Clinical and Electrophysiologic Features of Myotonic and Periodic Paralysis (PP) Disorders

Table 24-3. Classification of Channelopathies Associated With Periodic Paralysis

Table 24-4. Differential Diagnosis of Periodic Paralysis

1) Attack usually begins with sensation of heaviness or aching fatigue and progresses to weakness (proximal > distal); begins in most recently exercised muscles

2) Attacks are more severe and last longer (but less frequent) than hyperkalemic form

3) Weakness usually lasts several hours, but mild residual weakness may last for up to 3 to 4 days

4) Diurnal fluctuation: weakest during the night and early morning, best in midday

5) Attack may be severe and patient unable to move; the muscle may be electrically and mechanically inexcitable and reflexes lost at height of weakness

6) Respiratory function not usually compromised 7) Cranial musculature rarely affected 8) Affected muscle may feel swollen

i. Frequency of attacks 1) Typically occur once or twice weekly (less frequent

with increasing age) 2) Severe cases: attacks may be daily; may not be full

recovery between attacks k. Most patients develop permanent myopathy of variable

severity l. Diagnosis based on demonstration of weakness caused

by low levels of potassium (poor correlation between potassium level and clinical syndrome)

m. Potassium is released from muscle at end of an attack n. Low potassium levels between attacks suggest secondary

HypoPP o. Provocative maneuvers may be helpful (including oral

glucose load), continuous electrocardiographic (ECG) monitoring required

p. Genetic testing: preferred method of diagnosis q. Secondary causes of HypoPP: thyrotoxicosis, primary

hyperaldosteronism, potassium-depleting diuretics, gastrointestinal potassium wasting (diarrhea), renal potassium wasting, corticosteroid use, alcoholism, lithium

r. Muscle histopathology 1) May be normal or show minimal myopathic changes 2) Few vacuoles may be seen if permanent weakness

s. Treatment 1) Acute treatment with oral potassium 2) Prophylaxis with acetazolamide (prevention of attack

recurrence and improvement of weakness during each attack)

3) Dichlorphenamide (another carbonic anhydrase inhibitor)

4) Triamterene and spironolactone as adjunctive agents 5) Low sodium or low carbohydrate diets may be helpful

t. Prognosis and chances of permanent weakness: depends on frequency of episodic weakness

2. Thyrotoxic periodic paralysis a. Age at onset: usually between third and fifth decades b. Predisposition for Asians c. A secondary hypokalemic periodic paralysis d. Tendency to develop weakness with thyrotoxicosis may

be inherited as autosomal dominant e. Thyrotoxicosis usually precedes or occurs with the attack f. Symmetric proximal weakness most often affects legs

during attack g. Maximal weakness upon awakening h. Muscle stiffness and cramps precede weakness i. Respiratory and bulbar muscles relatively spared j. Symptoms of thyrotoxicosis k. Treatment

1) Acute attacks: replace potassium, avoid rebound hyperkalemia

2) Treat underlying thyroid disorder; propranolol for associated symptoms

3. Andersen’s syndrome a. Syndrome of periodic paralysis, cardiac arrhythmias,

dysmorphic features

b. Autosomal dominant inheritance, mutation of KCNJ2 gene on chromosome 17q23, encoding an inwardly rectifying potassium channel (Kir2.1)

c. Age at onset: usually childhood d. Some with permanent muscle weakness e. Cardiac dysrrhythmias: long QT syndrome, ventricular

extrasystoles f. Dysmorphic features: may include hypertelorism, broad

nose, low-set ears, short index finger, clinodactyly of fifth finger, syndactyly of toes, scoliosis, cryptorchidism

C. Sodium Channel Myotonias 1. Genetics and pathophysiology

a. Autosomal dominant inheritance with high penetrance in both sexes

b. Missense mutation affecting SCN4A gene (chromosome 17q23-25) encoding for α-subunit of the skeletal muscle sodium channel (SkM1, Nav1.4)

c. Four phenotypes (sodium channel myotonias): hyperkalemic periodic paralysis, paramyotonia congenita, potassium-aggravated sodium channel myotonias, and HypoPP type II

d. Potential mechanism: spontaneous reopening of mutant sodium channels after normal depolarization, causing increased sodium influx 1) Slight depolarization can cause hyperexitability and

myotonia 2) More prolonged depolarization causes paralysis and

inexcitability of muscle fiber 2. Familial hyperkalemic periodic paralysis (HyperPP)

a. Rest-induced or potassium-induced paralysis b. Age at onset: usually in childhood, but patients may

show signs and symptoms as early as first year of life c. Infantile onset: attacks may consist of a sudden change

in infant’s cry or infant may develop unusual stare with exposure to cold

d. First attack: usually in childhood, may be provoked by enforced sitting in school

e. Attacks 1) Usually frequent, focal, short duration (usually 15

minutes to 1-2 hours, up to 4-5 hours); may occur several times daily

2) Increase in frequency and severity with time 3) Milder and shorter duration than HypoPP 4) May be aborted by exercise early in episode 5) May be precipitated by exposure to cold, rest after

exercise or oral intake of potassium, emotional stress, pregnancy

6) May occur during sleep; may not be a precipitating factor f. Episodes more frequent when poor oral intake and high

potassium diet g. Severity of attacks may range from mild weakness (usual-

ly) and fatigue to severe paralysis h. Myotonia may or may not be present: generalized distri-

bution if present i. Serum potassium measured during an attack: not reli-

able; often normal but may be high or even low j. Creatine kinase: normal or slightly elevated levels k. Diagnosis by provocative testing: demonstration of

potassium sensitivity to potassium loading (infusion) 1) Potassium is administered shortly after exercise, and

patient is instructed to rest 2) Potassium levels are closely monitored 3) Generalized weakness occurs usually within 1 hour,

may last up to an hour, and may involve respiratory muscles

4) Must be avoided in patients with renal insufficiency 5) Continuous ECG monitoring is necessary for the

load 6) If negative, loading may be repeated

l. Muscle histopathology: usually normal, but vacuolar changes may eventually occur

m. Electrodiagnostic evaluation 1) CMAPs

a) Normal amplitude, with no decrement at slow or fast rates of repetitive stimulation

b) No change with cooling 2) Needle EMG

a) Myotonic discharges: long and slow discharges n. Secondary causes of HyperPP: renal failure, adrenal fail-

ure, potassium-sparing diuretics, hypoaldosteronism o. Treatment

1) Acute treatment may not be needed because of brevity of attacks

2) Ingestion of carbohydrates and sugars may prevent or abort attack

3) Prophylaxis with hydrochlorothiazide and carbonic anhydrase inhibitors (acetazolamide and dichlorphenamide)

3. Potassium-aggravated myotonia congenita (delayed myotonias): myotonia fluctuans and myotonia permanens a. Muscle stiffness provoked by exercise; has distinguishing

feature of initial nonmyotonic interval, unlike paradoxical myotonia (paramyotonia, discussed below)

b. “Warm-up phenomenon”: alleviation of muscle stiffness with continued muscle contraction and exercise (unlike paramyotonia)

c. Myotonia: variation in intensity, may be severe and cause patient to fall or to be unable to rise from a seated

position d. Stiffness occurs during rest after a period of exercise

(delayed) e. Exacerbation of myotonia when given potassium, and

improvement with administration of carbonic anhydrase inhibitors

f. Stiffness may affect rested muscles with quick movements such as quick saccades or forceful biting

g. Myotonic discharges on needle examination, not aggravated with cooling

h. Treatment: mexiletine and acetazolamide 4. Paramyotonia congenita

a. Autosomal dominant inheritance b. Mutation of gene SCN4A, encoding α-subunit of volt-

age-gated sodium channel c. Mutation affects fast inactivation and deactivation of

sodium channels, responsible for persistant membrane depolarization from cumulative increase of sodium flux during activation

d. Paradoxical myotonia: muscle stiffness or persistent involuntary muscle contraction after brief voluntary contraction that worsens with repeated muscle contraction or exercise (vs. true myotonia, in which repeated muscle contraction and exercise decrease muscle stiffness)

e. Muscle stiffness is extremely cold sensitive f. Age at onset: infancy or childhood g. Persistent eye closure or facial grimacing in infants after

crying or exposure to cold washcloth h. Weakness especially noted with exposure to cold i. Delayed opening of eyelids after repeated eyelid closure j. Action or percussion myotonia after limb cooling k. Electrodiagnostic evaluation

