Genetic Myopathies (Inherited Myopathies)
genetic myopathies (Inherited muscle diseases, Muscular dystrophies)
Muscle histology: Review
- Epimysium envelopes the muscle.
- Perimysium divides the muscle into fascicles.
- Endomysium lies within the muscle fascicle: it comprises a loose areolar connective tissue that maintains the extracellular environment for proper muscle cell functioning.
Muscle fascicle histology: Review
- The muscle cell is covered in endomysium.
- The cell has many nuclei.
- Dot-like myofibrils constitute the muscle cell milieu.
Muscle Cell Physiology: Review/Pathology Introduction
- Proteins stabilize myofibrils to the muscle cell and can be linked to well-defined related myopathies.
- Each Myofibril includes a Z-disk, which transects an I Band, flanked by A Bands.
- Repeating light and dark bands gives muscle fibers a striated appearance.
- Desmin filaments encircle the Z disks.
- Desmin-related myopathy (DRM) is an inherited disease which results in disorganized and weak skeletal muscle fibers. DRM can be fatal, as it also affects cardiac and smooth muscles.
- Plectin links the desmin filaments.
- Alpha-B-crystallin (a heat shock protein) protects desmin from stress-induced damange. Together: desmin, plectin, and alpha-B-crystallin constitute a Z-disk protection network.
- Dystrophin-associated glycoprotein complex (DAGC) comprises:
- Dystroglycan subcomplex, which links dystrophin to laminin, a key external lamina protein (called laminin-2 in skeletal muscle, which has an associated myopathic syndrome).
- Sarcoglycan subcomplex, which, when defective can cause sarcoglycanopathies – a similar manifestation of weakness as those from dystrophinopathies – and are a common cause of limb-girdle muscular dystrophy.
- Syntrophins are recruited to the sarcolemma and manage the assembly of other proteins.
- Dystrobrevins link desmin to dystrophin and syntrophin.
Muscular Dystrophies
Dystrophinopathies (Duchenne, Becker):
We include a pathological slide of a muscle from an individual with Duchenne muscular dystrophy (DMD).
Overview
- X-linked, Recessive form of muscular dystrophy that affects boys and occurs from a genetic mutation that prevents the synthesis of dystrophin.
- Muscle is replaced with fatty and fibrous connective tissue, which presents with pseudohypertrophic muscles: muscles that are enlarged from fat and connect tissue (not muscle).
- Duchenne Muscular Dystrophy is a severe dystrophinopathy wherein children are non-ambulatory at ~ age 13 – pseudohypertrophy of calf muscles is a notable clinical finding.
- Becker Muscular Dystrophy is a less severe dystrophinopathy in that patients aren't non-ambulatory until ~ age 40.
- As a helpful mnemonic add the treatment adage that the goal of corticosteroids is to: Make Duchenne boys into Becker men.
- Most severe form
- Manifests in childhood with proximal weakness (especially calf hypertrophy)
- Loss of ambulation ~ age 13
- Less severe form
- Manifests in early teens
- Loss of ambulation ~ age 40
Genetic & Diagnostic Characteristics of Duchenne & Becker Muscular Dystrophies
- Genetics
- X-Linked, Recessive
- Dystrophin gene mutation that leads to reduction/absence of dystrophin protein with resultant sarcolemma damage
- Diagnosis: Elevated CK (~20,000), Dystrophin Gene Deletion
- Treatment: Corticosteroids
Myotonic Dystrophy, Type 1
- Characterized by myotonia (eg, inability to release a grip) [relaxes with repetition vs. paramyotonia which worsens with repetition]. Responds to Mexilitine.
- Weakness of lower extremities, hands, neck, and face
- Additional systemic features
- Cataracts
- Cardiac conduction defects
- Early Frontal balding
Myotonic Dystrophy, Type 2
- Myotonia
- Weakness of neck, shoulders, elbows, and hips.
Genetic & Diagnostic Characteristics of the Myotonic Dystrophies
- Autosomal Dominant
- Anticpiation in DM-1 with the DMPK gene [CTG Trinucleotide repeats]
- EMG findings of myotonic discharges.
Oculopharyngeal Muscular Dystrophy
- Ptosis and dysphagia
- Onset > age 40
- Genetics
- Autosomal Dominant
- PABPN1 gene
- Asymmetric facial and scapular muscles (scapular winging) and humeral (upper arm) atrophy: difficulty whistling, closing eyes, throwing ball
- Symptoms appear in adolescence
- Genetics
- Autosomal Dominant
- D4Z4 contraction on chromosome 4q35 (Majority of genetic cause)
Limb-Girdle Muscular Dystrophies
- Present with proximal weakness at any age, manifesting with waddling gait, scapular winging, possible joint contractures.
