Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review

Abstract

Objective : To verify the diagnosis of channelopathies in two families and explore the mechanism of the overlap between periodic paralysis (PP) and paramyotonia congenita (PMC). Methods : We have studied two cases with overlapping symptoms of episodic weakness and stiffness in our clinical center using a series of assessment including detailed medical history, careful physical examination, laboratory analyses, muscle biopsy, electrophysiological evaluation, and genetic analysis. Results : The first proband and part of his family with the overlap of PMC and hyperkalemic periodic paralysis (HyperPP) has been identified as c.2111C > T (T704M) substitution of the gene SCN4A . The second proband and part of his family with the overlap of PMC and hypokalemic periodic paralysis type 2 (HypoPP2) has been identified as c.4343G > A (R1448H) substitution of the gene SCN4A . In addition, one member of the second family with overlapping symptoms has been identified as a novel mutation c.2111C > T without the mutation c.4343G > A. Conclusions : SCN4A gene mutations can cause the overlap of PMC and PP (especially the HypoPP2). The clinical symptoms of episodic weakness and stiffness could happen at a different time or temperature. Based on diagnosis assessments such as medical history and muscle biopsy, further evaluations on long-time exercise test, genetic analysis, and patch clamp electrophysiology test need to be done in order to verify the specific subtype of channelopathies. Furthermore, the improvement of one member in the pregnancy period can be used as a reference for the other female in the child-bearing period with T704M.

Paramyotonia congenita with persistent distal and facial muscle weakness: A case report with literature review

“…Patients described as having "no persistent/fixed weakness" or "no weakness," or "no abnormal findings in neurological examination" were considered "no persistent weakness" cases. In the 55 papers analyzed (more than 76 pedigrees, 267 cases; [6,10,14], and 23 had no description regarding weakness distribution [7,9]. Among 51 patients carrying the SCN4A T1313M mutation described in the 13 studies (more than 14 pedigrees; Table 3), 5/51 had persistent weakness [6,10,13], 17/50 had no weakness, and 29/51 had no description about weakness.…”

“…While persistent muscle weakness in PC patients is rare [2], a small number of case reports have reported patients who presented with mild weakness (mainly proximal dominant) [3][4][5][6][7][8][9][10][11][12][13][14]. Here, we present the detailed phenotype of a Japanese family with a history of PC accompanied by severe distal weakness together with masticatory muscle involvement.…”

“…, 46 patients (17.2%) had persistent weakness[3][4][5][6][7][8][9][10][11][12][13][14], 126 (47.2%) had no persistent weakness, and 95 (37.0%) had no description about weakness. Among those with persistent weakness, 8/46 (17%) were aged under 30 years, 17/46 (37%) were aged 30 years and above, and age was unknown in 21/46 (46%).…”

“…Among those with persistent weakness, 8/46 (17%) were aged under 30 years, 17/46 (37%) were aged 30 years and above, and age was unknown in 21/46 (46%). Of the 46 patients with persistent weakness, 17 had proximal weakness[3][4][5][10][11][12]14], six had mild distal hand weakness…”

The clinical and genetic heterogeneity analysis of five families with primary periodic paralysis

“…T704M mutation in the S5 segment of domain II can result in impaired fast or slow inactivation of Na V 1.4 channel, and, therefore, persistent increased sodium current and sarcolemmal depolarization, which can result in the symptom of paralysis [32,33]. It has been reported that T704M mutation can cause NormoPP [7,10].…”