1) Nerve conduction studies a) Normal nerve conduction b) Decrement to slow repetitive stimulation when

muscles are cooled (uncommon at rest) c) Short exercise test when muscle is cooled: sudden

decrease in amplitude with slow subsequent recovery on warming (unlike myotonic syndromes or periodic paralysis)

2) Needle examination a) Rare myotonic discharges: long, slow discharges,

as with myotonic dystrophy b) Small motor unit potentials with fibrillation poten-

tials may be observed late in disease course, likely reflect pathologic changes described below

c) Response to cooling (in sequence): increase in fibrillation potentials (disappear below 28ºC), disappearance of myotonic discharges, and electrical silence (below 20ºC)

d) Rewarming: slow return of voluntary and spontaneous activity

e) Single fiber EMG: increased jitter, with blocking l. Muscle histopathology: unremarkable; possibly nonspe-

cific changes such as central nuclei, fiber size variation, and hypertrophic, atrophic, or regenerative fibers

m. Treatment 1) Avoidance of precipitating factors such as cold or

exercise 2) Patients may become weak with potassium depletion 3) Prophylactic treatment with sodium channel blockers

such as mexiletine or tocainide

D. Chloride Channel Myotonias: myotonia congenita 1. General characteristics

a. Genetics and pathophysiology 1) Due to mutations of gene CLCN1 on chromosome

7q, encoding sarcolemmal voltage-gated chloride channel

2) Chloride channels: responsible for chloride current that is activated by depolarization

3) About 70% of conductance in resting muscle is due to chloride ion currents

4) Chloride channels act as buffer and cause large chloride current flow when there is any deviation from the resting muscle membrane potential; this avoids any spontaneous discharges that could be produced by increased muscle excitability from accumulation of potassium ions in T tubules; this duration of depolarization of T tubules is limited by resting chloride current

5) Mutation affecting chloride channel can reduce chloride conductance and cause myotonic activity

6) Autosomal recessive myotonia congenita (Becker dystrophy): usually caused by loss of functional channel proteins (due to several different mutations, including deletions and missense mutations)

7) Autosomal dominant myotonia congenita (Thomsen’s disease): usually caused by loss of function (dominant negative effect) or gain of abnormal function (such as increasing sodium conductance)

b. Thomsen’s disease: autosomal dominant myotonia congenita 1) Painless myotonia may be present in infancy (more

severe in males) 2) Age at onset: usually first apparent in early

adolescence 3) Nearly normal strength, with normal or mildly

increased muscle bulk 4) Milder than recessive form

5) Family members may be asymptomatic or have mild symptoms

6) Clinical course: constant, nonprogressive, but may be variable

7) Repetitive muscle use and exercise restores strength 8) Creatine kinase: levels occasionally may be mildly

elevated c. Becker’s disease: autosomal recessive myotonia congenita

1) Weakness, possibly muscle wasting 2) Both myotonia and weakness can improve with repet-

itive muscle contraction and exercise 3) Myotonia presents later and is more severe and dis-

abling than in Thomsen’s disease 4) Myotonia often presents early in the second decade

(often between 10 and 14 years), may be slowly progressive

5) Creatine kinase: higher levels than in Thomsen’s disease

6) Muscle hypertrophy in upper and lower limbs d. Clinical features

1) Myotonic muscle stiffness: most prominent with forceful contraction, often after a period of rest, subsides after exercise

2) Delayed opening of eyelids after forceful contractions 3) Lid-lag phenomenon: observed with sudden down-

ward gaze, immediately after sustained upward gaze 4) Delayed opening of fist after forceful contractions 5) Percussion myotonia 6) “Warm-up phenomenon”: strength returns to nor-

mal; myotonia (and accompanying stiffness) is reduced with repetitive activity and exercise

7) Myotonia may be painless or painful 8) Myotonia may be subjectively exacerbated by cold

(not electrophysiologically) and may be found in face, tongue, and limbs

9) Muscle hypertrophy a) Apparent bulking of muscles with repetitive severe

myotonic contractions (“work hypertrophy”) b) Muscles usually well developed despite weakness

e. Electrophysiology 1) Slow repetitive stimulation causes small decrement in

CMAP amplitude a) After brief forceful contraction (exercise), decre-

ment disappears (but CMAP amplitude diminished) and later reappears and is exaggerated progressively

2) Fast repetitive stimulation also causes decrement in CMAP amplitude; there may be a late facilitation

3) No decrease in CMAP amplitude after cooling 4) Needle examination

a) Myotonic discharges: higher frequencies and shorter durations than those of myotonic dystrophy or paramyotonia congenita

b) Normal motor unit potentials c) During period of transient weakness after brief

forceful contraction: decrease in amplitude of motor unit potentials, there may be electrical silence

A. Disorders of Glycogen Metabolism: glycogen storage disorders (GSDs)

1. Type II glycogenosis (acid maltase deficiency) a. Genetics and pathophysiology

1) Autosomal recessive inheritance: deficiency of lysosomal acid maltase (α-1,4-glucosidase), gene locus on chromosome 17q21-23

2) Residual enzyme activity inversely correlates with disease severity and age at onset

3) A small amount of glycogen is normally present, continuously degraded to glucose by lysosomal acid maltase

4) With deficient acid maltase, glycogen accumulates in lysosomes and cytoplasm

5) Muscle fiber damage secondary to intracellular glycogen accumulation and possibly lysosomal rupture and release of lysosomal enzymes

b. Pompe’s disease (severe infantile form) 1) Age at onset: within first few months of life 2) Cardiomegaly, macroglossia, hepatomegaly 3) Progressive weakness and hypotonia within first 3

months of life (including feeding and neuromuscular respiratory difficulties)

4) Death: usually within first month, generally from respiratory failure

c. Childhood acid maltase deficiency 1) Age at onset: first decade of life 2) Delayed motor development 3) Slowly progressive proximal muscle weakness (more

than distal), respiratory muscle weakness, calf hypertrophy

4) Cardiomegaly and hepatomegaly uncommon 5) Associated with basilar artery aneurysms, possibly

because of glycogen deposition in arterial smooth wall 6) Cause of death usually respiratory complications, res-

piratory failure d. Adult-onset form of acid maltase deficiency

1) Age at onset: variable, usually in the third or fourth

decade 2) Partially deficient enzyme 3) Proximal muscle weakness and atrophy, with possible

involvement of face and tongue 4) Hip adductors and pectoralis major muscles (sternal

head) may be selectively affected more severely 5) Respiratory involvement: one-third present with res-

piratory insufficiency, almost all eventually have respiratory involvement (usual cause of death)

6) Possible macroglossia 7) Cadiomegaly or hepatomegaly not seen

e. Laboratory tests 1) Creatine kinase: mildly elevated levels (more promi-

nent in the infantile form) 2) Liver enzymes may be elevated in children 3) Acid maltase activity may be measured in muscle, cul-

tured fibroblasts, lymphocytes, urine 4) Cultured fibroblasts as confirmatory test for patients

with low leukocyte activity 5) Acid maltase enzyme activity on cultured amniotic

fluid cells for prenatal diagnosis 6) Electrophysiology

a) Low-amplitude CMAPs in atrophic muscles b) Rapidly recruiting short-duration motor unit

potentials with increased insertional activity, fibrillation potentials, and possibly myotonic discharges seen more often in proximal muscles and diaphragm

f. Muscle histopathology: autophagic vacuolar myopathy (strongly acid phosphatase positive) with accumulation of glycogen in vacuoles (Fig. 24-11)

2. Type V glycogenosis (McArdle’s disease): myophosphorylase deficiency a. Autosomal recessive inheritance b. Pathophysiology

1) Myophosphorylase initiates muscle glycogen breakdown (encoding gene is on chromosome 11q13)

2) Glycogen phosphorylase cleaves α-1,4 glycosidic bonds between glycosyl residues and degrades glycogen chains until four glycosyl residues remain before a branch point; debranching enzyme then removes branches, simplifying glycogen chain complex

3) Different mutations of the gene identified; all essentially cause reduced enzyme activity

