Neuromuscular Diseases

X-LINKED DYSTROPHINOPATHIES (DMD AND BMD)

dren affected ●● Deficiency of membrane-associated protein

dystrophin ●● DMD (Duchenne) is most common muscular

dystrophy, average age of onset is 3-5 years ●● BMD (Becker) is a milder disease than DMD

with lesser degree of dystrophin deficiency; average age of onset 12 years

●● Delayed walking until 18 months or later, waddling gait, hip and shoulder weakness, difficulty running, climbing

fatty infiltration of muscle) ●● Elevated CPK levels at birth and continue to

rise to 3 years of age ●● Death secondary to respiratory insuffi-

ciency, infections, and cardiac involvement ●● Many cases sporadic with no family history

of affected members ●● Intermixed pattern of myofiber atrophy/

hypertrophy, hypercontracted large dark opaque fibers, myofiber necrosis, endomysial fibrosis

●● Diagnosis: Dystrophin immunostaining of biopsy/quantitative dystrophin analysis

relax a contracted muscle)

●● Severely hypotonic infant, bilateral facial weakness, involvement of intercostal/diaphragmatic muscles, respiratory insufficiency

transmitted ●● Family history of intellectual impairment,

cataracts, cardiac conduction defects, muscle weakness/wasting

repeats ●● Severe myofiber hypotrophy of type I, II, or

both ●● Myofiber immaturity: Fetal myotubes with

central nuclei, lack of myofibril ATPase staining centrally, lack of peripheral oxidase staining, incomplete myofiber type differentiation, fiber type disproportion

●● Subsarcolemmal location of acid phosphatase activity

GLYCOGEN STORAGE DISEASE

●● Skeletal muscle involvement is mild in most lysosomal enzyme deficiency diseases except Pompe disease (severe muscle involvement)

●● Type II GSD (Pompe disease) is most common

●● Type V, McArdle disease (myophosphorylase deficiency); VII, Tarui disease (phosphofructokinase deficiency), IX, X, and XI: manifest as exercise intolerance, muscle cramps, rhabdomyolysis, and myoglobinuria

Pompe disease

macroglossia, cardiac/hepatic enlargement ●● Non-obstructive HCM due to storage of gly-

cogen within cardiac muscle fibers

mosome 17 ●● Vacuolar myopathy ●● PAS stain reveals glycogen storage/sensi-

tive to diastase reaction ●● Storage of undegraded glycogen/neutral

lipids within myofibers ●● Positive acid phosphatase staining ●● EM: Free cytoplasmic and intralysosomal

glycogen

Danon disease

tal retardation ●● LAMP-2 deficiency ●● X-linked dominant

phosphorylation (OXPHOS) defects ●● Respiratory chain made of five complexes:

Types I-IV of mitochondrial electron transport chain and type V (ATPase synthetase complex)

●● Mitochondrial function depends on information derived from nuclear DNA (nDNA) and mitochondrial DNA (mtDNA)

heterogeneous ●● Muscle, kidney, heart involved ●● Ragged red fibers (RRFs); reddish granu-

lar staining on modified Gomori trichrome stains of frozen sections (subsarcolemmal or diffuse)

●● Oxidative NADH-trichrome stain and specific mitochondrial stain SDH: Mirror the staining of modified Gomori trichrome stain

●● More than 2% subsarcolemmal mitochondrial aggregates (larger than 4 µ in depth) support a diagnosis of mitochondrial myopathy (SDH histochemistry)

●● SDH activity absent in complex II deficiency (nuclear encoded). SDH stain is unaffected by mt(DNA) mutations

●● Stains identifying triglyceride accumulation (oil red O, Sudan Black, and Nile Red) increased in RRF indicating mitochondrial myopathy

●● Focal lack of COX activity within myofibers: KSS and MELAS syndromes

●● EM: Abnormal number/size/internal morphology of mitochondria

●● Large mitochondria with abnormal inclusions: Spiral and “parking lot” paracrystalline structures (deposits of CK)

●● Skeletal muscles supplied with energy by mitochondrial oxidation

●● Defect in CPT enzyme system produces impairment of transport of LCFA (longchain fatty acids) into mitochondria

glycemia, failure to thrive, CM, CNS abnormalities, hyperammonemia, and sudden death

●● MCAD (medium-chain acyl Co-A dehydrogenase) deficiency: most common

●● Primary carnitine deficiency and CPT II deficiency are also forms of lipid myopathies

●● Accumulation of lipid (triglycerides) within type I myofibers

parallel rows within myofibers, increase in mitochondrial size/number

ACUTE/INFANTILE SPINAL MUSCULAR ATROPHY (TYPE I/ WERDNIG-HOFFMAN DISEASE)

