Neuromuscular II (Muscle, NMJ, Autonomic)

Question 1

Triggers of hypOkalemic and hypERkalemic periodic paralysis.

Answer 1

HypOkalemic: exercise, emotional stress, cold, carbohydrates, ethanol

HypERkalemic: Resting after exercising and fasting

(ER = REst)

Question 2

Genes for hypOkalemic and hypERkalemic periodic paralysis.

Answer 2

HypOkalemic: CACNA1S (type 1) and SCN4A( type 2) - both AD

HypERkalemic: SCN4A, AD

(Note neither are K channels - unlike Andersen-Tawil, and different mutations in SCN4A can cause each)

Question 3

Syndrome with

1. Hypokalemic periodic paralysis,
2. Ventricular arrhythmias (long QT)
3. Dysmorphic features (mcrognathia, low set ears, widely spaced eyes, high arch or cleft palate, long narrow head)

Genetic cause?

Answer 3

Andersen-Tawil syndrome.

KCNJ2 mutation (an inward rectifier in skeletal and cardiac muscle), AD

Question 4

Which muscle fibers are preferentially atrophic in steroid myopathy?

Answer 4

Type II (fast)

Question 5

Congenital myopathy with significant prosis, extraocular muscle weakness, and bulbar weakness.

Answer 5

Centronuclear myopathy

(Comes in 3 forms: 1) AR slowly progressive infantile/early childhood type, 2) severe X-linked neonatal type, and 3) milder adult-onset AD type

(Myotubular myopathy is the most common form and is a severe X-linked form)

Question 6

Mechanism of action of LEMS

Answer 6

Antibodies against presynaptic V-gated Ca2+ channels

Question 7

Mechanism of action of botulinum toxin

Answer 7

Inhibiting exocytosis of presynaptic ACh vesicles

Question 8

Patterns of weakness in myotonic dystrophies type 1 and 2

Genetic cause for each

Answer 8

Type 1: Distal weakness and ptosis/facial weakness
AD CTG repeat in DMPK gene (myotonic dystrophy protein kinase)

Type 2: Proximal weakness
AD CCTG repeat (tetranucleotic repeat) in CNBP gene (ZNF9 Zn-finger protein)

(Bigger muscles = bigger number (2 v 1) and bigger repeat (4 v 3)

Question 9

Categories of congenital muscular dystrophy (CMD) (muscular dystrophies presenting at birth or in early infancy)

Answer 9

1) Collagenopathies (including Ullrich’s CMD and Bethlem myopathy)
2) Merosinopathies (including laminin-alpha-2-related CMDs)
3) Dystroglycanopathies (including Fukuama CMD, muscle-eye-brain disease, and Walker-Wurburg syndrome)

(In general, due to sarcolemmal membrane proteins or membrane-supporting structures)

Question 10

Muscular dystrophy presenting as floppy baby with skeletal muscle and bulbar weakness, as well as contractures, eye abnormalities and CNS abnormalities (seizures, developmental delay)

Genetic cause

Answer 10

Fukuyama-type congenital muscular dystrophy (FCMD) (A dystroglycanopathy CMD)

AR mutation in fukutin gene, leads to reduced alpha-dystroglycan

(Contrast to laminin-alpha-2 deficiency, merinopathy with floppy baby and contractures, but preserved intelligence and sparing of EOM/facial muscles)

Question 11

Muscular dystrophy presenting as floppy baby with truncal and axial weakness, as well as contractures and sometimes seizures, but with preserved intelligence and sparing of extraocular and facial muscles.

Genetic cause

Answer 11

Laminin-alpha-2 deficiency, a merosinopathy

Mutation in laminin-alpha-2 gene which encodes protein merosin

(Contrast to Fukuyama-type congenital muscular dystrophy (FCMD), A dystroglycanopathy CMD, which also has floppy baby and then contractures, but has intellectual disability and EOM/facial muscle weakness)

Question 12

Slowly progressive muscular dystrophya that preferentially involves upper arms (but sparing deltoids) and winged scapula, as well as facial muscle weakness, lower abdoinal muscles, and weak dorsiflexion with preserved plantarflexion

Genetic cause

Answer 12

Fascioscapulohumeral muscular dystrophy (FSHD)

(It’s in the name: facial weakness, winged scapula, upper arm atrophy around the humerus)

AD mutation due to deletions in D4Z4 sequence

Question 13

Muscular dystrophy presenting with dysphagia, dysphonia, slowly progressive ptosis, and late EOM weakness.

