Neuromuscular: Fiber Activity

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MUSCLE FIBER ACTIVITY & CRAMPS

Syndromes
Brody's syndrome
Complex repetitive discharges
Contracture: Muscle
Cramps
Cramp-Fasciculation
Dominant
Electrically silent
Familial
Electrical activity: No clinical Δ
Endplate Spikes
Fasciculations
Fibrillations
Miniature endplate potential
Minipolymyoclonus
Muscle pain
Muscle spasms
Myoedema
Myoglobinuria

Myokymia
Diffuse: Isaac's Syndrome
Hereditary
Localized: Radiation
Myopathy
Myotonic dystrophies
Neural origin
Neuromyotonia
Paramyotonia
Periodic paralyses
Hyper K⁺
Positive sharp waves
Rippling muscles
Satoyoshi Syndrome
Schwartz-Jampel
Spinal stenosis
Stiff-Person syndrome
Tetanus
Tremor, Myopathic

Myotonia
Comparative features
General features
Ion channels

Acquired
Chondrodystrophic: 1p34
Congenita
Acetazolamide-responsive: Na⁺
Becker's (Recessive): Cl^-
Thomsen's (Dominant): Cl^-
Cylindrical spirals
Dystrophy
Type I (DM1): 19q13
Type II (DM2; PROMM): 3q21
Fluctuans: Na⁺
Levior: Cl^-
Paramyotonia: Na⁺; Cl^-
Permanens: Na⁺

Muscle fiber activity

Neural origin
Amyotrophic Lateral Sclerosis
Black widow spider
Blepharospasm
Complex repetitive discharges
Crisponi syndrome
Dystonia variants
Fasciculations
Firing patterns
Geniospasm
Hemifacial spasm
Hyperexcitability
Differential diagnosis
Isaac's Syndrome
Motor neuron disorders
Motor neuropathies
Myokymia
Neuromyotonia
Palmaris brevis spasm
Polyneuropathy
Spinal:
Vascular; Compression
Startle syndrome (Hyperekplexia)
Strychnine
Stiff-Person Syndrome
Superior oblique myokymia
Tetanus
Tetany
Tremor
Whipple's

Myotonia

Comparative features
General features

Acquired
Chondrodystrophic: Perlecan; 1p34
Congenita
Acetazolamide-responsive: Na⁺
Becker's (Recessive): Cl^-
Thomsen's (Dominant): Cl^-
Dystrophy
Type I (DM1): DMPK; 19q13
Type II (DM2; PROMM): ZNF9; 3q21
Type III (DM3): VCP
Fluctuans: Na⁺
Levior: Cl^-
Paramyotonia: Na⁺; Cl^-
Permanens: Na⁺
Potassium activated myotonia: Na
Proximal Myopathy (PROMM): ZNF9; 3q21

Myotonia: General features ⁵⁶

Clinical: Delayed relaxation of skeletal muscle following voluntary contraction
- Present with initial activity
- Usually abates after repeated muscle activity
- Paradoxical myotonia (in paramyotonia) worsens with repeated activity
- Delayed myotonia
  - Appears after a period of muscle contraction
  - Seen in myotonia fluctuans
- Some syndromes associated with episodic muscle weakness
- Age of onset
  - Birth: Myotonia congenita & paramyotonia
  - Teens & adult: Myotonic dystrophy; PROMM
- Multiple specific myotonic syndromes
- A variety of pharmacological agents can exacerbate or treat myotonia.
Classification by ion channel disorder
- Na⁺ channel myotonic disorders
  - Features
    - Fluctuations over time in individuals: Common
    - Variation among families: Common; Day-to Day
    - Worse with cold
    - Paradoxical myotonia
    - Eyelid myotonia
    - Transient paralysis
  - Syndromes: Dominant; Potassium-aggravated myotonia (PAM)
    - Myotonia fluctuans
    - Myotonia permanens
    - Acetazolamide responsive myotonia
    - PAM families more common than Cl^- mediated
- Cl^- channel myotonic disorders
  - Features
    - Fluctuations over time in individuals: Unusual but may occur
    - Variation among families: Uncommon; Over weeks to months when present
    - Muscle hypertrophy
    - Warm-up effect
  - Syndromes
    - Becker's (Recessive)
    - Thomsen's (Dominant)
    - Myotonia Levior (Dominant)
    - Animal myotonias
      - Dominant: Goats
      - Recessive: Mice (transposon insertion); Horses (D592A); Brazilian Murrah water buffalo (c.396C>T, splicing)
- Other causes: Dystrophic myotonia
  - Features: Extramuscular common
  - Types
    - DM1
    - DM2
Myotonia: Electodiagnostic & Physiology
- Electrophysiology: Increased excitability of muscle fibers
- Repetitive action potentials
  - In individual muscle fibers
  - Occur in response to mechanical or electrical stimulation
- Myotonia: Mexiletine response ¹⁵
  - Drug effect: Na⁺ channel blocker
  - Effective in treatment of myotonia
    - Best response when drug blocks voltage-dependent mutant channels
    - Some effect in severe cases with blockade of wild type channels
    - Me7 derivative: More effective than Mexiletine; Inhibits Na⁺ channels in M2 gating mode
  - Mexiletine not effective in treating hyperkalemic periodic paralysis

Myotonia Congenita, Dominant (Thomsen)

● Muscle Chloride Channel (CLCN1)

; Chromosome 7q34; Dominant

History: First description 1876 Arch Psychiat Nervenkr 6, 702-718
- Julius Thomsen
  - Danish physician
  - Reported myotonia congenita in himself & his family
- "Tonische Krämpfe in willkürlich beweglichen Muskein in Folge von ererbter psychischer Disposition."
Myotonia congenita: Epidemiology
- Most common skeletal muscle channelopathy
- Prevalence in England: 0.52/100,000
- Similar prevalence of: Dominant; Recessive & Sporadic MC
Genetic features
- Mutations ⁶⁵
  - > 95 identified
  - General location: TM1 domain; Not in intracellular domain
  - Most mutations: Missense; Loss of function
  - Common mutations: Gly230Glu; Trp303Arg
  - Dominant only: Gly200Arg; Ile290Met; R317Q; Pro480Leu
  - Dominant & Recessive: Gly230Glu; Ala313Thr; Arg317Gln; Arg338Gln; Ile556Asn; Arg894X
  - Other: S132C, L283F, T310M, T550M
  - General penetrance of dominant mutations: 93%
  - Functional effects
    - Altered voltage dependence of activation: 1st half of transmembrane domains
    - No currents: 2nd half of the transmembrane domain
  - Animals: Spontaneous CLCN1 mutations in goat, mouse, dog, cat, pony, water buffalo, pig
- Allelic disorders
  - Myotonia Congenita, Recessive (Becker)
  - Paramyotonia
CLCN1 protein: Genetic-Physiology Correlations ⁵⁴
- Normal ClC-1 channels
  - CLCN1: Location & Structure
    - Expressed predominantly in skeletal muscle fibers
    - Locations: T-tubules & Outer sarcolemmal membrane
    - Homodimer: 2 identical subunits composed of 18 α-helices
  - CLCN1: Physiology
    - Accounts for 80% of total sarcolemma conductance at rest
    - Cl^- conductance: Necessary to stabilize membrane potential
    - 3 Cl^- binding sites
      - S_int, S_cen, S_ext
      - Act as selectivity filter
    - ClC-1 C-terminal domain: Relevant for protein expression, slow gating, & intracellular modulation
    - 2 Ion conductance pores
      - Fast gate: Regulates function of independent protopores,
      - Slow gate: Controls opening & closing of two subunits simultaneously
    - Cl^- gating & permeation closely linked
    - Inward rectification
    - Ion selectivity: Cl^- > Thiocyanate > Br > NO₃ > I > CH₃SO₃
- Mutations in ClC-1 channels: Effect types
  - Functional effect
    - Delay in terminating muscle contraction after voluntary activity
  - Dominant negative
    - Interfere with dimer & tetramer formation:
  - Channel functions: Cl^- conductance through channels (repolarizing) is eliminated or reduced
    - Frame shift mutations: Complete loss of channel protein
    - Missense: Several mechanisms of pathological channel function
      - General ⁶⁰
        
        1st half of transmembrane domain: Altered voltage dependence of activation
        
        2nd half of transmembrane domain: Absent currents
        
        TM1 domain: Dominant
        TM2 domain: Recessive; No shift in voltage dependance
        
        Intracellular domain: Not dominant
      - Cystathionine-β-synthase 2 (CBS2) domain: Common (slow) gating Δ
      - Positive shift in voltage range over which gating occurs: Gly200Arg
        
        Channel open probability near 0 at resting potential
      - Change in channel selectivity: G230E
        
        Outward rectification at positive potentials
        Higher cation:anion permeability ratio than wild type
        Ion selectivity: Thiocyanate > NO₃ > I > Br > Cl^- > CH₃SO₃
      - Voltage or [Cl^-]_in dependent alterations in channel function
        
        S132C
        
        Homodimeric channels: [Cl^-]_in-dependent hyperpolarization-induced activation
        
        Heterodimeric channels: Depolarization induced activation with shifted activation
        
        L283F
        
        Deactivation defect at high [Cl^-]_in
        
        T310M
        
        Activation curve: Shifted at normal [Cl^-]_in; Normal at high [Cl^-]_in
      - Aleration of ER-resident co-chaperone, FKBP8, network
  - Myotonia Congenita: Ion events
    - Reduced Cl^- conductance ± Increased cation conductance
      - K⁺ accumulates normally in T-tubules after action potentials
      - Produces membrane depolarization 10x > normal
      - Even more depolarization if mutant channel is permeable to cations
    - Heightened after-depolarization can achieve threshold
      - Results in: Spontaneous triggering of action potentials
    - Integrity of T-tubule required for myotonic discharge
  - Mutations with Dominant and Recessive phenotypes
    - ? Lower expression of mutant allele in recessive families
- Other disorders involving ClC-1
  - DM-1 & DM-2: Reduced ClC-1 expression 2° to aberrant splicing
  - Huntington�s disease: Reduced ClC-1 Cl^- currents 2° to aberrant splicing
  - DM-2 & HoPP: CLCN1 polymorphisms may modify disease manifestations
  - Aging: Reduced ClC-1 expression
  - Disuse: Positive modulation of ClC-1
Clinical features
- Onset: Infancy to Adult
- Variable penetrance: 90% symptomatic
- Myotonia
  - Usually mild
  - Course: Often constant; May be variable over time
  - 90% by EMG; 50% percussion
  - Variability
    - Exacerbations: Myotonia may be worse with cold or stress
    - Long term fluctuations in myotonia: Some mutations (Gly200Arg)
      - Symptom free for weeks to months
      - Symptoms increased by cold, humger, fatigue & emotional upset
    - Myotonia and weakness with pregnancy: Some mutations (Gly230Glu; T310M)
- Muscle hypertrophy
- Myalgias: In occasional patients
- "Warm-up" phenomenon (Reduced myotonia after repeated activity)
- Muscle strength
  - Normal at rest: Many patients
  - Proximal muscles
    - Functional difficulties (Climbing stairs)
    - Mild fixed weakness in some
  - Distal weakness: May occur with exercise
Lab
- CK: Slightly elevated or Normal
- EMG
  - Myotonia
    - Present even in early childhood
    - Distal > Proximal
    - Warming up effect: Myotonia reduced after a period of maximal contraction
  - Motor unit potentials: Normal, no myopathy
  - Repetitive nerve stimulation
    - Decrement
      - Especially at high stimulation frequencies (30 Hz)
      - Present with some mutations (P480L; R894X) & not others ²²
    - No intratetanic facilitation
  - No effect of cooling
- Muscle pathology
Pharmacology:
- Aggravated by
  - β2-agonists: Fenoterol; Ritodrine
  - Monocarboxylic amino acids
  - Depolarizing muscle relaxants
- Treated by
  - Quinine (200 to 1,200 mg/d)
  - Mexiletine (150 to 1,000 mg/day)
  - Dilantin (300 to 400 mg/day; therapeutic level of 10 to 20 μl/mL)
  - Procainamide (125 to 1,000 mg /day)
  - Tocainide (bone marrow suppression is a side effect)
  - Carbamazepine
  - Acetazolamide (125 to 750 mg/day)
  - ? Ranolazine

Myotonia Congenita, Recessive (Becker)

● Muscle Chloride Channel (CLCN1)

; Chromosome 7q34; Recessive

Epidemiology
Genetic features
- Mutations ⁶⁵
  - Most CLCN1 mutations produce recessive syndromes
  - General: Loss of function
  - Common mutations: Gly285Glu; c.18013A>T (splice site)
  - Point mutations
    - Many missense mutations: > 20 identified
    - Location: From N terminus to transmembrane domain XII
  - Other mutations
    - Deletions: Nucleotides 1282-1285 & 1437-1450
    - Nonsense: Q74stop; E193X
    - Splice site nucleotide 979
    - Exon deletions & duplications (6%)
  - Compound heterozygotes: Many patients; Some homozygotes
- Allelic disorders
  - Myotonia Congenita, Dominant (Thomsen)
  - Paramyotonia
- Heterozygotes: Increased frequency in DM2
- Mouse (Recessive mutations)
  - Arrested development of righting response (ADR)
    - ETn transposon insertion
  - Myotonic (MTO)
CLCN1 protein
- Physiology: Activating current on hyperpolarization vs. deactivation in wild type
  - No or reduced opening at voltages positive to Cl^- equilibrium potential: M485V
  - Right shift (to more + potentials) of voltage dependence of open probability of ClC-1 channels: I329T; R338Q
  - Inward rectification permits Cl^- efflux but not influx
  - No physiological mechanism identified for some mutations: Y150C; Y261C
  - Low conductance myotonia: Mutation of both ClC-1 alleles causes summated loss of function > 60%
- Muscle ClC-1 protein expression ⁴⁶
  - Reduced on surface membrane
  - May also be reduced in DM1 & DM2
  - Normal with Na⁺ channel myotonia or Thomsen disease
Clinical features
- Onset: Ages 4 to 12; Legs
- Myotonia
  - With "warm-up" phenomenon
  - More severe than in dominant (Thomsen) form
- Muscle hypertrophy
  - Especially legs & gluteals
  - ? Males > Females
- Strength
  - Initially normal
  - Rapid decrease with short exercise
  - Returns to normal with further muscle contraction
  - ± Mild distal weakness
- Carriers: Myotonia in EMG of males but not females
EMG
- Myotonia
  - Distal > Proximal
  - Warm up effect: Less myotonia after maximal contraction
- Motor units: Mildly myopathic
- Decremental CMAP response
  - Especially: At high stimulation frequency (30 Hz); Following exercise
  - No effect of cooling

Myotonia levior

● Muscle Chloride Channel (CLCN1); Chromosome 7q34; Dominant

Mutation: Gln552Arg
Clinical features
- Myotonia: Mild
- Onset: Late
- No muscle hypertrophy

Paramyotonia syndromes ⁶⁴

● Sodium Channel - α subunit (SCN4A)

; Chromosome 17q23.3; Dominant
● Muscle Chloride Channel (CLCN1)

