Episodic Muscle

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EPISODIC MUSCLE WEAKNESS

Comparative features

Andersen syndrome
CIDP
Electrolyte disorders
Hypophosphatemia
Barium intoxication
Myasthenia Gravis
Congenital: ChAT deficiency
Myoglobinuria/ Rhabdomyolysis
Myotonia syndromes
Paramyotonia

Periodic Paralysis
Hyperkalemic
Hypokalemic
Mitochondrial
RYR1
Porphyria, Acute Intermittent
X-linked episodic weakness

Non-muscle disorders
Cataplexy
Relapsing neuropathies
Spinal: AVM

Hypokalemic Periodic Paralysis

Hereditary
Ca⁺⁺ channel: CACNA1S; 1q32
Na⁺ channel: SCN4A; 17q23
Gitelman: SLC12A3; 16q13
K⁺ channel
KCNE3: 11q13
KCNJ2: 17q24
KCNJ5: 11q24
Renal tubular acidosis: SLC4A1; 17q21
HOPP + CNS: ATP1A2; 1q23
Thyrotoxic (TTPP)
1: CACNA1S; 1q32
2: KCNJ18; 17p11
3: 17q24.3
Acquired
K⁺ wasting
Dengue fever
Pathology

Hypokalemic periodic paralysis, Hereditary: General features
- Epidemiology
  - Prevalence: 0.1 to 1 per 100,000; 0.13/100,000 in United Kingdom
  - Similar frequency to genetically defined hyperkalemic periodic paralysis
- Types
  - Ca⁺⁺ channel: CACNA1S; Most common
  - Na⁺ channel: SCN4A
  - K⁺ channel: KCNE3
  - Thyrotoxic (K⁺ channel): KCNJ18
  - Distal renal tubular acidosis: SLC4A1
  - Chinese ancestry: 17q24.3 locus; May be sporadic
  - Andersen syndrome: KCNJ2; K⁺ levels may be increased or decreased
- General features with Na⁺, K⁺ & Ca⁺⁺ channel mutations
  - Genetic
    - Mutations
      - Loss of function
      - Location (> 90%)
        
        Arginine residues in voltage sensitive S4 segments
        Consistent with gating pore cation leak hypothesis
    - Inheritance: Dominant
    - New mutations: 30%
  - Mutation effects on channel
    - Loss of function
    - Loss of positive charge
    - Mutations disrupt gating of pore at hyperpolarized potentials: Different types of leaks
      - Non-selective cation
      - Proton specific pore
  - Clinical
    - Onset: 1st or 2nd decade
    - Females
      - Less severe disease
      - Fewer attacks
      - Attacks may disappear during pregnancy
      - Lower penetrance: Some families as low as 28%
    - Attacks
      - Variable frequencies within families
      - Onset time: Night or Early morning
      - Prodrome day prior to an attack
        
        Paraesthesias & Discomfort
        
        Fatigue
        
        Behavioural & Cognitive changes
      - Weakness
        
        Flaccid
        
        Proximal > Distal
        
        Legs & Arms
        
        Occasionally asymmetric or focal: Monoparesis at presentation in some
      - Provocative factors
        