4) Symptoms of exercise-induced fatigue and contractures may not be due to depleted ATP stores (there may be increased calcium sensitivity, increased extracellular potassium causing depolarization of muscle membrane, and increased intracellular adenosine diphosphate [ADP], inhibiting ADP dissociation

from actin-myosin cross-bridges) c. Age at onset: usually first decade d. Male predominance e. Presents with exercise intolerance f. Symptoms (usually noted with high-intensity activities

such as weight lifting): exercise intolerance, myalgia, cramps

g. Sensation of “hitting a barrier,” followed by muscle pain, cramps, possibly contractures (electrical silence on EMG) if exercise continues

h. “Second wind” phenomenon with low-intensity activities: reduced level of exercise after brief rest period following onset of muscle pain or cramps 1) Likely due to use of metabolism of fatty acids, instead

of glycogen metabolism, for source of acetyl-CoA i. Myoglobinuria, rhabdomyolysis, possibly renal failure j. Some patients may develop progressive proximal weak-

ness in adulthood as presentation k. One-third may have fixed weakness after age 40 (possibly

due to collective muscle damage) l. Laboratory tests

1) Creatine kinase: elevated levels (variable) 2) Hyperuricemia 3) Ischemic forearm exercise test

a) Intravenous catheter placed b) Baseline lactate and ammonia levels determined c) Blood pressure cuff placed (proximal to the

catheter) and inflated to approximately 20 mm Hg above systolic blood pressure

d) Exercise for 1 minute by rapid opening and closing of hand

e) Blood pressure cuff removed and serum lactate and ammonia levels measured at 1, 2, 4, 6, and 10 minutes

f) Normal response: 3-to 5-fold increase in lactate and ammonia levels

g) If neither level increases: test is inadequate and needs to be repeated

h) 3-to 5-fold increase in ammonia level without an increase in lactate level: suggests glycogen metabolism disorder

i) In glycolytic disorders, increase in ammonia level is often exaggerated

j) If the ischemic forearm test is abnormal, muscle biochemical analysis may be performed

4) Electrophysiologic studies a) Motor and sensory nerve conduction studies: usu-

ally normal interictally b) With permanent weakness, CMAP amplitude may

be reduced, may be myopathic small motor unit potentials

c) Electrical silence of severe muscle cramps and contractures

d) Decremental response after brief exercise or rapid stimulation (20 Hz for 50 seconds) because of energy failure and electrical silence in some muscle fibers

5) Muscle histopathology a) Subsarcolemmal and intermyofibrillary accumula-

tion of glycogen and vacuoles b) Type I fiber atrophy c) Occasionally, muscle necrosis and regeneration

m. Treatment 1) High protein diet for most patients 2) Better exercise tolerance may be achieved with admin-

istration of oral glucose or fructose loads or glucagon administration

3. Glycogenosis type III: Cori disease (debrancher deficiency) a. Genetics and molecular biochemistry

1) Autosomal recessive inheritance (chromosome 1p) 2) Glycogen branches are removed as follows:

a) Oligo-(α1,4-α1,4)-glucantransferase (glycosyl 4:4 transferase): removes outer three of four glycosyl units at end of each branch

b) Amylo-α-(1,6)-glucosidase activity removes remaining glycosyl unit that has α-1,6 linkage to glycogen complex

3) Debranching enzyme complex is responsible for

removing branches and simplifying glycogen chain complex, so ongoing glycogen myophosphorylase activity can further decrease glycogen chain

4) Deficiency of enzyme causes glycogen accumulation in muscle and, to some degree, in peripheral nerves

b. Clinical features 1) Disease types

a) GSD type IIIa (85%) i) Deficiency of the debrancher enzyme in both

liver and muscle ii) Slowly progressive weakness iii) Age at onset: usually third or fourth decade

b) GSD type IIIb (15%): liver involvement only i) Benign disease, presenting in infancy and child-

hood with hepatomegaly, failure to thrive, fasting hypoglycemia

ii) Some patients with liver failure 2) Infantile onset

a) Recurrent hypoglycemia, seizures, predominant liver dysfunction and hepatomegaly, severe cardiomegaly

b) Death before age 5 years 3) Childhood onset

a) Liver dysfunction and hepatomegaly, seizures, recurrent hypoglycemia, growth retardation

b) Transient muscle weakness, resolves by puberty 4) Adult onset

a) Age at onset: after third decade b) Slowly progressive muscle weakness and atrophy

(distal or proximal) c) Liver dysfunction and mild cardiomyopathy may

be seen d) 50% of patients: myalgias, muscle cramps, stiff-

ness, and exercise intolerance e) Associated with distal sensorimotor

polyneuropathy c. Laboratory features

1) Muscle, fibroblasts, or lymphocyte biochemical assays 2) Creatine kinase: elevated levels at rest, 5 to 45 times

normal 3) ECG: may show conduction defects and arrhythmias

(echocardiography may show ventricular hypertrophy)

4) Electrophysiology a) Nerve conduction studies: may show axonal neu-

ropathy (caused by glycogen accumulating in peripheral nerves)

b) Needle examination i) May show combination of denervation and

myopathic features distally

ii) Myopathic features with fibrillation potentials, complex repetitive discharges, and myotonic discharges

5) Muscle histopathology: vacuolar myopathy with abnormal subsarcolemmal and intermyofibrillary glycogen accumulation; similar to acid maltase deficiency except for poor acid phosphatase staining, suggesting glycogen accumulation is not primarily lysosomal

4. Glycogenosis type IV: Andersen’s disease (branching enzyme deficiency) a. Pathophysiology and genetics

1) Autosomal recessive inheritance (linked to chromosome 3)

2) Mutation of 1,4-α-glucan branching enzyme (responsible for production of branched glycogen molecule)

3) Result: accumulation of abnormal linear glycogen chains with few branch points

b. Phenotypic heterogeneity c. Liver disease predominates clinical picture d. Infantile and childhood onset: rapidly progressive disor-

der with splenomegaly, hepatomegaly (with cirrhosis and liver failure), and sometimes muscle weakness and atrophy with hypotonia

e. Death: usually before age 4 years, usually from liver failure or gastrointestinal tract bleeding

f. Hydrops fetalis may occur if congenital g. Cardiomegaly in some patients h. Primarily CNS involvement: polyglucosan body disease

phenotype; adults with progressive upper and lower motor neuron weakness, sensory neuropathy, cerebellar ataxia, and dementia

i. Laboratory features 1) Creatine kinase: levels sometimes elevated 2) Electrodiagnostic evaluation may show features of

axonal sensorimotor peripheral neuropathy in adults 3) Muscle histopathology: polyglucosan bodies (PAS-

positive filamentous polysaccharide deposition) in CNS, peripheral nerves, muscle, skin, liver

j. Treatment: liver transplantation may be beneficial, especially for children with liver cirrhosis and portal hypertension

5. Glycogenosis type VII: phosphofructokinase deficiency (Tarui’s disease) a. Autosomal recessive inheritance b. Absence or reduced phosphofructokinase levels in muscle

or red blood cells c. Several mutations identified in gene for M isoform of

phosphofructokinase on chromosome 1 d. Clinical features similar to McArdle’s disease (exercise

intolerance with muscle pain, cramps, contractures) e. Male predominance (9:1) f. Age at onset: usually second to fourth decades g. Exercise intolerance, with muscle pain, cramps, contrac-

tures, “second wind phenomenon,” and myoglobinuria, similar to McArdle’s disease but less severe and less frequent

h. Exercise intolerance may be exacerbated with high carbohydrate meals, which may reduce serum free fatty acid levels

i. Late onset: fixed proximal (occasionally scapuloperoneal) myopathy, usually with exercise intolerance when younger

j. Other features: hemolytic anemia, hyperuricemia and gout, hyperbilirubinemia, gastric ulcers, hepatomegaly

k. Other variants 1) Severe infantile form with fixed weakness, respiratory

failure, cardiomyopathy a) Some with arthrogryposis, corneal clouding,

seizures, cortical blindness 2) Hemolytic anemia without myopathy

l. Laboratory features 1) Creatine kinase: high levels 2) Hyperbilirubinemia 3) Hyperuricemia (due to degradation of ATP to adeno-

sine monophosphate [AMP], which is metabolized to uric acid and other purine metabolites)

4) No lactate level increase on ischemic exercise test 5) Diagnosis: biochemical and histochemical analysis

demonstrating phosphofructokinase deficiency and reduced activity and staining

m. Muscle histopathology 1) Subsarcolemmal glycogen accumulation and vacuoles 2) Glycogen content may be normal or high 3) Myopathic dystrophic changes 4) PAS-positive polysaccharide bodies possible