; Chromosome 7q34; Dominant

Nosology
- Paramyotonia: "Abnormal" myotonia
- Paradoxical myotonia: Myotonia worsening with repetitive exercise
- Paramyotonia congenita of Eulenburg (PMC)
- Myotonia increased by exposure to cold
- Paralysis periodica paramyotonia
Genetics
- SCN4A Mutation locations
  - Cytoplasmic loops between repeats II & II and III & IV (inactivation gate)
  - Transmembrane segments S2, S3 & S4
    - Especially cytoplasmic side of membrane
  - Paramyotonia correlations
    - Pure paramyotonia: G1456E; L1433R
    - Paramyotonia ± Episodic weakness with exercise: R1448C
    - Overall: Exon 24 mutations commonly cause paramyotonia
  - Quarter horses: Phe-to-Leu mutation in transmembrane domain IVS-3
- CLCN1
  - Mutation: F428S
  - Allelic disorders
    - Myotonia Congenita, Recessive (Becker)
    - Myotonia Congenita, Dominant (Thomsen)
Electrophysiology: SCN4A mutation effects
- Functional defects in Na⁺ channels: Abnormal inactivation; Less voltage dependence
  - Disruption of fast inactivation of Na⁺ channel
    - Na⁺ ions continue to leak into cell
  - Some mutations also disrupt slow Na⁺ channel inactivation
    - Weakness is common with these mutations
  - Inactivation is prolonged from open channel state, but normal from closed state
  - Channel conductance: Permeation of Na⁺ ions through pore is normal
- Poor inactivation of Na⁺ channel: Electrophysiologic consequences
  - Prolongs action potential
  - Reduces membrane repolarization
  - Clinical correlates
    - Mild depolarization (> 5mV) produces repetitive discharges (myotonia)
    - More severe depolarization (> 20mV) produces weakness
Paramyotonia: Clinical
- Weakness or Myotonia (stiffness): May occur individually
- Myotonia
  - Mechanisms
    - Na channel inactivation: Mild slowing
    - Membrane depolarization
  - Clinical
    - Onset age: Infancy or Early Childhood
    - Worse with
      - Cold, especially during exercise
      - Exercise
    - Location: Face, Neck & Upper extremities most involved
- Episodic weakness
  - Mechanisms
    - Very slow Na channel inactivation
    - Muscle action potential blockade
  - Episodes
    - Onset age: Adolescence or Never
    - Precipitants
      - Exercise
      - Cold exposure: Ice cream; Swimming in cold water
      - Spontaneous
      - Some patients worse after K⁺ load
    - Exacerbated by: Hyperthyroidism
    - Duration: Episodes usually last few minutes, but occasionally days
  - Muscles involved: Diffuse or Selective to muscles exposed to precipitants (cold)
- Muscle size: May be increased or normal
- Cardiac arrhythmias: Some patients
- Course
  - Non-progressive
  - Life span: Normal
- Associated with: Hyper K⁺ periodic paralysis
- Therapy
  - Myotonia: Antiarrhythmic drugs
    - Mexiletine: 150 to 1,000 mg/day (50 to 100 mg tid)
      - Use-dependent blockade of sodium channels
      - Reduces repetitive series of action potentials: Reduced muscle stiffness
    - Carbamazepine: 100�200mg, 2�3x/day)
    - ? Tocainide
  - Weakness: K⁺-sensitive
    - Hydrochlorothiazide (250 to 1,000 mg/day)
    - ± Supplemental K⁺
    - Acetazolamide (125 to 1,000 mg/d)
    - Dichlorphenamide (50 to 150 mg/day)
  - Weakness: Paramyotonia
    - Mexiletine 150 to 1,000 mg/day
    - ? Tocainide
    - K⁺
EMG
- Myotonia
  - Less prominent than in other myotonias
    - May be absent at normal temperature
  - Action potentials
    - Frequency: 20 to 50 Hz
    - Burst length: > 1 minute
- Cooling effects
  - Initial
    - Repetitive spontaneous motor unit discharges (Fibrillations)
    - Disappear < 28°C
  - Increased cooling
    - Depolarization: Myotonia disappears
    - Paralysis: Electrically silent
- Short exercise test, with muscle cooled: CMAP
  - Amplitude: Reduced
  - Course of change: Persistent change up to 1 hour
  - Differential diagnosis: DM1 & Chloride channel myotonias reduction lasts only minutes
Laboratory
- Serum CK: Often mildly high
- Serum K⁺
  - Cold-induced: Normal
  - Weakness not temperature related: May be high
Variants: Clinical "myotonia" syndromes
- Potassium aggravated myotonia (PAM)
  - SCN4A genetics
    - Mutations: Ser804Phe; Ile1160Val; Gly1306Ala;
      Gly1306Val; Gly 1306Glu; Val1589Met
    - Allelic disorders
      - Paramyotonia congenita
      - Hyperkalemic periodic paralysis (HYPP)
      - Hypokalemic periodic paralysis (HOKPP)
  - Clinical
    - Attacks precipitated by: K⁺ load
    - No weakness
    - Discomfort: Muscle pain & stiffness
    - Variable features: Syndromes include
      - Myotonia fluctuans
      - Myotonia permanens
      - Acetazolamide responsive myotonia
      - Episodic neonatal apnea: Neonatal laryngospasm
  - Laboratory
    - Serum CK: May be high
    - Muscle ultrastructure: T-tubule dilatation; Subsarcolemmal vacuoles
- Paramyotonia congenita (PMC)
  - SCN4A Mutations
  - CLCN1 Mutation ¹⁸
    - F428S: Missense
    - Channels: Normal physiology; Low expression
  - Clinical
    - Onset age: 1st decade
    - "Weakness": Due to paramyotonia, precipitated by hypokalemia
    - Exacerbated by: Cold
  - Muscle pathology: Tubular aggregates in some patients
- Paramyotonia congenita without cold paralysis
  - Epidemiology: Irish family
  - Mutation: Val1293Ile
  - Clinical
    - Onset
      - Age: Childhood
      - Spasms of muscle stiffness: Preferentially affect hands & face
    - Myotonia
      - Worsens with exertion (Paradoxical myotonia)
      - Most marked exacerbation: Cold weather
    - No periodic paralysis or progressive weakness
  - EMG
    - Myotonic discharges: Profuse
    - Cooling: 78% drop in CMAP amplitude

Myotonia Fluctuans

● Sodium Channel - α subunit (SCN4A; Na_v1.4)

; Chromosome 17q23.3; Dominant

Genetics
- SCN4A Mutations: Missense; Exons 22 & 14
Clinical features
- Myotonia
  - Mild
  - Varies in severity from day to day
  - Delayed myotonia
    - Appears after a period of muscle contraction
    - Stiffness develops during rest, 20 to 40 minutes after exercise
    - Lasts for ~1 hour
  - Stiffness exacerbated by
    - Potassium
    - Depolarizing agents (e.g. suxamethonium)
      - May interfere with respiration
- No weakness or cold sensitivity
EMG
- Myotonia: Increased after exercise

Myotonia Permanens

● Sodium Channel - α subunit (SCN4A; Na_v1.4)

; Chromosome 17q23.3; Dominant or Sporadic

Genetics: SCN4A Mutations
- Heterozygous
- Missense: Gly1306Glu
  - G1306A causes: Myotonia fluctuans
  - G1306V causes: Intermediate myotonic phenotype
- Region coding for hinge of channel inactivation gate
Mutation effects on Na⁺ channel function
- All mutations at 1306 site: Reduced sodium channel inactivation
- Only myotonia permanens mutation (G1306E) causes a left shift of activation curve
  - Decreased electrical threshhold
Clinical Features
- Severe continuous myotonia
  - May interfere with respiration
  - Worse with: Exercise; K⁺ rich foods
- No paralysis
- Marked muscle hypertrophy
Laboratory
- EMG: Constant myotonic activity
- Serum CK: Increased 6x to 8x normal
  - High CK also seen in: Recessive Cl^- channel myotonia

Acetazolamide-responsive Myotonia Congenita

● Sodium Channel - α subunit (SCN4A; Na_v1.4)

; Chromosome 17q23.3; Dominant

Genetics
- SCN4A Mutation: Ile1160Val
Clinical features
- Muscle hypertrophy
- "Paradoxical" Myotonia: Worse with repeated activity
- Muscle pain & stiffness
  - Aggravated by potassium
  - Improved by acetazolamide
- No weakness

Myotonic Dystrophy (DM1)

● Myotonin protein kinase; Chromosome 19; Dominant

Proximal Myotonic Myopathy (PROMM; DM2)

● CCHC-type Zinc finger Nucleic acid-Binding Protein (CNBP; Zinc finger protein 9 (ZNF9))

; Chromosome 3q21.3; Dominant

DM2: Epidemiology
- Most families European, especially German/Polish
- Anticipation ⁶
  - Mild: 0.5 to 1.9 decades (vs 2.9 decades in myotonic dystrophy)
  - ? More prominent with paternal transmission
Genetics: Mutation in CCTG repeat sequence in intron 1 of ZNF9 gene ¹²
- Normal CCTG repeat sequence
  - Complex repeat motif: (TG)_n(TCTG)_n(CCTG)_n
  - Size: 104 to 176 base pairs
  - Interruptions: GCTG + TCTG motifs, or one or two TCTG motifs
- CCTG expansion
  - (CCTG)_n repeat size: Range 75 to ~11,000; Mean ~5000
  - Interruptions: None
  - No clear relation of CCTG repeat size with: Onset age; Disease severity
  - Somatic instability
    - Different repeat sizes in different tissues
    - Age: Size of CCTG repeat increases over time in individuals
    - Especially great: Peripheral blood
    - Greater than in DM1
  - Intergenerational features
    - Repeat size in blood of affected child: Shorter than parent
- Genetics & DM2 disease pathogenesis
  - CCTG expansion produces RNA with excessive repeats
  - RNA with expanded repeats located focally in muscle cell nucleus
  - CCTG expression at RNA level may be pathogenic
  - Functional effects of long repeat RNA
    - Abnormal splicing of muscle CLC1 (chloride) channel RNA
    - Altered splicing adds exon 7a to Cl^- channel RNA
    - Aberrantly spliced RNA produces altered Cl^- channel protein with reduced function
    - Reduced Cl^- channel function produces myotonia
    - Longer repeat RNA produces more abnormal splicing of Cl^- channel: More myotonia
    - Effect is expressed as mosaic
      - Some muscle fibers with more reduction of Cl^- channel than others
    - Similar effect of elongated CTG repeat sequence in DM1
- Genetic association
  - CLCN1: Increased frequency of coexisting recessive mutations
- Clinical-Genetic correlations
  - Unclear correlation between repeat length & disease severity
  - Homozygous for CCTG repeats: Not different from heterozygotes ²⁸
- Other disease expansions in transcribed but untranslated DNA
  - DM1 (CTG)
  - SCA8 (CTG)
  - SCA10 (ATTCT)
CNBP (ZNF9) protein
- ZNF9 expression: Most abundant in heart & Skeletal muscle
- Single stranded DNA-binding
- Sterol regulatory element: Involved in sterol-mediated repression
- Subcellular location: Cytoplasmic, also in endoplasmic reticulum
Clinical features
- Onset ⁶³
  - Age
    - Congenital to 60 years
    - Maternal inheritance: Earlier onset (Often < 30 years)
    - No relation to patient sex
  - May be related to pregnancy (21%) with paternal inheritance
  - Muscle (60%): Stiffness or Pain
  - Non-muscular: Cardiac; Cataracts
  - Early onset ³⁹: Hypotonia; Myotonia not usually present
- Intrafamilial variability
- Weakness
  - Proximal: Legs > Arms; Hip flexors & extensors early
  - Distal arms: May be involved early; Thumb & Finger flexors
  - Face: Weak in 12%
  - Normal: Distal legs; Respiratory
  - Variation: Over hours
  - Progression: Slow
- Muscle Enlargement: Calf
- Muscle Pain or Discomfort ²⁹: 56% to 75%
  - Stimuli
    - Exercise-related, or at rest
    - Temperature-modulated: Increased with cold
    - Palpation-induced
    - No relation to myotonia
  - Proximal; Legs > Arms
  - Painful stiffness
  - Variable from day-to-day
- Myotonia
  - Symptomatic: Asymmetric
  - Intermittent: Exacerbations during pregnancy
  - Temperature sensitive (Warm more; Cold less)
  - Induced by: Grip; Percussion
- CNS
  - Clinical: Usually normal; Occasional CNS signs
  - Imaging
    - MRI: White matter hyperintensity on T₂ weighted images
    - Reduction of frontal & parietal gray matter
    - Abnormal thalamic gray matter & hippocampus
    - White matter lesions: > 50%; Extent correlated with psychomotor speed
    - More severe in DM1 than DM2
- Systemic
  - Cataracts: 100% over 20 years with slit lamp
  - Cardiac arrhythmias: 20%; Conduction defects
  - Diabetes mellitus: 20%
  - Hearing loss (60%) ⁵⁰
    - Mild to Moderate
    - Cochlear sensorineural
    - More with increased age
  - Fertility: Normal or Reduced
  - Cardiovascular autonomic function: Normal
- Anesthesia & Muscle relaxant risk: Minor
- See: Comparison to DM1
Lab ⁴²
- Serum & Blood
  - CK
    - Mild elevation (< 10x) (85%)
    - May be high in asymptomatic DM2 patients ³⁰
  - FSH: High
  - IgG level: Reduced
  - Cholesterol: High (62%)
  - Lymphopenia (54%)
- EMG
  - Myotonia
  - CMAP amplitude increased with exercise
    - Progressively reduced (by 40%) during rest
      - 20 to 40 min after initial increment (60% of patients)
    - No decrement: On short exercise, or slow or rapid repetitive stimulation
    - Normals: Mild increase in CMAP amplitude after exercise
  - Myopathic motor unit potentials: Proximal > Distal
- MRI: Muscles involved ³²
  - Selective muscle involvement: Erector spinae; Gluteus maximus
  - Abnormality more common
    - Females
    - Increasing age
  - Abnormality less common
    - Males
    - Milder weakness
    - Myalgias
- Muscle biopsy
  - Internal nuclei: Type 2 muscle fibers
  - Fiber size variation: Type 2 atrophy
  - Pyknotic nuclear clumps
    - Especially type 2 fibers
    - Beter seen by myosin heavy chain histochemistry
  - No fiber type grouping
- Cell pathology: Intranuclear inclusions
- CNS MRI: White matter disease ⁴³
  - Prominent callosal body & limbic system involvement
  - Less grey matter pathology than DM1
Prognosis: More benign than DM1 myotonic dystrophy

DM2: Hypertrophic calves

PROMM

● Locus not linked to 3q21; Autosomal Dominant

German family
Myotonia
Weakness; Proximal
Cataracts
MRI: White matter changes

Acquired myotonia: Drug toxicity

Hyperkalemic periodic paralysis

Andersen: KCNJ2; 17q24
K⁺ channel: KCNE3; 11q13
Na⁺ channel: SCN4A; 17q23

Hyperkalemic periodic paralysis
● Sodium Channel - α subunit (SCN4A)