        Carbohydrate-rich meals
        
        Rest after exercise
        
        Cold > Heat
        
        Stress
        
        Medications: β-Agonists, Corticosteroids, Insulin
        
        Gastroenteritis
    - Weakness: Fixed
      - Onset: Mean > 40 years; Range 8 to 66 years
      - Independent of attack episodes
      - Frequency: 25% to 30%
    - No associated myotonia
    - Tendon reflexes: Reduced
    - Other: Increased risk
      - Post-operative complications related to anesthesia: Malignant hyperthermia
    - Treatment
      - K⁺: Oral intake
      - Acetazolamide: More likely to benefit CACNA1S (60%) than SCN4A (20%)
    - External link: YouTube video
  - Laboratory
    - Serum K⁺: Low during attacks
    - Serum CK: Often elevated during attacks
    - NCV & EMG during attacks
      - CMAP amplitudes: Small
      - Insertional activity: Reduced
      - Spontaneous activity: Fibrillations; Positive sharp waves
      - Motor unit potentials: Increased polyphasia
  - Pathology: Muscle
    - T-tubules & Sarcoplasmic reticulum: Proliferation; Regeneration; Dilation
    - Tubular aggregates
    - Vacuoles
    - Muscle fibers contain increased Na⁺ & reduced K⁺
  - Historical
    - Elizabeth Barrett Browning: May have had Hypokalemic periodic paralysis ¹³
Hypokalemic periodic paralysis: HOKPP1
● L-type Calcium Channel, α1 subunit (Dihydropyridine Receptor; DHPR; CACNA1S; CACNL1A3; Ca_v1.1) ; Chromosome 1q32.1; Dominant
- Epidemiology
  - 60% of HypoPP families
  - Male > Female
- Genetic features
  - Most common gene mutated in hypokalemic periodic paralysis
  - Mutations
    - Pattern: Most are are substitutions of Arg by neutral amino acid
    - Locations: Voltage sensor (S4) segments of CACNA1S
    - 8 mutations described
      - Domain II: Arg528His
      - Val876Glu, Arg897Ser, Arg900Gly, Arg900Ser, His916Gln, Arg1086Cys
      - Domain IV: Arg1239His (Common); Arg1239Gly
  - Allelic disorders
    - Hypokalemic periodic paralysis 1 (HOKPP1)
    - Malignant hyperthermia 5
    - Thyrotoxic hypokalemic periodic paralysis 1 (TTPP1), Susceptibility
    - Congenital myopathy, Recessive or Dominant
    - Fetal akinesia: Recessive; Mutations Met222Lys Arg789Cys
    - Mouse: Muscular dysgenesis
    - Myotonic dystrophy (DM1): Modifier
      - Alternative splicing of CACNA1S exon 29 is repressed
      - Correlates with: Increased channel conductance & voltage sensitivity
- CACNA1S channel: Pathophysiology
  - Normal CACNA1S channel
    - L-type
    - 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
    - Na⁺ leak
    - Resting membrane potential drops to -58 mv
    - Enhances inactivation of Ca⁺⁺ channel: Channel nearly closed
    - No Action potential propagation
    - Fiber paralyzed
  - 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 age: 1 year to 4th decade; 60% < 16 years
    - Attacks
      - Frequency: Common; May be asymptomatic
      - Onset time: Often begin in early morning hours
      - Severity: Variable
    - Weakness
      - Truncal musculature
      - Proximal or Distal
      - Cranial nerves: Often spared; Jaw opening weak
      - May begin in recently exercised muscles
      - Respiratory muscle: Spared
    - Duration of attack: Hours to Days
    - Triggers on preceding day
      - Physical activity
      - Carbohydrate-rich meal
      - Cold
      - Alcohol
    - Less in later life, 40's and 50's
  - Rhabdomyolysis
    - CACNA1S mutations: R528H; R1086C; R1086H; R1239G; R1239H
  - Other features associated with attack
    - Myotonia: Not in limbs (Excludes diagnosis); Focal in eyelids
    - Oliguria
    - Obstipation
    - Diaphoresis
  - After attack
    - Muscle discomfort
    - Polyuria
  - Permanent residual weakness
    - Onset: Most often > 40 years of age
    - Often progresses slowly over years
  - Some patients
    - Muscle rigidity
    - Calf hypertrophy
  - Penetrance: Male 100%; Female 50%
- Clinical features with specific mutations
  - Arg528His ⁴
    - 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
    - Low K+ level during episodes: 1.7 ± 0.6
    - Acetazolamide treatment helpful in 60%
    - Pathology: Vacuoles
  - Arg1239His ⁴
    - 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%
    - Low K+ level during episodes: Mean = 2.2 ± 0.6
    - Acetazolamide treatment helpful in 60%
  - Arg897Ser ¹⁰
    - Epidemiology: Turkish child
    - Mutation
      - Location: S4 segment of domain III
      - Effect: Loss of charge
    - Onset: Birth; Hypotonia
    - Paralysis episodes
      - Onset age: 1 year
      - Frequency: Up to 1 per day
      - Duration: 10 to 30 minutes
      - Trigger event: None
      - Pain: None
      - Increasing age: Less frequent, longer episodes
    - Between episodes: Diffuse 4/5 weakness develops
    - Serum CK: Normal
- Laboratory
  - Serum K⁺
    - During attacks: Low
    - Between attacks: Normal or High (During recovery periods)
  - Serum CK: Increased during attacks
  - Electrodiagnostic
    - EMG
      - Between attacks: Normal
      - During attacks: Irritability or Reduced insertional activity
    - CMAP amplitude
      - Reduced during attacks
      - 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
- CACNA1S variant syndrome: Malignant hyperthermia 5 (MHS5)
  - Epidemiology: 1% of MH cases
  - Genetics
    - Inheritance: Dominant
    - Mutations
      - Arg174Trp; Arg1086His; Arg1086Ser; Arg1086Cys; Arg1086Leu; Thr1354Ser
      - Location: Cytoplasmic loop betweeen S3 and S4; ? Region that interacts with ryanodyne receptor
      - Many other possible variants
  - Clinical
    - Triggered by
      - Volatile Halogenated anaesthetics
        
