Hyung Jun Park

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic neuromuscular disorders caused by pathogenic variants in genes encoding proteins essential for neuromuscular junction development and function. Downstream of tyrosine kinase 7 (DOK7)-related CMS has been reported frequently in Europe, North America, and Japan, but not in Korea. A 7-year-old girl presented with gait disturbance, frequent falls, and difficulty climbing stairs, which had begun at 4 years of age. Examination revealed mild symmetric proximal weakness without ocular or bulbar involvement, and her serum creatine kinase level was normal. She was initially diagnosed with congenital myopathy. At 24 years of age, whole-exome sequencing identified compound heterozygous pathogenic variants in DOK7 (c.[539G>C];[1124_1127dup]), confirming DOK7 CMS. On clinical re-evaluation, she had stable proximal weakness, and repetitive nerve stimulation demonstrated a significant decremental response in the trapezius muscle. After 1 month of oral ephedrine therapy at 50 mg/day, her endurance and stair-climbing ability improved substantially. We report the first Korean case of DOK7 CMS with a favorable therapeutic response to ephedrine, emphasizing the need to consider CMS in the differential diagnosis of congenital myopathy.

Objectives: Recent studies have reported conflicting results regarding the mortality risk in patients with myasthenia gravis (MG); however, evidence from East Asian populations remains limited. Understanding the mortality patterns and risk factors of MG is essential for improving patient outcomes. We conducted a nationwide, retrospective cohort study using data from the Korean National Health Insurance Service database to investigate mortality and its associated factors in patients with MG. Methods: Incident MG cases diagnosed between 2005 and 2020 were identified based on validated operational definitions and matched 1:5 with age- and sex-matched controls. All-cause mortality was assessed using Kaplan–Meier analysis, and mortality-associated risk factors were identified by multivariate Cox regression after adjusting for variables. Results: This study included 21,642 patients with MG and 108,210 matched controls. The MG group showed a significantly higher mortality rate than that in controls (144.40 vs. 92.60 per 10,000 person-years; adjusted hazard ratio 1.41, 95% CI 1.34–1.49). Risk factors associated with increased mortality included older age, male sex, high comorbidity burden, high-dose corticosteroid use (≥15 mg/day), thymoma, and myasthenic crisis. Thymectomies were associated with reduced mortality. The leading causes of death included malignancy, cardiac disease, and MG. Myasthenic crisis and thymoma were respectively associated with early mortality and a gradual increase in late mortality. Conclusion: This study demonstrated increased mortality in Korean patients with MG, identifying key disease- and treatment-related risk factors. These findings underscore the need for early risk stratification, comorbidity management, and individualized treatment approaches to improve long-term outcomes.

Adenylosuccinate synthase 1 (ADSS1)‐deficient myopathy is an ultra‐rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a noninvasive biomarker approach to phenotype (fine‐)motor skills, communication and cognition in adults with ADSS1‐deficient myopathy. Five individuals with ADSS1‐deficient myopathy and five age‐sex‐matched healthy controls (HCs) underwent a multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech and voice production and cognitive test batteries, (iii) patient‐reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI), and (vi) plasma proteomics. ADSS1‐deficient myopathy participants vs. HCs demonstrated reduced performance on the 9‐Hole Peg and grip strength tests as well as lower self‐reported mobility. Analysis of speech and voice performance revealed asthenia (vocal weakness) ( p = 0.02), lower intelligibility ( p = 0.008), and worse voice quality during the sustained vowel task ( p = 0.03) in the ADSS1‐deficient myopathy cohort. Cognitive functioning remained unaffected in patients with ADSS1‐deficient myopathy. On EIM, ADSS1‐deficient myopathy participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper‐ and lower‐extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliff's δ = 0.5–0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced ( p = 0.04) Neurotrophin‐3 (NTF3; implicated in neuronal development, survival, and differentiation) levels in the ADSS1‐deficient myopathy cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand‐motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1‐deficient myopathy. This multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and noninvasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1‐deficient myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra‐rare condition.