; Chromosome 17q23.3; Dominant

Genetics
- Mutations ⁴
  - Locations: Thr704Met; Ser906Thr; Ala1156Thr; Met1360Val; R1448C; Met1592Val
  - Mechanism of action: Defective inactivation of Na⁺ channel
- Allelic disorders
Genetic-Clinical correlations
- Thr704Met
  - Permanent weakness common
  - Most frequent mutation: 60% of HRPP cases
- Met1592Val
  - Myotonic
  - Non-Dystrophic
  - Frequency: 30% of HRPP cases
- Ala1156Thr & Met1360Val: Reduced penetrance

Physiology: "Gain of function" mutations

Mechanisms of Episodic Weakness
Extracellular K⁺ increase: 2° to K⁺ intake, or Rest after exercise ↓ Membrane depolarization: Mild ↓ Na+ channels open: Abnormal Na⁺ channels to non-inactivating mode ↓ ↑ Persistent inward Na⁺ current ↑ ↓ ↑ í Extracellular K⁺ increase Sustained depolarization of muscle membrane î ↑ ↓ K⁺ efflux Inactivation of normal Na⁺ channels ↓ Loss of electrical excitability of muscle membrane ↓ Weakness

Mechanisms of Episodic Weakness

Extracellular K⁺ increase: 2° to K⁺ intake, or Rest after exercise
↓
Membrane depolarization: Mild
↓
Na+ channels open: Abnormal Na⁺ channels to non-inactivating mode
↓ ↑
Persistent inward Na⁺ current ↑
↓ ↑ í Extracellular K⁺ increase
Sustained depolarization of muscle membrane î ↑
↓ K⁺ efflux
Inactivation of normal Na⁺ channels
↓
Loss of electrical excitability of muscle membrane
↓
Weakness

Clinical features
- Episodic weakness: Flaccid
  - Onset: 1st decade
  - Distribution
    - Usually proximal & symmetric
    - Occasionally distal & asymmetric in exercised muscles
  - More frequent with increasing age
  - Onset
    - Early am before breakfast
    - During rest after exercise
    - May be associated with paresthesias
  - Lasts 15 to 60 minutes: Occasionally hours or days
  - Provoked by
  - Relieved by: Carbohydrate intake; Mild exercise
  - Prognosis: Weakness
    - May become permanent with some SCN4A mutations (Thr704Met)
    - Others (Met1592Val) only episodic
  - Comparison of attacks to hypokalemic periodic paralysis
    - Frequency: Greater
    - Duration: Shorter
- Myotonia ± Paramyotonia
  - Episodic
  - Present between episodes of weakness
  - Frequency: In majority of patients on EMG
  - Stiffness with cooling less common than in paramyotonia
- Cardiac dysrhythmias: Rule out Andersen's syndrome
Laboratory
- Attacks associated with high serum K⁺ (>4.5 mEq/l) & high urinary K⁺
- Serum CK: Normal to 300 U/L
- CMAP amplitude
  - Increased immediately after sustained (5 min) maximal contraction
  - Progressively reduced (by 40%) during rest 20 to 40 min after initial increment (80% of patients)
  - Normals: Mildly increased CMAP amplitude after exercise
Provocative tests
- Oral K⁺ load
  - Only if renal & cardiac function & serum K⁺ normal
  - Perform fasting, in am, after exercise
  - 0.05 g/kg KCl in sugar-free liquid over 3 minutes
  - If negative may give 0.10 to 0.15 g/kg KCl
  - Monitor electrolytes, EKG & strength every 20 minutes
  - Weakness typically most at 90 to 180 minutes
- Exercise
  - Bicycle ergometer
    - 30 minutes
    - Pulse to 120 to 160
  - Then absolute bed rest
  - Measure serum K⁺
    - Normal: K⁺ rises during exercise; Then falls to near preexercise level
    - Hyperkalemic PP: 10 to 20 minutes after exercise ® 2nd hyperkalemic period & Paralysis
Treatment
- Many attacks brief & do not need treatment
- Acute attack: Carbohydrate ingestion
- Chronic: Acetazolamide; Thiazide diuretics
- Mexiletine: Myotonia; No benefit for weakness:
? Variant: Normokalemic periodic paralysis
Animal disease: Quarter Horses
- Genetic
  - Offspring of American Quarter Horse sire, Impressive
  - Phe1421Leu mutation in transmembrane domain IVS-3
- Clinical
  - Weakness may be severe
  - Muscle hypertrophy
  - Homozygotes more severe than heterozygotes: Laryngeal & Pharyngeal dysfunction

● Andersen's syndrome: K⁺ sensitive periodic paralysis with Cardiac dysrhythmias & Dysmorphic features

Rippling Muscle Syndromes ¹⁷

Acquired
Hereditary
Dominant
RMD1: 1q41
RMD2: Caveolin-3; 3p25
Lipodystrophy (CGL4): Cavin; 17q21
Recessive
Omani
RMR: Caveolin-3; 3p25

Rippling Muscle Syndromes: Hereditary, Dominant

● RMD1

: Chromosome 1q41; Dominant
● RMD2

: Caveolin-3 (CAV3)

; Chromosome 3p25.3; Dominant
● ? Other loci; Dominant ⁹

Epidemiology
- Most families: CAV3 mutation
- 1 family: 1q41 linkage
CAV3 Genetics
- Caveolin-3 mutations: Missense
  - R26Q: AD-RMD; HyperCKemia
  - Asp27Glu: Variable phenotype, AD-RMD; Distal weakness; LGMD & Intrafamilial variation
  - A45T: AD-RMD & HyperCKemia with muscle discomfort
  - Ala45Val: AD-RMD
  - A46T: AD-RMD; Benign & Non-progressive; Normal strength ⁴⁰
  - Ser52Gly: Rippling muscle disease
  - F97del: Variable phenotype; RMD, LGMD or High CK
  - P104L: AD-RMD & LGMD1C
  - Homozygous L86P & A92T: Rippling muscle disease, Severe
- Allelic disorders: Caveolin-3
  - Rippling muscle disease 2, Recessive
  - LGMD 1C
  - Increased CK with normal strength
  - Distal myopathy, Tateyama type, Dominant (MPDT)
  - Cardiomyopathy, familial hypertrophic
  - Long QT syndrome 9
Caveolin-3 protein
Clinical features
- Epidemiology
  - Females less involved than males
  - Variable within families
- Onset
  - Usual: 1st or 2nd decades
  - Range: 5 to 54 years
  - 15% asymptomatic
- Discomfort
  - Muscle cramps, pain & stiffness
  - Legs > Arms
  - Neck stiffness in some patients
  - Worse with: Exercise; Occasionally cold
  - Toe walking: On awakening or after rest
- Rippling of muscle: Wave-like
  - Evoked by: Muscle stretch
  - Moves laterally along muscle over 5 to 20 seconds (0.6 M/s)
  - 10x slower than muscle fiber action potential
  - Electrically silent
  - Frequency: Present in 60% of patients
  - Localization: Especially prominent in large proximal muscles
- Mounding of muscle (Myoedema)
  - Evoked by percussion: All patients
  - Rapid
  - Prominent in thenar eminence
  - Differential diagnosis: Malnutrition; Cachexia; Hypothyroidism
- Rapid Contraction (PIRC)
  - Evoked by: Muscle percussion (Mild); Pressure
    - Amplitude increases with strength of percussion
    - No habituation
  - Frequency: Common; Up to 100%
  - Rapid onset
  - Duration: Up to 30 seconds
  - Painful in 30%
  - Distribution: Generalized or in isolated muscles
  - Clinically similar to myotonia or myoedema
- Muscle hypertrophy: Calf or Generalized
- Weakness: Some mutations (Asp27Glu)
  - Proximal or Distal
  - Scapular winging
  - May be exacerbated by dantrolene
- Systemic
  - Strabismus: Intermittent
  - Pigmenturia: Recurrent
  - Cardiomyopathy: Some genetic types
    - Hypertrophic
    - Arrhythmias
    - A46V mutation
Laboratory
- EMG
  - Muscle activity is electrically silent
  - Some increased insertional activity
  - Normal during rippling or mounding
- Serum CK
  - Usually high: Up to 10x Elevated
  - Occasionally Normal
- Muscle pathology
  - Muscle fiber size: Varied
  - Type 2 fiber hypertrophy
  - Central nuclei
  - Dysferlin staining reduced, especially with compound heterozygous mutations
  - Caveolin staining: Reduced
  - Ultrastructure: More severe changes in homozygous mutations
    - Absence of caveolae in sarcolemma
    - Plasmalemma: Discontinuities; Papillary projections
    - Subsarcolemmal vacuoles
- Muscle physiology: Altered Ca⁺⁺ regulation by sarcoplasmic reticulum
  - "After-contraction" of single muscle fibers
  - Altered release or uptake of Ca⁺⁺ by sarcoplasmic reticulum
Treatment
- Dantrolene: May increase weakness
- Benzodiazepines

Rippling Muscle Syndromes: Hereditary, Recessive ¹⁴

Rippling Muscles, Recessive
● Caveolin-3

; Chromosome 3p25.3; Recessive or More severe dominant

Mutations
- Homozygous L86P or A92T ²¹
- Often truncating
Clinical
- Motor development: Delayed
- Muscle stiffness: Severe; Permanent
- Percussion/pressure-induced rapid muscle contractions
- Muscle hypertrophy
- Ankle contractures: L86P mutation
- Proximal weakness: A92T mutation
Laboratory
- Serum CK: 1,500 to 5,000
- Muscle pathology
  - Variation muscle fiber size
  - Muscle fiber hypertrophy
  - Atrophic muscle fibers
  - Internal nuclei: Increased
  - Caveolin-3: Reduced in muscle
  - Caveolae: Absent in sarcolemma
  - Ultrastructure: More severe changes in homozygous mutations
    - Complete absence of caveolae in the sarcolemma
    - Plasmalemma: Discontinuities; Papillary projections
    - Subsarcolemmal vacuoles

Rippling Muscles, Recessive
● Recessive

Epidemiology
- Oman families
Onset
- Childhood
- Motor development: Delayed
- Fatigue
Clinical: Severe
- Muscle features
  - Involvement of proximal & distal muscles
  - Rippling
  - Mounding
  - Hypertrophy: Generalized; Including face
  - Tone: Normal
  - Strength: Normal
- Skeletal
  - Bone age: Delayed
  - Short stature
  - Contractures: Ankle
- Cardiac: Variably present
  - Intraventricular septum: Thickened
  - Arrhythmia: Ventricular ectopy & tachycardia; PVCs
  - Sudden death
Laboratory
- Serum CK: Very high; 1,000 to 6,000
- EMG: No spontaneous activity
- Muscle pathology
  - Fiber size: Varied; Some hypertrophy
  - Occasional central nuclei
External link: Movies - Stephan laboratory
- Case1
- Case 3

Rippling Muscle Syndrome, Sporadic ³

Associated with
- Thymoma
- Myasthenia gravis: Rippling muscles may precede dx of MG
Clinical features
- Onset: Teens to 8th decade
- Cramps
  - Induced by exercise or touching muscle
  - Spread: Transverse direction across muscle
- Muscle hyperactivity
  - Rippling muscles
  - Percussion-induced rapid muscle contractions (PIRC)
  - May be painful
  - Distribution: Cranial; Proximal; Distal
- Bulbar: Dysphagia; Dysarthria
- Weakness: Proximal; Some patients
- Myalgias
- Sensation & Tendon reflexes: Normal
- Similar to hereditary rippling muscle syndrome
- Associations
  - MG: 10%
  - Neoplasm: 10%
- Treatment
  - Immunosuppression: Prednisone or Azathioprine; Benefit over 2 to 4 months
  - Exacerbated by Pyridostigmine
Laboratory
- Serum CK: Mildly elevated up to 2600
- Muscle biopsy
  - Inflammation, lymphocytic: CD4 & B-cells; Some patients
  - Myopathic: Varied fiber size
  - MHC-1: Upregulated, especially in fibers with reduced caveolin-3
  - Caveolin-3: Reduced in mosaic pattern; Reduced or Normal by Western blot
  - Dysferlin: Abnormal staining; Western blot normal
  - Cavin-4 staining: Mosaic pattern; 50% to 90% of fibers reduced
  - Complement: Deposition on muscle fiber surface
  - MHC1: Upregulated by muscle fibers
- EMG: Normal or Myopathic; Cramps are silent
- MRI: Myopathic changes in muscle
- Serum Antibodies
  - Skeletal muscle: Titin
  - IgG vs Caveolae-Associated Protein 4 (Cavin-4) ⁶¹
    - Frequency: 80%
    - Antibody type: IgG1
    - Levels: 1:1600 to 1:6400
  - AChR binding: 40%

Schwartz-Jampel Syndrome (Chondrodystrophic myotonia) ^²⁴

● Perlecan (HSPG2)

; Chromosome 1p36.12; Recessive

From: Ho et al. BMC Neurology

Gene
- Mutations
  - Truncation (insertions or deletions) most common
  - Missense or splicing in some patients
- Null mutations in
  - Dyssegmental dysplasia, Silverman-Handmaker type
Perlecan
- Heparan sulfate proteoglycan
- Major component of basement membranes & interstitial matrix in cartilage
- Functions
  - Coreceptor for FGF2
  - Interacts with basement membrane components & cell surface receptors
    - β1 integrin
    - Domain V binds to: Heparin; Fibulin-2; α dystroglycan
    - Domain IV binds to: Nidogen-1 & and -2; Fibulin-2; Fibronectin; Heparin
  - Localizes acetylcholinesterase to NMJs
  - Protects cartilage components from hydrolysis
Type 1A
- Clinical features
  - Onset
    - Childhood, Usually < 3 years
    - Respiratory & Feeding difficulties
    - Prenatal
      - Impaired swallowing: Polyhydramnios; Absent stomach bubble
      - Skeletal: Contractures; Short femurs
  - Neuromuscular
    - Muscle stiffness
      - Myotonia: Onset after birth
      - Face: Fixed expression, Pursed lips, Small mouth
      - Thighs
      - Waddling gait
      - Crouched stance
      - Treatment: Carbamazepine
    - Muscle hypertrophy: Especially thighs; Generalized
    - Malignant Hyperthermia: Increased risk during anesthesia
    - Tendon reflexes: Reduced
  - Mental retardation: Mild; Rare
  - Skeletal
    - Bone dysplasia (moderate)
      - Micrognathia
      - Spine: Platyspondyly; Cleft vertebrae
      - Reduced height
      - Kyphoscoliosis
    - Contractures: Progress until mid-adolescence
  - Ocular
    - Myopia
    - Cataracts
    - Blepharophimosis
    - Medial displacement of outer canthi
  - Hirsutism
  - Small testes
  - Anesthetic problems
    - Mechanical difficulty during intubation: Microstomia & jaw muscle rigidity
    - Limitation of respiratory excursion: Deformity of the spine and chest
- Laboratory
  - EMG: Continuous muscle discharges
    - Myotonia or Complex repetitive discharges
    - Present from age 7 months
    - No modulation of frequency or amplitude
    - ? Activity due to Muscle or Neural basis
  - Serum CK: Mildly high or Normal
  - Muscle biopsy
    - Histochemistry: Fiber type changes; Internal nuclei; Varied fiber size
    - Perlecan: Reduced or mutated molecule secreted into extracellular matrix
  - X-rays: Osteochondrodysplasia
Type 1B
- Perlecan mutations
- Onset: Birth
- More severe bone dysplasia: Like Kneist