        Desflurane
        
        Enflurane
        
        Halothane
        
        Isoflurane
        
        Methoxyflurane
        
        Sevoflurane
      - Depolarizing Neuromuscular Blocker: Succinylcholine
    - Tachycardia
    - Hypercapnia
    - Hyperthermia
    - Muscle rigidity
    - Rhabdomyolysis
    - Treatment: Dantrolene
  - Laboratory
    - Acidosis
    - Serum CK: High
    - Tests
      - in vitro contracture (IVCT) of biopsied muscle
      - Caffeine Halothane contracture testing
- CACNA1S variant syndrome: Thyrotoxic hypokalemic periodic paralysis 1 (TTPP1), Susceptibility
  - Epidemiology: Locations
    - Most common in
      - Asian males: Chinese, Japanese, Vietnamese, Filipino, Korean
      - Southern Chinese: 2%
    - North America: 0.1% to 0.2%
  - Genetics
    - Inheritance: Dominant
    - Mutations: Single-nucleotide polymorphisms (SNPs)
  - Clinical
    - Weakness: Episodic attacks
    - Course: Paralysis syndrome resolves with treatment of hyperthyroidism
  - Laboratory
    - Associated with: Hypokalemia
    - Individuals have: Hyperthyroidism
- CACNA1S variant syndrome: Congenital myopathy (CMYO18) ¹⁶
  - Nosology: DHPRM; CMYP18; CMYO18
  - Epidemiology: 14 patients, 8 families
  - Genetics
    - Inheritance: Recessive, Dominant or de novo
    - Mutations: Deletions, Stop & Missense
      - Dominant Missense: Pro742Gln; Pro742Ser; Leu1367Val
      - Recessive Missense: Glu100Lys; Phe275Leu
  - CACNA1S protein effects
    - CACNA1S levels: Reduced
    - Ca⁺⁺ release induced by depolarization: Impaired
  - Clinical
    - Onset age: Neonatal
    - Hypotonia: Perinatal
    - Motor, early
      - Development: Delayed
      - Feeding difficulty
    - Weakness
      - Severe
      - Axial & Generalized
      - Respiratory
      - Face
      - Course: Slow progression
    - Ophthalmoplegia (40%)
    - Skeletal
      - Palate: High arched
      - Scoliosis (60%)
    - Cardiac: Normal
  - Laboratory
    - Muscle biopsy
      - Fiber size: Varied
      - Intermyofibrillar network: Abnormal; "Alveolar"; Mini-cores or Irregular
      - Type 1 muscle fibers: All or Most
      - Nuclei: Internal or Central
      - Ultrastructure
        