Introduction Spinal muscular atrophy (SMA) is a genetic motor neuron disorder, marked by progressive skeletal and respiratory muscle weakness. The recent approval of nusinersen has transformed the therapeutic landscape for SMA patients, particularly children. However, as randomized controlled studies and long-term real-world evidence in adults remain limited, this study focuses on the efficacy of nusinersen in adults with SMA in South Korea. Method Clinical data were retrospectively collected from adult patients who began nusinersen in tertiary neurology centers across the country, with 19 patients eventually being enrolled. Results The results showed that Hammersmith Functional Motor Scale-Expanded scores improved significantly by 2.28 (p = 0.0002) in all patients after 12 months. Following the dropout of 4 patients who failed to meet insurance reimburse criteria, improvements of 4.55 (p = 0.0010) and 6.57 (p = 0.0156) points were noted in the remaining 15 patients after 24 and 36 months, respectively. At these time points, 40%, 82%, and 86% of patients, respectively, accomplished clinically meaningful improvements. Type 2 SMA patients exhibited a faster drug response compared to type 3a patients. Out of 176 injections, seven adverse events were reported, including post-puncture headache and injection site pain. Conclusions Our multicenter real-world study demonstrates the sustained efficacy and manageable safety profile of nusinersen in adult SMA patients, supporting the long-term use in this population.

Choi Y, et al. Yonsei Med J. 2026 Jan;67(1):34-41. https://doi.org/10.3349/ymj.2024.0500

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disorder caused by expanded CTG repeats in the 3′ untranslated region of the DMPK gene, which produce toxic CUG-expanded RNA. This mutant RNA forms nuclear foci that sequester MBNL proteins and disrupt alternative splicing across numerous genes, leading to clinical manifestations involving skeletal muscle, the heart, respiratory function, endocrine systems, and the central nervous system. Current management is supportive and focuses on physical therapy, mexiletine for myotonia, cardiac surveillance, ventilatory assistance, and behavioral or cognitive interventions. Advances in molecular pathogenesis have accelerated the development of diseasemodifying therapies aimed at the root cause. Four major therapeutic strategies are emerging: reduction of toxic DMPK transcripts via antisense oligonucleotides or siRNAs; restoration of MBNL function through steric-blocking oligonucleotides, peptide-conjugated modalities, or anti-miR approaches; modulation of dysregulated signaling pathways such as GSK3β; and gene-or genome-editing technologies, including AAV-mediated RNA interference and CRISPR/Cas9-based repeat excision. Several investigational agents-such as AOC 1001, DYNE-101, EDODM1, and ATX-01-have demonstrated promising molecular and early clinical improvements in phase 1/2 studies. These advances mark a significant transition from symptomatic care to precise molecular correction. As these therapeutic platforms continue to mature, DM1 may soon shift from a largely untreatable condition to a biologically modifiable disease with meaningful clinical impact.

Introduction/Aims: Adenylosuccinate synthase‐like 1 (ADSS1) myopathy is an ultra‐rare disorder caused by biallelic pathogenic variants in the ADSS1 gene. This results in progressive muscle weakness, fatigue, dysphagia, and, in severe cases, cardiomyopathy and respiratory failure. The aim of the study was to evaluate how ADSS1 myopathy impacts patients' lives and to comprehensively assess their quality of life. Methods: We conducted individual interviews in 31 participants with ADSS1 myopathy from six countries. Participants engaged in structured interviews, which included both open‐ended questions and the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Thematic analysis was employed to identify the primary concerns, symptoms, and quality‐of‐life challenges faced by patients. Results: From individual interviews, the decline in mobility and motor skills (54.8%) and muscle weakness (48.3%) primarily impacting the lower extremities emerged as the most frequently reported bothersome symptoms. The most reported concerns were decline in mobility, motor skills, and gait disturbance (58.0%). Only 5% of the patients reported no impact of ADSS1 myopathy on their work or social life. The INQoL questionnaire identified 20 patients (64.5%) with pain, with the most common location being the lower extremities, while fatigue was reported by all patients except one. The most identified treatment priorities were improving motor function (51.6%) and halting disease progression (48.3%). Discussion: This study highlights the significant physical and psychosocial burden of ADSS1 myopathy, with progressive muscle weakness and multisystem involvement affecting daily life. The findings underscore the need for early diagnosis and multidisciplinary care approaches.