Schwartz-Jampel Type 2/Stuve-Wiedemann syndrome (SWS) ²⁶

● Leukemia Inhibitory Factor Receptor (LIFR)

; Chromosome 5p13.1; Recessive

LIFR genetics: Null mutations
LIF receptor protein
- Binds several cytokines
  - LIF
  - OSM
  - Ciliary neurotrophic factor (CNTF)
  - Cardiotrophin 1
  - Neurotrophin-1/B-cell stimulating factor 3
- Related proteins causing syndromes
  - Cold-induced sweating 1 (Crisponi)
  - Cold induced sweating 2
Clinical
- Onset age: Birth
- Congenital features
  - Hypotonia
  - Respiratory & feeding difficulties
  - Hyperthermic episodes
  - High mortality in infancy
- Skeletal
  - Joint contractures
  - Bent bone dysplasia: Campomelic-metaphyseal (Like Pyle disease )
    - Bowing of lower limbs
    - Internal cortical thickening
    - Wide metaphyses: Abnormal trabecular pattern
    - Camptodactyly
  - Spontaneous fractures
  - Short stature
- Autonomic
  - Malignant Hyperthermia: Recurrent episodes
  - Temperature instability
  - Corneal reflex: Absent
  - Smooth tongue
  - ? Pathogenesis: ? Due to Impairment of STAT3 signaling
    - Reduced induction of cholinergic & peptidic properties of sympathetic neurons
- Tendon reflexes: Reduced
Laboratory
- Mitochondrial disorder: Complex I and IV activity reduced
LIFR knockout mouse
- Reduction of fetal bone volume: Increased number of osteoclasts
- Reduction of astrocyte numbers in spinal cord & brain
- Perinatal death

Brody disease ⁵³

● Ca⁺⁺ ATPase (ATP2A1; SERCA1)

; Chromosome 16p11.2; Recessive

Epidemiology
- > 40 families
- Male preponderance
- Rare: 1 in 10,000,000 births
Genetics: ATP2A1 Gene mutations ⁵
- Present in some, but not all, recessive Brody's syndrome families
- Types
  - Common: Stop or Frameshift; Also splice site (c.1287G>A)
  - Missense: Glu183Lys, Ile235Asn, Arg560Cys, Glu749Lys, Pro789Leu, Leu922Pro
- No ATP2A1 mutations: Dominant families
- Heterozygotes: Asymptomatic
Ca⁺⁺ ATPase protein
- Location: Fast-twitch skeletal muscle sarcoplasmic reticulum
- Lower cytoplasmic Ca⁺⁺: Pumps Ca⁺⁺ to luminal or extracellular spaces
- Promotes muscle fiber relaxation after contraction
- Neonatal & adult isoforms produced by alternative splicing
- Distribution: Type 2 muscle fibers
- Complex with: RyR1; Calsequestrin 1
- Reduced activity in CAPN3-deficient cells
Clinical features
- Onset
  - Age: Childhood; 1st decade
  - Limb muscles
  - Cramps; Myalgia; Stiffness; Fatigability
- Muscle symptoms
  - Stiffness: Exercise-induced
  - Cramps: Often painless
  - Fatigue
  - Myalgias
    - Frequency: 50%
    - Exercise related
    - More common in patients without ATP2A1 mutations
- Stiffness: Impaired muscle relaxation
  - Delayed relaxation after repetitive contraction
  - Distribution
    - Generalized
    - Limbs, distal
    - Face (Eyelids)
  - Exercise induced
    - Onset: Minutes after onset of exercise
    - Worse with progressive exercise
  - Cold
    - Symptoms worsen (70%)
    - Increased delay of muscle relaxation after repetitive contractions
  - Rest: Improvement of symptoms after seconds to minutes
  - No percussion-induced contractions
- Strength
  - Resting
    - Normal (93%)
    - Proximal, mild (7%)
    - Symptomatic weakness: Some patients with normal strenth
  - Exercise, During: Reduced
  - Exercise, After: Strength returns to normal within minutes
- Muscle size
  - May be: Large
  - No atrophy
- Rhabdomyolysis or Malignant Hyperthermia
  - Some patients (10%)
  - May be only clinical feature of disease
  - CK may increase with exercise to 10,000 without clinically significand rhabdomyolysis
- Course
  - Progression: None or Slow
  - Permanent weakness: Rare
  - Disability: Common
- Treatment: ? Dantrolene; Nifedipine; Verapamil
Laboratory
- Serum CK: May be mildly elevated
- EMG
  - Cramps: Electrically silent
  - Normal motor units
  - Some with myopathic features
- RNS: Pseudo-Increment ⁵²
- Muscle pathology
  - Type II fibers: Atrophy; Predominance (75%)
  - No myopathic changes
  - ATP2A1 (SERCA 1) levels
    - Staining: Absent with truncating, but not missense, mutations
    - Western blot: Reduced or Absent
    - Activity: Reduced
  - Myonuclei
    - Internal: Common
    - May be clumped, vacuolated, or polyploid
Animal disorder
- Cattle congenital pseudomyotonia (PMT): Chianina & Romagnola Italian cattle
Clinical variant: Brody syndrome ⁴⁵
- Genetics
  - No ATP2A1 mutations
  - Inheritance
    - Dominant or Recessive
    - Italian family: Dominant; Cosegregates with balanced translocation (2;7)(p11.2;p12.1)
- ATP2A1 protein
  - Patients may have reduced activity
- Clinical
  - Onset: Teens or Later
  - Selective muscular involvement
  - Myalgia: More frequent

Myokymia & Benign Neonatal Epilepsy (BFNS1) ¹³

● KCNQ2

; Chromosome 20q13.33; Dominant

Epidemiology: > 15 families
Genetics
- Mutations: R207W; Missense or Deletion
- Allelic disorders
  - Peripheral nerve hyperexcitability
  - Other
KCNQ2 Physiology: Mutation
- Shifts voltage dependence to more positive voltages
- Slows depolarization-induced activation
Clinical
- Onset: Neonatal convulsions
- Myalgias: Childhood
- Myokymia
  - Increased with age
  - Exacerbated by: Fever, Cold, Alcohol & Pregnancy
  - Distribution: Trunk; Limbs; Not face
  - EMG
    - Spontaneous discharges of grouped motor unit potentials
    - Repetitive discharges after nerve stimulus
    - Activity inhibited by NMJ blockade
  - Treatment: Carbamazepine
- Neonatal epilepsy, Benign
Variant syndrome: Peripheral nerve hyperexcitability (Myokymia)
- Epidemiology: Egyptian patient
- Genetics
  - KCNQ2 mutation: R207Q; Heterozygous
  - Inheritance: Dominant
- KCNQ2 channel (K_v7.2): Mutation effects
  - Abnormal voltage-dependent activation
    - Depolarizing shifts of conductance-voltage relationships
    - Marked slowing of activation time course
  - Mechanisms
    - R207Q & R207W: Dominant negative effect on wild type channels
    - Other mutations cause neonatal seizures by haploinsufficiency
- Clinical
  - Onset: 1st decade; Cramps
  - Continuous muscle activity
    - Small amplitude movements of fingers
    - Cramps: Exercise-induced
    - Muscle stiffness: Episodic
      - Generalized: Most prominent distally
      - Duration: Up to 30 minutes
      - Exacerbated by physical exertion & anxiety
    - Most prominent distally
  - No seizures
  - Treatments
    - Lamotrigine (200 mg/day): Partial improvement
    - Retigabine
      - Activator of neuronal Kv7 channels
      - Reverses depolarizing shift
- Laboratory
  - EMG: Spontaneous irregular multiplets (Myokymic discharges)
  - Motor & sensory nerve conduction studies: Normal
  - Potentials generated in distal axons
- Other: Differential diagnosis

Global Developmental delay, Myokymia & Peripheral Nerve Hyperexcitability ⁶²

● Leucine-rich gene, glioma-inactivated, 3 (LGI3)

; Chromosome 8p21.3; Recessive

Nosology: Intellectual developmental disorder + Muscle tone abnormalities & Distal skeletal defects (IDDMDS)
Epidemiology: 16 families
Genetics
- Mutations: Loss of function
LGI3 protein
- Widely expressed in brain & sensory & motor neurons
- Co-localizes & interacts with endocytosis-associated proteins & Syntaxin-1
- May regulate neuronal endocytosis & exocytosis
- Induces neurite outgrowth in dorsal root ganglia explants
- Axon: Juxtaparanodal membrane; Co-localizes with K_v1.1 & K_v1.2
- LGI & EPTP family: Also see Lgi1, Lgi4
- Mutation effect: Disturbed Kv1 channel distribution
- Skin: Melanogenic; Keratinocyte migration
Clinical
- Onset age: Early childhood
- Global Developmental delay
- Intellectual disability
- Myokymia: Face
- Mouth: Small; Limited opening
- Tendon reflexes: Often reduced
- Distal deformities
- Hernias (25%): Diaphragm; Abdominal
Laboratory
- Electrodiagnostic
  - NCV: Normal velocities
  - Myokymia (70%)
- Brain MRI: Normal
- Muscle biopsy: Non-diagnostic
- EEG: Seizure activity in some

Myoedema

Localized, persistent, electrically silent swelling of muscle after percussion
Duration: Few seconds
Differs from dimpling due to myotonia
Due to local contraction after release of calcium from the sarcoplasmic reticulum
Disease associations: Cachexia; Myxedema; Hyponatremia; Rabies; Occasional normals

Muscle Spasms & Dwarfism

Familial
Dwarfism + Spasms
Schwartz-Jampel
Sporadic
Satoyoshi

Familial Muscle Spasms & Dwarfism

● Dominant; ? Autosomal or X-linked

Epidemiology: 1 Argentinian family, 2 brothers
Clinical features
- Onset: 8 to 10 years
- Spasms
  - Painful
  - Trunk & limb muscle contractions
  - Spread from one muscle to another
  - Episodes of contractions: Minutes to hours
  - Duration of individual contractions: 5 to 30 seconds each
  - Stimulus: Tapping on muscle
- Muscle size: Large
- Skeletal
  - Short stature
  - Face: Large nose & Low-set ears
- Hair
  - Scalp: Thin
  - Body: None
- Intellect: Normal

Satoyoshi Syndrome

³⁶

Nosology: �komura�gaeri� disease
Epidemiology
- Frequency: 50 patients described
- Female > Male
- Sporadic: All patients
- Common: Asian children
Clinical
- Onset
  - Age: 4 to 52 years; Mean 11 years; Usual < 15 years
  - Muscle spasms
- Muscle
  - Muscle spasms
    - Progressive
    - Painful
    - Intermittent
    - Distribution: Face; Trunk; Limbs
    - Exacerbated by: Exercise; Anxiety
    - May be asymmetric
    - May involve several muscles at once
  - Myoglobinuria
- Systemic
  - GI (50%): Diarrhea; Malabsorption; Abdominal spasms
  - Endocrine: Amenorrhea; Hypoplastic uterus & Ovaries
  - Alopecia universalis
- Skeletal
  - Bone pathology: Slipped epiphyses; Cysts; Fatigue fractures; Osteolysis; Bone fragmentation at tendon insertions
  - Short stature: ? Related to poor nutrition
- Lifespan: Shortened
- Treatment
  - Immune
    - Corticosteroids ²³
    - IVIg
    - Tacrolimus
    - Plasma exchange
  - Spasms: Dantrolene
- Clinical associations: Autoimmune disorders
  - Myasthenia gravis
  - Idiopathic thrombocytopenia
  - Nephritis
Laboratory
- Serum antibodies
  - Binds to 90 kDa protein in brain, stomach & duodenal tissue
  - ANA: Often positive
- Serum CK: Normal
- NCV: Normal
- EMG
  - Rest: Normal
  - Spontaneous muscle fiber activity
  - Spasms
    - Continuous muscle fiber discharges (10 Hz)
    - Myokymia
    - Involuntary contractions: Amplitude may be 4x of maximal voluntary contractions
- Skin: Lymphocytic inflammation

Cramps

Clinical features
- Onset: Acute
- Duration: Short
- Muscle contraction: Strong; Palpable
- Relief: Stretching muscle
Common type: In normals
- Muscle contractions
  - Onset: Sudden, Involuntary
  - Painful
  - Individual muscles
- Precipitants
  - 2° to hyperexcitable terminal nerve arborization
  - Most often following voluntary contractions: Especially Contraction of shortened muscle
  - Occasionally during rest or sleep
  - 10 Hz electrical stimulation
- Relief: Passive muscle stretch; Local massage
- Location
  - Usually involve single muscles rather than groups
  - Especially gastrocnemius
  - Local cramps in other muscles often associated with denervation or other neuromuscular disorders
- Common sequelae
  - Muscle soreness & swelling
  - High serum CK
- EMG: Cramp discharge from individual motor unit
  - Triphasic action (Motor unit) potentials: Irregular
  - Firing properties
    - Rate of discharge: Usual 40 to 60 Hz; Range 20 to 150 Hz
    - Duration of discharge: < 500 ms
  - Origin: Motor nerve terminals
- EMG: Clinical cramp of muscle
  - Multiple motor neurons firing (Cramp discharges) synchronously
  - Interference pattern or Several motor units
  - Often involve large areas of muscle
Systemic disorders associated with cramps
- Dehydration: Hidrosis; Diuretics; Hemodialysis
- Metabolic: Low Sodium, Magnesium, Calcium, Glucose
- Endocrine: Thyroid (Hyper- or Hypo-); Adrenal insufficiency
- Pregnancy
- Drugs & toxins
Neuromuscular disorders associated with cramps
- Nerve
  - Motor system disorders
  - Other denervation
    - Spinal stenosis
    - Polyneuropathies
  - Spontaneous activity syndromes
    - Episodic ataxia 1 (EA1)
    - Neuromyotonia (Isaac's syndrome)
    - Stiff-person syndrome
    - Cramp-fasciculation syndromes
- Muscle
  - Becker muscular dystrophy
  - Type II muscle fiber predominance
Familial cramp disorders
- Cramp syndromes: Autosomal dominant
  - Familial cramp syndrome
  - Familial dwarfism with muscle spasms
  - Satoyoshi syndrome
  - Muscle cramp & neuropathy syndrome
  - HANAC
  - Cramps & myalgias
- Becker muscular dystrophy
- Electrically silent

Treatments for cramps

Normalize metabolic abnormalities
Quinine sulfate: 260 mg qhs or bid
Carbamazepine: 200 mg bid or tid
Phenytoin: 300 mg qd
Tocainide: 200 to 400 mg bid
Verapamil: 120 mg qd

Amitriptyline: 25 to 100 mg qhs
Vitamin E: 400 IU qd
Riboflavin: 100 mg qd
Diphenhydramine: 50 mg qd
Calcium: 0.5 to 1 g elemental Ca⁺⁺ qd