        Areas of myofibrillar disorganization
        
        SR: Dilatation
    - Muscle MRI
      - Anterior > Posterior Thigh involvement
      - Semitendinosus may be more involved than other posterior muscles
    - Serum CK: Normal or High
- 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
● Sodium Channel - α subunit (SCN4A; Na_v1.4) ; Chromosome 17q23.3; Dominant
- Epidemiology: 20% of HypoPP families
- Genetics: SCN4A Mutations
  - Location: Voltage sensor of domain 2 of SCN4A
  - Type: Point missense; Arg669His, Arg672His, Arg672Gly, Arg672Ser, R1132Q, P1158S
  - Mutations in SCN4A cause
    - Dominant
      - Paramyotonia congenita
      - Hyperkalemic periodic paralysis
      - Hypokalemic periodic paralysis (HOKPP2)
      - Myotonia Congenita, Acetazolamide-responsive
      - Myotonia Permanens
      - Myotonia Fluctuans
      - Malignant hyperthermia
      - Myasthenic syndrome
      - Myotonia + Myopathy (Asn1180Ile)
      - Sudden infant death (SIDS) 1.4% ¹⁷
    - Recessive
      - Fetal hypokinesia
      - Congenital myopathy/CFTD
    - Quarter horses: Hyperkalemic periodic paralysis
- SCN4A (Na_v1.4) protein
- Clinical: Comparison to Calcium Channel Hypo K⁺ periodic paralysis syndrome
  - Clinical features: Many similar to CACNL1A3 (CACNA1S)
  - Arg672Gly mutation: Clinical features ⁴
    - Single family
    - Onset: 9 years in males & females
    - Full penetrance in males & females at age 20
    - Myalgias: Most common after episodes
    - Permanent weakness: ~45%
    - Low K+ level during episodes: 1.4 (1 patient)
    - 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
- 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
  - Channel changes with hypokalemic weakness: Associated with pathologic depolarizing current ¹¹
    - Not blocked by
      - Tetrodotoxin (Blocks ion pore of voltage gated Na⁺ channels
      - Nitrendipine (Blocks L-type calcium channels)
    - Associated with ion flow through 2nd pore in Na⁺ channels: Gating pore
    - Paramyotonia mutations: Do not produce gating pore current
Hypokalemic periodic paralysis: HOKPP3
● KCNE3 ; Chromosome 11q13.4; ? Dominant
- Genetics
  - Mutation
    - Missense Arg83His
    - Same mutation found in controls & unaffected family members ⁹
  - Allelic disorder: Hyperkalemic periodic paralysis
- 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
- KCNE3 variant: Hyperkalemic periodic paralysis
  - Clinical
    - Onset
      - Age: 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
● SLC4A1 Chromosome 17q21.31; Recessive or Dominant
● Chromosome 7q33-q34 & Other loci
- Epidemiology: Endemic in Northeast Thailand
- SLCA4A1
  - Mutation: Recessive Gly701Asp
  - Allelic with: Spherocytosis 4 ; Hemolytic anemia
- SLC4A1 protein
  - Major glycoprotein of the erythrocyte membrane
  - Mediates exchange of chloride & bicarbonate across phospholipid bilayer
- Periodic paralysis: Hypokalemic ²
  - Clinical
    - Episodes
      - Frequency: Numerous
      - Duration: Hours
      - Precipitating factors: ?
    - Weakness
    - Tendon reflexes: Reduced or Absent
    - Treatment: K⁺; Bicarbonate; Not acetazolamide (Exacerbates acidosis)
  - Laboratory
    - Hyperchloremic acidosis
    - Urine: 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
    - Intoxication (Glycyrrhizinic acid)
      - Sources: Licorice; Sambuca
      - Mechanism: Inhibition of 11-β-hydroxysteroid dehydrogenase
    - 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 paralysis 2 (TTPP2) ⁶
● KCNJ 18 (Kir 2.6) ; Chromosome 17p11.2; Dominant or Sporadic
- Epidemiology
  - Frequency in hyperthyroid patients
    - Most common in
      - Asians: ~ 2% Incidence; Up to 10% of hyperthyroid patients
      - Latin Americans
    - Also relatively common in Native Americans
    - North America: 0.1% Incidence
    - Most cases sporadic
  - Frequency in TPP patients
    - United States, Brazil, France & Singapore: 25% to 33%
    - Hong Kong & Thailand: 0% to 2%
  - Male predominance (83% to 95%)
- Genetics
  - KCNJ18 mutations
    - Most common: Loss of function; Arg399X, Gln407X
    - Other: T354M; Lys366Arg; Arg205His; I144fs (c.428 delC)
    - Present in 33% of TPP patients
  - Other possible loci
    - Sporadic case had mutation of KCNE3 (HOPP3)
    - CACN1AS polymorphisms possibly associated with susceptibility
      - Intron & 5' nucleotide substitutions
    - SCN4A: No mutations in most patients
    - 17q24.3 locus: Near KCNJ2
- KCNJ 18 channel
  - Inwardly rectifying potassium channel activity: Strong
  - Strong homology with KCNJ12
  - Located in skeletal muscle
  - Transcriptionally regulated by thyroid hormone
  - May contribute to cell membrane excitability
- Clinical
  - Onset
    - Age: Adult, young; 14 to 51 years
    - Proximal weakness
    - Prodromal symptom: Muscle discomfort & Cramps
  - Attacks
    - Similar to patterns in non-thyrotoxic patients
    - Often occur in random pattern without obvious stimulus
    - Precipitated by
      - Carbohydrate challenge ± insulin
      - High carbohydrate load & Heavy meals
      - Muscle cooling
      - Rest after exercise
      - Thyroxine ingestion
    - Single or multiple episodes: Especially at night
    - Course
      - Attack: May be aborted by exercise
      - Attacks: Abate when thyrotoxicosis resolves
      - ? Seasonal
        