B. Lipid Metabolism and Related Disorders 1. Physiology of lipid metabolism

a. Mobilization of fatty acids 1) Free fatty acids (FFAs) move through adipocyte cell

membranes and are bound immediately by albumin 2) Albumin-bound FFAs are transported to muscle and

other tissues, where they are oxidized for ATP generation

b. Transport of FFAs across inner mitochondrial membrane 1) First, FFAs must be transferred across inner mito-

chondrial membrane to be oxidized 2) Long-chain FFAs do not readily pass mitochondrial

membranes and must be modified (unlike short-

chain and medium-chain FFAs) 3) Long-chain FFAs first combine with coenzyme (CoA)

in reaction catalyzed by acyl CoA synthetase to make fatty acyl CoA

4) Fatty acyl CoA combines with cytosolic carnitine in reaction catalyzed by carnitine palmitoyltransferase 1 (CPT1) located on outer mitochondrial membrane, producing free CoA released into cytosol and fatty acyl carnitine

5) Fatty acyl carnitine complex is transported across inner mitochondrial membrane in exchange for carnitine, the latter being transported out of mitochondrion in opposite direction to combine with another fatty acyl CoA

6) Fatty acyl carnitine complex (now inside mitochondrion) combines with free CoA in reaction catalyzed by carnitine palmitoyltransferase 2 (CPT2) located on inner mitochondrial membrane, producing fatty acyl CoA and free carnitine, which is transported outside mitochondrion in exchange for another fatty acyl carnitine complex

c. β-Oxidation of FFAs 1) Repetitive series of enzymatic reactions to eventually

break down fatty acyl CoA to acetyl CoA 2) Occurs inside mitochondrial matrix 3) Each acetyl CoA provides 12 ATP molecules when

converted into carbon dioxide and water by Krebs’ cycle

4) Reactions of β-oxidation also yield NADH and reduced form of flavin adenine dinucleotide (FADH2), which provide ATP when oxidized by electron transport chain

2. General characteristics of disorders of fatty acid metabolism a. Failure of FFA oxidation to meet increased metabolic

demand b. Failure of long-chain FFA transfer across mitochondrial

membrane makes this unavailable for use by affected tissue; may cause abnormal accumulation of excess FFAs and chronic myopathy (lipid storage myopathy) or cause rhabdomyolysis and myoglobinuria when metabolic demand increases

c. Defective long-chain FFA metabolism: more severe presentation than lipid storage diseases involving short-or medium-chain FFAs

d. Symptomatic hypoglycemia: reduced synthesis of acetyl CoA reduces ketogenesis (reduced ketones in times of increased metabolic demand), causing increased use of peripheral glucose

e. Cardiac and skeletal muscles depend on metabolism of

long-chain FFAs for energy: dysfunction produces myopathy and cardiomyopathy

f. With exercise (increased metabolic demand), glycogen stores and plasma glucose are depleted, rhabdomyolysis may occur

g. Symptoms are induced by 1) Exercise 2) Fasting (in which predominant energy source is

ketones) 3) Exposure to cold and body’s natural response to

increase core temperature, including shivering (muscle metabolism highly dependent on oxidation of long-chain FFAs); rhabdomyolysis may occur

4) Infection 3. Carnitine deficiency

a. Secondary carnitine deficiency: organic acidurias, mitochondrial respiratory chain defects, malnutrition, renal failure, medications (including valproate)

b. Primary carnitine deficiency: primary defect of carnitine transport system (two phenotypes: primary systemic carnitine deficiency, primary muscle carnitine deficiency)

c. Autosomal recessive inheritance (primary carnitine deficiency)

d. Primary muscle carnitine deficiency 1) Slowly progressive cardiomyopathy (dilated or

hypertrophic) 2) Myopathy: progressive proximal weakness with atro-

phy, worsens during pregnancy 3) Not associated with encephalopathy

e. Primary systemic carnitine deficiency (age at onset: 3 months-2 years) 1) Recurrent episodes of encephalopathy related to

hypoglycemia and hypoketonemia 2) Hepatomegaly 3) Muscle involvement: progressive proximal myopathy,

not a prominent feature f. Reduced plasma and tissue carnitine levels in primary

systemic and secondary carnitine deficiency (only muscle carnitine levels decreased in primary muscle carnitine deficiency)

g. Creatine kinase: normal or elevated (especially with fasting) levels

h. Urine ketones are elevated with fasting i. Treatment: oral carnitine supplementation

4. CPT2 deficiency a. Autosomal recessive inheritance b. CPT2 deficiency type 1

1) Most common disorder of lipid metabolism 2) Juvenile-adult onset 3) Myoglobinuria (induced by exercise, fever, exposure

to cold, fasting, low carbohydrate/high fat diet, concurrent treatment with valproate)

4) Muscular pain and stiffness induced by exertion and exercise, may be followed by myoglobinuria and weakness if continued presence of precipitating factor

5) Severe myoglobinuria may cause acute tubular necrosis

6) Malignant hyperthermia induced by general anesthesia or postoperative myoglobinuria reported: may be prevented by intravenous glucose before and during general anesthesia

7) Creatine kinase a) Normal or mildly elevated (50%) levels between

episodes b) High levels with rhabdomyolysis

c. CPT2 deficiency type 2 1) Infantile onset 2) Severely affected phenotype (often fatal): may present

with seizures, coma, respiratory distress 3) Static encephalopathy may result from hypoglycemic

episodes 4) Psychomotor developmental delay 5) Hepatomegaly 6) Cardiomegaly, cardiac arrhythmias 7) Laboratory analysis: hypoketotic hypoglycemia, ele-

vated liver enzymes, increased plasma creatine kinase, and often low plasma levels of carnitine

d. CPT2 deficiency type 3 1) Neonatal onset 2) Most severe CPT deficiency phenotype 3) Hyporeflexia, hypotonia, seizures, respiratory distress,

generalized seizures, lethargy 4) Laboratory findings: hypoketotic hypoglycemia,

hyperammonemia, metabolic acidosis

A. Mitochondrial Genetics 1. Maternal inheritance of disorders linked to mutations of

mitochondrial DNA (mtDNA), with minor exception of paternal transmission of mtDNA in skeletal muscle

2. Most mitochondrial proteins encoded by nuclear DNA 3. Mutations in mtDNA are more likely to cause mito-

chondrial phenotypic disease than mutations of nuclear mtDNA because mtDNA a. Lacks introns b. Some lack termination codon c. Rapid replication with lack of proofreading and muta-

tion rate greater than nuclear DNA

d. Poor repair mechanisms 4. Mutant mitochondrial genomes passed on randomly to

daughter cells during mitosis or meiosis a. Normal homoplasty: daughter cells contain no mutant

mitochondrial genomes b. Mutant homoplasty: daughter cells contain predomi-

nantly mutant mitochondrial genomes c. Heteroplasty: daughter cells contain some mutant

genome (variable distribution of mtDNA mutations in different cells or tissues)

5. Variability of phenotypic expression depends on a. Proportion of mutant mitochondria within each cell b. Threshold effect

1) Proportion of mutant genome needs to be above a certain threshold to cause clinical manifestation

2) Tissue-specific thresholds c. Segregation: during cell division, relative cellular propor-

tion of mutant mtDNA may shift between generations d. Genetic and phenotypic heterogeneity within individual

and families with identical mutations

B. Pathology 1. Abnormal mitochondria seen with modified Gomori

trichrome staining: subsarcolemmal accumulation of abnormal mitochondria, “ragged red” appearance (hence, “ragged red fibers” [RRFs])

2. Cytochrome oxidase (COX) stain: affected by mtDNA mutations, unstained muscle fibers indicate mitochondrial disease

3. Succinate dehydrogenase (SDH) stain: affected by nuclear DNA mutations, dark staining of muscle fibers with mitochondrial accumulation (“ragged blue fibers,” SDH equivalents of RRFs)

