Myopathies Flashcards
- Nemoline Myopathy: Phenotypes
Phenotype heterogeneity:
Severe neonatal congential form -Resp failure, joint contractures, feeding difficuties, slowly progressive or non-progressive weakness if survive.
Intermediate infantile congenital form- hypotonic infant, delayed or incomplete motor development, may be wheelchair bound by age 10. *narrow high arched palate, micrognathia, chest deformities and fiber contractures. Non-progressive but slow deterioration
Mild infantile congenital form - hypotonia, feeding difficulties at birth.
Multicore (Minicore) Disease
Congenital myopathy associated with multifocal degeneration of muscle fibers
Inheritance Pattern: AR or sporadic
Onset: Infancy or early childhood with hypotonia and delayed motor milestones
Sx: Prox>>distal weakness, facial weakness (mild), bulbar involvement and hypernasal speech
Cardiorespiratory involvment is rare - may have nocturnal hypoventilation
Nemaline Myopathy: Genetics
Inheritance pattern: AD (most), AR
Genetic heterogeneity:
- NEM2 (nebulin gene) chromosome 2q21-22 (Nebulin contributes to the z-disk)
- alpha actin gene (ACTA1) on chromosome 1q
- tropomyosin gene (TPM2) on chromosome 1q - encodes alpha tropomyosin on thin filaments
*cardiac involvement is rare
Myofibrillar (desmin-related)myopathy (now considered a muscular dystrophy: Muscle Biopsy
Subsarcolemmal accumulation of dense granular and filamentous amorphous materal: reacts intensely for actin; may contain dsemin
Variation in muscle fiber ssize, rimmed vacuoles, centrally located nuclei
Multicore disease diagnosis
CK: normal to mildly elevated
EMG: Normal early in the disease, later myopathic
Muscle Bx: Variation in fiber size, internal nuclei, muscle fiber splitting
Type I fiber predominance
Type I fibers may be smaller than normal and type II fibers may be hypertrophied.
*Multiple small cores in individual fibers with decreased activity on reduced form of NADH and oxidative stains (lack mito)
Malignant Hyperthermia
Central Core Disease
DAMM protein complex: Intracellar (subsarcolemmal)
Alpha dystrobrevin (binds dystrophin)
Filamin 2
Syncoilin
Syntrophins (bind to dystrophin and dystrophin-related proteins such as dystrobrevin
Dystrophin (rod shaped cytoskeletal protein with no transmembrane regions (consists of five different domains):
- Actin binding domain (exon 1-8), N-terminal domain, links dydtrophin to f-actin cytoskeleton
- Rod domain -largest domain (exon 9-62)
- WW domain
- Cysteine-rich domain (exons 63-69) - attachment of the subsarcolemmal complex
- C-terminal (exons 70-79)
Dystrophinopathies: Inheritance
X-linked recessive, Xp21
Most are large deletions (65%)
Duplications 5%
small deletions or point mutations (30%)
Barth’s Syndrome
X-linked recessive
Xp28, gene encoding Tafazzin protein
Infancy onset, mild limb-girdle girdle weakness
Cardiomyopathy, short stature and neutropenia
Dystrophinopathies: Female carriers
Usually asymptomatic - adequate sarcolemmal dystrophin is produced by teh x-chromosome
-8% of female carriers may have mild to moderate myopathy (due to innactivation of normal wild-type x chromosome and increased number of dystrophin - negative fibers.
Myofibrillar (desmin-related)myopathy (now considered a muscular dystrophy): Inheritance
Genetic and phenotypic heterogeneity
AD -most
2q, 10q, 11q, 12q
accumulation of desmimn, alphabeta-crystallin, dystrophin, neutral cell adhesion molecule, cdc2 kinase
Myofibrillar (desmin-related)myopathy (now considered a muscular dystrophy: Clinical presentation
variable features. age may vary from child to adulthood
*Distal weakness=/>proximal
Periphearl neuropathy in 60% of patients
Cardiomyopathy (hypertrophic and arrhythmogenic
Hearling loss, palatal weakness, cataracts reported in certain subtypes
Dystrophin-Associated Muscle Membrane Protein Complex (DAMM)
Membrane associated proteins that span the sarcomlemma and provide mechanical support to the sarcolemma. It also provides support to the sarcolemma and stability between intracellular cytoskeleton and extracellular
Emery Dreifuss Muscular Dystrophy: Diagnostic workup
Labs: mildly elevated CPK or normal
Muscle Biopsy: VAriation in muscle fiber size, minimal necrosis with regeneration and increase in connective tissue. REduced or absent emerin immunostaining in muscle or skin.
Myotubular (centronuclear) Myopathy: inheritance pattern
AD, AR, sporadic (rare), most common X-linked recessive (Xq27.3-q28)
missense assoicated with a mild phenotype
truncated mutation is associated with severe phenotype
*gene product: tyrosine phophatase (myotubularin) - signal transport in late myogenesis. In utero. Most common in utero.
Myotubular (centronuclear) Myopathy: Muscle Biopsy
Small type I fibers with cnetral nuclei
type I fiber predominance often small and atrophied
Central palor on ATPase staining
Radial distribution of sarcoplasmic strands apperent on NADH rxn
Normal to mildly increased interstitual connective tissue
Central Core Disease Muscle Biopsy
Muscular Dystrophies
Progressive degeneration of muscles and production of connective tissue replacing fibers.
Dystrophinopathies (Duchenne and Becker muscular dystrophies)
Limb-Girdle dystrophies
Myotonic dystrophy
Facioscapulohumeral and scapuloperoneal dystrophy
Oculopharyngeal muscular dystrophy
Distal myopathies
Emery-Dreifuss muscular dystrophy
Congenital muscular dystrophies
alpha-sarcoglycan, adhalin
LGMD2D
Nemaline Myopathy: Muscle Biospy
Type I fiber predominance and atrophy
Fiber type disproportion: small type I and relatively large type II
Sarcoplasmic rods (nemaline bodies) - short granular-appearing composed of alpha actin, actin and z-disk proteins
Intranucular rods: severe congenital or adult - onset phenotypes-*May be associated with severe disease or worse prognosis
Emery Dreifuss Muscular Dystrophy (EMD-1 and EMD-2): Inheritance
1:100,000
EMD-1: X-linked recessive (STA gene on Xq28 - nuclear membrain protein emerin)
EMD-2: Austomal dominant or recessive (LMNA gene on 1q21.23 - nuclear
Multicore (Minicore) disease Muscle Biopsy
Myotubular (centronuclear) Myopathy: Presentation
Hypotonia at birth, resp distress, extraocular and neck/axial muscles affected,
*macrocephaly *narrow face and *long digits
*carries with mild facial weakness.
Associated with pyloric stenosis, spherocytosis, gallbladder and kidney stones, rapid linear skeletal bone grown and genital abn (small penis/hypospadius)
autosomal forms have a milder clinic form
LGMD1C
Associated with Calveolin-3 gene mutation
Congenital Fiber Type Disproportion
Nonspecific histologic findings likely in congenital myopathies and other conditions
-Dx of exclusion in patient with reduction of type I fibers and congential myopathy
Autosomal Dominant Muscular dystrophies
FSHD
OPMD
Myotonic Dystrophy Type I and II
LGMD Type I
Emery Dreifuss Muscular Dystrophy: Clinical Features
Early to middle childhood
Scapulohumeroperoneal or limb-girdle distribution
EMD1: early onset limb contractures
EMD2: contractures follow weakness, loss of ambulation more common
cardiomyopathy with conduction abn: after second or third decades