- Cardiomyopathy or respiratory compromise are key potential complications
- Diagnosis: Elevated CK, genetic testing, and immunohistochemical muscle biopsy staining
- Genetics
- Various genetic pathologies involving muscle cell proteins: sarcolemmal, cytosolic, nuclear envelope.
- Notable forms: -LMNA gene [lamin A/C], CAPN3 gene [calpainopathy], DYSF gene [dysferlinopathy], SGC genes [sarcoglycanopathies]
- Skeletal & cardiac muscle are affected
- Early contractures (joint deformities)
- Upper arm/lower leg wasting
- Genetics
- X-linked
- EMD gene (most commonly), which forms emerin: a nuclear envelope protein.
- LMNA gene (less commonly), which forms lamin A/C
Congenital Myopathies
Central Core Myopathy
- Floppy infants
- Associated skeletal abnormalities: scoliosis, hip dislocation, joint deformities
- Risk of malignant hyperthermia from anesthetics
- Pathology: microscopic cores in the center of muscle fibers
- Genetics
- Autosomal Dominant
- RYR1 gene for the Ryanodine Receptor 1, which forms a channel that releases calcium from muscle cells
Nemaline Rod Myopathy
- Infant onset is most common – Hypotonia and poor respiration
- Adults - Proximal weakness and skeletal abnormalities (scoliosis and contractures)
- Abnormal clumps of threaded filaments (hence: "nema" for "thread") in muscle fibers that can look like rods.
- Genetics
- Autosomal recessive.
- Mutations in sarcommeric proteins.
Metabolic Myopathies
Pompe Disease (Acid Maltase Deficiency)
- Infantile-onset (classic vs non-classic): myopathy, hypotonia, hepatomegaly, congenital heart defects
- Late-onset: Progressive weakness and respiratory failure.
- Genetics
- Autosomal recessive.
- GAA gene for acid alpha-glucosidase (acid maltase), which is key for break-down of glycogen to glucose within lysosomes.
McArdle Disease (Glycogen Storage Disease Type V)
- Exercise-induced Pain/Cramps/Fatigue, which alleviates with rest ("Second Wind" phenomenon).
- Severe forms cause rhabdomyolysis with myoglobinuria.
- Genetics
- PYCM gene for myophosphorylase, which is specific to muscle. It breaks down glycogen to glucose-1-phosphate.
- Forearm ischemic exercise test: lactate [no change], ammonia [normal increase].
- Muscle biopsy: lack of phosphorylase. Subsarcolemmal glycogen deposits.
- Treatment: Enzyme replacement therapy, Avoidance of maximal exercise, High-protein and low carbohydrate diet.
Carnitine Palmitoyltransferase Deficiency 2
- Lipid metabolism disorder that prevents the body from using fat for energy during periods of fasting.
- Carnitine Palmitoyltransferase 2 (CPT2) is involved in inner mitochondrial membrane transport – deficiency comprises mitochondrial fatty oxidation.
- Three forms of the disorder (from most severe to least): lethal neonatal, infantile hepato-cardio-muscle, and myopathic.
- Myopathic form causes: myalgias and rhabdomyolysis.
- Genetics
- CPT2 gene mutation involving fatty acid oxidation within mitochondria.
- Long-chain fatty acids must attach to carnitine to enter mitochondria. Once inside, CPT2 removes carnitine for fatty oxidation – without CPT2, fatty acids can't be used for energy.
- Treatment: High carbohydrate, Low fat diet.
Channelopathies
Myotonia Congenita (Thomsen & Becker Disease)
- Abnormal muscle excitability that is NON-dystrophic, exacerbated in cold.
- Muscle stiffness. Myotonia (eg, inability to release a grip) [relaxes with repetition vs. paramyotonia which worsens with repetition]. Responds to Mexilitine.
- Genetics
- CLCN1 gene – chloride channelopathy, SCN4A – sodium channelopathy
- Thomsen – Autosomal Dominant. Becker – Autosomal Recessive.
Familial Periodic Paralysis
- Flaccid weakness in the setting of hypokalemia or hyperkalemia that can last hours to days.
- Triggered by intense exercise, large carbohydrate meal, viral infection, or medications.
- Genetics
- Autosomal Dominant
- CACNA1S gene – calcium channelopathy, SCN4A – sodium channelopathy
- Don't forget other potential causes of episodic weakness: Myasthenia Gravis, Lambert-Eaton, Thryotoxicosis, and Metabolic Derangement – calcium, phosphorous, magnesium, sodium.
- Maternally-inherited
- Ragged red fibers / Subsarcolemmal accumulation of abnormal mitochondria