        More common in May-October (Summer)
        
        Less common in December-March
    - Duration of episodes: Hours to Days; Usual 2 to 6 hours
    - Weakness: Distribution
      - Legs > Arms; Proximal > Distal
      - May selectively involve recently exercised muscles
      - Severe attacks may involve: Respiration; Bulbar function
      - Occasionally asymmetric
      - Sphincters not involved
    - Tendon reflexes: Reduced or Absent
  - Systemic
    - Thyrotoxicosis
      - Usually symptomatic
      - May be subclinical
      - Family history: Common
    - Cardiac arrhythmias: Sinus tachycardia commmon; Occasional ventricular tachycardia
    - 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
    - May be severely reduced
    - Occasionally: Normal, especially if drawn after attack
    - Lower than in non-thyrotoxic familial hypokalemic periodic paralysis
  - TSH: Low
  - Hypophosphatemia: Occasional
  - Renal: Retention of Na⁺ & K⁺; Oliguria
  - Electrodiagnostic
    - CMAP reduced during attacks
    - Epinephrine has no effect on size of CMAP
    - EMG: Myopathic during attacks
  - Muscle pathology
    - Vacuolar dilation of sarcoplasmic reticulum during attacks
    - Tubular aggregates
    - Muscle Na⁺-K⁺ pumps: Increased
- Treatment
  - Correct thyrotoxicosis
  - β-adrenergic blocking agents
  - Potassium: Oral
  - NOT
    - Acetazolamide
    - Glucose may exacerbate hypokalemia
Hypokalemic periodic paralysis: Thyrotoxic periodic paralysis 3 (TTPP3) ¹²
● Chromosome 17q24.3; Sporadic
- Epidemiology: Chinese ancestry (China, Japan & Thailand)
- Genetics: Loci
  - Alleles
    - T at rs312691
    - A at rs623011
    - rs312692
    - rs312736
    - rs992072
    - rs393743
  - Risk: 2.4 to 3.3-fold increased
  - Downstream of KCNJ2 (Andersen disease) & KCNJ16 genes
- Clinical
  - Onset age: Mean 27 years
  - Sex: Male predominant (> 95%)
- Other associations
  - Thyroid disease: Graves
  - Sporadic periodic paralysis without thyroid disease

Periodic paralysis, K⁺ sensitive, with Cardiac arrhythmias (Andersen Syndrome) ¹⁸

● KCNJ2 (Kir2.1)