C. Myoclonic Epilepsy With Ragged Red Fibers (MERRF)

1. Genetics a. Mitochondrial inheritance b. Most affected individuals have point mutations of mito-

chondrial genome (mtDNA) affecting the transfer RNA gene

2. Clinical features (variable phenotypic expression) a. Age at onset: late adolescence to early adulthood b. Proximal muscular weakness c. Myoclonus, at rest or stimulus-sensitive d. Generalized seizure disorder (including myoclonic and

generalized tonic-clonic seizures), may be photosensitive e. Ataxia, dementia, hearing loss (40% of patients), optic

atrophy (20%) f. Distal sensorimotor peripheral neuropathy

g. Other: short stature (10% of patients), multiple lipomatoses, cardiomyopathy

h. No ptosis or ophthalmoplegia 3. Laboratory features

a. Creatine kinase: normal or slightly elevated levels b. Serum lactate: elevated levels c. Epileptiform activity on electroencephalography (EEG) d. Pathology: also includes neuronal loss and gliosis of red

nucleus, substantia nigra, inferior olivary nuclei, optic nerves

e. Neuroimaging evidence of cerebral or cerebellar atrophy, with latter corresponding with degenerative changes in cerebellar hemispheres and dentate nucleus

4. Muscle histopathology a. RRF on modified Gomori trichrome stain b. Reduced or absent COX staining

D. Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)

1. Associated with several mtDNA point mutations (genetic heterogeneity)

2. Clinical features (phenotypic heterogeneity) a. Age at onset: usually in childhood (range, 3-40 years) b. Proximal muscle weakness (87% of patients) and atro-

phy (Fig. 24-12) c. Easy fatiguability (15%-18% of patients) d. Episodic encephalopathy (nonfocal) characterized by

headaches, vomiting, seizures, loss of consciousness e. Stroke-like focal episodes

1) Focal events that do not conform to arterial vascular territory

2) May represent neuronal hyperexcitability f. Recurrent headaches g. Seizures h. Short stature i. Normal early developmental milestones with eventual

dementia in some cases j. Other features (less common): myoclonus, hearing loss,

optic atrophy, pigmentary retinopathy, cardiomyopathy with CHF, progressive external ophthalmoplegia, diabetes mellitus

3. Neuroimaging characteristics a. Basal ganglia calcification b. Cerebral, cerebellar, and brainstem atrophy c. MRI

1) Multifocal laminar cortical areas of high T2 signal with some involvement of juxtacortical white matter and relative sparing of deep white matter

2) Normal or increased signal on apparent diffusion coefficient maps in region of acute stroke-like event

(in contrast to ischemic infarction): supports a metabolic insult as the underlying pathophysiology

d. Proton magnetic resonance spectroscopy: region of acute stroke-like event may have increased lactate/creatine ratio and decreased N-acetylaspartate/creatine ratio

4. Muscle histopathology (Fig. 24-12) a. RRFs on modified Gomori trichrome stain b. Unlike other disorders caused by mtDNA, RRFs react

with COX staining 5. Management

a. Treatment strategies 1) Supplementation of respiratory chain components 2) Removal of noxious metabolites 3) Administration of artificial electron acceptors

b. Coenzyme Q10 1) Theoretically may help in transference of electrons

from complexes I and II to III 2) Possible decrease in lactate and pyruvate levels in cere-

brospinal fluid (CSF) c. Dichloroacetate

1) Targets the lactate accumulating in tissues 2) Inhibits phosphorylation of pyruvate dehydrogenase

complex, leaving active form free to oxidize pyruvate to acetyl CoA

3) Acts to decrease levels of pyruvate available for conversion into lactate

d. Genetic counseling

E. Kearns-Sayre Syndrome 1. Molecular genetics

a. Single large mtDNA mutations of varying size b. Usually sporadic (rarely inherited)

2. Clinical features a. Age at onset: 20 years or younger b. Progressive external ophthalmoplegia c. Retinitis pigmentosa d. Heart block and arrhythmias e. Proximal muscle weakness f. Short stature g. Sensorineural hearing loss h. Dementia i. Ataxia j. Endocrinopathies (e.g., diabetes mellitus) k. Potential for respiratory insufficiency and decreased ven-

tilatory drive with CNS depressants, surgery, and infection

3. Laboratory features a. Elevated levels of serum lactate and pyruvate and CSF

protein b. Nerve conduction studies: normal, rarely axonal

nant and maternally inherited forms; sporadic subtype may be variant of Kearns-Sayre syndrome

b. Age at onset: childhood or adolescence c. Gradual progression d. Ptosis and external ophthalmoplegia with or without

muscle weakness e. No systemic manifestation, including cardiac involve-

ment, endocrinopathy, retinopathy f. Potential for respiratory insufficiency and decreased ven-

tilatory drive with CNS depressants, surgery, and infection

2. Laboratory features a. Creatine kinase and lactate: normal or elevated levels b. CSF protein: concentration may be increased

polyneuropathy c. EMG: may show myopathic motor unit potentials

4. Muscle histopathology a. RRFs seen on modified Gomori trichrome stain b. COX-stained fibers are reduced or absent

5. Treatment a. Specific treatment for complications, e.g., hormone

replacement for endocrinopathies, pacemaker insertion for cardiac conduction defects

b. Poor prognosis

F. Progressive External Ophthalmoplegia 1. Clinical features

a. Genetically heterogeneous: may have autosomal domi-

c. EMG: may show myopathic motor unit potentials 3. Treatment: treat complications

G. Autosomal Recessive Cardiomyopathy and Ophthalmoplegia

1. Autosomal recessive inheritance; mutation may involve nuclear genes regulating mitochondrial genome

2. Childhood-onset progressive external ophthalmoplegia 3. Facial and proximal limb muscle weakness 4. Cardiomyopathy 5. No other systemic manifestations 6. Myopathic motor unit potentials and RRFs

H. Mitochondrial DNA Depletion Syndrome 1. Autosomal recessive involving nuclear genes responsible

for regulating mitochondrial genome 2. Fatal infantile myopathy

a. Severe early-onset form b. Begins at birth with generalized hypotonia, proximal more

than distal progressive weakness, feeding difficulties, respiratory failure, and death (usually within first year of life)

c. Other features may include ptosis, ophthalmoplegia, peripheral neuropathy, renal tubular necrosis, seizures, liver failure, cardiomyopathy

3. Benign infantile myopathy a. Severe early onset of weakness, hypotonia, and respiratory

and feeding difficulties b. Improvement in strength during first year, with some

possible delay in motor development c. Usually normal life expectancy

I. Focal Mitochondrial Depletion 1. Autosomal recessive inheritance 2. Phenotypic heterogeneity 3. Clinical presentation can range from infantile onset

hypotonia, weakness, developmental delay to adolescent to adult onset of proximal muscle weakness and myoglobinuria and fatigue

J. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

1. Mutations in mtDNA and chromomosome 22 2. Age at onset: usually before 20 years 3. Earliest sign referable to gastrointestinal dysmotility 4. Generalized weakness and atrophy most prominent

distally 5. Sensory neuropathy 6. Ophthalmoplegia, ptosis, retinal degeneration 7. Hearing loss, facial weakness, dysarthria, hoarseness 8. Mental retardation

9. Ataxia 10. MRI: leukoencephalopathy involving cerebral and

cerebellar white matter 11. EMG: neuropathic and myopathic motor unit

potentials 12. Muscle biopsy: RRFs with increased NADH and

SDH staining 13. Abnormal mitochondria with paracrystalline inclu-

sions in muscle fibers and Schwann cells 14. Neuronal loss and fibrosis in autonomic ganglia and

celiac, myenteric, and Auerbach’s plexuses

A. General Concepts 1. Epidemiology

a. Dermatomyositis affects children and adults (more frequently females)

b. Polymyositis affects adults and rarely children c. Inclusion body myositis occurs more frequently in adults

older than 50 (three times more frequent in men than women, more common in whites than African Americans)

2. Proximal weakness with subacute monophasic or polyphasic clinical presentation a. Weakness of neck flexor, limb-girdle, and proximal

muscles b. Inclusion body myositis may present insidiously, involv-

ing predominantly finger flexors, hip flexors, quadriceps (latter spared in familial form, Nonaka distal myopathy); may be asymmetric

3. Progression: subacute (over weeks or months) for polymyositis and dermatomyositis, slow for inclusion body myositis

4. Facial muscles normal in polymyositis and dermatomyositis (except for advanced cases); mild facial weakness may be seen in up to 60% of cases of sporadic inclusion body myositis a. Marked facial weakness is not expected and raises possi-

bility of another diagnosis 5. Esophageal dysmotility and dysphagia (due to involve-

ment of striated muscle of pharynx and upper esophagus) observed in up to 30% of patients with polymyositis and dermatomyositis and up to 60% of those with inclusion body myositis

