Episodic Muscle

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EPISODIC MUSCLE WEAKNESS

Comparative features

Andersen syndrome
CIDP
Electrolyte disorders
Hyperkalemic Periodic Paralysis
Hypokalemic Periodic Paralysis
Hereditary
Ca⁺⁺ channel
Na⁺ channel
Renal tubular acidosis, Distal
Thyrotoxic
Acquired
K⁺ wasting
Myasthenia Gravis
Congenital: ChAT deficiency
Myoglobinuria/ Rhabdomyolysis
Myotonia syndromes
Paramyotonia
Porphyria, Acute Intermittent
X-linked episodic weakness

Non-muscle disorders
Cataplexy
Relapsing neuropathies
Spinal: AVM

Hyperkalemic Periodic Paralysis & Paramyotonia
l Sodium Channel - α subunit; Chromosome 17q13; Dominant
Hypokalemic Periodic Paralysis
- Hereditary
  l L-type Calcium Channel, α1 subunit ; Chromosome 1q31; Dominant
  l Sodium Channel - α subunit; Chromosome 17q13; Dominant
  l K⁺ channel (KCNE3); Chromosome 11q13-q14; ? Dominant
- Potassium wasting syndromes
- Thyrotoxic
  l ? Proclivity inherited as Autosomal Dominant
Periodic paralysis, K⁺ sensitive, with cardiac arrhythmias (Andersen Syndrome)
Electrolyte Disorders: Other
- Hypophosphatemia
- Barium intoxication
  - Treatment: Sodium sulfate (10 ml of 10% solution q30min)
X-linked episodic weakness
Myoglobinuria/ Rhabdomyolysis

Hypokalemic Periodic Paralysis

Hereditary
Ca⁺⁺ channel
K⁺ channel
Na⁺ channel
Renal tubular acidosis, Distal
Thyrotoxic
Acquired
K⁺ wasting