Genetic cause

Answer 13

Oculopharyngeal muscular dystrophy (OPMD; it’s in the name)

AD GCG trinucleotide repeat in poly-A-binding protein 2 gene 9chromosome 14q11)

Question 14

Syndrome with exercise-induced muscle weakness and cramps which may improve with brief rest - “second wind phenomenon.”

Genetic cause

Similar presentation syndrome with hemolysis and gouty arthritis

Answer 14

McArdle’s disease (a glycogen storage disease)

Myophosphorylase deficiency (This enzyme helps convert glycogen to glucose-6-phosphate, so will be less able to release glucose to replete stores)

Similar syndrome: Tarui disease, glycogen storage disease due to phosphofructokinase (PFK) deficiency (PFK helps convert glucose-6-phosphate to glucose-1-phosphate for use) (also leads to RBC problems)

Question 15

Syndrome with myotonia especially prominent in eyelids that is worsened with repeated exercise (no “warm up” phenomenon).

Genetic cause

Answer 15

Paramyotonia congenita

AD disorder of SCN4A (same gene implicated in hypERkalemic periodic paralysis type 2, hypOkalemic periodic paralysis, and congenital myasthenic syndrome 16)

Question 16

Genetic distal myopathy with initial presentation with foot drop and later involvement of distal arms, sparing proximal and bulbar muscles, with rimmed vacuoles on muscle biopsy and tubular filaments on EM (similar to inclusion body myositis, but without inflammation)

Genetic cause

Answer 16

Nonaka myopathy

AR myopathy due to GNE gene

(Contrast with Miyoshi myopathy, which classically presents with plantarflexion weakness (posterior compartment of lower leg)

Question 17

Genetic, early onset proximal myopathy with risk of malignant hyperthermia with anesthesia

Genetic cause

Answer 17

Central core myopathy (NAD staining while show central pallor due to absence of mitochondria)

AD mutation in RYR1

Question 18

Acute generalized autonomic failure developing over weeks.

Associated lab test?

Answer 18

Autonomic ganglionopathy aka acute pandysautonomia.

Antibody against ganglionic nicotinic AChR (seen in 1/2 of pts) (can in some cases be paraneoplastic)

Question 19

Myopathy presenting in early adulthood with distal weakness, particularly plantarflexion (posterior compartment of lower leg)

Genetic cause

Answer 19

Miyoshi myopathy

AR mutation in dysferlin (also a/w limb-girdle muscular dystrophy type 2B).

(Less commonly due to ANO5 gene mutation)

(Contrast with Nonaka myopathy, which classically presents with dorsiflexion weakness (anterior compartment of lower leg)

Question 20

Perifascicular atrophy (atrophic fibers in the borders of the fascicles) is seen on muscle biopsy in…?

Answer 20

Dermatomyositis

Question 21

Pathology associated with pure autonomic failure

Answer 21

Synuclein deposition and neuronal loss in the intermediolateral nuclei of the spinal cord (autonomic)

Question 22

Inflammatory infiltrate surrounding muscle fibers without perifascicular atrophy or rimmed vacuoles is seen on muscle biopsy in…?

Answer 22

Polymyositis

Question 23

Rimmed vacuoles are seen on muscle biopsy in…?

Answer 23

Inclusion body myositis

(Also seen: endomysial inflammation and groups of atrophic fibers)

Question 24

Antibody associated with polymyositis > dermatomyositis

Answer 24

Anti-Jo-1

Question 25

Treatment of polymyositis

Answer 25

Steroids -> steroid-sparing agents (MTX, azathioprine)

Question 26

Adult-onset myopathy with weakness of wrist and finger flexors, quadiceps, and anterior tibial muscles

Answer 26

Inclusion body myositis

Question 27

Inheritence patterns of limb-girdle muscular dystrophies type 1 nd type 2?

Answer 27

Type 1: AD
Type 2: AR

(Each has multiple genes)

Question 28

Antibody in LEMS

Paraneolastic LEMS?

Answer 28

Presynaptic P/Q-type Ca2+ channel

Paraneoplastic: SOX1 (most commonly SCLC, not specific for LEMS)

Question 29

Acute/subacute myopathy with proximal>distal weakness, EOM and bulbar weakness, with biopsy showing eosinophilic infiltrate and parasite

Answer 29

Trichonosis

Question 30

Myopathy associated with rod-like structures below the sarcollema

Answer 30

Nemaline myopathy (these path findings are known as nemaline bodies or nemaline rods)

(This is clinically and genetically heterogenous)

Question 31

Pompe’s disease:

Genetic cause?