6. Muscular atrophy and wasting and reduced deep tendon reflexes, with severe weakness and prolonged progression

7. Other associated features

a. Respiratory involvement: generalized respiratory muscle weakness and interstitial lung disease (anti-tRNA synthetase [Anti-Jo-1] antibody present in up to 50% of patients with interstitial lung disease)

b. Cardiac involvement (nonspecific ST-T changes, bundle branch block, and arrhythmias)

8. Creatine kinase: usually elevated levels but may be normal or mildly elevated in long-standing cases such as inclusion body myositis

9. Antibodies associated with primary myositis syndromes a. Anti-Jo-1 (anti-histidyl-ERNA synthetase) antibodies:

observed in 20% of patients with dermatomyositis and polymyositis, associated with interstitial lung disease, associated with relatively severe disease phenotype

b. Anti-signal recognition particle: observed in 5% of patients (specificity of 93% when present)

c. Anti-Mi-2: associated with 15% to 35% of patients with dermatomyositis and 5% to 9% of those with polymyositis; associated with relatively mild disease phenotype

10. Antibodies associated with overlap syndromes a. Anti-PM/Scl (IgG) antibody: observed in 24% of

patients with polymyositis/scleroderma overlap syndrome; up to 88% of seropositive patients have this overlap syndrome

b. Anti-Ro/SSA antibodies and anti-La/SSB: associated with Sjögren’s syndrome and corresponding overlap syndrome

c. Anti-U1 snRNP: nonspecific antibody associated with overlap syndromes of systemic lupus erythematosus, systemic scleroderma, rheumatoid arthritis, or mixed connective tissue disease

d. Anti-U2 snRNP: associated with scleroderma 11. Immunopathogenesis

a. Polymyositis and inclusion body myositis 1) Cytotoxicity mediated by cytotoxic CD8+ T cells:

release perforins and granzyme granules, causing muscle fiber necrosis

2) Cell death by apoptosis has a small role, given strong anti-apoptotic mechanisms

3) Nonimmune degenerative processes in inclusion body myositis a) Presence of amyloid deposits in some vacuolated

muscle fibers b) Accompanied by β-amyloid precursor protein,

chymotrypsin, apolipoprotein E, and phosphorylated tau

c) Mitochondrial abnormalities and mitochondrial deletions in 70% of muscles affected by inclusion body myositis (importance unclear)

b. Dermatomyositis

1) Humoral attack on endomysial blood vessels and capillaries, causing early changes in endothelial cells (obliteration, necrosis, thrombi)

2) Changes mediated primarily by activation of complement and deposition of C5b-9 complement membrane attack complex on small blood vessels, followed by induction of cytokines and endothelial expression of cell adhesion molecules

3) Vascular endothelial injury leads to destruction of capillaries, microinfarctions, muscle fiber destruction, and perifascicular atrophy

12. Risk of malignancy a. Highest risk in adults with dermatomyositis b. 30% to 40%: overall risk of developing malignancy with

dermatomyositis (most commonly, ovarian and lung) c. 15%: overall risk of developing malignancy with

polymyositis (most commonly, lymphoma [nonHodgkin’s] and lung)

13. Treatment of inflammatory myopathies a. Corticosteroids (first-line treatment, usually prednisone):

weakness usually improves after the creatine kinase normalizes; patients initially may receive high-dose methylprednisolone or dexamethasone

b. Second-line treatment: azathioprine, methotrexate, mycophenolate mofetil

c. Third-line treatment: cyclosporine, cyclophosphamide, intravenous immunoglobulin, and plasma exchange

d. Same approach can be taken for treating inclusion body myositis: treatment has been shown to provide benefit or to slow disease progression

B. Polymyositis 1. Idiopathic

a. Symmetrical proximal weakness, including neck muscles b. Associated with myalgias and elevated creatine kinase

levels c. Oculopharyngeal and esophageal involvement:

dysphagia d. Cardiac involvement e. Respiratory involvement f. EMG: positive sharp waves, fibrillation potentials, rapid

recruitment of short-duration polyphasic motor unit potentials

2. Overlap syndromes a. Myositis secondary to systemic inflammatory illness and

not as a consequence of disuse atrophy or chronic corticosteroid use

b. Younger age at onset (mean, 35 years) c. Predominantly females d. Treatment may be modified according to underlying

condition e. Prognosis depends on underlying condition f. Scleroderma-myositis

1) Systemic features: Raynaud’s phenomenon, thick shiny skin, gastrointestinal tract dysmotility, cardiac involvement (pericarditis, myocardial fibrosis), sensorimotor peripheral neuropathy

2) Localized or systemic 3) Mild, nonprogressive weakness 4) Creatine kinase: normal or mildly elevated levels 5) Positive antinuclear antibody (ANA) and anti-PM/Scl

(IgG) antibody g. Mixed connective tissue disease

1) Clinical features of dermatomyositis with systemic lupus erythematosus and scleroderma

2) Edema of hands 3) Lupus-like erythematous rash 4) Raynaud’s phenomenon 5) Hepatosplenomegaly, lymphadenopathy 6) Synovitis 7) Myositis (often severe), myalgias 8) Pulmonary involvement common

h. Other associated inflammatory conditions: mixed connective tissue disease, systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis

3. Anti-Jo-1 antibody syndrome (anti-synthetase syndrome) a. Polymyositis associated with anti-Jo-1 antibodies (IgG1

antibodies targeted at histidyl tRNA synthetase) b. 20% to 25% of patients with polymyositis have anti-Jo-1

antibodies c. Patients with polymyositis and interstitial lung disease:

antibodies positive in 50% to 75%, negative in 20% to 25%

d. Predominantly females e. Proximal symmetric myopathic weakness with myalgias,

systemic features including seronegative, nonerosive arthritis and Raynaud’s phenomenon (associated with relatively severe muscle and systemic disease)

f. “Mechanic’s hands”: thickening of skin over hands and fingers

g. Pulmonary involvement: interstitial lung disease h. Other laboratory markers: elevated creatine kinase level,

erythrocyte sedimentation rate, and ANA and anti-Ro52 titers

i. Linked to DR3, DRw52, DQA1*0501 HLA haplotypes j. Pulmonary disease may be responsive to corticosteroids

4. Muscle histopathology of polymyositis (Fig. 24-13) a. Invasion and destruction of nonnecrotic muscle fibers by

endomysial, perimysial, and perivascular mononuclear

inflammatory cell aggregates (T cells and macrophages) with characteristic autoaggressive behavior (as compared with perivascular inflammation in dermatomyositis)

b. Nonspecific findings: necrotic and regenerating muscle fibers, increase in central nuclei, muscle fiber size variation

c. Lack of perifascicular atrophy, microvascular injury, microvascular deposition of membrane attack complexes, and endothelial hyperplasia and inclusions (microtubules)

C. Dermatomyositis 1. Characteristic heliotrope rash accompanying or preced-

ing weakness a. Primarily involves periorbital regions (associated with

periorbital edema), anterior neck and upper chest (V sign), shoulders (shawl sign), buttocks, and extensor surfaces of fingers (Gottron’s sign), knuckles (Fig. 24-14), elbows, and knees

b. Erythematous, scaly periungual regions c. Calcinosis: subcutaneous calcifications in up to 50% of

children affected d. Rash may occur without muscle involvement

2. Proximal pattern of muscle weakness and myalgias 3. Other organs involved

a. Cardiac involvement: pericarditis, myocarditis, cardiomyopathy with CHF

b. Pulmonary involvement: interstitial lung disease associated with antibodies to histidyl tRNA synthetase (Jo-1)

c. Other systemic vasculitic manifestations may include gastrointestinal involvement, renal involvement, or other systemic features (e.g., arthralgias)

4. Laboratory features a. Creatine kinase: usually elevated levels, poor correlation

with severity of weakness b. Other markers that potentially may be elevated:

aldolase, myoglobin, lactate dehydrogenase, erythrocyte sedimentation rate, ANA, myositis-specific antibodies (specific HLA haplotypes), anti-Jo-1 antibodies (often with interstitial lung disease)

5. Muscle histopathology of dermatomyositis (Fig. 24-15) a. Characteristic perifasicular atrophy, microvascular injury,

microvascular deposition of membrane attack complex, endothelial microtubular inclusions and hyperplasia (arterioles and capillaries), ongoing endothelial injury and regeneration

b. Perimysial inflammatory cell aggregates (least prominent in endomysial region) consist of B and CD4+ T lymphocytes