Also see: Muscle pain

Electrical activity with few clinical manifestations

Pseudomyotonia (e.g. in acid maltase deficiency)
Fibrillations: Denervation; Inflammatory myopathies

Electrically silent cramps

Muscle contractures
- Painful prolonged muscle contraction
- Provoked by
  - Depletion of muscle energy stores
  - Continuous muscle contraction; Ischemia
- Electrically silent
- Association: Glycogen metabolic disorders
Rippling muscle syndrome
Brody's syndrome
Myoedema

Myopathic Tremor ⁵⁸

Clinical features: General
- Onset
  - Age: Infancy
  - Weakness
    - Tremor may precede onset
    - When present: Often distal
- Physiology
  - High frequency
  - Amplitude: High or Fine
  - Postural & Kinetic: Not at rest
  - No intermuscular synchronization
  - Stable during weight loading
- ADL: No impairment
Disorders: Myopathies involving contractile (sarcomere) elements
- MYOTREM: MYBPC1
  - Mutations producing increased binding to myosin
  - Deregulation of cross-bridge cycling during sarcomere contraction
- Distal myopathy: MYH7
  - Missense mutations in C-terminal tail
- Myopathy + Ophthalmoplegia: MYH2
  - Mutation: E706K
- CFTD: MYL2
  - Mutations: Recessive, Truncating
- NEM5: TNNT1
  - Mutations: Nonsense or Truncating
  - Weakness: Severe
- Congenital hypercontractile syndrome: TPM3
- Distal myopathy: Titin
- OPML1: NUTM2B-AS1
- Animal models: NEB
Also see: Tremor + Neuropathy
- SMA
- CMT1A
- MAG

Tetanus ²⁰

Clinical features
Clostridium tetani
Diagnosis
Epidemiology
Mechanism of action
Prophylaxis
Protein structure
Treatment

History
Case description

C Bell 1865: From NLM

Putnam

Tetanus toxin (Tetanospasmin)

: Protein structure

Produced as a protein (protoxin) with molecular weight 150 kDa
30% to 40% homology to botulinum toxins
Cleaved into heavy (100 kDa) & light chain (50 kDa) subunits linked by disulfide bond
Double chain product more, or equally, active compared to single chain
Protein domains & Functions
- Light chain
  - Contain tetrahedral zinc binding motif
    - 2 histidines, glutamate & water molecule
    - Resembles amino acid sequence of thermolysin-like endoproteases
  - Cleavage of synaptobrevin: Prevents release of transmitter from presynaptic terminal
- Heavy chain, Carboxyl terminal
  - Immunogenic
  - Neuronal cell binding
  - Ganglioside binding
  - Retrograde transport
- Heavy chain, N-terminal
  - Endosome
Produced by Clostridium tetani
- Under anaerobic conditions
- Released by autolysis as a prototoxin
- Genetic information resides on plasmids
- Spores ubiquitous; More in warm, manure-rich soil
Link: Saier classification

Tetanus toxin: Mechanism of action

Membrane binding
- Receptors
  - Gangliosides with more than one neuraminic acid, e.g. GT1b
  - Protein receptor: SV2C
  - C-terminal of tetanus heavy chain binds to gangliosides & Receptor
Uptake by endocytosis
Retrograde transport
- Mediated by tetanus heavy chain
- N-terminal forms pores in lipid bilayers
  - ? marks vesicles for retrograde transport
Transsynaptic transport to inhibitory presynaptic terminals
Light chain of tetanus toxin moves from vesicle to cytosol
- Facilitated by low pH in vesicle
- Pore formed by N-terminal of heavy chain
Inhibits release of inhibitory transmitters: Glycine or GABA
- Cleaves synaptobrevin II (involved in synaptic vesicle release)
- Cleavage occurs at Glutamate 76
Produces unrestrained reflex activity of skeletal muscles & autonomic nervous system
Lethal dose: 500pg/kg
2nd most potent microbial toxin: After botulinum toxin

Clostridium toxins	Target proteins cleaved
Tetanus Botulinum A B C D E F G	VAMP (Synaptobrevin) SNAP-25 VAMP (Synaptobrevin) SNAP-25; Syntaxin VAMP (Synaptobrevin) SNAP-25 VAMP (Synaptobrevin) VAMP (Synaptobrevin)

Clostridium tetani
- Gram positive bacilli
- Spore producing
  - Spores resistant to: Heat, usual antiseptics & chemical agents
  - Spores destroyed by: Autoclaving at 120°C for 15 minutes; Boiling for at least 4 hours
- Anaerobic: Obligate
- Distribution in environment: Wide
  - Soil
  - Intestinal flora
    - Animals: Horses, sheep, cattle, dogs, cats, rats, chickens
    - Humans: 10%; Especially in agricultural areas
- Toxin production
  - Due to plasmid contained in some C. tetani organisms
  - 2 toxins produced
    - Tetanospasmin: Disease producing
    - Tetanolysin : Uncertain effects
- External link: Microvet
Tetanus: Epidemiology
- Prior tetanus does not provide immunity
- Deaths
  - 800,000 to 1,000,000 per year
  - Most in Africa and Southeast Asia
  - 50% Neonatal tetanus
  - Causes of death
    - Respiratory failure
    - Autonomic dysfunction
    - Prolonged critical illness
- Geography
  - Neonatal tetanus (from umbilical stump infections)
    - Common in 3rd world; 500,000 deaths/year
    - Rare in U.S.
  - Western
    - Generalized type
    - Most common in elderly, blacks, young males & older females
    - Low or absent anti-tetanus titers
- Mortality
  - Highest in elderly
    - > 50% over 60 years
    - Possibly related to a decline in protective levels of antibodies
  - Low in US adults < 30 years
  - Greatly reduced by supportive ventilation: Especially Neonatal tetanus
- Primary immunization
  - > 90% of patients never completed series
  - Full immunization: ~ 100% protective
  - Immunization of mother prevents neonatal tetanus in child
  - Risk factors
    - Incomplete vaccine deployment among population
    - Quality of vaccine: Method of storage
- Source of toxin
  - Acute wound in 75%
  - Wound types: Puncture, laceration or abrasion; Drug abuse; Burns...
Tetanus: Clinical features & types
- Presentation
  - 3 to 21 days after injury (rarely months)
  - More severe disease: Shorter incubation periods; Especially < 7 days
- Localized type
  - Uncommon
  - Painful spasms in muscles near region of injury
  - Self-limited, lasting < 2 weeks
  - Occasionally becomes generalized
  - Mortality: 1% to 16%; Due to generalization
- Cephalic type
  - Frequency: 6%
  - Infection types: Otitis media; Head injuries; Tongue piercing
  - Localization: Cranial nerves
    - Facial weakness: Most common
    - Other: EOM (6, 3, 4): Hypoglossal
    - Trismus: Follows other cranial nerve involvement
  - May progress to generalized tetanus
  - Prognosis
    - Often poor: Mortality 15% to 30%
    - Milder disease reported
- Neonatal type
  - Frequency
    - Developing countries: Common; 500,000 deaths per year
    - Developed world: Rare
  - Causes
    - Unhygienic child birth practices: Traditional midwifery
      - Cutting umbilical cord with grass or dirty scissors
      - Smearing cow dung or ghee (clarified butter) on umbilical stump
    - Social taboos
    - Improper immunization of pregnant mothers
  - Onset
    - Time: 5 to 15 days after birth
    - Signs: Poor sucking; Excessive crying; Vomiting
  - Progresses to
    - Trismus
    - Dysphagia
    - Generalized spasms: May be more severe than in adults
    - Fever
    - Seizures
  - Prognosis: Death (70%) unless agressive medical management
- Generalized type
  - Most common form
  - Onset
    - Head & Neck often affected first: Dysphagia may be presenting symptom ³³
    - Trismus: Increased tone in masseter
    - Other: Reflex spasms, Neck rigidity, Stiffness
  - Clinical features
    - Muscle rigidity
      - Face: Risus sardonicus
      - Trunk
    - Tetanic "spasms"
      - Distribution: May be generalized
      - Duration: May last second to minutes
      - Stimuli: Noise; Touch; Movement
      - Often painful
      - "Spatula test": Spatula inserted into pharynx
        
        Positive result: Patient bites spatula due to masseter spasm
        
        Negative result: Gag & Expelling of spatula
    - Respiratory insufficiency
    - Autonomic overactivity
      - Blood prressure: Hypertension; Hypotension
      - Dysrhythmias: Tachycardia, episodic; Bradycardia & Asystole
      - Urinary retention
      - Peripheral vasoconstriction
      - Hidrosis
      - Hyperpyrexia
    - Secondary injuries
      - Fractures
      - Complications of immobilizing illness
      - Rhabdomyolysis
    - Sensation: Normal
    - Mental status: Normal
  - Prognosis worse
    - Short incubation period
    - Internal or facial site of infection
    - Lack of immune protection
    - After intramuscular injections of quinine
  - Time course
    - Worst at 4 to 14 days
    - Recovery over months
Tetanus: Diagnosis
- Clinical - no specific test
- History: Unusual with
  - Hx of immunization in past 10 years
  - Serum levels of anti-toxin > 0.01 IU/ml
- EMG
  - Motor unit activity
    - Spontaneous
    - Continuous
    - No voluntarily suppression
  - Stretcth reflex: Absent silent period after reflex, or motor-evoked, response
- Wound cultures: Positive in 30% to 50%
- Rule out: Drug withdrawal; Dystonic reaction; Meningitis; Stiff-person
Tetanus: Treatment
- Neutralization of circulating toxin
  - 3,000 to 6,000 U of human tetanus immune globulin, i.m.
- Intensive care unit management
  - Respiratory support
  - Prevent metabolic complications
- Prevent muscle spasms
  - Anti-spasm drugs
    - Diazepam: Up to 20 mg q 2 to 6 hours
    - Baclofen
  - Neuromuscular blocking agents, if necessary
  - Magnesium sulfate: If respiratory support is not available
- Dysautonomia treatment
  - Benzodiazepines
  - Morphine
  - Magnesium sulphate
  - Adrenergic blockers
  - Baclofen
- Elimination of toxin source by surgical excision
  - Delay debridement until several hours after anti-toxin treatment
  - Obtain specimens for culture
  - Antibiotic Rx
    - Metronidazole
    - Also: Penicillin G, Erythromycin, Tetracycline
Tetanus: Prophylaxis
- Tetanus-diphtheria toxoid
  - A safe vaccine
  - Use for all wounds in patients with
    - < 3 previous doses, or
    - > 5 to 10 years since last dose
- Tetanus immune globulin
  - Unclean or major wounds in patients with fewer than 3 previous doses of toxoid

Isaac's Syndrome

Associated disorders
Clinical
Differential diagnosis
EMG
Laboratory

Clinical Features
- Onset age
  - Range: 9 to 80 years
  - Most < 60 years
  - Mean 46 years
- Symptoms fluctuate
  - In severity over periods of months
  - Precipitated by exercise or muscle contraction
- Movements
  - Often visible
  - Types
  - Muscle twitching: Symptomatic in 12% to 40%
  - Cramps & Stiffness
    - Stiffness at rest
    - May be induced or exacerbated by exercise
    - Distribution
      - Distal > Proximal
      - Face, tongue & Pharyngeal muscles may be involved
    - Intermittent
    - Delayed muscle relaxation
    - No percussion induced contraction
    - Muscle activity continues during sleep
- Motor: Other
  - Fatigue: Associated with Isaac's; Does not predict MG or Polyneuropathy
  - Weakness
    - Absent or Mild (30%)
    - Especially in overactive muscles
  - Muscle hypertrophy (20%)
- Sensory symptoms (30%): Paresthesias, Numbness
- Autonomic: Hyperhidrosis (33% to 55%)
- Tendon reflexes: Often normal
- Mental disturbances (25%)
  - Morvan's syndrome
  - Personality change
  - Insomnia
  - Irritability
- Course: Fluctuations, but no spontaneous remissions
- Isaac's syndrome: Treatment
  - Symptomatic
    - Carbamazepine (200 to 600 mg/day)
    - Phenytoin (200 to 400 mg/day)
    - Mexiletine
  - Immunosuppression
    - Plasma Exchange (short-term benefit)
    - Prednisone
EMG ¹⁶: Spontaneous axonal action potentials
- General: Peripheral nerve hyperexcitability
  - Origin of activity: Potentials arise along course of motor axon, especially distally
  - Increased excitability of nodal membrane
  - Potentials persist during general anesthesia
  - Muscle activity eliminated by NMJ blockade
  - Distribution: Limbs > Trunk & Face
- Fasciculations
  - May be only sign of disease & occur without myokymia
  - Less disability when only EMG feature
  - May be doublets, triplets or multiplets
- Myokymia
  - Myokymic discharges: Properties
    - Rhythmic (Repetitive)
    - Grouped
    - Spontaneous
    - Same motor unit(s)
    - "Grouped fasciculations"
  - Clinical features
    - Involuntary rippling or quivering of muscles
  - EMG patterns: Types
    - Continuous recurrent uniform slower firing (1-5 Hz)
      - Mild myokymia
      - Sounds like: Marching soldiers
    - Spontaneous rapid bursts of motor unit potentials
      - Frequency of potentials within bursts: Range 5 to 70 Hz; Usual 40 to 60 Hz
      - 2 to 7 potentials per burst
      - Burst duration: Brief (Less than 1 second)
      - Frequency of bursts: 0.1 to 3 per second
      - Pattern of bursts: Double, triple or multiple
      - Recurrence pattern: Regular or Irregular
    - Post-radiation vs other myokymia ⁵⁷
      - Burst-to-silence ratio: Increased
      - Peak number: Greater
      - ≥ 2 muscles involved
  - Mechanism
    - Commonly caused by loss of function of voltage-gated potassium channels (VGKC)
    - Channel disorder results in decreased outward potassium current
    - Originate in distal axon
  - Course: May persist after treatment
  - Isaacs syndrome
    - Myokymia is present in some, but not all, patients
    - May develop on subsequent study
  - See
    - Myokymia image
    - Differential diagnosis
- Neuromyotonia
  - More persistent activity & muscle contraction
  - Spontaneous bursts of single motor unit potentials
    - Prolonged (Several seconds)
    - 40 to 300 Hz
    - Decrementing
    - Bursts very irregular
    - Associated with persistent muscle contraction
  - Often reduced by treatment
- Repetitive F-waves
Associated disorders
- Neoplasm
  - Lung, Thymus & Hodgkin's
  - Isaac's syndrome often predated neoplasm
- Penicillamine
- Polyneuropathy: Sensory-Motor
- IgM M-protein
- Myasthenia gravis & Anti-AChR antibodies
  - Frequency: 10% to 20%
  - With thymoma: Patients > 40 years
  - Overactivity begins with or after MG
- HIV infection
- Morvan's fibrillary chorea
- Other associated immune or systemic disorders
  - Thyroid
  - Diabetes
  - SIADH
Myokymia & Peripheral nerve hyperexcitability: Differential diagnosis
- Isaac's Syndrome
- Benign myokymia
  - Repetitive single polyphasic action potentials with varying shapes
- Cramp-fasciculation syndrome
  - Neuromyotonia without fibrillations
  - ? Mild variant of Isaac's
- Satoyoshi
- Hereditary
  - Gamstorp-Wohlfart Syndrome : Autosomal Dominant
    - Myokymia; Myotonia; Muscle wasting; Hyperhidrosis
  - Episodic Ataxia/Myokymia Syndromes
    - EA 1: KCNA1
    - EA 3: 1q42
    - EA 8: 1p36
  - SCA12: PPP2R2B
  - Distal spinal muscular atrophy
    - Dominant ⁴⁴
    - Recessive: HINT1; 5q31
  - KCNQ2
    - Myokymia & Benign neonatal epilepsy
    - Peripheral nerve hyperexcitability
  - Lgi3
  - Schwartz-Jampel syndrome: HSPG2
  - Familial dyskinesia with facial myokymia: ADCY5
  - NDGOA: UCHL1
  - Jack Russell Terriers: Ataxia + Neuromyotonia
- Drugs: Penicillamine; Clozapine; Oxaliplatin; Gabapentin
- Toxins: Herbicide; Insecticide; Toluene
- Polyneuropathies
  - Immune: Guillain-Barré; CIDP
  - Toxic: Gold; Mercury; Gold; Silver; Alcohol
- Motor neuron disease
- Systemic disease
  - Hypocalcemia: Hypoparathyroid
  - ? Addison's
  - Amyloidosis: Acquired with M-protein
  - ? K⁺ channel blockade: 4-aminopyridine
  - Thyroid: Hyper- or Hypo
  - Uremia
- Focal myokymia or neuromyotonia
  - Focal nerve lesions
    - Multifocal motor neuropathy
    - Demyelination/Remyelination
    - Radiation injury to nerve or plexus
    - Median nerve: Carpal tunnel syndrome
    - Radiculopathy: Cervical; Lumbar
  - Toxic: Rattlesnakes - Timber
    - Mojave (binds to Ca⁺⁺ dihydropyridine receptor)
  - Faciolingual
    - Machado Joseph Syndrome (SCA3)
    - Multiple sclerosis
    - Brainstem neoplasm: Glioma; Schwannoma
    - PEO & Scoliosis
    - Familial Dyskinesia & Facial myokymia
    - Immune: K⁺ channel antibodies
    - Amyloid: Gelsolin
  - Transposed muscle flaps
  - Other localized neuromyotonia
    - Finger flexion ⁸
    - Eyelid
    - Superior oblique
    - Hemifacial spasm: Occasional
Isaac's syndrome: Laboratory
- Serum CK: Elevated in 50%
- Antibodies
  - Potassium channel complex antibodies ⁴¹
    - Prevalence
      - 28% to 100%
      - Frequency of antibodies depends on antigen used
    - Antibody targets
      - General: Antibodies bind to
        
