A 39-yr-old female with potassium-aggravated myotonia due to p.Q1633E in SCN4A experienced painful muscle stiffness triggered by exercise, potassium-rich fruits, and cold exposure, which progressed into a rigid state. Needle electromyography (EMG) during muscle stiffness showed synchronous, rhythmic, and regular activities starting at ∼60 Hz and ∼6 mV. A 37-yr-old male with myotonia permanens due to a splicing-affecting indel variant in intron 21 of SCN4A experienced cold-induced myotonia. EMG recordings during muscle stiffness showed similar synchronous, rhythmic, and regular activities starting at ∼80 Hz and 6.5 mV. In both patients, the frequencies and amplitudes were gradually decreased with relief of muscle stiffness. In either patient, single motor unit potentials by spontaneous activity were not explicitly recognized. In both patients, the activities produced a characteristic sound which, while similar in pitch to the "dive bomber" sound of classical myotonia, lacked its typical waxing and waning quality. The activities were similar to the Piper rhythm that was originally reported in fatigued normal muscle. Visual inspection of EMG activities in the literature revealed that similar Piper rhythm-like EMG activities were presented in Satoyoshi disease, myotonia permanens, paramyotonia congenita, and a rare form of nondystrophic myotonia. In Satoyoshi disease and fatigued normal skeletal muscle, the activities during muscle stiffness were less than 60 Hz, whereas in sodium channelopathies, they started at 60 Hz or higher, which may be a hallmark of hyperexcitability of the muscle membrane in sodium channelopathies.NEW & NOTEWORTHY In two patients with sodium channel myotonia representing potassium-aggravated myotonia and myotonia permanens, needle EMG showed Piper rhythm-like activities during muscle stiffness. Inspection of EMG recordings in the literature revealed similar Piper rhythm-like EMG activities in Satoyoshi disease, myotonia permanens, paramyotonia congenita, and a rare form of nondystrophic myotonia. Piper rhythm-like EMG activities starting at 60 Hz or higher, synchronizing with muscle stiffness, may be a hallmark of hyperexcitability of muscle membrane in sodium channelopathies.

Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous neurodegenerative disorder, primarily defined by progressive lower-limb spasticity and weakness. Among the numerous genes implicated, pathogenic variants in the spastic paraplegia 7 (SPG7) gene represent one of the most common causes of HSP, whereas mutations in SCN4A, a skeletal muscle ion channel gene, are typically associated with a diverse spectrum of phenotypes, including hyperkalemic and hypokalemic periodic paralysis, potassium-aggravated myotonia, and congenital paramyotonia. To date, however, the coexistence of pathogenic variants in SPG7 and SCN4A within the same pedigree, and their potential pathogenic interplay, has not been documented. In this study, we performed comprehensive genetic profiling, including whole-exome sequencing, mitochondrial genome analysis, dynamic mutation screening, copy number variation assessment, and Sanger sequencing. We identified a novel heterozygous SPG7 variant (c.578A>G; p.E193G) alongside a known pathogenic SCN4A missense mutation (c.2111C>T; p.T704M). Remarkably, individuals harboring both variants presented with highly complex phenotypes that combined classical HSP manifestations with ion channel dysfunctions, such as congenital paramyotonia and hypokalemic periodic paralysis. These findings provide the first evidence of a possible genetic interaction between SPG7 and SCN4A, expanding the recognized clinical and molecular spectrum of HSP. Our results underscore the diagnostic value of multi-gene testing in patients with atypical or overlapping neuromuscular symptoms and highlight the importance of considering potential polygenic contributions when interpreting the clinical heterogeneity of HSP.

2例患儿为同胞姐弟，分别为7岁和2岁，均表现为发作性肢体活动障碍，感染、运动、食用香蕉后加重，幼时有发作性憋气、睁眼困难。基因检测发现2例患儿均为SCN4A基因22号外显子c.3917G>A（p.G1306E）发生错义变异，经基因深度测序发现患儿母亲该位点存在嵌合变异，变异率1.0236%，父亲为野生型，2例患儿确诊为钾加重性肌强直。给予低钾饮食、乙酰唑胺治疗，随诊8个月症状明显改善。.

We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.

The non-dystrophic myotonias are inherited skeletal muscle disorders characterized by skeletal muscle stiffness after voluntary contraction, without muscle atrophy. Based on their clinical features, non-dystrophic myotonias are classified into myotonia congenita, paramyotonia congenita, and sodium channel myotonia. Using whole-exome next-generation sequencing, we identified a L703P mutation (c.2108T>C, p.L703P) in SCN4A in a Chinese family diagnosed with non-dystrophic myotonias. The clinical findings of patients in this family included muscle stiffness and hypertrophy. The biophysical properties of wildtype and mutant channels were investigated using whole-cell patch clamp. L703P causes both gain-of-function and loss-of-function changes in Nav1.4 properties, including decreased current density, impaired recovery, enhanced activation and slow inactivation. Our study demonstrates that L703P is a pathogenic variant for myotonia, and provides additional electrophysiological information for understanding the pathogenic mechanism of SCN4A-associated channelopathies.