; Chromosome 17q24.3; Dominant

Nosology: Andersen cardiodysrhythmic periodic paralysis
Genetics ³
- Mutations
  - Most are missense
  - Some are inframe deletions
- Allelic disorders
KCNJ2 protein
- 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
Clinical
- General
  - Triad features
  - Intrafamilial variability
    - Partial manifestations: Common
    - Arg67Try mutation: Ventricular arrhythmia in females (81%); Periodic paralysis in males (40%)
- Cardiac: Ventricular arrhythmia may segregate in females
  - Symptoms: Syncope; Suden death
  - Arrhythmia
    - Bigeminy
    - Bidirectional ventricular tachycardia
    - Increased Q-T interval (Early)
    - Premature ventricular contractions
    - Polymorphic ventricular tachycardia
    - Heart block
      - Long QT syndrome 7
  - Other EKG
    - U waves: Prominent
  - Semilunar valve abnormalities
  - Treatment
    - Amiodarone
    - Poor response to classical therapy
  - Cardiac malformation: Occasional
- Episodic weakness: May segregate in males
  - Onset age: 2 to 18 years
  - Duration of episodes: 1 hour to days
  - Proximal > Distal
  - Precipitants: K⁺; Exercise; None
  - No myotonia
- Permanent weakness: Occasional
  - Proximal ≥ Distal
  - Course
    - Daily fluctuations
    - Progressive over years
- 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
- Treatment ⁵
  - K⁺ Rx
    - Oral K⁺ may improve weakness in patients with low K⁺
    - In some families increasing K⁺: Improves arrhythmia; Exacerbates weakness
  - Acetazolamide: 250 to 500 mg 2x/day
Laboratory
- Serum K⁺ during attack: May be high, low, or normal
- Serum CK: Mildly high
- EMG: Myopathic
- CMAP amplitude: Small; Increased with exercise
- Muscle pathology: Tubular aggregates

Periodic paralysis, Hypokalemic ¹⁵

● KCNJ5 (Kir3.4)

; Chromosome 11q24.3; Dominant

Epidemiology: 1 patient
Genetics
- Mutation: G387R
- Same mutation in: Long QT syndrome 13
KCNJ5 protein
- Mutation effect: Inhibition of inwardly rectifying potassium current
Clinical
- Onset age: 31 years
- Weakness: Episodic
  - Frequency: Several times per year
  - Duration: 1 to 10 days
  - Progressive over days
  - Legs > Arms
Family history: Cardiac arrhythmias
Laboratory
- CMAP amplitues: Decrement with prolonged exercise
- ECG during paralytic attack: Prominent U waves; Possible sinus arrest
- Serum K⁺ during attack: Low (2.0 mEq/L)
- Plasma aldosterone: Normal

X-linked Episodic Prolonged Muscle Weakness (EMWX) ¹

● Chromosome Xp22.3; Recessive

Clinical
- Onset age: 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
- Pain: Myalgia & Cramps
- Episodic dystonia: Occasional; ± Tremor
Laboratory
- Peripheral neuropathy (1 older patient): Axonal
- Muscle biopsy ultrastructure (1 patient)
  - Sarcoplasmic reticulum: Dilation & proliferation
- Basal ganglia calcification

Episodic Muscle Weakness, Mitochondrial & Motor neuropathy ¹⁴

● ATP synthase 6 (mtATP6)

● ATP synthase 8 (mtATP8)

Epidemiology: 6 families
Genetics
- Mutations
  - Homoplasmic
  - mtATP6: T9176C; T9185C; T8993C
  - MtATP8: T8403C
- Inheritance: Maternal or Sporadic
- Also see: Hereditary motor neuropathy, Distal
- Allelic disorders: mtATP6; mtATP8
mtATPase 6 & mtATPase 8: Complex V
Clinical
- Onset age: Childhood to 60 years
- Episodic weakness
  - Symmetric
  - Location: Often selectively in distal legs or hands
  - Frequency: Daily to Monthly
  - Duration: 1 to 24 hours
  - Precipitating factors: Rest after exercise; Prolonged sitting; Exercise (Some patients); Cold
  - Treatment: Acetazolamide
- Weakness: Distal legs
- Muscle size: Distal wasting
- Gait disorder (100%)
- Skeletal: Pes cavus (100%)
- Tendon reflexes: Reduced or Increased
- Ataxia: Sensory; 1 family
- Spasticity (50%): Legs
- Diplopia: Downgaze; 1 family
- Cognitive: Usually normal
Laboratory
- Serum lactate: Normal
- Complex V activity: Normal or Reduced in fibroblasts
- NCV: Motor neuropathy; CMAP amplitude reduced
- EMG: Denervation, Legs > Arms
- Brain MRI: Normal
- Muscle biopsy: Normal
- Serum K⁺ during attack: Normal

