Rhabdomyolysis and Metabolic Myopathy

Gene: CACNA1S

Comment on list classification: Second most common cause of malignant hyperthermia susceptibility after RYR1, but it is still a rare cause.

Created: 14 Apr 2023, 8:45 a.m. | Last Modified: 14 Apr 2023, 8:45 a.m.

Panel Version: 0.119

Green List (high evidence)

Primary phenotype hypokalemic episodic paralysis. Additional progressive myopathy phenotype seen in some individuals with hypoPP. Some reports of CACNA1S variants in congenital myopathy

PMID 35509735: 1 case: history consistent with episodic paralysis, developed progressive myopathy in 3rd decade (vacuolar histology), 200 gene myopathy panel (NGS + MLPA) identified CACNA1S pathogenic variant (p.Arg1239His). Segregated variant to affected father (pedigree states vacuolar myopathy)

PMID 28012042: 3 cases (infants) of congenital myopathy with single CACNA1S pathogenic variants (de novo) identified on exome sequencing, assumed dominant disease. Same paper also 4 cases of congenital myopathy with biallelic CACNA1S pathogenic variants. Western blot assays for CACNA1S protein in dominant cases below level of detection, suggesting loss of function mechanism. ?these 7 cases too young to display hypoPP phenotype

PMID 34763287: 1 case: 60yo with myopathy, CACNA1S missense variant on panel testing

Created: 8 Dec 2022, 6:30 a.m. | Last Modified: 8 Dec 2022, 6:30 a.m.

Panel Version: 0.133

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hypokalemic periodic paralysis (MIM#170400)

Publications

• 35509735, 34763287, 28012042

Mode of pathogenicity
Other

Green List (high evidence)

11 patients from 7 families reported with perinatal hypotonia and weakness. AR / AD inheritance observed, PMID 28012042

Created: 15 Jun 2020, 8:51 a.m. | Last Modified: 15 Jun 2020, 8:51 a.m.

Panel Version: 0.185

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Myopathy, congenital, due to dihydropyridine receptor defect, MIM# 620246

Publications

• 28012042

Green List (high evidence)

PMID: 32104981 - 1 Japanese family with consistent childhood onset hypokalemic periodic paralysis. The proband manifested symptoms at 6 years old and her children at 4- and 2 years of age. Motor and language development normal.

PMID: 19118277 - Arg mutations within the S4 segments are enriched in this gene, including recurring mutations p.Arg528Gly, p.Arg528His, p.Arg1239Gly and p.Arg1239His. One patient with a novel missense was specifically noted as having onset "in the second decade".

PMID: 31380823 - 1 patient with onset at 14 years old following vigorous exercise

PMID: 30325262 - 5 patients with adult onset myopathy (60-80 years old). Some have reported skeletal muscle defects.

PMID: 30319441 - describes both LOF and GOF mechanisms for this gene

Summary: a wide age of onset but multiple paediatric reports.
Sources: Expert list

Created: 15 Jun 2020, 3:47 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Hypokalemic periodic paralysis, type 1 170400

Publications

• PMID: 32104981
• 19118277
• 31380823
• 30325262
• 30319441

Mode of pathogenicity
Other