        Molecules (Antigens): Associated with fast voltage-gated potassium channels (VGKCs)
        
        Locations: Paranodes & Internodes
      - Potassium channel-associated molecules: Often primary targets of "K⁺ channel" antibodies
        
        General: 2 or more antibodies commonly (60%) present in individual patients
        Contactin-associated protein-2 (Caspr2) antibody
        
        Caspr2 (CNTNAP2) ⁵⁵
        
        Protein: Strongly associated with Kv1.1, Kv1.2 & KCNAB2 subunit at juxtaparanodes
        
        Mutations: Epilepsy; Cognitive decline & Peripheral nerve involvement
        
        Antibody
        
        Frequency: 20%
        
        Antigenic target ⁴⁷
        
        Multiple regions of Caspr2 extracellular domain
        
        Common targets: Discoidin-like domain; N-terminal half of Caspr2
        Not tertiary structure or glycosylation
        
        Type: IgG₄ (100%); IgG₁ (63%)
        Associated with high VGKC-RIA titer
        Location: Serum ± CSF
        
        Clinical: Antibody associated with
        
        Epidemiology
        
        Sex: Male predominance (80% to 90%)
        
        Age: Mean 70 years
        
        Clinical syndromes: Often several features
        
        Neural hyperexcitability: Neuromyotonia or Morvan�s syndrome
        
        Epidemiology
        
        Frequency: 30% to 55% of Caspr2 Ab+ patients
        
        No HLA-DRB1*11:01 association
        
        Clinical
        
        Peripheral nerve
        
        Hyperexcitabilty (PNH): Motor
        
        Pain (52%)
        Dysautonomia
        
        CNS
        
        Ataxia
        
        Hyperkinetic movements
        
        Sleep disorders (Agrypnia excitata): Insomnia
        
        Associations
        
        Thymoma
        
        Myasthenia gravis
        
        Other antibodies: Lgi1; DCC
        
        Limbic encephalitis
        
        HLA-DRB1*11:01 association
        
        Clinical
        
        Anterograde amnesia
        Temporal lobe epilepsy
        Ataxia
        
        Laboratory
        
        Brain MRI: Mesial temporal lobe signal
        Serum titers: Higher
        
        CSF: More frequently positive
        
        Weight loss
        
        Neoplasm associations
        
        Thymoma
        
        Present in 80% of Caspr2+ PNH patients
        
        0% to 32% of patients with Caspr2 Ab have thymoma
        
        Other occasional: Lung; Endometrial
        
        Course: Relapses common
        Treatments
        
        Corticosteroids
        
        IVIg
        
        Plasma exchange
        Rituximab
        
        Laboratory
        
        HLA association: DRB1*11:01
        
        Leucine-rich, glioma inactivated 1 protein (Lgi1) antibody
        
        Lgi1 protein
        
        Expression
        
        Peripheral nerves: Weak but present
        
        Hippocampus
        
        Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 & KCNAB1
        Enhances AMPA receptor-mediated synaptic transmission
        
        Slows channel inactivation
        
        Precludes channel closure mediated by KCNAB1 subunit
        
        Ligand for ADAM22
        
        Lgi1 mutations: Temporal lobe epilepsy
        Antibody
        
        Frequency: 55% of limbic encephalitis
        Type: IgG₄
        
        Location: Serum more often than CSF
        
        Epidemiology
        
        Sex: Male predominance (60% to 70%)
        
        Age: Mean 60 years
        
        Clinical: Antibody associated with
        
        Limbic encephalitis
        
        Polyneuropathy ⁵⁹
        
        Sensory loss
        
        Pain (19%)
        
        Onset: Concurrent with, or after, CNS features
        
        Truncal involvement 42%
        
        Frequency: > 90%
        
        May occur without other disease features
        
        Treatment: May respond to immunotherapy
        
        NCV: Often normal
        Skin biopsy: Small axons in skin lost
        
        Dysautonomia
        
        Seizures: Faciobrachial dystonic (FBDS) (50%)
        Hyponatremia (60%)
        No neoplasm
        
        Possible treatments
        
        Corticosteroids
        
        IVIg
        
        ? Rituximab
        
        Course
        
        Relapses common: Up to 7 years after 1st episode
        
        Laboratory
        
        MRI: Medial temporal lobe signal (66%)
        CSF: Normal
        HLA association: DRB1*07:01
        
        Tag-1/contactin-2
        
        Antibody frequency 5%
        
        Neoplasm associated
        
        DPPX
      - K⁺ channel targets ⁴⁸
        
        General
        
        Often intracellular domain
        
        No strong clinical or therapeutic correlations
        
        Channels
        
        Voltage gated, α-dendrotoxin sensitive: 50%
        
        KCNA6 (K_v1.6) : 83%
        
        KCNA2 (K_v1.2)
        KCNA1 (K_v1.1)
        
        KCNA1 mutations in: Episodic ataxia
        
        KCNA4 (K_v1.4): Myasthenia gravis
    - Neoplasm associations
      - More common with associated thymoma
      - Small cell lung cancer: SOX1 antibodies
      - Endometrial adenocarcinoma: 1 patient
    - Clinical: Syndromes with K⁺ channel antibodies
      - Isaacs
      - Cramp-fasciculation syndrome
      - Morvan's fibrillary chorea
      - Limbic encephalitis
      - Epilepsy, adult onset
      - Painful polyneuropathies (50%)
        
        Length dependent: No
        
        Isolated pain syndrome: 28%
        
        Associated syndromes: Neuronal hyperactivity
        May improve with corticosteroid treatment
        
        K-channel complex antibody subtype: Lgi1; CASPR2; Unidentified antigens
    - Antibody positive patients often immunotherapy responsive
  - Nicotinic AChR: α3 subunit (50%)
  - Nicotinic AChR α1 subunit: With thymoma
- Laboratory: Other
  - Nerve conduction studies: Usually normal
  - CSF occasionally abnormal: Oligoclonal bands; Mildly high protein
  - Muscle biopsy: Fiber hypertrophy; Type I predominance

Familial Dyskinesia & Facial Myokymia ¹⁰

● Adenylate cyclase 5 (ADCY5)

; Chromosome 3q21.1; Dominant

Epidemiology: 6 families; 12 sporadic cases
Genetics
- Mutations: Missense; R418W or R418Q (Often de novo), Ala726Thr
- Somatic mosaicism in some patients
ADCY5 protein
- Role in synthesis of cAMP & pyrophosphate from ATP
  - Stimulated through G-protein-coupled receptors
- Component of μ- & δ-opioid receptor signal transduction
- High in striatum & myocardium
Clinical
- Onset age: 0.5 to 19 years
- Movements
  - Choreiform or Dystonic
  - Brief & Jerky
  - Distribution
    - More prominent in distal upper limbs
    - Also involve face & neck
    - Bulbar: Dysarthria
  - Early ages: Paroxysmal over days to weeks
  - Painful
  - 3rd decade: May become constant
  - Later age: May be reduced
  - Worsened by: Anxiety
- Gait disorder: Slow progression
- Myokymia
  - Facial: Perioral & Periocular
  - EMG may show hand involvement
- Tendon reflexes: Brisk in legs
- Tone
  - Axial: Reduced
  - Limbs: Increased
- Cardiomyopathy: 4th & 5th decade; Dilated
- Strength: Normal
- Cognitive: Normal or Mildly reduced
Laboratory
- EMG: Myokymia in face & tongue
- Brain MRI: Normal

Stiff-person (Stiffman) syndrome

Antibodies
Associated disorders
Clinical features
Laboratory
Treatment
Variants

Clinical features ⁷

Epidemiology
- Female (70%) > Male (30%)
- Usually sporadic
- Prevalence
  - General: 1 in 1,250,000
  - May be more prevalent in: African-Americnas
- Familial syndromes: May be associated with SCA1 & SCA3
Prodrome: Pains & tightness in axial muscles
Onset
- Age
  - Childhood or Adult
  - Anti-GAD antibody positive: Mean 41 years; Most common 3rd to 5th decades; Range 5 to 70 years
- Prodromes: Episodic stiffness or falling
- Course: Slowly progressive (insidious); Occasional rapid onset
- Reported hereditary forms : May be hyperekplexia
Stiffness
- Distribution
  - Especially in axial & proximal limb muscles
  - Legs > Arms
  - Asymmetric, or Prominent in 1 leg (30%)
- Involvement of limbs impairs walking
- Hyperlordosis: Lumbar; Limits truncal flexion
- Fluctuates over time: Reduced in sleep
Muscle spasms
- Triggers
  - Stretching
  - Emotion
  - Sensory stimulation
  - Fear of open spaces
  - May occur spontaneously
- Course of spasm
  - Sudden myoclonic jerk: May produce falling
  - Followed by tonic activity that subsides over seconds
- Usually bilateral
- Typical movements
  - Arms: Extension & Pronation
  - Trunk: Extension
  - Legs: Extension & mild abduction; Foot inversion
- Co-contraction of agonist & antogonists
  - Abdominal & thoracic paraspinous muscles
  - Spasms may produce little movement due to co-contraction around joints
- Discomfort: May be associated with severe pain
- May be severe enough to cause fractures
- Relaxation of spasms: Sleep & Benzodiazepines
- Disability: Cane or Walker commonly needed 2° frequent falls
Reflexes
- Tendon reflexes: Normal or Increased
- Abdominal cutaneous: May be lost
- Startle responses: Increased
Gait: "Tin soldier"
Autonomic dysfunction
Extraocular movements: Some patients
- Gaze-holding nystagmus
- Limited abduction
- Vertical & horizontal ocular misalignment
- Deficient smooth pursuit
- Impaired saccade initiation
Otherwise normal neurologic exam: Most patients
Disease course
- Usual: Slow progression or static over years
- Focal syndromes may progress to more generalized involvement
- Sudden death: Occasional patient
- Trismus unusual
  - Cardiac arrhythmias
  - Restrictive respiratory arrest
  - Rapid tapering of intrathecal baclofen

Associated disorders

Epilepsy
- Treated with anti-GABA agents
- Suggests PERM variant
Diabetes mellitus, type I (30% to 60%)
Neoplasms
- Breast cancer
- Other: Lung; Thymoma
Immune disorders, Other (67%)
- Thyroiditis (13%)
- Pernicious anemia (7%)
- Myasthenia gravis
- Ovarian or adrenal failure
- Vitiligo
- Similar immune disorders may occur in family members
  - More common with anti-GAD antibodies
HLA: DRβ1 0301 (40% to 70%)

Laboratory

Serum CK: Transiently elevated
ANA (30%)
Anti-GAD antibodies
CSF
- Oligoclonal bands (60%)
- Protein high (20%)
- Pleocytosis: 10% in SPS; 63% in PERM variant
- Normal: 40% in SPS; 12% in PERM variant
- Anti-GAD antibodies: May be present
  - Usually lower titer than in serum
  - Intrathecal anti-GAD synthesis may occur
CNS MRI: Non-diagnostic
EMG
- Continuous action potentials
  - Indistinguishable from voluntary activity: Normal motor units
  - Persist during attempts at relaxation
  - Most prominent in axial muscles
- Persistent bursts
  - Duration: 50 to 60 ms
  - Rate: 5 - 6 Hz
  - Rhythmic
  - Synchronous
- Interruption of bursts by spasms: Rapid activity; Full interference pattern; > 4 sec
- Activity reduced by intravenous diazepam
- No fibrillations or grouped rhythmic discharges
- Poor relaxation after contraction
CNS pathology
- Perivascular inflammation
- Spinal cord: Neuronal loss
- Lateral vestibular nucleus: Loss of neurons

Disease mechanisms

Pathophysiology
- Disorder of presynaptic inhibition of Ia terminals
  - Exaggerated polysynaptic reflexes
  - ? Defect in descending control pathways
- Normal motor neuron excitability & Renshaw cell function
- Differs from tetanus which produces defective segmental inhibition & hyperexcitable motor neurons
Pharmacology & Pathways
- Descending monoaminergic reticulospinal pathways
  - Inhibit short latency spinal flexor reflex afferents
  - Facilitate long latency spinal flexor pathways
  - ? Relative overactivity in SPS
  - Monoaminergic inhibition reduces spasms & stiffness: Clonidine; Tizanidine
- GABA activity: Inhibitory
  - ? Relative underactivity
  - Enhanced GABA-ergic inhibition reduces spasms & stiffness: Baclofen; Diazepam