Pathology

Hypokalemic periodic paralysis: Hereditary
- Types
- General features with Na⁺, K⁺ & Ca⁺⁺ channel mutations
  - Loss of function mutations
  - No associated myotonia
  - T-tubules & Sarcoplasmic reticulum: Proliferation; Regeneration; Dilation
  - Muscle fibers contain increased Na⁺ & redujced K⁺
Hypokalemic periodic paralysis: HOKPP1
l L-type Calcium Channel, α1 subunit (Dihydropyridine Receptor) (CACNA1S) ; Chromosome 1q31; Dominant
- Genetic features: CACNA1S (CACNL1A3) Mutations
  - Most common gene mutated in hypokalemic periodic paralysis
  - Mutations: All are Arg substitutions in voltage sensor (S4) segments of the channel protein
    - Domain II: Arg528His
    - Arg1086Cys & Arg1086 Cys: 1 Family each
    - Domain IV: Arg1239His (Common); Arg1239Gly
  - Same gene as 1 family with malignant hyperthermia
    - Different location of mutation: S3 to S4 cytoplasmic loop
  - CACN1AS polymorphisms possibly associated with susceptibility to thyrotoxic hypokalemic periodic paralysis
- Pathophysiology
  - Normal channel
    - 2 roles
      - Slow-voltage-activated Ca⁺⁺ channel
      - Voltage sensitive element: Excitation-contraction (EC) coupling with ryanodine receptor
      - Coupled to ryanodine receptor via II-III loop interlinker
      - Not important as ion conducting channel
    - Location: Triadic junctions of t-tubular system
  - Human mutation: Enhances inactivation of Ca⁺⁺ channel
  - Defect in control of muscle resting membrane potential
  - Muscle membrane is depolarized during attacks: Causes Reduced nerve-evoked muscle activity
    - Ca⁺⁺ channel defect: Causes increased intracellular Ca⁺⁺
    - Na⁺ channel α-subunit RNA is reduced
      - Na⁺ channels reduced in membrane: Weakness occurs with excitation failure
      - Reduced skeletal muscle Na⁺ current also occurs with mutations in Na⁺ channels
    - Leads to increased K⁺ uptake by skeletal muscle: Produces membrane depolarization
  - Conduction velocity in muscle fibers: Slow
- Clinical features: Hypokalemic periodic paralysis
  - Episodic weakness: Enhanced by hypo K⁺ in serum
    - Onset: Early childhood to 30's; 60% < 16 years
    - Attacks begin in early morning hours
    - Truncal musculature is weak; Cranial nerves spared
    - Duration of attack: Hours to days
    - Triggers on preceding day
      - Physical activity; Carbohydrate-rich meal; Cold
    - Myotonia: Focal in eyelids; Not in limbs
    - Less in later life, 40's and 50's
  - Rhabdomyolysis
    - CACNA1S mutations: R528H; R1086C; R1086H; R1239G; R1239H
  - Permanent residual weakness
    - Onset: Most often > 40 years of age
    - Often progresses slowly over years
  - Penetrance: Male 100%; Female 50%
- Clinical features with specific mutations
  - Arg528His⁴
    - Common
    - Later onset: Mean 14.5 years in males; 11.8 years in females
    - Reduced penetrance in females (50%)
    - Myalgias: Most common during episodes
    - Permanent weakness: ~25%; May occur in female with no history of atacks
    - K+ level during episodes: 1.7
    - Acetazolamide treatment helpful in 60%
    - Pathology: Vacuoles
  - Arg1239His⁴
    - Common
    - Onset: 10.4 years in males; 8.8 years in females
    - Reduced penetrance in females (70%)
    - Some patients with only single attack: Triggered by acute stress
    - Myalgias: Most common during episodes
    - Permanent weakness: ~30%
    - K+ level during episodes: 2.2
    - Acetazolamide treatment helpful in 60%
- Laboratory
  - Serum CK: Increased during attacks
  - Electrodiagnostic
    - CMAP reduced during attacks
    - 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: Mild increase in CMAP amplitude after exercise
    - Epinephrine reduces size of CMAP
  - Provocative test: Glucose ± insulin
- Muscle pathology
  - Vacuoles: Clear; Central
  - Tubular aggregates
  - Myopathy: Varied muscle fiber size; Split fibers; Internal nuclei
  - Angular muscle fibers
  - Vacuolar dilation of sarcoplasmic reticulum during attacks
- Mouse disease: Muscular dysgenesis (mdg)
  - Homozygous truncation mutation of CACNA1S
  - Frame shift deletion: Truncates α1 subunit
  - Causes loss of both L-type Ca⁺⁺ currents & EC coupling
  - Action potentials do not trigger contractions
  - Animals die at birth due to respiratory failure
Hypokalemic periodic paralysis: HOKPP2
l Sodium Channel - α subunit ; Chromosome 17q13; Dominant
- Genetics: SCN4A Mutations
  - Location: Voltage sensor of domain 2 of SCN4A
  - Type: Point missense; Arg669His, Arg672His, Arg672Gly, Arg672Ser, P1158S
  - Other mutations in SCN4A cause
- Electrophysiology
  - Excised muscle fibers depolarized & weak in low-K⁺ solution
  - Action potentials: Slow & Small
  - Reduced number of excitable sodium channels, especially at sustained membrane depolarization
- Clinical: Comparison to Calcium Channel Hypo K⁺ periodic paralysis syndrome
  - Clinical features: Many similar to CACNL1A3
  - Arg672Gly mutation: Clinical features⁴
    - Single family
    - Onset: 9 years in males & females
    - Full penetrance in males & females at age 20
    - Myalgias: Most common after episodes
    - Permanent weakness: ~45%
    - K+ level during episodes: 1.4
    - Pathology: Tubular aggregates in type 2 muscle fibers
    - Acetazolamide treatment often deleterious
  - P1158S mutation
    - Mutant channel: Disordered slow inactivation
    - Periodic paralysis + Myotonia
    - Exacerbated by cold
Hypokalemic periodic paralysis: HOKPP3
l KCNE3 ; Chromosome 11q13-q14; ? Dominant
- Mutation
  - Missense Arg83His
  - Same mutation found in controls & unaffected family members⁹
- Clinical: 2 families with different phenotypes
  - Hypokalemic periodic paralysis
    - Onset: Episodes of paralytic weakness; Age 14 to 20 years
    - Episodes
      - Weakness: Legs
      - Duration: Hours to days
      - Precipitants: Strenuous exercise followed by rest; Prolonged sitting; Not high carbohydrate meals
      - Time of onset: Awakening or During wakefulness
      - Recovery: Facilitated by alcohol
      - Muscle pathology: Vacuoles; Tubular aggregates
  - Hyperkalemic periodic paralysis
    - Onset: 22 months; Episodes of weakness
    - Episodes
      - Weakness: Legs & Arms
      - Time of onset: Sleep
      - Duration: 12 hours
      - Improvement with carbohydrate loading
      - No myotonia
Distal Renal Tubular Acidosis
l SLC4A1 Chromosome 17q21-q22; Recessive or Dominant
l Chromosome 7q33-q34 & Other loci
- SLCA4A1 Mutation: Recessive Gly701Asp
  - Other mutations produce: Spherocytosis; Hemolytic anemia
- SLC4A1 protein
  - Major glycoprotein of the erythrocyte membrane
  - Mediates exchange of chloride & bicarbonate across the phospholipid bilayer
- Periodic paralysis: Hypokalemic²
  - Endemic in Northeast Thailand
  - Clinical
    - Numerous episodes: Duration of hours
    - Weakness
    - Tendon reflexes: Reduced or Absent
  - Treatment: K⁺; Bicarbonate; Not acetazolamide (Exacerbates acidosis)
  - Laboratory
    - Hyperchloremic acidosis
    - Urine with alkaline pH & Reduced ammonia
    - EMG: Reduced interference pattern
    - Thyroid normal
- Skeletal: Growth failure; Osteomalacia with pathologic fractures
Hypokalemic (periodic) paralysis: Potassium wasting syndromes
- Urinary
  - Alkaline urine & metabolic acidosis
    - Hyperaldosteronism
    - Angiotensin converting enzyme dysfunction
    - Licorice intoxication
    - Mineralocorticoid excess
    - Renal tubular acidosis
      - Sjögren's syndrome
      - Fanconi's syndrome
  - Alkaline urine & azotemia: Amphotericin B
  - Acidosis
    - Ammonium chloride ingestion
    - Ureterocolostomies: Bilateral
    - Diabetic coma: Recovery
    - Renal tubular necrosis: Recovery
    - Distal renal tubular acidosis
  - Other
    - Gossypol toxicity (with low K⁺ diet)
    - Tea: Excessive amounts
    - cis-platinum
- Gastrointestinal
  - Non-tropical sprue
  - Laxative abuse
  - Severe diarrhea or vomiting
  - Draining GI fistula
Hypokalemic periodic paralysis: Thyrotoxic periodic paralysis⁶
l ? Proclivity to disease inherited as Autosomal Dominant; Sporadic
- Genetics
  - Sporadic case had mutation of KCNE3 (HOPP3)
  - CACN1AS polymorphisms possibly associated with susceptibility
    - Intron & 5' nucleotide substitutions
  - No SCN4A mutations in most patients
- Epidemiology
  - Frequency in hyperthyroid patients
    - Most common in Asians: ~ 2% Incidence; Up to 10% of hyperthyroid patients
    - Also relatively common in Native Americans
    - North America: 0.1% Incidence
  - Male predominance (83% to 95%)
- Clinical
  - Onset
    - Age: 18 to 40 years
    - Proximal weakness
    - Muscle discomfort & Cramps
  - Weakness
    - Duration of episodes: Hours to Days
    - Distribution
      - Legs > Arms; Proximal > Distal
      - May selectively involve recently exercised muscles
      - Severe attacks may involve: Respiration; Bulbar function
      - Sphincters not involved
    - Attacks
      - Often occur in random pattern without obvious stimulus
      - Precipitated by
        
