© 2021 MJH Life Sciences™ and Neurology Live. All rights reserved.
About 30% of patients with periodic paralysis have unknown genetic mutation, making identification and treatment a challenge. Here: key points on genetics, testing, and subtypes of PPP.
Primary periodic paralysis (PPP):
Caused by mutations in calcium, potassium, and sodium channel genes[1]
Usually autosomal dominant inheritance[2]
Offspring have 50% risk of inheriting the genetic mutation
Penetrance: ≥90% in males, lower in females; penetrance varies, may be reduced
Unknown proportion of de novo mutations
Confirmatory in 70% of cases
About 30% have no indentifiable genetic mutation
Gene-targeted testing: Multigene panel
Requires determination of specific genes
Recommended for hypoPP with characteristic clinical findings
Comprehensive genome testing: Exome sequencing (most common), genome sequencing
Does not require determination of specific genes
Used when PPP diagnosis unclear or with atypical clinical findings
Prevalence: 1 in 200,000; most common cause of PPP
Mutations almost exclusively affect skeletal muscle
Mutations in sodium or calcium channel genes
Cause leakage current during the resting potential, increases susceptibility to depolarization of muscle fiber and inexcitability when K+ is low outside the cell
About 30% have unknown genetic mutation
CACNA1S calcium channel gene:
SCN4A sodium channel gene:
HypoPP1 and hypoPP2 are clinically similar
Prevalence: 1 in 100,000
Mutations almost exclusively affect skeletal muscle
SCN4A can cause hypoPP, hyperPP, normoPP, or essential tremor
Variants work through different mechanisms and result in different clinical disorders
HyoPP: 10 variants
NormoPP: 3 variants
Hyper PP: 11 variants
Paramyotonia congenita (PMC): 14 variants
Sodium channel myotonias/potassium aggravated myotonia: 5 variants
Tremor: 1 variant (one case reported)
Congenital myasthenic syndrome (CMD): variant unknown (one case reported)
Prevalence: 1 in 1,000,000
Caused by mutations in potassium channel gene KCNJ2
KCJN2 mutation linked to
References
1. Statland JM, Fontaine B, Hanna MG, et al. Review of the diagnosis and treatment of periodic paralysis. Muscle Nerve. 2018;57:522-530.
2. Weber F, Lehmann-Horn F. Hypokalemic Periodic Paralysis. 2002 Apr 30 [Updated 2018 Jul 26]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. https://www.ncbi.nlm.nih.gov/books/NBK1338. Accessed September 17, 2018.