| DIAGNOSTIC MATRIX FOR HYPOKALEMIC PERIODIC PARALYSIS |
| Disease |
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Hypokalemic Periodic Paralysis |
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Hypokalemic
Periodic Paralysis |
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Hypokalemic Periodic Paralysis |
| Channelopathy |
Type I (Calcium Channel) |
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Type II (Sodium Channel) |
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Type III (Potassium Channel) |
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| Gene locus &
Protein |
Calcium Channel (CACNA1S) |
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Sodium Channel (SCN4A) |
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Potassium Channel (KCNE3) |
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Alpha-1 subunit (Dihydropyridine Receptor) 1q31-32 |
Alpha subunit Chromosome 17q13; Dominant |
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Chromosome 11q13-q14 ? Dominant |
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Argenine (Arg) substitutions in voltage sensor (S4) |
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Voltage sensor of domain 2 SCN4A |
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Missense Arg83His |
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Domain II: Arg528His and Arg1086Cys |
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Type: Point missense; Arg669His, Arg672Gly,
Arg672Ser |
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Domaine IV: Arg1239His (common); Arg1239Gly |
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Shares SCN4A with |
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Same Gene as Malignant hyperthermia |
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Paramyotonia congenits |
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Hyperkalemic Periodic Paralyis |
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Acetazolamide-responsive Myotonia Congenita |
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Myotonia Permanens |
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Myotonia Fluctuans |
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| Pathophysiology |
Slow-voltage-activated Ca channel |
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Voltage-sensitive
element: Excitation-contraction (EC) coupling |
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with ryanodine receptor. |
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Couple to ryanodine receptor via II-III Loop
interlinker |
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| Location |
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Triadic junctions of t-tublar system |
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| Human mutation: |
Enhances inactivation of CA channel |
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Defect in control of muscle resting membrane
potential |
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Muscle membrane is
depolarized during attacks. |
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causes reduced nerv-evoked muscle activity |
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| Clinical Features |
Episodic Weakness |
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Many similar to CACNL1A3 |
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Low serum potassium |
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K+ during episodes: 1.4 |
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| Onset |
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Early childhood to 3rd decade, some later |
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Evidence limited to single family |
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60% before 16
years of age |
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Onset 9 years in Male and Female |
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14 to 20 years |
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Attacks commonly begin in early morning hours |
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At awakening or during wakefullnes |
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| Duration of Attacks |
Hours to days |
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Hours to days |
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| Triggers |
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Physical Activity (often on preceding day) |
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Exercise followed by rest |
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Strenuous exercise followed by rest |
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Carbohydrate-rich meal |
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Prolonged sitting |
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Cold |
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Emotional Stress |
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| Myotonia |
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Focal in eyelids (rare in limbs) |
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Myalgias: Most common after episodes |
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| Permanent Weakness |
Most frequently after 4th decade, some earlier |
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Approximately 45% |
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Progresses slowly through the years |
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| Penetrance |
Reported as 100% Male 50% Female |
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100% in Males and Females |
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Some families report variability on penetrance |
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Penetrance and Clinical Features variable with
specific mutation |
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| Laboratory Results |
Serum CK increase during attacks |
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Electrophysiology |
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Exercised muscle fibers depolarized & weak in
low-K+ solution |
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Action potentials: slow and small |
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Reduced number of excitable sodium channels |
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Especially at sustained membrane depolarization |
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| Electrodiagnostics |
CMAP reduced during attacks |
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| CMAP amplitude |
Increased immediately after sustained (5 min)
maximal contraction |
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Progressively reduced (by 40%) during test 20- 40
minutes after |
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initial increment (80% of patients) |
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Epinephrine reduces sixe of CMAP |
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| Provocative testing |
Glucose with or without insuline (see review) |
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| Muscle Pathology |
Vacuoles: Clear, Central |
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Vacuoles |
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Tubular aggregates |
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Tubular aggregates in type 2 muscle fibers |
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and tubular aggregates |
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Myopathy: Varied muscle fiber size; split fibers;
Internal Nuclei |
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Angular muscle fibers |
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Vacuolar dilation of sarcoplasmic reticulum during
attacks |
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| Therapy |
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Carbonic anhydrase inhibitors |
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Acetazolamide often deliterious |
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potasium supplementation |
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dietary management |
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| References: |
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| Abbott, et al,
Cell, Vol. 104, 217–231, 2001 |
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| Adams, Victor, and
Roper, 1997, Principles of Neurology, 6th Edition, McGraw Hill |
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| Ashcroft, 2000,
Ione Channels and Disease, Academic Press |
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| Bulman, et al,
Neurology 1999 Dec 53:1932-6 |
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| Cannon, SC,
Clinical Neuroscience Research 1 (2001) 104-117 |
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| Jurkat-Rott
, Proc Natl Acad Sci U S A 2000 Aug 97:9549-54 |
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| Rudel, Hanna, and
Lehmann-Horn, 1999, Muscle Diseases, Butterworth Heinemann |
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| Sternberg, et al, Brain
2001 Jun 124:1091-9 |
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