D. Inclusion Body Myositis 1. Clinical features

a. Age at onset: typically older than 30 years b. Common presentation: slowly progressive painless

weakness (variable distribution) c. Weakness involves both proximal and distal muscles,

with characteristic distribution of weakness affecting finger and wrist flexors (more than wrist extensors) and quadriceps muscles

d. Muscle atrophy may be proportional to weakness (Fig. 24-16)

e. Duration of illness: usually more than 6 months, slowly progressive course

2. Laboratory features a. Creatine kinase: normal or mildly elevated levels (80%

of patients) b. Erythrocyte sedimentation rate and autoantibodies may

be increased in 10% to 20% of patients c. Monoclonal gammopathy (23% of patients) d. EMG

1) Usually nonspecific myopathic features with increased insertional activity, short-duration low-amplitude motor unit potentials; long-duration high-amplitude motor unit potentials in 1/3 of cases, complex repetitive discharges

2) Long-duration high-amplitude motor unit potentials may reflect chronicity of disease rather than neurogenic involvement

3) Nerve conduction studies: usually normal (alterna-

tively, mild peripheral neuropathy or mononeuropathy in 10%-30% of patients)

4) In advanced cases, CMAP amplitudes may be reduced

e. Muscle histopathology of inclusion body myositis (Fig. 24-17) 1) Vacuoles within muscle fibers rimmed with granular

material and filaments a) May contain paired helical filaments containing

phosphorylated tau protein b) Intracellular β-amyloid deposition in vacuoles

(visualized with polarized light)

2) Focal invasion of nonnecrotic muscle fibers 3) Endomysial inflammatory infiltrates (predominantly

CD8+ cells) 4) Inflammatory response potentially may be secondary

to degenerative process f. Treatment: prednisone, methotrexate, azathioprine usu-

ally not beneficial g. Variants

1) IBM2 (Nonaka myopathy, hereditary inclusion body myopathy linked to chromosome 9p) (see above)

2) IBM3, caused by missense mutation in gene encoding myosin heavy chain IIa (chromosome 17p)

3) Inclusion body myopathy with dementia and Paget’s disease of bone a) Autosomal dominant inheritance, linked to chro-

mosome 9p b) Age at onset: third and fourth decades c) Proximal and distal weakness of arms and legs,

including scapular winging; cranial nerve involvement d) Slow progression e) Paget’s disease of bone (mean age at onset, 35

years): affects spine, hip and pelvis, skull f) Dementia: frontotemporal dementia with features

of aphasia and personality changes g) Cardiomyopathy late in disease course h) Creatine kinase: normal to mildly elevated levels

E. Sarcoid Myopathy 1. Systemic, multiorgan disorder of unknown cause, char-

acterized by granulomatous lesions often involving pul-

monary and lymphatic systems 2. Epidemiology: 10 to 20 times more frequent in

African Americans than whites, F > M (slightly) 3. Usual presenting symptoms of arthritis and erythema

nodosum

4. Large percentage of patients have muscle involvement (presence of granulomas), most of whom are asymptomatic

5. Presentations of muscle disease a. Asymptomatic: most patients do not have signs or

symptoms of muscle involvement (presence of granulomas)

b. Chronic myositis: muscle weakness and atrophy (proximal > distal); may be myalgias, cramps, contractures

c. Acute myositis: painful myalgias common, with proximal weakness

d. Nodular myositis: granulomatous nodules may be palpated or found on biopsy even if asymptomatic

6. Painful myalgias common 7. Skeletal muscle is often involved, and there is often

muscle lesion even in absence of symptoms 8. Diagnostic investigation to include chest films (to

examine for hilar adenopathy); serum angiotensin-converting enzyme, calcium, and creatine kinase (may be normal or mildly elevated); muscle biopsy

9. Muscle histopathology consistent with noncaseating granulomas with giant cells, epithelioid cells, and lymphocytes, often perivascular distribution (Fig. 24-18)

10. Treatment and prognosis a. Frequent spontaneous remissions are the rule b. Corticosteroids (prednisone) often provide best relief c. Corticosteroid-refractory patients may benefit from

methotrexate

F. Myositis Related to Vasculitis 1. Polyarteritis nodosa: symmetric or asymmetric weak-

ness and myalgias in context of fevers, arthralgias, glomerulosclerosis, distal peripheral neuropathy, and mononeuritis multiplex (Fig. 24-19)

2. Churg-Strauss syndrome: necrotizing granulomatous arteritis, fever, vasculitic myositis, eosinophilia, asthma

3. Wegener’s granulomatosis: necrotizing granulomatous arteritis, glomerulonephritis, cranial mononeuropathies, mononeuritis multiplex, vasulitic myositis

A. Bacterial Infections 1. Clostridial myonecrosis

a. Caused by Clostridium perfringens b. Acute onset of myalgias, local tenderness, myofascial

edema, and serosanguinous, malodorous discharge c. Inciting event: often trauma, sepsis, abdominal surgery

2. Streptococcal myonecrosis a. Caused by group A β-hemolytic streptococci b. Bacterial invasion of the trauma sites c. Erythema, sloughing of skin, myofascial necrosis; may be

followed by bacteremia, sepsis, death 3. Legionnaires’ disease

a. Caused by Legionella pneumophila (gram-negative aerobic bacillus)

b. Polymyositis (necrotizing myopathy): painful proximal weakness, elevated creatine kinase levels, rhabdomyolysis, myoglobinuria

4. Neuroborreliosis (Lyme disease) a. Caused by Borrelia burgdorferi b. Diffuse inflammatory myositis with diffuse weakness,

myalgias, muscle tenderness, cramps

B. Viral Infections 1. Orthomyxoviruses: influenza A and B (rarely C)

a. Abrupt onset of myalgias (especially in calves and thighs), generalized weakness, muscle tenderness, myoedema

b. Myoglobinuria (may cause acute tubular necrosis), elevated levels of creatine kinase and aldolase, elevated liver function enzymes

c. Natural history of myositis: self-limited course, resolves within 2 to 3 months after onset

d. Muscle biopsy usually not indicated e. Muscle histopathology: necrotizing myositis

2. Acute coxsackie-related myositis: symptoms are pre-

dominantly fatigue and muscle pains, occurring up to 10 days after initial phase of viral illness, which may or may not be accompanied by diffuse myositis (generalized weakness), myoglobinuria, and myoedema

3. Myositis related to human immunodeficiency virus (HIV) a. Commonly a complication of fully developed acquired

immunodeficiency syndrome (AIDS); may present early in course of HIV infection

b. Symmetric, painless proximal muscle weakness, myalgias, with or without atrophy

c. Creatine kinase: elevated levels d. Pathologic features of HIV-1-associated inflammatory

myositis 1) HIV polymyositis: involves endomysial

inflammation 2) HIV inclusion body myositis: inflammatory myopa-

thy associated with vacuolated fibers 3) HIV necrotizing myopathy: minimal inflammation

and predominant features of muscle fiber necrosis 4) HIV myopathy with nemaline rod bodies: rare

e. HIV wasting syndrome 1) Severe fatigue, myalgias, diffuse muscle atrophy 2) Normal muscle enzyme levels 3) Strength: normal or may be mild weakness dispro-

portional to degree of atrophy

A. Acquired Metabolic Myopathies 1. Disorders of glucocorticoid excess: corticosteroid

myopathy a. Due to exogenous (corticosteroid intake) or endogenous

(Cushing’s disease) glucocorticoid excess b. Exogenous and endogenous causes of steroid myopathy

produce similar clinical and histopathologic features c. Corticosteroids likely to induce steroid myopathy: tri-

amcinolone (most likely), dexamethasone, betamethasone

d. Likely due to increased muscle protein catabolism e. Preferential type II fiber atrophy f. Myopathy may occur several weeks after onset of steroid

therapy, but typically occurs after chronic administration of high-dose oral corticosteroids

g. Severe acute quadriplegic myopathy rarely occurs with administration of high-dose intravenous corticosteroids, marked by generalized muscle weakness with or without respiratory involvement and severe elevation of the serum creatine kinase level

h. Chronic corticosteroid myopathy (most common presentation of corticosteroid myopathy): proximal muscle weakness with some atrophy in patients given high-dose corticosteroids for prolonged periods

i. Gradual onset of proximal muscle weakness and atrophy, myalgias (legs > arms)

j. Cranial and sphincter muscles spared k. Clinical course worsened with fasting and inactivity l. Other stigmata of glucocorticoid excess: “moon facies,”

fragile skin, osteoporosis, weight gain, hypertension, glucose intolerance, hirsutism, growth retardation in children

m. Creatine kinase: normal levels n. EMG: often normal, may show mild proximal

myopathic motor unit potentials o. Muscle histopathology: type II fiber atrophy p. Treatment