        Carbohydrate challenge ± insulin
        
        Muscle cooling
        
        Rest after exercise
        
        Thyroxine ingestion
      - Single or multiple episodes: Especially at night
      - ? Seasonal
        
        More common in May-October (Summer)
        
        Less common in December-March
      - May be aborted by exercise
      - Abate when thyrotoxicosis resolves
  - Systemic
    - Thyrotoxicosis: May be subclinical
    - ± Cardiac arrhythmias: Sinus tachycardia commmon
    - Weight loss
    - Nausea & Vomiting
    - Difficulty with micturition
  - Course: Resolves without morbidity after treatment of thyroid disease
- Laboratory
  - Serum K⁺
    - Usually Hypokalemia: < 2.5 μmol/L
    - Occasionally normal
  - TSH: Low
  - Hypophosphatemia: Occasional
  - Renal: Retention of Na⁺ & K⁺; Oliguria
  - Electrodiagnostic
    - CMAP reduced during attacks
    - Epinephrine has no effect on size of CMAP
  - Muscle pathology
    - Vacuolar dilation of sarcoplasmic reticulum during attacks
    - Muscle Na⁺-K⁺ pumps: Increased
- Treatment
  - Correct thyrotoxicosis
  - β-adrenergic blocking agents
  - NOT acetazolamide

Periodic paralysis, K⁺ sensitive, with cardiac arrhythmias (Andersen Syndrome)

l KCNJ2 (Kir2.1)

