Neuromuscle Flashcards
Calcium channelopathy
Hypokalemic periodic paralysis (CACNA1S)
chloride channelopathy
myotonia congenita, paramyotonia congenita
potassium channelopathy
hypokalemic periodic paralysis
sodium channelopathy
hypokalemic periodic paralysis (SCN4A), hyperkalemic periodic paralyis (SCN4A), paramyotonia congenita, sodium channel myotonia (acetazolamide-responsive myotonia, myotonia fluctuans, myotonia permanens)
Central Core Myopathy
AD due to RYR1 mutation on 19q.
Cores seen in type 1 fibers. Cores lack mitochondria and oxidative enzyme activity
Centronuclear myopathy
X-linked (neonatal severe aka myotubular myopathy) dominant (adult onset and milder), and recessive forms (slowly progressive early childhood)
ptosis and extraocular muscle weakness in addition to hypotonia and skeletal muscle weakness. Also facial, pharyngeal, laryngeal and neck weakness
Biopsy: central nuclei, type I fibers predominate and are small.
Nemaline Rod Myopathy
May be static or progressive
Neonatal form: respiratory failure, severe hypotonia, early death
Children: high-arched palate and long, narrow face
Muscle biopsy: rods in cytoplasm of muscle fibers (dark red-blue structures seen with Gomori trichrome stain
Classic Congenital Muscular Dystrophy, aka merosinopathies
Merosin-negative (Aka laminin alpha-2-negative)–hypotonia, weakness, feeding difficulties. Progressive contractures and do not ambulate. MRI with T2 white matter changes.
Merosin-positive: present at birth with hypotonia, diffuse weakness, facial weakness, and contractures of feet and hips. More likely to ambulate; no cerebral WM abnormalities
3 forms of dystroglycanopathies (syndromic congenital muscular dystrophy)
- Fukuyama congenital muscular dystrophy–primarily in Japan; assoc with mutations in gene 9q. weakness and ocular and CNS abnormalities with patients hypotonic with contractures at hip, knee and ankles. Babies typically don’t learn to walk. Typically cognitive delay and sz. BMRI shows abnl gyration and WM changes in frontal lobes
- Muscle-eye brain disease-defect in POMGnT1 on 1p
- Walker-warburg–mutation in POMT1 on 9q
All 3 associated with hypoglycosylated alpha-dystroglycan
Miyoshi Myopathy
AKA Early Adult Onset Distal Myopathy Type II
Autosomal recessive or sporadic due to mutation in the dysferlin gene on 2p.
Allelic with Limb-Girdle Muscular Dystrophy
First affects the posterior compartment of the legs (gastroc and soleus).
Extensor digiti minimi spared
Patients have high CK (10-100x normal)
Welander (Late Adult Type 1) Distal Myopathy
Due to defect on 2p but not allelic with Miyoshi myopathy
AD, onset later in adult life (40-60 yo)
Starts in the hands, and later affects legs
Muscle biopsy shows myopathic changes and rimmed vacuoles.
Emery-Dreifuss Muscular Dystrophy
X-linked: EMD gene on Xq, encodes Emerin
Autosmal: LMNA gene on 1q, encodes lamin A/C
Early joint contractures (ELBOWS, ANKLES, NECK), weakness in a humeroperoneal distribution (biceps and triceps often affected first then distal leg), and cardiac abnormalities OFTEN REQUIRING PACEMAKER
No pseudohypertrophy of calves
Normal IQ
Facioscapulohumeral Muscular Dystrophy
Presents by age 20 usually. AD inheritance. Deletion of D4Z4 repeats on chromosome 4q
Asymmetric weakness involving the face, muscles that stabilize the scapula, proximal upper extremities and dorsiflexors of the foot.
Face weakness results in difficulty closing the eyes tightly, whistling, and using straw. Sleep with eyes open.
Weak biceps and triceps but deltoids spared.
SCAPULAR WINGING
May have sensorineural hearing loss.
May be associated with Coat’s Dz: characterized by an exudate telangiectasia of the retina and retinal detachment.
Masseters, temporalis muscle, EOMs, pharyngeal and respiratory muscles usually spared.
Cardiac involvement rare and IQ typically normal.