Antibodies: Stiff-person syndromes

Antigen target: Glutamic acid decarboxylase (GAD2; GAD65)
- Anti-GAD antibodies ⁴⁹
  - Titers
    - Levels: Low to High
    - Vary with clinical syndromes
  - Location of antibodies
    - Present in serum & CSF
    - Usually higher titer in serum
  - GAD epitope structure: Linear & Conformational
  - GAD targets
    - GAD65: Main clinical biomarker
    - GAD67: Commonly co-exist with GAD65 antibodies; Rarely autoantigenic in isolation
  - Tissue staining pattern: GABAergic nerve terminals
  - Susceptibility allele: DQB1*0201
- GAD65 antibodies: Associated disorders
Other antibodies with Stiff-person syndrome
- Pancreatic islet cell (60%)
  - Also found in type I diabetes: Lower titer, diffuse staining pattern
- Amphiphysin (128kDa) : Associated with breast cancer
- 80 kDa protein
- Purkinje cell cytoplasm
- DPPX (DPP6): Progressive Encephalomyelitis with Rigidity & Myoclonus (PERM)
- GlyRα1 ⁵¹
  - Sensitivity in SPS: 8.5%
  - False positivity in normal controls: 4%
  - Effect in SPS sera: GlyRα1 modulation
  - Clinical syndromes: SPS; Stiff limb or trunk; Hyperekplexia; Neuropsychiatric
  - Treatment: Improvement of SPS with corticosteroids or IVIg
- Oligoclonal bands in CSF: 50%

Therapy (Rarely completely effective)

Symptomatic
- Keppra (levetiracetam): 500 mg bid
- Diazepam (very high doses; 20 mg to 300 mg/day); Clonazepam
  - May exacerbate depression
- Baclofen
  - Baclofen (Oral): Adjunct medication
  - Baclofen pump (Intrathecal)
    - Indication: Severe syndromes
    - Acute withdrawal has been fatal
- Valproate
- Tiagabine: 6 mg qd
Immunomodulating therapies
- Corticosteroids: High dose solumedrol with tapering; Improvement over months
- Intravenous immunoglobulin
- Plasma exchange
- Rituximab ³¹

Stiffperson syndrome: Variants

Focal SPS
- Clinical
  - Onset age: 35 to 60 years
  - Stiffness & Spasms
    - Locations
      - Most common: Legs
      - Also: Trunk
    - Stimuli: Especially voluntary movement; Also reflex stimuli
    - Leg syndromes
      - Asymmetric
      - Posturing of feet
      - Trunk spared
  - Stiff arm syndrome: May suggest paraneoplastic disorder
  - Treatment (Partial): Baclofen & Diazepam
- Laboratory
  - Anti-GAD antibodies: Present
  - Females with extremity stiffness
    - R/O breast adenocarcinoma with amphiphysin antibodies
Subacute (Brainstem) Encephalomyelitis (PERM)
- Onset: Subacute (Weeks)
- Clinical
  - Stiffness
    - Distal > Proximal at disease onset
    - Rigidity
  - Spasms: Episodic
  - Muscle wasting & weakness
  - Autonomic
    - Hyperhidrosis: Associated with spasms
    - Hyperthermia
    - Failure may occur
  - Cranial nerves
    - EOM: Nystagmus & Ophthalmoplegia
    - Blindness
    - Deafness
    - Dysarthria
  - Other CNS
    - Encephalopathy
    - Long tract signs
    - Vertigo
    - Intellect preserved in some
    - Myelopathy
  - Progression
    - Months
    - Death in 1 to 39 months
    - Some mild cases
    - Some cases may evolve from SPS presentation
  - Associated disorders: Report of Lymphoma
- Laboratory
  - CSF: Inflammatory
  - Neurophysiology
    - Similar to SPS
    - Brainstem myoclonus
  - Antibodies: GAD65; DPPX; GlyRα1
- Pathology
  - Inflammation: Perivascular
  - Gliosis: Spinal cord, Pons & Medulla
  - Neuronal loss: Spinal gray
Jerking Stiffperson Syndrome
- Clinical
  - Stiffness: Axial & Lower limb
  - Later features
    - Brainstem myoclonus
    - Upper motor neuron signs
    - PERM
  - Progression over decade
- Antibodies: GAD65
Paraneoplastic SPS: Suggestive features
- SPS confined to upper limbs
- Rapid disease progression: To fixed joint deformities
- Associated sensory ganglionopathy
- Neoplasms: Breast; Small cell lung
- Antibodies: Amphiphysin I; GAD
Cerebellar syndrome with anti-GAD antibodies ²⁷
- Epidemiology
  - Onset age: 20 to 74 years
  - Females
- Clinical
  - Onset: Slowly progressive
  - Ataxia: Limb & Trunk; Nystagmus; Dysarthria (50%)
  - Stiffness (15%)
  - No brainstem involvement
  - Associated disorders
    - ID Diabetes mellitus (Late-onset)
    - Thyroiditis
    - Poly-endocrine syndrome
  - Treatment: Not described
- Laboratory
  - Anti-GAD antibodies: High titer
  - Anti-parietal cell Ab: Common
  - MRI: Non-diagnostic
Differential diagnosis
- Hyperekplexia (Stiff-baby syndrome)
- Childhood onset: DYT1 gene mutations
- Rule out: Associated perniciaous anemia

Strychnine ¹¹

Actions
- Blocks glycine receptors: Competitive antagonist
- Blocks inhibitory neurons in brainstem & spinal cord
Sources
- Rodenticide
- Adulteration of street drugs
- Herbal remedies: made with Strychnos nux-vomica
Metabolism
- Chemical type: Alkaloid
- Intake: Oral with GI absorption
- Hepatic metabolism: 1/2 life 10 to 16 hours
- Some urine excretion: Up to 20%
Clinical syndrome
- Onset: Acute; 10 to 20 minutes after ingestion
- Inital signs: Nervousness; Hyperalert; Confusion
- Stiffness
  - Early: Face & Neck
  - Later: Generalized rigidity
  - May be triggered by minimal stimuli
  - Duration: 1/2 to 2 minutes
  - Respiratory arrest my occur during spasm
  - Muscle contraction may cause rhabdomyolysis
  - Tendon reflexes: Increased
- CNS: Agitation; Delusions; Disorientation
Diagnosis: Urine toxicology (Liquid chromatography)
Differential diagnosis: Tetanus (No CNS)
Treatment
- Gastric lavage
- Stiffness: Benzodiazepines; Barbiturates
- Rhabdomyolysis: Fluids; pH management
- Prophylactic ventilation in severe cases
Also see: Hyperekplexia (Startle disease)
External links: USDA

Hyperekplexia (Startle disease)

● Glycine receptor, α-1 subunit (strychnine binding)

; Chromosome 5q33.1; Dominant or Recessive

Clinical features
- Stiffness, myoclonus & after sudden stimulus
- Onset: as early as infancy with hypertonia or myoclonus
- Onset & severity vary within families
- Treatment: Clonazepam
Mouse models: Spasmodic & Oscillator

Muscle Fibers & Nerves: Activity Patterns

Muscle fibers
Axon firing patterns
Complex repetitive discharges
Cramp
Endplate Spikes
Fasciculations
Fibrillations
Insertion activity
Miniature endplate potentials (MEPPs)
Positive Sharp Waves

Also see: Spontaneous activity

Neural Origin
Amyotrophic Lateral Sclerosis
Black widow spider
Blepharospasm
Complex repetitive discharges
Cramp
Dystonia variants
Fasciculations
Geniospasm
Isaac's Syndrome
Motor neuropathies & neuron disorders
Motor units
Muscle fiber activity
Myokymia
Neuromyotonia
Polyneuropathy
Startle syndrome (Hyperekplexia)
Stiff-person Syndrome
Tetanus
Tetany
Tremor
Whipple's

Motor Unit Potentials

Definition: Extracellular compound potential of muscle fibers in a motor unit
Most influenced by: Muscle fibers near elactrode
Morphology
- Duration
  - Normal: 5 to 18 ms; Reflects most fibers in motor unit
  - Shorter: Proximal & Bulbofacial muscles; Myopathy; Early reinnervation
  - Increased with: Age; Chronic denervation with reinnervation
- Amplitude
  - Reflects mostly muscle fibers near electrode
  - Normal: 100 μV to 2 mv
  - Lower: Myopathy
  - Higher: Denervation with Reinnervation
- Phases
  - Normal: 2 to 4
  - Polyphasia
    - Normal: 5% to 10% of units; Deltoid ≤ 25%
    - Polyphasia: May be myopathy or neuropathy
  - Satellite potentials
    - Late linked phases
    - Unstable
    - Often due to collateral sprouting with reinnervation
- Stability
  - Motor units are usually stable
  - Instability: May be due to NMJ or Neuropathic processes
- Number
  - Reduced with: Increasing age, esxpecially over 60 years

Fibrillations

Definition
- Spontaneous action potentials in a single muscle fiber
- Extracellular recording
General
- Electrophysiologic markers of denervation of muscle fibers
- Not visible on physical examination
Properties
- Duration: 1 to 5 msec
- Amplitude: Changes with time after denervation
  - Range: 20 to 600 μV; Generally < 1000 μV
  - 1st 2 months: 600 μV
  - 6 months: 300 μV
  - 1 year: 10 μV to 100 μV
- Waveform
  - Diphasic or Triphasic
  - Initial positivity
  - Differ from endplate potentials which have initial negativity
- Firing rate
  - Range: 0.5 to 30 per second; Average 13
  - Rhythm: Usually regular; May slow gradually
  - Increases with: Muscle warming; Cholinesterase inhibitors
- Influences
  - Increased: Warming; Cholinesterase inhibitors; Needle electrode movement
  - Decreased: Hypoxia
Other EMG properties
- Sound: "Rain on the roof"
- Onset after muscle denervation: 10 to 21 days
- May change to positive sharp waves with movement of EMG needle
- Very profuse fibrillations
  - May be recorded with simultaneous denervation of many muscle fibers
  - Common causes: Trauma; Infarction (with Vasculitis)
- Paraspinous muscles: May persist for years after surgery
Causes
- Common: Denervation
  - Due to decreased resting membrane potential in denervated muscle
- Other: Inflammatory myopathy; Newborns
Fibrillations: Illustration

Positive Sharp Waves

Spontaneous depolarization of single muscle fiber
Configuration: Biphasic
- Initial: Positive (down) wave with duration < 5 ms
- Followed by: Wide negative wave with duration 10 to 100 ms
- Amplitude: 20 to 200 μV
- Duration: 10-30 ms
Rhythm: Regular
Frequency: 0.5 to 30 Hz
Stable
Involuntary
Stimulus: Recording electrode ³⁸
- 2 populations
  - May be induced by EMG electrode: Short maximal depolarizing times (Mean 1.3 ms)
  - Other PSWs are blocked fibrillations: Longer maximal depolarizing times (Mean 2.1 ms)
  - Both populations propagate away from recording electrode
- PSWs never observed with subcutaneous electrode
Causes
- Muscle denervation
- Same spectrum as fibrillations
Positive Sharp Waves: Illustration

Endplate Spikes

Shape
- Amplitude: 100 to 300 μV
- Duration: 2 to 4 ms
- Configuration: Initial negative; Biphasic
Discharge patterns
- Frequency: High; 5 to 100 Hz
- Rhythm: Irregular
Generation
- Initiated by needle electrode
- Activity in nerve terminals generates propagated potentials in muscle fibers
Associated with: Endplate noise

Miniature endplate potentials (MEPPs)

Generation
- Spontaneous release of individual quanta of acetylcholine
Recording location: Near neuromuscular junctions
Shape
- Amplitude: 10 to 40 μV
- Duration: 0.5 to 2 ms
- Configuration: Negative; Monophasic
Discharge patterns
- Irregular
- Frequency: 20 to 40 Hz
EMG sound: Sea shell
clinical correlate: Pain with EMG

Motor Axons: Firing Patterns

Increased force usually due to both
- Motor unit: Increased firing rate
- Additional motor units firing
- Ratio of firing frequency to number of different motor units: 5:1
- Firing frequency features
  - Usual maximum: 30 to 50 Hz
  - Ballistic quick contractions: Up to 100 Hz
  - Slow twitch muscles: Maximum 15 Hz
Smallest contraction
- Single motor unit fires rhythmically at 4 to 5 Hz
- Motor units firing at < 4 to 5 Hz: Not under voluntary control
Activation
- Definition: Ability to increase firing rate
- Central process
- Disorders: CNS disease; Pain; Poor cooperation
Recruitment
- Definition
  - Ability to add motor units as motor neuron firing rate increases
  - Frequency: 5 to 20 Hz
- Reduced recruitment & Recruitment interval
  - Fewer motor units firing for degree of effort
  - Individual motor units firing at more rapid rate (gt; 10 Hz)
  - Usual causes: Motor unit loss; Early reinnervation
  - Also: End stage myopathy
  - May be only EMG change in: Acute neuropathy; Demyelination
- Early recruitment & increased recruitment interval: Myopathy
Interference Pattern
- May be reduced due to reduced: Recruitment or Activation or Both
- ALS: Classic disorder with both reduced
  - Recruitment (PNS; Motor unit loss), and
  - Activation (CNS; UMN disorder)
Other
- Muscle fiber activity
- Spontaneous activity

Fasciculations

Brief discharges of individual axons
- Cause contraction of muscle fibers in all, or part of, motor unit
- Produce visible rippling of muscle
- Origin
  - May originate
    - Locations: Cell body, anywhere along course of axon or axon terminal
    - Most often originate: Distal axon
  - Properties: 2 types
    - Axonal origin
      - May have short interspike intervals
      - Refractory period 3 to 4 msec
      - ISI 5 msec
    - Proximal (Cell body) origin
      - Refractory period 17 to 46 msec
      - ISI 80 msec
- EMG appearance: Single motor unit or Part of motor unit
- Onset
  - Often spontaneous
  - May be precipitated by: Muscle percussion or contraction, fatigue, cold
- Discharge frequency & patterns
  - Rhythm: Irregular
  - Size & Shape: Same as motor unit potentials
  - Rate & Disease association
    - Benign
      - Short interval between discharges (0.5s to 1s)
      - More common in gastrocnemius
    - Motor neuron disease ³⁷
      - Longer interval between discharges (3.5s)
        