1) Reduce dose of exogenous corticosteroid to lowest possible dose (alternate-day regimen preferred)

2) Change to a nonfluorinated preparation if possible 3) Physical therapy and exercise to prevent disuse atro-

phy (also type IIB fiber atrophy) 4) Adequate nutrition to avoid protein deprivation 5) Treatment of underlying Cushing’s syndrome

(endogenous source): removal of the corticosteroidor corticotropin (ACTH)-producing tumor (e.g., adrenal adenoma, ACTH-producing pituitary adenoma, or ectopic ACTH source)

2. Thyrotoxic myopathy a. Myopathic weakness: proximal weakness, disproportion-

al to degree of atrophy; present in most patients, but presenting complaint of only 5%

b. Distal weakness may occur c. Common complaints: myalgias, fatigue, exercise

intolerance d. Respiratory insufficiency e. Tendon reflexes appear brisk because of shortened relax-

ation times f. Other features of thyrotoxicosis: weight loss, palpita-

tions, tachycardia, anxiety, insomnia, tremors, heat intolerance, warm skin

g. Creatine kinase: normal levels h. With treatment of the underlying hyperthyroidism, mus-

cle strength improves gradually over several months 3. Thyrotoxic periodic paralysis: secondary form of

HypoPP (see above) 4. Hypothyroid myopathy

a. Proximal weakness, myalgias, cramps, fatigue b. Myoedema and enlargement of muscles c. Slow movements: slow muscle contractions with delayed

relaxation d. Associated with polyneuropathy and entrapment neu-

ropathies (most often median nerve at the wrist) e. Elevated creatine kinase level (in symptomatic patients,

often tenfold more than normal) and myoglobin 5. Hyperparathyroidism-related myopathy

a. May be primary (due to parathyroid adenoma or hyperplasia) or secondary (renal failure and impaired kidney production of 1,25-dihydroxyvitamin D)

b. Most patients experience generalized weakness, fatigue, and muscle stiffness

c. Myopathy occurs in 2% to 10% of patients d. Proximal symmetric weakness and atrophy (affect legs >

arms) e. Relative sparing of bulbar muscles and sphincter

function f. Myalgias g. Increased tendon reflexes h. May be a concomitant polyneuropathy i. Creatine kinase: normal levels

6. Critical illness myopathy a. Risk factors include: renal failure, concomitant presence

of critical illness neuropathy, administration of corticosteroids and neuromuscular junction blocking agents

b. Often occurs in context of multiorgan failure, including renal failure, sepsis, systemic inflammatory response syndrome

c. Diffuse flaccid paresis, including weakness of bulbar and respiratory muscles (difficulty weaning from ventilator when intubated, ventilator dependence)

d. Often concomitant occurrence of critical illness neuropathy

e. Electrodiagnostic evaluation 1) Nerve conduction studies: low-amplitude, broad-

ened, long-duration CMAPs; relative preservation of the sensory responses; low-amplitude or absent sensory nerve action potentials may indicate concomitant neuropathy

2) Needle EMG: increased insertional activity with fibrillation potentials and positive sharp waves may be present

3) Muscle-evoked CMAP (responses obtained with direct muscle stimulation) may be compared with nerve-evoked CMAP to help differentiate critical illness neuropathy from myopathy (but both may be present)

B. Toxic Myopathies 1. Exogenous corticosteroid myopathy (see above) 2. Colchicine myopathy

a. Most often affects men older than 50 b. Renal insufficiency: a risk factor c. Subacute onset of proximal weakness d. Clinical and electrophysiologic myotonia may be present e. Creatine kinase: elevated levels f. Muscle weakness and elevated creatine kinase levels

resolve within 4 to 6 weeks after discontinuation of offending agent

g. Pathophysiology 1) Colchicine interacts with tubulin, inhibiting polymer-

ization of microtubules 2) Causes disruption of muscle microtubule-dependent

cytoskeletal network, which leads to deficient transport and intracellular accumulation of lysosomes and autophagic vacuoles (vacuolar myopathy)

3. Zidovudine (AZT) myopathy a. Toxic mitochondrial myopathy (accompanied by T

cell-mediated inflammatory response) b. Clinical presentation mimics HIV-1-associated inflam-

matory myositis (see above) c. Muscle weakness in patients infected with HIV is often

multifactorial d. Progressive proximal weakness, fatigue, myalgias, elevat-

ed creatine kinase levels e. Clinical presentation variable: range from mild myalgias

with no weakness to severe proximal weakness f. Creatine kinase: normal to moderately increased levels g. Often, recovery several months after discontinuation of

AZT h. Histopathology: mitochondrial changes

1) RRFs 2) Mitochondrial abnormalities seen on electron

microscopy 3) Scattered interstitial lymphocytic infiltrates (possibly

T cell-mediated inflammatory response) 4. Myopathy related to HMG-CoA reductase inhibitors

(e.g., lovastatin, simvastatin) a. “Statin myopathy” refers to spectrum of phenotypes b. Clinical phenotype may be predominantly that of myal-

gias (muscle pain) without true myositis and elevated creatine kinase levels or there may be myositis with elevated creatine kinase levels and rhabdomyolysis

c. Myalgias without true myositis commonly occur transiently with initiation of therapy, without progression to myositis

d. Onset of symptoms: usually about 2 to 3 months after initiation of statin therapy (up to 2 years)

e. Incidence of myalgias, as high as 20%; incidence of true myositis, 0.2%

f. Risk factors: female sex, old age, short stature, hypothyroidism, renal insufficiency, severe hepatobiliary disease, perioperative period, high dose of offending statin, polypharmacy and concomitant use of gemfibrozil, nicotinic acid, cyclosporine, colchicine, calcium-channel blockers, nefazodone, or erythromycin

g. Statin-induced myositis has been associated with reduced concentrations of coenzyme Q10

h. Histopathology of statin-induced myositis: muscle fiber necrosis, regeneration, mononuclear cell infiltration

i. Treatment: discontinuation of the offending drug j. Persistence of symptoms several months after discontinu-

ation of the drug indicates different diagnosis 5. Myopathy related to fibric acid derivatives (e.g., clofi-

brate, gemfibrozil) a. Necrotizing myopathy often occurring within 2 to 3

months after starting the drug b. Generalized cramps, weakness, muscle tenderness c. Associated with elevated creatine kinase levels and

myoglobinuria 6. Alcohol-induced myopathy

a. Acute alcoholic myopathy 1) Necrotizing myopathy in setting of chronic heavy

alcohol use, with or without episodes of binge drinking

2) Painful diffuse weakness accompanied by myoedema and myonecrosis, with variable severity

3) Myoglobinuria, which may be followed by acute tubular necrosis and renal failure

4) Patients who develop an attack are predisposed to have another episode if alcohol abuse continues

b. Acute hypokalemic alcoholic myopathy 1) Observed with chronic alcoholism and alcohol

withdrawal 2) Acute-onset vacuolar myopathy 3) Acute, painless muscle weakness without myoedema

or muscle tenderness 4) Hypokalemia 5) Creatine kinase: markedly elevated levels 6) Muscle histopathology: vacuolar myonecrosis 7) Reversible with repletion of potassium: response

noted within first week, complete recovery expected by 2 weeks

c. Chronic alcoholic myopathy 1) Debated entity 2) Myalgias, cramps, proximal weakness 3) Creatine kinase: elevated levels 4) Myoglobinuria 5) Often associated with other alcohol-related complica-

tions, including dilated cardiomyopathy and peripheral neuropathy

6) Muscle histopathology: type II fiber atrophy, variation of fiber size, subsarcolemmal nuclei, sparse muscle fiber necrosis and regeneration, “moth-eaten” fibers

1. Which of the following is not true about nemaline myopathy? a. The most common presentation is congenital

hypotonia b.Motor development may be normal c. Extraocular muscles are often involved and there

may be partial or complete ophthalmoplegia d.Patients are intelligent and have no psychomotor

retardation e. Patients with infantile-onset nemaline myopathy

present with an open mouth appearance due to facial diplegia

MATCHING. Toxic myopathies. Match the appropriate myopathic syndrome in the right column with the corresponding cause in the left column.