Limb Girdle Muscular Dystrophy
Number of diseases characterized by proximal muscle weakness, affecting shoulder and/or pelvic girdle. Facial and extraocular muscles tend to be spared. Some patients have cardiomyopathy
LGMD 1 is AD
LGMD1A-myotilin defect
LGMD1B-Lamin A/C defect ( like EDMD, has cardiocmyopathy and conduction defects)
LGMD1C-defective caveolin-3: has high CK
LGMD2 is AR
LGMD2A -calpain deficiency =>early contractures
LGMD2B-defective dysferlin->allelic with Miyoshi myopathy and causes similar findings of early gastrocnemius and soleus weakness
Sarcoglycanopathies=LGMD2C, 2D, 2E, 2F and LGMD2I(defective fukutin-related protein) resemble DMD or BMD
Oculopharyngeal Muscular Dystrophy
Presents in middle age with asymmetric ptosis, due to asymmetric involvement of the levator palpebrae muscles. NOT associated with diplopia
Pharyngeal weakness results in dysphagia and dysarthria
AD. Due to GCG repeat expansion in the PAPB2 gene on 14q. More common in French Canadians
Muscle biopsy shows rimmed vacuoles and fiber size variation with intranuclear tubular filaments.
CK and aldolase levels normal
Myotonic Dystrophy Type 1
DMPK gene, 19q13.32 CTG repeats Classic range: 100-1000 Congenital: >1000 (maternal inheritance) Babies have hypotonia, facial diplegia, feeding and respiratory difficulties and decreased reflexes. Joint deformities ranging from clubfoot to arthrogryposis. Delayed dev with cognition impaired. Myotonia develops around age 2 yo.
Cataracts, cardiac arrythmias, increased risk of malignancy, T1DM, thyroid disorders, respiratory issues,
Primary myopathic carnitine deficiency
Progressive proximal muscle weakness and atrophy beginning in childhood or early adulthood.
Muscle biopsy shows lipid storage
Tx with carnitine
Primary systemic deficiency of carnitine
Presents in childhood
Episodes resembling Reye’s syndrome characterized by vomiting, encephalopathy, hepatomegaly, hyperammoniemia and hypoglycemia.
Progressive weakness and cardiomyopathy.
Muscle biopsy shows lipid storage
Carnitine Palmitoyl Transferase-II Deficiency
Adult myopathic form of CPT-II deficiency is the most common metabolic recurrent myoglobinuria
Defect on chromosome I. Presents typically in adolescence
Tenderness and swelling of muscles with sustained aerobic exercise or stressors such as infection.
Associated with increased CK and myoglobinuria. Pts normal between episodes.
EMG with Lambert-Eaton and Myasthenia Gravis
Lambert Eaton:
Low amplitude CMAPs; CMAP decrement (greater than 10% drop) with rep stim at 2-5 Hz and CMAP increases significantly with rep stim at 20-50 Hz
MG: CMAP decrement (greater than 10% drop) with rep stim at 2-5 Hz. Single fiber EMG shows blocking and increased jitter of muscle fiber potentials. May have CMAP increase with rep stim at 20-50 Hz only with severe MG
CMT1a vs HNPP
CMT1a=duplication or point mutation in PMP-22.
foot deformity: pes cavus and hammar toes, wasting of hands, feet and distal leg muscles and mild distal sensory loss. Enlarged nerves. Path shows demyelination and onion bulbs.
HNPP=deletion of PMP-22
multiple or recurrent compression neuropathies or a mild generalized demyelinating neuropathy. See focal myelin thickening called tomaculi.
Sites for compression neuropathies: median nerve at wrist, radial nerve at spiral groove, ulnar nerve at elbow and peroneal nerve at the knee.
multifocal motor neuropathy with conduction block
present at 40 yo and more common in males
Asymmetric distal weakness and atrophy, usually in the upper extremities.
Associated with anti-GM1 antibodies and conduction blocks along motor fibers at sites where compression usually does not occur.
POEMS
Polyneuropathy Organomegaly Endocrinopathy M protein--due to an underlying plasma-cell proliferative disorder (typically multiple myeloma) Skin changes
Serum paraprotein (typically IgG or IgA) detected in 80% of POEMS pts.
Avg age of onset is 50, more men than women
Often fatal in 5 years
Tangier Disease
Deficiency of alpha-lipoprotein
Mutation in ATP binding cassette-1 (ABCA1) gene on 9q
Large orange tonsils, lymphadenopathy, splenomegaly
Sensory neuropathy affecting the distal upper extremities and atrophy of the intrinsic muscles of the hand
Electrodiagnostic studies show both axonal and demyelinating features.
Lab findings: dec. cholesterol and LDL, very low HDL
Parsonage-Turner Syndrome
AKA neuralgic amyotrophy or idiopathic brachial plexopathy
Characterized by pain in the shoulder girdle followed by weakness. Paresthesias may be present . Muscle atrophy follows the weakness.
Long thoracic, musculocutaneous, axillary and anterior interosseous nerves commonly affected.
May be preceded by viral syndrome or immunization
Miller-Fisher Syndrome
Ophthalmoparesis, ataxia, areflexia
Descending weakness with truncal ataxia.
In 90% of cases, anti-GQ1b antibodies are present.
Spinobulbar Muscular Atrophy (Kennedy’s Disease)
X-linked recessive motor neuron disease in males
Most common form of adult onset spinal muscular atrophy.