Muscle biopsy finding

Answer 31

AR, acid maltase deficiency

Path vacuolated sarcoplasm with glycogen accumulation

(Pompe’s disease is the rapidly progressive, infantile acid maltase deficiency. There is also a childhood form (2nd year of life) and adult form (slowly progressive, usually not other organ problems)

Question 32

Mechanism of transient neonatal myasthenia

Answer 32

Mother with MG with transplacental antibody transmission

Question 33

Differentiating features on exam and testing between congenital myasthenia due to:
1. AChR deficiency
2. Acetylcholinesterase deficiency

Answer 33

AChR deficiency: normal pupillary reflex, response to edrophonium/pyridostigmine

Acetylcholineserase deficiency: delayed pupillary reflex, no response to edrophonium/pyridostigmine (and may worsen)

Question 34

Muscular dystrophy associated with contractures at elbows, neck, and neck, and weakness un upper arms and shoulder girdle first, with no pseudo-hypertrophy, and with frequent cardiac conduction abnormalities

Genetic cause?

Answer 34

Emery-Dreifuss muscular dystrophy

Two genetic forms, both mutations in nuclear membrane protein
1. X-linked mutation in emerin (nuclear membrane protein)
2. AD mutation in LMNA (Lamin A/C, nuclear membrane protein)

Question 35

Muscular dystrophy with neonatal weakness, contractures and distal hyperlaxity, and protrusion of the calcanei.

Genetic cause

Answer 35

Ullrich’s congenital muscular dystrophy

AD, Mutation in collagen type VI (Bethlehem myopathy is another collagenopathy CMD that also leads to weakness and contractures wwith hyperextensible IP joints)

Question 36

Severe muscular dystrophy associated with ocular malformations and severe brain malformations (hydrocephalus, aqueductal stenosis, cerebellar hypoplasia, cortical abnormalities)

Genetic cause

What is a related, somewhat milder disease?

Answer 36

Walker-Warburg syndrome (most severe CMD)

AR, can be in multiple genes leading to impaired glycosylation of α-dystroglycan

Related: Muscle-eye-brain disease (also AR dystroglyanopathy due to mutation in POMGNT1)

Question 37

Where do sympatetic fibers to facial sweat glands separate from sympathetic fibers to eye?

Answer 37

Carotid bifurcation (Sympathetic fibers to sweat glands travel with ECA, not ICA)

(Superior cervcal ganglion carrying 3rd-order neurons, is medial or anteromedial to the ICA, at level of C2-C3)

Question 38

Brain region the regulates the detrusor reflex

Brain region the regulates voluntary control of urination

Answer 38

Detrusor reflex: Pontine micturation center

Voluntary: Medial frontal micturation centers in the paracentral lobules (medial continuation of the precentral gyrus)

Question 39

Neurologic structure absent in Hirschsprung’s disease

Answer 39

Myenteric plexus (aka Auerbach’s plexus; regulates gut motility)

(The other autonomic plexus of the GI tract, the submucosal (Meissner’s) plexus, more regulates secretory function)

Question 40

Congenital muscular dystrophy with slowly progressive weakness of lower > upper extremity weakness, often associated with peripheral neuropathy and cardiac involvement including conduction abnormalities

Genetic cause

Answer 40

Myofibrillary myopathy

Mixed genetics: can be AD or AR, and can be in multiple genes (myotilin, desmin, alphabeta-crystalin)

Question 41

What is a clinical difference between myotonia congenita and paramyotonia congenita?

Answer 41

Myotonia congenita has “warm up” phenomenons: myotonia improves with repetitive muscle activation

Paramyotonia congenita does not

Question 42

Syndrome with myotonia that improves with repetitive muscle activation (“warm up” phenomenon)

Genetic cause

Answer 42

Mytonia congenita

Two types, both mutations in CLCN1 (V-dep Cl- channel):
1. Thomsen’s disease: AD, earlier onset (1st decade) but milder
2. Becker’s disease: AR, later onset (2nd decade) but more severe

Question 43

What medications can aggravate myotonia in myotonia congenita?

Answer 43

Propofol and depolarizing neuromuscular blocking agents (succinylcholine)

(Recovery may be prolonged, mexiletine to treat)

Question 44

Condition classically associated with thumb and finger flexion weakness with preserved finger abduction (dorsal interossei)

Answer 44

Inclusion body myositis

Question 45

Antibodies that can be associated with statin-related autoimmune myopathies

Answer 45

HMG CoA reductase

SRP (signal recognition peptide)

Question 46

Mechanism of action of droxidopa in treating orthostatic hypotension

Answer 46

Prodrug of norepinephrine