Gene analysis included all genes related to HypoPP and/or pelvic girdle myopathy identified by the Geneyx analysis software.
Hypokalemic periodic paralysis (HypoPP) is a rare genetic muscle disease marked by episodic weakness linked to reduced serum potassium, often provoked by physical effort, stress, or high-carbohydrate consumption. Typically having an autosomal dominant inheritance, HypoPP is frequently caused by genetic changes in the CACNA1S or SCN4A genes, with higher penetrance in males. Symptoms usually emerge prior to age 20 and can progress to proximal myopathy after age 50. Treatment involves potassium supplementation and preventive measures like avoiding known triggers or using medications such as acetazolamide, though efficacy varies by genotype.
Fourteen patients from five Mallorcan families, initially believed to be unrelated, were clinically evaluated for sporadic paralysis or proximal lower limb debility. Genetic analysis was performed using exome sequencing (ES) with Illumina platforms. Variant annotation and quality filtering were performed using DRAGEN, and variants were interpreted using databases including ClinVar, HGMD, and Geneyx Analysis software, which guided prioritization of genes related to HypoPP and pelvic girdle myopathy. After the CACNA1S p.Arg897Lys variant was found, targeted Sanger analysis was performed for family members. To estimate a common ancestor, a homozygosity haplotype method was applied to exome data from families 3-5.
Affected individuals exhibited a spectrum of HypoPP and progressive pelvic girdle myopathy, with onset of periodic paralysis in adolescence in some and myopathy manifesting after age 50 in others. Clinical severity varied from mild, infrequent attacks responding to potassium to severe, recurrent episodes requiring hospitalization, often without creatine kinase elevation except in a few cases (max 2,276 IU/L). Electromyography revealed denervation potentials, myotonic‐like discharges, and reduced interference patterns correlating with disease severity. All affected individuals harbored the CACNA1S c.2690G>A (p.Arg897Lys) variant, classified as pathogenic. Three families also shared a ~10 Mb haplotype around CACNA1S, indicating a founder common ancestor approximately 4.5 generations ago. Muscle magnetic resonance imaging (MRI) demonstrated characteristic fatty degeneration in proximal and posterior compartments with relative sparing of gracilis and sartorius muscles.
In summary, this study characterized the biggest documented cohort of patients with the CACNA1S p.Arg897Lys variant, confirming its pathogenicity in HypoPP with permanent myopathy. Three families shared a ~10 Mb haplotype around CACNA1S gene, suggesting a common ancestor within 2-8 generations. Unlike prior reports, most patients were female (64%), and 71% showed isolated pelvic girdle myopathy, often with onset in the mid-50s. Preventive therapies showed limited benefit. The marked clinical variability highlights diagnostic challenges, with delays exceeding 40 years in some cases.