        Fasciculation frequency not related to disease duration or weakness
      - Accompanied by fibrillations
      - Grouped occurrence from multiple units
      - More common with strength deterioration
      - Related to cortical hyperexcitability
      - Common in: Proximal muscles with some weakness
    - Difference from Voluntary activity (Motor unit potentials)
      - Begin firing at 4 to 8 Hz: Differs among muscles
    - Appearance may be increased by: Alkalosis
    - Not influenced by: Mild contraction of agonist or antagonist muscles
Differential diagnosis
- Benign fasciculations
- Motor neuropathies & motor neuron disorders
- Cramp-Fasciculation syndromes
- Metabolic disorders: Hyperparathyroid; Hyperthyroid; Hypomagnesemia
- Kennedy disease: Facial Twitching
- Pharmacologic
  - Anti-Cholinesterases; Caffeine; Theophylline; Terbutaline; Lithium
Movie: Ultrasound image
Fasciculations: Variants
- Benign fasciculations
  - Common in gastrocnemius in otherwise normal patients
  - Affect same site repetitively
  - Normal strength in fasciculating muscles
  - Exacerbated by exercise, hyperventilation & tension
  - May be associated with tendency to cramp
- Contraction fasciculations
  - Initiation: By muscle contraction
  - Ending: When muscle contraction ceases
  - Common in motor neuron disorders: Especially in
    - BSMA: Face & Tongue
    - ALS: Tongue
- Minipolymyoclonus
  - Small amplitude movements: Especially of fingers & toes
  - Due to fasciculations of enlarged motor units
- Synchronous fasciculations
  - Location: In muscles supplied by different nerves or on opposite sides
  - May be related to: Spinal disorder; Reflex origin by spindle afferent
- Doublets, Triplets & Multiplets
  - Motor units that fire spontaneously in groups
  - Clinical correlations
    - Same general significance as singlet fasciculations
    - Common causes
      - Hyperexcitability: Hypocalcemic tetany; Hyperventilation
      - May occur during voluntary contraction
    - Muscles: Distal

Insertional Activity

Cause: Insertion of needle electrode into muscle
Normal discharge pattern
- Short burst (300 to 500 ms)
- Duration: Just exceeds movement of needle
Abnormal
- Increased insertion activity: Myotonia; Denervation; Immune myopathies
- Decreased insertion activity: Chronic muscle damage with fibrosis

Complex repetitive discharges

Tetany with carpopedal spasm

Pathophysiology
- Abnormal Ca⁺⁺ control of Na⁺ channels
- Axonal hyperexcitability: Due to
  - Membrane depolarization
  - Reduced action potential threshold
- Spontaneous repetitive discharges
  - Frequency: 5 to 15 Hz most common
  - Source: Arise in peripheral axons
Causes
- Ion changes
  - Hypocalcemia
  - Hypoparathyroidism
  - Hypomagnesemia
- Alkalosis: Respiratory
- Normocalcemic tetany: Rare
  - Acquired: Associated with neoplasm
  - Hereditary: Dominant with epilepsy
Exacerbated by: Hyperventilation; Ischemia
EMG
- Spontaneous axon discharges
  - High rates: Up to 300 Hz
- Repetitive discharges: Doublets or Multiplets
- Intense spasm: Maximal interference pattern
- Normal doublets occur at < 10 Hz
Diagnosis: Ischemic forearm test
Treatment: Calcium; Magnesium; Phenytoin

Barker

Geniospasm (GSM1) (Trembling chin)

● Chromosome 9q13-q21; Dominant

Clinical
- Onset age
  - Infancy & Childhood
  - Most common: Childhood & adolescence
- Vertical movements of the tip of the chin & quivering of lower lip
- Occur spontaneously; Or with stress, concentration, emotion
- Duration: Minutes
- Associated with: Nocturnal tongue biting
- Reduced frequency with increasing age
Other causes of chin quivering
- BSMA; Oral-facial-digital syndrome I
- Kennedy syndrome

Palmaris brevis spasm syndrome ²

From: M. Al-Lozi

Movie
From: R Bucelli

Palmaris brevis spasm

Palmaris brevis muscle
- Location: Hypothenar emininence; Subcutaneous
- Nerve: Ulnar, Superficial branch
- Action: Creases & ripples in overlying skin
- Not under voluntary control
Clinical features
- Epidemiology
  - Age of onset: 37 to 76 years
  - Males > Females
  - Triggers: Nerve damage or entrapmant; Idiopathic
- Contractions of palmaris brevis muscle
  - Location of activity:
    - Isolated to palmaris brevis muscle
    - Bilateral or unilateral
    - None in other muscles
  - Spontaneous
  - Timing: Irregular
  - Produce dimpling of ulnar side of hand
- Influences
  - Precipitating factor: Prolonged use of computer mouse & keyboard
  - Contractions increased: Stress; Excitement; Occasionally moving 5th finger
  - Contractions decreased: Rest; Sleep; Muscle stretch; Distal nerve block
- Sensory change: Variable
- Systemic (Some patients): Myalgia & Exercise intolerance
- Course: Benign; Over years
- Treatment
  - Dilantin in 1 patient
  - No improvement from ulnar block at elbow
EMG
- Rest: High frequency discharges with irregular occurrence
- Motor units: Normal amplitude, duration & morphology

Superior Oblique Myokymia

Disorder of ocular motility
- Symptom: Paroxysmal oscillopsia
- Monocular torsional and vertical eye movements
- Right sided predominance: 80%
- Due to intermittent contractions of the superior oblique muscle
Course: Recurring
EMG: Spontaneous bursts of motor unit potentials
Pathology: Arterial contact at root exit zone of symptomatic trochlear (IV) nerve ¹⁹

Dopa responsive dystonia

Differential diagnosis: Spastic paraparesis; Congenital myopathy

Crisponi syndrome

● Cytokine Receptor-Like Factor 1 (CRLF1)

; Chromosome 19p13.11; Recessive

Genetics
- Allelic with: Cold-induced sweating syndrome 1
Clinical
- Onset age: Congenital
- Movements: Often episodic
  - Contraction of the facial muscles: "Trismus"
    - Stimuli: Tactile stimuli & crying
  - Neck muscle hypertonia & opisthotonus
  - Generalized muscle contractions: Episodes
    - Occur several times each day
    - Stimuli: External
  - Seizures
  - Hypertonia
- Anomalies
  - Facial: Large face, Chubby cheeks, Broad nose
  - Bilateral camptodactyly
  - Scoliosis
- Breathing disorders: Central apnea; Hypopnea
- Fever: Episodic
- Feeding difficulty
Course
- Excitability may wane over 1st year
- Death: Some patients; < 1 month to childhood

Whipple's

Myoclonic ocular and facial jerks (Myorhythmia)
Ophthalmoplegia: Supranuclear
Dementia

Muscle Cramp Syndromes: Autosomal Dominant

Familial cramp syndrome
Familial dwarfism with muscle spasms
Muscle cramp & neuropathy syndrome
HANAC
Cramps & myalgias

Muscle cramp & Neuropathy syndrome ¹
● Autosomal Dominant

Cramps
- Onset: Childhood to 20's
- Peak symptoms: Teens & 20's
- Duration: 2 to 3 minutes
- Painful; Limbs & Trunk
- Induction
  - Repeated movements or Maintaining a specific posture
  - Also occur during full relaxation and sleep
Electrophysiology
- EMG: Chronic denervation; No fasciculations or myokymia
- NCV: Mild reduction in SNAP & CMAP amplitudes in legs
Nerve biopsy: Reduced number of Myelinated axons

Familial Cramp Syndrome

● Autosomal Dominant

Onset age: 10 to 15 years
Cramps disappear after age 25
Serum CK: High
Pathophysiology: Neurogenic origin
Muscle biopsy: Denervation

Hereditary Angiopathy, Nephropathy, Aneurysms & Muscle Cramps (HANAC)

³⁵
● Collagen Type IV α1 (COL4A1)

; Chromosome 13q34; Dominant or de novo

Epidemiology: > 130 patients with HANAC
Genetics
- Mutation locations: Located in glycine coding regions in exons 24 & 25
- Mutation effects
  - Dominant negative
  - COL4A1 General: Reduced secretion; Intracellular accumulation
  - Intracellular accumulation
    - More with mutations closer to carboxy-terminus of triple-helical domain
  - Myopathy: More with mutations nearest amino terminus
- Allelic disorders: Other COL4A1 mutations
  - Brain
    - Brain small vessel disease 1 (BSVD1), Dominant
      - ± Hemorrhage or Ocular disorders
      - Porencephaly I
    - Infantile Hemiparesis
    - Schizencephaly
    - Microangiopathy & Leukoencephalopathy, Pontine, Dominant (PADMAL)
  - Eye
    - Anterior segment dysgenesis
    - Optic nerve dysgenesis
    - Glaucoma, Secondary
    - Retina: Hemorrhages
    - Cataract: Congenital
- Incomplete penetrance
- Similar spectrum of disorders with COL4A2 mutations
COL4A1 protein
- Roles in muscle, myelination, vessels
- Vascular basement membranes with COL4A2
  - Form sheetlike basement membranes: Separate epithelium from connective tissue
- Collagens
HANAC: Clinical
- Nephropathy
  - Hematuria: Persistent; Microscopic or Gross
  - Cysts: Bilateral; Large or Small
- Angiopathy
  - Affects both small vessels and large arteries
  - Causes
    - Leukoencephalopathy
      - Bilateral
      - Supratentorial (Fronto-Parietal)
    - Retinal arteriolar tortuosity
    - Intracranial aneurysms
      - Small
      - Multiple
      - Extra or intradural carotid siphon
      - Unruptured
    - Brain microbleeds
      - Basal ganglia
      - Supratentorial white matter
      - Infratentorial: Cerebellum, Pons
  - Raynaud phenomenon
  - Supraventricular arrhythmia
- Neuromuscular
  - Cramps (15%)
    - Painful
    - Paroxysmal: Last seconds to minutes, occasionally hours
    - Triggers: Exercise; Alcohol
    - EMG: Electrically silent
  - Weakness
    - Proximal
    - Mild
  - Rhabdomyolysis ⁶⁷
    - Onset: Early childhood
    - Recurrent: Associated with systemic disorders & infections
    - Muscle
      - Fiber type size disporportion: Type 1 fibers smaller than type 2
      - Ultrastructure
        
        Capillary endothelial cells: Dilated endoplasmic reticulum
        
        Basement membrane
        
        Reduced density around endothelial cells & muscle fibers
        
        Collagen disarray
Laboratory
- Serum CK: High, 2x to 7x (20%)
- Brain MRI: Leukoencephalopathy
- EMG: Normal
- Muscle biopsy: Patchy pathology (Gly773Arg mutation)
  - Fiber size: Marked variation
  - Endomysial fibrosis
  - Fat replacement: Focal
  - Fiber types: Normal
  - COX & SDH staining: Reduced in muscle fibers in myopathic areas
- Peripheral nerve: Hypomyelination in mouse models

HANAC

FLAIR hyperintensities +
Foci of prior hemorrhage

Hypointense lesions: Multiple, Small

Also see

Familial dwarfism with muscle spasms
Satoyoshi syndrome

Sporadic Cramp Syndromes

Cramp-Fasciculation syndromes ⁶⁶

Clinical
- Onset age: Young to middle aged adults
- Cramps: Muscle contractions
  - Sudden onset
  - Painful
  - Involuntary
  - Associated with palpable hardening of muscle
  - Location: Calf & Quadriceps
  - Relieved by: Muscle extension
- Associated with: Muscle pain & Fasciculations; Stiffness
- Fasciculations
  - Discreet
  - Rapid,
  - Repetitive
  - Non-painful
- Strength: Normal
- Systemic associations
  - Toxic syndromes
    - Mydriasis
    - Hot flashes
    - Headache
  - Neoplasms: Much less common than in neuromyotonia
Laboratory
- Anti-K⁺ channel antibodies (CASPR2): Few patients ²⁵
- Repetitive nerve stimulation (Posterior tibial at 1, 2 & 5 Hz) ³⁴
  - Often produces after-discharges, cramp potentials, or continuous motor unit activity
- EMG
  - Spontaneous motor unit activity (Fasculations)
  - Slow repetitive nerve stimulation: Provokes after-discharges of motor unit action potentials
Rule out
- Dietary
  - Glutamate analogs: Umami (Monosodium Glutamate)
  - White Lupin seed (Lupinus spp.; Alkaloids) (External link)
- Anti-Cholinesterase medications
- Small fiber neuropathy
- Hypothyroid
- Neuromyotonia
- Local disorders
  - Post-Radiation
  - Radiculopathy
- Hereditary
  - Fabry disease
  - CANVAS

Pregnancy-associated cramps

Frequency: 10% to 30% of pregnancies
Onset: Most common in 2nd trimester
Symptoms
- Duration: ~ 8 weeks
- Frequency: Every other day
- Location: Legs
More common
- As pregnancy progresses
- At night: Rarely occur only in daytime
- ? Association with low serum magnesium
Treatment
- ? Magnesium lactate or citrate taken as 5mmol in the morning and 10mmol in the evening
No relationship to
- Other complications of pregnancy
- Fetal outcome

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Return to Ion Channel Disorders
Return to Myopathy & NMJ Index

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12/17/2024

MUSCLE FIBER ACTIVITY & CRAMPS

Myotonia

Myotonia: General features 56

Myotonia Congenita, Dominant (Thomsen)

Myotonia Congenita, Recessive (Becker)

Myotonia levior

Paramyotonia syndromes 64

Myotonia Fluctuans

Myotonia Permanens

Acetazolamide-responsive Myotonia Congenita

Myotonic Dystrophy (DM1)

Proximal Myotonic Myopathy (PROMM; DM2)

PROMM

Acquired myotonia: Drug toxicity

Hyperkalemic periodic paralysis

Rippling Muscle Syndromes 17

Schwartz-Jampel Syndrome (Chondrodystrophic myotonia) 24

Schwartz-Jampel Type 2/Stuve-Wiedemann syndrome (SWS) 26

Brody disease 53

Myokymia & Benign Neonatal Epilepsy (BFNS1) 13

Global Developmental delay, Myokymia & Peripheral Nerve Hyperexcitability 62

Myoedema

Muscle Spasms & Dwarfism

Cramps

Electrical activity with few clinical manifestations

Electrically silent cramps

Myopathic Tremor 58

Tetanus 20

Isaac's Syndrome

Familial Dyskinesia & Facial Myokymia 10

Stiff-person (Stiffman) syndrome

Strychnine 11

Hyperekplexia (Startle disease)

Muscle Fibers & Nerves: Activity Patterns

Motor Unit Potentials

Fibrillations

Positive Sharp Waves

Endplate Spikes

Miniature endplate potentials (MEPPs)

Motor Axons: Firing Patterns

Fasciculations

Insertional Activity

Complex repetitive discharges

Tetany with carpopedal spasm

Geniospasm (GSM1) (Trembling chin)

Palmaris brevis spasm syndrome 2

Superior Oblique Myokymia

Dopa responsive dystonia

Crisponi syndrome

Whipple's

Muscle Cramp Syndromes: Autosomal Dominant

Sporadic Cramp Syndromes

Myotonia: General features ⁵⁶

Paramyotonia syndromes ⁶⁴

Rippling Muscle Syndromes ¹⁷

Schwartz-Jampel Syndrome (Chondrodystrophic myotonia) ^²⁴

Schwartz-Jampel Type 2/Stuve-Wiedemann syndrome (SWS) ²⁶

Brody disease ⁵³

Myokymia & Benign Neonatal Epilepsy (BFNS1) ¹³

Global Developmental delay, Myokymia & Peripheral Nerve Hyperexcitability ⁶²

Myopathic Tremor ⁵⁸

Tetanus ²⁰

Familial Dyskinesia & Facial Myokymia ¹⁰

Strychnine ¹¹

Palmaris brevis spasm syndrome ²