Hypokalemic periodic paralysis associated with the atypical CACNA1S c.2690G>A (p.Arg897Lys) variant: , 2025, Barrachina-Esteve et al

[Hutan]

Hypokalemic periodic paralysis associated with the atypical CACNA1S c.2690G>A (p.Arg897Lys) variant: description of 14 affected individuals from five families

Spoiler: Authors

Barrachina-Esteve, Oriol; Ventayol-Guirado, Marc; Asensio, Victor J; Heine-Suñer, Damià; Corrales, Ricardo; Vidal, Noemí; Ivanovski, Trajche; Arbós, Clara; Agirre, Maite; Montalà, Carles; Ballabriga, Jordi; Valero, Ana; Rosselló, M Magdalena; Dávila, Pablo; Mestre, Margalida; Sánchez, Ana; Deyá, Elena; Legarda, Inés; Espino, Ana; Olivé, Montse; Miralles, Francesc

Abstract
This study describes five families (14 individuals) with hypokalemic periodic paralysis carrying a heterozygous pathogenic variant NM_000069.3:c.2690G>A (p.Arg897Lys) in the Calcium Voltage-Gated Channel Subunit Alpha1 S (CACNA1S) gene.

The clinical exam showed pelvic weakness was common (10/14, with three being too young to exclude this age-dependent myopathy). Electromyography showed myogenic changes, and the long exercise test did not reveal a significant reduction of compound muscle action potential amplitude. Muscle MRI in three patients demonstrated involvement of axial musculature, the pelvic girdle, thighs (with relative sparing of sartorius and gracilis), and legs (especially the gastrocnemius muscles).

A homozygosity haplotype analysis in three families revealed a shared segment of approximately 10 million base pairs, suggesting a common ancestor 2-8 generations ago.

Web | DOI | Neuromuscular Disorders

 

[Hutan]

Periodic paralysis is a rare muscular disorder caused by dysfunction of an ion channel in muscle fibers, leading to episodes of painless muscle weaknesstriggered by physical exertion, stress, or carbohydrate intake [1].

Hypokalemic periodic paralysis (HypoPP) is characterized by weaknessepisodes associated with low serum potassium levels (<3 mmol/L). The condition affects approximately 1 in 100,000 individuals and is commonly caused by mutations in the Calcium Voltage-Gated Channel Subunit Alpha1 S (CACNA1S) gene or in the Sodium Voltage-Gated Channel Alpha Subunit 4 (SCN4A) gene. HypoPP is inherited in an autosomal dominant manner, with higher penetrance and attack frequency in males, leading to a male-to-female ratio of 3-4:1 [1,2].

Three individuals developed proximal myopathy at ages 46, 55, and 59 (two with pelvic girdle myopathy, one unspecified). Magnetic Resonance Imaging (MRI) from one of the patients revealed fatty infiltration in the paraspinal muscles, gluteus, soleus, and medial gastrocnemius muscles, while the quadriceps, gracilis, sartorius, semimembranosus, and semitendinosus muscles were grossly spared. A muscle biopsy showed vacuolar changes and T-tubular aggregates.

 

[Hutan]

A recent paper about periodic paralysis.

Posting due to the mention of the CACNA1S gene, in the same family as CACNA1e a gene mentioned in the DecodeME study. I was also intrigued by the mention of the pelvic girdle myopathy, it reminded me of the currently unreplicated body scans o people with ME/CFS by a Stanford researcher that seemed to suggest muscle inflammation in that area.

Also due to the mention of SCN4A. A member reported this:

Analyzing my WGS with Franklin Genoox (many geneticians at hospitals use it), and then having LLMs analyze it (here are the pro versions better) lead me to two important discoveries. There will probably be a mice study just on my genetic variant done at one of the top research labs in both genetics and mitochondrial disease.

I also suffer from stiff muscles, muscle cramps and extreme muscle pain. It worsens just by walking/standing up. I found a channelopathy variant which there is a published study that says it is pathogenic. The gene is in SCN4A. My university hospital welcomed the study (although there werent used to patients analyzing their own DNA). The plan is for me to try a drug against natrium channelopathy (non dystrophic myotonia).