HypoKPP Diagnostic Matrix
DIAGNOSTIC MATRIX FOR HYPOKALEMIC PERIODIC PARALYSIS
Disease   Hypokalemic Periodic Paralysis   Hypokalemic Periodic Paralysis   Hypokalemic Periodic Paralysis
Channelopathy Type I (Calcium Channel)   Type II (Sodium Channel)   Type III (Potassium Channel)
                             
Gene locus & Protein Calcium Channel (CACNA1S)   Sodium Channel (SCN4A)   Potassium Channel (KCNE3)
  Alpha-1 subunit (Dihydropyridine Receptor) 1q31-32 Alpha subunit Chromosome 17q13; Dominant   Chromosome 11q13-q14 ? Dominant
  Argenine (Arg) substitutions in voltage sensor (S4)   Voltage sensor of domain 2 SCN4A   Missense Arg83His  
  Domain II: Arg528His and Arg1086Cys   Type: Point missense; Arg669His, Arg672Gly, Arg672Ser  
  Domaine IV: Arg1239His (common); Arg1239Gly   Shares SCN4A with    
  Same Gene as Malignant hyperthermia     Paramyotonia congenits    
        Hyperkalemic Periodic Paralyis    
      Acetazolamide-responsive Myotonia Congenita  
      Myotonia Permanens    
                Myotonia Fluctuans          
Pathophysiology Slow-voltage-activated Ca channel      
  Voltage-sensitive element: Excitation-contraction (EC) coupling    
  with ryanodine receptor.      
  Couple to ryanodine receptor via II-III Loop interlinker      
                             
Location   Triadic junctions of t-tublar system      
                             
Human mutation: Enhances inactivation of CA channel      
  Defect in control of muscle resting membrane potential    
  Muscle membrane is depolarized during attacks.      
  causes reduced nerv-evoked muscle activity      
                             
Clinical Features Episodic Weakness   Many similar to CACNL1A3    
  Low serum potassium   K+ during episodes: 1.4    
                             
Onset   Early childhood to 3rd decade, some later   Evidence limited to single family    
  60% before 16 years of age   Onset 9 years in Male and Female   14 to 20 years  
  Attacks commonly begin in early morning hours     At awakening or during wakefullnes
                             
Duration of Attacks Hours to days     Hours to days  
                             
Triggers   Physical Activity (often on preceding day)      
  Exercise followed by rest     Strenuous exercise followed by rest
  Carbohydrate-rich meal     Prolonged sitting  
  Cold      
    Emotional Stress                      
Myotonia   Focal in eyelids (rare in limbs)   Myalgias: Most common after episodes    
                             
Permanent Weakness Most frequently after 4th decade, some earlier   Approximately 45%    
  Progresses slowly through the years      
                             
Penetrance Reported as 100% Male 50% Female   100% in Males and Females    
  Some families report variability on penetrance      
  Penetrance and Clinical Features variable with specific mutation    
                             
Laboratory Results Serum CK increase during attacks      
         
  Electrophysiology     Exercised muscle fibers depolarized & weak in low-K+ solution  
    Action potentials: slow and small    
    Reduced number of excitable sodium channels    
              Especially at sustained membrane depolarization        
Electrodiagnostics CMAP reduced during attacks      
CMAP amplitude Increased immediately after sustained (5 min) maximal contraction    
  Progressively reduced (by 40%) during test 20- 40 minutes after    
  initial increment (80% of patients)      
  Epinephrine reduces sixe of CMAP      
                             
Provocative testing Glucose with or without insuline (see review)      
                             
Muscle Pathology Vacuoles: Clear, Central     Vacuoles  
  Tubular aggregates   Tubular aggregates in type 2 muscle fibers   and tubular aggregates  
  Myopathy: Varied muscle fiber size; split fibers; Internal Nuclei    
  Angular muscle fibers      
    Vacuolar dilation of sarcoplasmic reticulum during attacks                
Therapy   Carbonic anhydrase inhibitors   Acetazolamide often deliterious    
  potasium supplementation        
  dietary management        
References:    
Abbott, et al, Cell, Vol. 104, 217231, 2001      
Adams, Victor, and Roper, 1997, Principles of Neurology, 6th Edition, McGraw Hill
Ashcroft, 2000, Ione Channels and Disease, Academic Press  
Bulman, et al, Neurology 1999 Dec 53:1932-6  
Cannon, SC, Clinical Neuroscience Research 1 (2001) 104-117    
Jurkat-Rott , Proc Natl Acad Sci U S A 2000 Aug 97:9549-54    
Rudel, Hanna, and Lehmann-Horn, 1999, Muscle Diseases, Butterworth Heinemann    
Sternberg, et al, Brain 2001 Jun 124:1091-9