; Chromosome 17q23; Dominant

Genetics³: Most mutations are missense; Some are inframe deletions
KCNJ2 protein
- Inwardly rectifying K⁺ channel
- Plays role in hyperpolarization needed for myoblast fusion
- Mutated protein expression
  - Loss of function
  - Dominant negative
  - Produces reduced inwardly rectifying K⁺ current
- Tissue functions
  - Cardiac & skeletal muscle function
  - Also: Developmental signaling
Intrafamilial variability
- Partial manifestations common
- Arg67Try mutation: Venrtricular arrhythmia in females (81%); Periodic paralysis in males (40%)
Clinical
- Cardiac: Venrtricular arrhythmia may segregate in females
  - Arrhythmia
    - Bigeminy
    - Bidirectional ventricular tachycardia
    - Increased Q-T interval (Early)
  - Semilunar valve abnormalities
  - Heart block
  - Symptoms: Syncope; Suden death
  - Treatment
    - Amiodarone
    - Poor response to classical therapy
  - Cardiac malformation: Occasional
- Episodic weakness: May segregate in males
  - Onset: 2 to 18 years
  - Duration: 1 hour to days
  - Proximal > Distal
  - Precipitants: K⁺; Exercise; None
  - No myotonia
- Permanent weakness: Occasional
  - Proximal & Distal
- Skeletal
  - Short stature
  - Clinodactyly: Lateral or medial curvature of finger or toe
  - Syndactyly
  - Scoliosis
- Face
  - Hypertelorism
  - Mandible hypoplasia
  - Low-set ears
  - Broad forehead
  - Malar hypoplasia
- Kidney, Hypoplastic: Occasional
Lab: Serum K⁺ during attack may be high, low, or normal
Treatment⁵
- K⁺ Rx
  - Oral K⁺ may improve weakness in patients with low K⁺
  - In some families increasing K⁺: Improves arrhythmia; Exacerbates weakness
- Acetazolamide
Muscle pathology: Tubular aggregates

X-LINKED EPISODIC PROLONGED MUSCLE WEAKNESS SYNDROME¹

l Chromosome Xp22.3; Recessive

Onset: 0.5 to 8 years
Episodes of weakness
- # Episodes in individual patients: 1 to 10
- Duration of episodes: 1 day to 12 months
- Less frequent with greater age
- Asymptomatic periods: Up to 9 years
- Strength between episodes: Normal
- Antecedent events: Viral illness
- Severity of weakness: Variable
  - Mild: Weakness predominantly proximal
  - Severe
    - Diffuse
    - Loss of head control
    - Bulbar dysfunction
    - Tendon reflexes reduced
    - Respiratory function reduced
- Distribution of weaknesss
  - Proximal ± Distal
  - Ptosis
  - ± Bulbar (Dysphagia)
- Tendon reflexes: Reduced during exacerbations
Other clinical
- Pain: Myalgia & Cramps
- Episodic dystonia: Occasional; ± Tremor
Laboratory
- Peripheral neuropathy (1 older patient): Axonal
- Muscle biopsy ultrastructure (1 case): Dilation & proliferation of sarcoplasmic reticulum
- Basal ganglia calcification