●● Degeneration of neurons in anterior horn of spinal cord

●● Denervation, weakness/atrophy of skeletal muscles

●● Symmetrical weakness, hypotonia, proximal more than distal, pectus excavatum

motor nerve conduction ●● Grouped myofiber hypertrophy and

atrophy ●● Atrophic myofibers have rounded edge

instead of sharp angular shapes ●● Hypertrophic fibers usually type I ●● Alkaline phosphatase positive myofibers

due to myofiber regeneration (indicative of progressive neuromuscular process)

●● Skin biopsy/muscle biopsy contain nerve twiglets helping in diagnosis

SURAL NERVE BIOPSY

●● Evaluation of hereditary neuropathies and storage disorders

●● Nerve teasing studies to differentiate between segmental demyelination and primary axonal degeneration

HEREDITARY NEUROPATHIES

Dejerine-Sottas disease

●● HMSN (hereditary motor and sensory neuropathy) type III

●● Infancy, weakness, hypotonia, loss of tendon reflexes

●● Hypertrophic neuropathy, reduction of large myelinated nerve fibers

disease (HMSN type I) ●● EM studies for evaluation of myelinated

axons

leukodystrophy, Krabbe disease, Fabry disease, neuronal ceroid lipofuscinoses

EM STUDIES

●● Skin/muscle biopsies: Suggest storage disorder; further confirmed by appropriate biochemical studies

●● Krabbe disease → curved tubular/prismatic inclusions of galactocerebroside

●● Metachromatic leukodystrophy (MLD) → tuftstone prismatic lamellae of sulfatide

●● Fabry disease → myelin figures/parallel lamellae of glycosphingolipid galactosylceramide (endothelium and nerves)

BIOCHEMICAL ANALYSIS

●● Enzyme assays on fibroblast culture/ leukocyte specimens

●● Krabbe disease → galactocerebroside betagalactosidase

very long-chain fatty acids (fibroblasts and leukocytes)

●● Autoimmune disorder manifesting as skeletal muscle weakness/fatigability

or may show type II atrophy ●● Autoantibodies destroy the acetylcholine

receptors at neuromuscular junction

tractile/structural/other proteins of muscle ●● Structural abnormalities of myofibers

●● Accumulation of abnormal proteins in sarcoplasm

NEMALINE ROD MYOPATHY

phic facial features, chest deformities, normal intelligence

●● Death from respiratory failure, recurrent pulmonary infections, CM

genic features ●● EM: Type I myofibers contain subsarcolem-

mal needle-shaped thread like structures ●● Modified Gomori trichrome: Subsar-

colemmal reddish purple rods ●● Type I myofiber predominance/hypotrophy

CENTRONUCLEAR (MYOTUBULAR) MYOPATHY

●● Congenital/late onset/adult forms of disease

●● Similar morphological features as nemaline rod myopathy

fetal myotubules ●● Central nuclei/central basophilic granular

staining (due to mitochondria and autophagic vacuoles)

●● ATPase stain: Perinuclear halo due to lack of myofilaments

●● NADH-trichrome stain: Oxidative mosaic pattern due to oxidative enzyme activity in center of myofibers

CENTRONUCLEAR MYOPATHY ASSOCIATED WITH FIBER SIZE DISPROPORTION

●● Myofiber size disproportion such as type I hypotrophy with predominance of type I fibers

●● Pattern of fiber size disproportion can be variable with type II hypotrophy or mixed

malignant hyperthermia, rarely associated with CM

(due to lack of normal sarcoplasmic reticulum pattern)

●● NADH-trichrome: Target cells usually show pale single and central cores of staining, cores may be eccentric or multiple

●● ATPase: Marked predominance of target fibers

●● Modified Gomori trichrome: Cores seen as solid, central smudged area

●● Cytochrome oxidase: Mimics pattern of oxidative stain (NADH-Tr); central area devoid of mitochondrial activity

CONGENITAL FIBER-TYPE DISPROPORTION

hypotonia, contractures, facial dysmorphia, respiratory failure

I myofibers, indicating persistent fetal morphology/maturational delay of myofibers

●● Type I hypotrophic fibers are at least 12% smaller than type II fibers

●● Type I predominance indicates more than 55% fibers show type I histochemical staining

DERMATOMYOSITIS

infiltration ●● Systemic vasculopathy ●● Perifascicular myofiber atrophy ●● Scattered myofiber degeneration/regenera-

tion/atrophy ●● Alkaline phosphatase activity in perifas-

cicular connective tissue

FOCAL MYOSITIS

tender/lower extremity ●● Histologically florid; degeneration/regen-

eration of muscle fibers, interstitial lymphocytic infiltration, fibrosis

JUVENILE DERMATOMYOSITIS (JDM)

●● Selective fiber atrophy at periphery of fascicles

phages, T cells, and rarely B cell ●● Acute intimal arteriopathy ●● Occlusive changes in chronic arteriopathy;

ischemic damage to the gut/skin/muscle

POLYMYOSITIS