A Rare Genetic Disorder That Causes Episodes of Flaccid Paralysis

September 17, 2018

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:

40% to 60% of cases
Also called HypoPP type 1
May ↑ risk for malignant hyperthermia (extremely rare, precautions needed during anesthesia)

SCN4A sodium channel gene:

7% to 14% of cases
Also called HypoPP type 2
About 50% with SCN4A mutation respond to acetazolamide, which may worsen symptoms
Nonresponders may respond to dichlorphenamide

HypoPP1 and hypoPP2 are clinically similar

Prevalence: 1 in 100,000
Mutations almost exclusively affect skeletal muscle

Caused by mutations in sodium channel gene SCN4A
Associated with gain of function, usually impairs channel inactivation or occasionally enhances activation

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

60% of cases
40% have no identifiable genetic mutation
Encodes inward rectifier potassium channel which stabilizes the resting potential of skeletal muscle and cardiac cells

KCJN2 mutation linked to

Hyperkalemic episodes: 15% of patients
Normokalemic episodes: 20% of patients
Hypokalemic episodes: remainder
58% to 78% with KCJN2 have characteristic triad of flaccid muscle paralysis, cardiac abnormalities, and distinctive facial/skeletal features
Ventricular arrythmias common with KCJN2

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.