HEREDITARY PERIODIC PARALYSIS & MYOTONIA SYNDROMES:
Comparative Features

	Hypo K⁺ Periodic Paralysis	Thyrotoxic Hypo K⁺ Periodic Paralysis	Hyper K⁺ Periodic Paralysis	K⁺- sensitive Myotonia *	Para- myotonia	Myotonia congenita		Andersen syndrome	X-linked paralysis
	Hypo K⁺ Periodic Paralysis	Thyrotoxic Hypo K⁺ Periodic Paralysis	Hyper K⁺ Periodic Paralysis	K⁺- sensitive Myotonia *	Para- myotonia	Thomsen's	Becker's	Andersen syndrome	X-linked paralysis
Inheritance/ Chromosome	Dominant 1q31-q32	? Dominant Proclivity	Dominant 17q23-q25	Dominant 17q23-q25	Dominant 17q23-q25	Dominant 7q35	Recessive 7q35	Dominant 17q23	Recessive Xp22
Channel defect	Ca⁺⁺: CACNA1S α₁-subunit Other	Na⁺-K⁺ pumps é in Muscle	Na⁺: SCN4A α-subunit KCNE3	Na⁺: SCN4A α-subunit	Na⁺: SCN4A α-subunit	Cl^-: CLCN1	Cl^-: CLCN1	K⁺: KCNJ2	?
Functional defect	?	?	ê Fast & slow Inactivation	Mild ê Fast Inactivation	ê Fast Inactivation	ê Cl^- Conduct	ê Cl^- Conduct	ê K⁺ Conduct	?
Penetrance	ê Females	ê Females	High	High	High	High	High	Variable	? High
Onset	5 to 35 years	20 to 40 years	< 10 years	< 10 years	< 10 years	Congenital	Congenital	2 to 18 years	0.5 to 8 years
Weakness duration	2 to 24 hours	Hours to Days	1/2 to 4 hours	None	2 to 24 hours	None	Transient	1 to 36 hours	1 day to 1 year
Maximum weakness	Severe	Mild to Severe	Mild to Severe	None	Mild	None	Mild	Moderate	Mild to Severe
Cold	± é Paralysis	± é Paralysis	± é Paralysis	é Paralysis	é Paralysis	No effect	No effect		No effect
K⁺-effects	ê Paralysis	ê Paralysis	é Paralysis	é Paralysis	ê Paralysis	No effect	No effect	é Paralysis	No effect
Attack precipitants	Carbohydrates Activity ® Rest	Carbohydrates Activity ® Rest	Fasting	é K⁺	Cold; ê K⁺	None	None	K⁺	Viral illness
Myotonia	Rare Eyelids only	None	± Present Exercise: ê	Mild to Severe Exercise: é	Moderate Exercise: é	Moderate Constant	Severe Constant	None	None
Muscle hypertrophy	Absent	Absent	Present	Present	Present	Present	Present	Absent	Absent
Sensory symptoms	Absent	Absent	Present	?	Absent	Absent	Absent	Absent	Absent
Drug treatment	K⁺ Acetazolamide Dichlor- phenamide	ê Thyrotoxicosis β-adrenergic blockade	Thiazide Acetazolamide Dichlor- phenamide	Mexiletine Thiazide	Mexiletine	Numerous	Numerous	?	?

* Includes acetazolamide-responsive myotonia, myotonia fluctuans, & myotonia permanens

Licorice intoxication

General
- Origin: Sweet root of various species of Glycyrrhiza
- Toxic agent: Glycyrrhizic acid
  - Sost patients with toxic effects at 400 mg/d
  - Sensitive subjects with effects at 100 mg/d
  - Effects may be potentiated by increased salt intake
- External links: Botanicals; licorice.org; KSU
Substances containing licorice
- Candy
- Oriental herbs
- Tea sweetener (Arabs; "sus")⁸
- p-aminosalicylic acid (Anti-tuberculous)
- Carbenoxylone sodium (Anti-ulcer)
- boisson de coco: French alcoholic beverage
- Chewing tobacco
Disease mechanism
- Chronic licorice ingestion
- Inhibits 11 β-hydroxysteroid dehydrogenase
  - Inhibits renal conversion of cortisone to inactive cortisol
  - Cortisol activates renal mineralocorticoid receptors
- Potassium wasting
Clinical features
- Weakness
  - General
    - Proximal & Distal
    - Symmetric
  - Posterior neck ⁷
- Rhabdomyolysis
Laboratory
- Serum K⁺: Low; 1.7 to 3 mEq/L
- Serum CK: Mildly high

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References
1. Am J Hum Genet 1999;65
2. Lancet 2000;355:1612
3. Cell 2001;105:511-519
4. Brain 2001;124:1091-1099
5. Neurology 2002;59:466
6. Internal Medicine Journal 2003;33:91�94
7. Clinical Neurology and Neurosurgery 2003;105:286-287
8. Mayo Clin Proc 2003;78:767-768
9. Neurology 2004;62:1012-1015

9/29/2007

EPISODIC MUSCLE WEAKNESS

Hypokalemic Periodic Paralysis

Periodic paralysis, K+ sensitive, with cardiac arrhythmias (Andersen Syndrome)

X-LINKED EPISODIC PROLONGED MUSCLE WEAKNESS SYNDROME1

HEREDITARY PERIODIC PARALYSIS & MYOTONIA SYNDROMES: Comparative Features

Licorice intoxication

Periodic paralysis, K⁺ sensitive, with cardiac arrhythmias (Andersen Syndrome)

X-LINKED EPISODIC PROLONGED MUSCLE WEAKNESS SYNDROME¹

HEREDITARY PERIODIC PARALYSIS & MYOTONIA SYNDROMES:
Comparative Features