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	Weakness & Motor PN
	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	Weakness & Motor PN
Channel or gene defect	Ca⁺⁺: CACNA1S α₁-subunit Other	KCNJ 18 (Kir 2.6)	Na⁺: SCN4A α-subunit KCNE3	Na⁺: SCN4A α-subunit	Na⁺: SCN4A α-subunit	Cl^-: CLCN1	Cl^-: CLCN1	K⁺: KCNJ2	?	mtAPT6 mtATP8
Inheritance/ Locus	Dominant 1q32.1	Dominant 17p11.2	Dominant 17q23.3	Dominant 17q23.3	Dominant 17q23.3	Dominant 7q34	Recessive 7q34	Dominant 17q23.3	Recessive Xp22	Maternal or Sporadic
Functional defect	?	?	↓ Fast & slow Inactivation	Mild ↓ Fast Inactivation	↓ Fast Inactivation	↓ Cl^- Conduct	↓ Cl^- Conduct	↓ K⁺ Conduct	?	?
Penetrance	↓ Females	↓ 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	Childhood 60 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	1 to 24 hours Permanent: Distal legs
Maximum weakness	Severe	Mild to Severe	Mild to Severe	None	Mild	None	Mild	Moderate	Mild to Severe	Moderate Distal
Cold	± ↑ Paralysis	± ↑ Paralysis	± ↑ Paralysis	↑ Paralysis	↑ Paralysis	No effect	No effect		No effect	Occasional
K⁺-effects	↓ Paralysis	↓ Paralysis	↑ Paralysis	↑ Paralysis	↓ Paralysis	No effect	No effect	↑ Paralysis	No effect	No effect
Attack precipitants	Carbohydrates Rest after Activity	Carbohydrates Rest after Activity	Fasting	↑ K⁺	Cold; ↓ K⁺	None	None	K⁺	Viral illness	Rest
Myotonia	Rare Eyelids only	None	± Present Exercise: ↓	Mild to Severe Exercise: ↑	Moderate Exercise: ↑	Moderate Constant	Severe Constant	None	None	None
Muscles large	No	No	Yes	Yes	Yes	Yes	Yes	No	No	No
Sensory symptoms	Absent	Absent	Present	?	Absent	Absent	Absent	Absent	Absent	Absent
Drug treatment	K⁺ Acetazolamide Dichlor- phenamide	↓ Thyrotoxicosis β-adrenergic blockade	Thiazide Acetazolamide Dichlor- phenamide	Mexiletine Thiazide	Mexiletine	Numerous	Numerous	?	?	Acetazolamide

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

Non-Dystrophic Myotonias: General features

Chloride (Cl^-) channel disorders
- Severe: More
- Myotonia: Diffuse
- Prominent: Limb pain, Weakness & Stiffness
Sodium (Na⁺) channel disorders
- Triggers: Common; Exercise, Temperature changes (Cold exposure)
- Face & Periocular muscles: More commonly involved
- Muscle bulk: Normal
- Tendon reflexes: Normal

Licorice intoxication

General
- Origin: Sweet root of various species of Glycyrrhiza
- Toxic agent: Glycyrrhizic acid
  - Most 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
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

Return to Neuromuscular home page
Return to Ion Channel Syndromes
Return to Myotonic Syndromes
Return to Myopathy & NMJ Index

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, Nat Rev Endocrinol 2011 May 10
7. Clinical Neurology and Neurosurgery 2003;105:286-287
8. Mayo Clin Proc 2003;78:767-768
9. Neurology 2004;62:1012-1015
10. J Med Genet 2008;45:686�688
11. Neurology 2011;76:1635�1641
12. Nature Genet 2012; Online Aug, Clin Chim Acta 2012 Aug 15
13. Perspect Biol Med 2011;54:479-503
14. Neurology 2013; Online October
15. Neurology 2014; Online Feb
16. Acta Neuropathol 2016 Dec 23
17. Lancet 2018;391:1483-1492
18. Front Neurol 2024;15:1423320

10/9/2024

EPISODIC MUSCLE WEAKNESS

Hypokalemic Periodic Paralysis

Periodic paralysis, K+ sensitive, with Cardiac arrhythmias (Andersen Syndrome) 18

Periodic paralysis, Hypokalemic 15

X-linked Episodic Prolonged Muscle Weakness (EMWX) 1