CAG expansion in androgen receptor gene.
Muscle cramps in adolescence
Proximal limb and facial weakness later and facial fasciculations may be present.
Tongue fasciculations and atrophy
Dysarthria and swallowing difficulties.
Hyporeflexia, decreased vibration sense
Assoc. with gynecomastia, impotence, and testicular atrophys. Abnormal sex hormone levels.
Treatment of Hypokalemic Periodic Paralysis
Acetazolamide or potassium-sparing diuretics
Treatment of Hyperkalemic Periodic Paralysis
Thiazide diuretics
Glucose during an attack
Nonaka myopathy
AR distal myopathy with onset in early adulthood
Characterized by foot drop assoc. with weakness of anterior tibial muscles and eventually muscles of upper extremities affected.
Involvement of proximal muscles and bulbar muscles is rare.
Muscle biopsy shows: rimmed vacuoles and electron microscopy shows tubular filaments
Acid maltase deficiency=alpha-1,4-glucosidase deficiency
Pompe dz or glycogenosis type II
Muscle biopsy: vacuolated sarcoplasm with glycogen accumulation that stains strongly with acid phosphatase
Ullrich’s Congenital Muscular Dystrophy
Presents with neonatal weakness, contractures and distal hyperlaxity, as well as protrustion of the calcanei
Mutations in collagen type VI gene, thought to be related to Bethlem myopathy
Myofibrillar Congenital Muscular Dystrophy
AD or AR
Affects M and F equally
Slowly progressive weakness of the muscles of limbs and trunk, affecting proximal and distal muscles but more the lower than the upper extremities
Cardiac involvement with conduction defects in 25% of cases
Path: focal dissolution of myofibrils and subsarcolemmal accumulation of dense granular and filamentous material, variation of fiber sizes, rimmed vacuoles and central nucleation
Mutations in proteins myotilin, desmin and alpha-Beta-crystallin
Myotonia Congenita: two types
Thomsen’s dz: AD; painless myotonia in 1st decade of life
Becker’s dz: AR; weakness after severe episodes of myotonia in 2nd decade of life.
Channelopathy: voltage-dep chloride channel gene
Myotonia with “warm-up” phenomenon: myotonia improves after repetitive muscle activation
Tx: mexiletine
Bethlehem myopathy
AD
Mutations in collagen type VI
weakness and contractures of elbow and ankles
hyperextensible interphalangeal joints
Conus medullaris syndrome
sensory deficits in a saddle distribution, usually bilateral and symmetric.
Pain often symmetric but not typically radicular
Lower extremity symmetric weakness and sometimes mildly decreased to absent reflexes
Bowel and bladder dysfunction early in course
Cauda equina syndrome
distinctive radicular pain with asymmetric distribution
motor deficits asymmetric with hyporeflexia
bowel and bladder function affected later in course and less frequently
LMN signs and no UMN signs
Primary lateral sclerosis
UMN signs at least 3 years from symptom onset without LMN dysfunction
Considered on spectrum of ALS
Spasticity prominent feature
Often in 6th decade of life with progressive spastic tetraparesis and later, CN involvement
Progressive muscular atrophy
On “spectrum of ALS” but motor neuron disease that affects only LMN.
Often presents with focal asymmetric distal weakness that later involves more proximal regions
bulbar and respiratory dysfunction later in course compared to ALS
- early joint contractures (elbow and ankles)
- weakness in biceps and triceps first, then distal leg (foot drop)
- cardiac conduction defects
Emery-Dreifuss Muscular Dystrophy:
X-linked recessive (emerin)
Autosomal dom or recessive (lamin A/C)
- weak gastrocs and soleus but extensor digiti minimi spared
- very high CK
Miyoshi Myopathy (Early Adult Onset Distal Myopathy Type II)
myopathy that starts in adult with weak fingers and wrist extensors
Welander (Late Adult Type 1) Distal Myopathy
- proximal muscle weakness affecting shoulder and/or pelvic
- facial and extraocular muscles spared
- dystrophic changes on biopsy
Limb Girdle Muscular Dystrophy
1A (Myotilin): Distal weakness
1B (LMNA): Cardiac arrhythmias
1C (CAV3): Mainly rippling muscles & Myalgias; child onset
1E & 2R (Desmin): Distal weakness; Cardiomyopathy
2V: Glycogen storage disease
2B: dysferlin (similar to Miyoshi myopathy)
Sarcoglycanopathies (2C, 2D, 2E, and 2F) and 2I (due to fukutin-related protein) resemble DMD or BMD.
Middle aged patient with progressive asymmetric ptosis, extraocular muscle weakness without diplopia, and pharyngeal weakness
Oculopharyngeal muscular dystrophy
