脊髄性筋萎縮症

BACKGROUND: Lumbar puncture is particularly challenging in patients with abnormal spinal anatomy, such as severe scoliosis or obesity. Conventional ultrasound‑assisted neuraxial techniques have two fundamental limitations: inaccurate projection of the probe's geometric center onto the skin when the probe is tilted and difficulty replicating the exact probe angle during needle insertion. These limitations often result in multiple needle passes, prolonged procedure time, and increased patient discomfort and complication risk. We developed an ultrasound‑assisted technique designed to standardize needle trajectory by eliminating the need for lateromedial and craniocaudal angulation through positional adjustment and report its technical feasibility in a case series. CASE PRESENTATION: This angle‑free technique was applied to two patients with spinal muscular atrophy requiring repeated intrathecal nusinersen injections. Both patients had extremely complex spinal anatomy, including high body mass index (30 and 35.1 kg/m²) and severe scoliosis (Cobb angles 90° and 83°). The technique followed a four‑step protocol: (1) planning using available imaging; (2) ultrasound‑guided positioning; (3) marking the needle insertion point; and (4) inserting the needle parallel to the floor and perpendicular to the bed edge without lateromedial or craniocaudal angulation. All 22 procedures (11 per patient) were completed successfully without persistent neurological complications. First‑attempt success rates were 81.8% in Case 1 and 100% in Case 2, with first‑pass success rates of 45.5% and 54.5%, respectively. Longitudinal data across sequential procedures showed a rapid decreasing trend in both the number of needle passes and needling time. CONCLUSIONS: This angle‑free ultrasound‑assisted lumbar puncture appears technically feasible for patients with complex spinal anatomy. The structured "4P" protocol (planning, positioning, perpendicular, and parallel) may offer a practical guide for clinical adoption. The observed reduction in needle passes and needling time may suggest potential learnability, but this finding is preliminary and requires confirmation. Further investigation is warranted to definitively establish its learning curve.

Spinal muscular atrophy (SMA) is a common fatal genetic disorder with high carrier rate. For prevention program and treatment plan of this disease, a comprehensive assay is practically needed to gain multi-genetic information, enabling effective molecular screening and accurate clinical classification. In this study, a novel single-tube MALDI-TOF MS assay was developed to simultaneously analyze the copy number of SMN1, SMN2, NAIP, H4F5, GTF2H2, and identify six common loss-of-function variants in SMN1, as well as identify Hybrid SMN. The results of this assay were 100% consistent with the predetermined values in 158 genotype-known samples. Furthermore, a cohort of 162 clinical simples were double-blindly detected to evaluate this assay, and the results showed a 100% overall concordance with comparative methods. Herein, this novel MALDI-TOF MS assay is practical, cost-effective, and multi-genetic information available, which suitable for large-scale molecular screening and routine clinical diagnosis of SMA.

BACKGROUND AND OBJECTIVES: Spinal and bulbar muscular atrophy (SBMA) is a rare neuromuscular disorder without effective treatments available. There is an unmet need to identify biomarkers reflecting underlying disease processes and sufficiently responsive to detect slow changes to enable future clinical trials. Muscle MRI is a responsive measure of muscle volume and fat content, a pathologic hallmark of SBMA that precedes functional changes. We therefore assessed muscle MRI as a potential imaging biomarker for detecting change in SBMA severity. METHODS: This was a noninterventional, longitudinal study enrolling patients with confirmed SBMA diagnosis and evidence of muscle fat replacement. All patients were assessed by MRI and clinical measures at baseline and at 6-month intervals for up to 18 months. Whole-body Dixon MRI scans were analyzed using AMRA Researcher, assessing 19 muscle groups bilaterally and quantifying lean muscle volume (LMV), muscle fat fraction (MFF), and muscle fat infiltration (MFI). Rate of change was calculated for whole-body and regional muscle composite measures. Key clinical outcome measures included the Spinal Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) and 2-minute walk test (2MWT). Correlation between muscle MRI measures and clinical assessments was calculated using Spearman correlation analysis, and responsiveness to change was evaluated using standardized response mean (SRM). RESULTS: We included 26 patients with a mean age of 57.6 ± 7.12 years (range:44-71 years), mean SBMAFRS 40.6 ± 3.85 (range:33-48), and a mean baseline 2MWT distance of 126.09 ± 39.83 m (range:39.0-194.0). The mean changes and (SRM) over 12 months in whole-body muscle MRI were LMV -4.38 ± 2.48% (-1.76), MFF 2.49 ± 1.38p.p. (1.81), and MFI 0.79 ± 0.51p.p. (1.55) (p < 0.001). Baseline whole-body LMV/MFF/MFI showed moderate correlation to SBMAFRS (r:0.46/-0.41/-0.51, respectively) and modified SBMAFRS (r:0.50/-0.63/-0.67, respectively). Thigh LMV/MFF/MFI showed moderate correlation to 2MWT (r: 0.73/-0.53/-0.55). DISCUSSION: Consistent and reproducible decreases in whole-body and regional muscle LMV composites over time and increases in MFF and MFI were observed across SBMA patients. Baseline MRI assessments reflect disease severity correlating with SBMAFRS and 2MWT functional measures. SRM of muscle MRI was higher than SRMs of functional measures, indicating that muscle MRI is a responsive biomarker that tracks disease progression and potentially treatment effects in future clinical trials.

The therapeutic application of base editors is limited by their large sizes, which are beyond the packaging capabilities of adeno-associated viral (AAV) vectors. Despite recent progress that has identified many compact CRISPR proteins, the resulting miniature base editors often exhibit reduced activities and limited targeting scope. Here, we introduce a zinc finger protein (ZFP)-enhanced miniature base editor (zmBE), which integrates programmable ZFPs to improve efficiencies and targeting scopes of miniature base editors, including those based on Un1Cas12f1 and OgeuIscB. Utilizing protein language models to optimize ZFPs designed by modular assembly further simplifies the development of zmBEs. Leveraging these methodologies, we engineer a zmBE that effectively induces the SMN2 exon 7 T:A(6) > C:G conversion, restores the exon 7 inclusion, and improves spinal muscular atrophy in a murine model after being delivered via a single AAV vector. Our study provides a versatile platform for developing miniature base editors for in vivo therapeutic applications.

BACKGROUND: An understanding of the natural history and progression of spinal muscular atrophy (SMA) in untreated children, is crucial for the identification of responsive outcome measures that are used to demonstrate the effectiveness of disease-modifying therapies (DMTs). However, there have been no such studies from India. OBJECTIVES: This retrospective registry-based study was aimed at outlining the progression of type 2 SMA among children, with a median age of ten years, over a span of two years. METHODOLOGY: Data from 30 drug-naïve children diagnosed with type 2 SMA were included in the study. A semi-structured pre-tested proforma was used to collect the baseline characteristics of the participants. The outcome variables were the neuromotor function scores based on Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), and the motor milestones established by the World Health Organization (WHO) modified to include attainment of head control. RESULTS: At the one-year follow-up, clinically relevant decrements in HFMSE and RULM scores were noted in 52% and 26% of the patients, respectively. After two years, these figures rose to 67% and 37%, respectively, suggesting an earlier loss of function of the lower extremities in these children compared to the upper extremities. Motor milestone loss was not observed in any of the children. Swallowing difficulty was significantly associated with a decrease in the HFMSE score. At the end of the two-year follow-up period, the cumulative survival was found to be 0.88, and the mean survival time was estimated to be 29 months. CONCLUSION: Our results align with earlier studies indicating that disease progression in type 2 SMA varies among children, highlighting its heterogeneous nature.