球脊髄性筋萎縮症

Recently instituted world-wide newborn screening programs for spinal muscular atrophy (SMA) permit identification of at-risk individuals prior to clinical presentation of the disease. Early intervention with one or more of the available disease-modifying therapies has dramatically changed the clinical course for individuals affected by SMA. These therapies that yield such impressive results in pediatric SMA populations frequently provide more muted responses in adolescent and adult individuals with SMA. Many treated individuals experience plateau effects and pursue combination treatments to hopefully boost functional outcomes. In addition, individuals with SMA are also now living longer and experience altered disease phenotypes and challenges, such as severe and progressive scoliosis, bulbar issues and neurocognitive issues. Thus, although recent years are marked by significant advances in our understanding of disease pathogenesis and in the development and implementation of therapies to treat SMA, there are still ongoing challenges and unmet needs that will require new and innovate solutions to more fully address the needs of individuals with SMA. In this review, we provide an overview of SMA disease, including a discussion of the many diverse primary defects that have been documented in many different tissues of individuals with SMA and models of the disease, and provide an overview of the therapeutics currently available and in development to treat SMA.

MicroRNAs (miRNAs) have emerged as critical regulators in the pathogenesis of polyglutamine (PolyQ) diseases-a group of fatal neurodegenerative disorders caused by CAG repeat expansions, such as Huntington's disease, spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal and bulbar muscular atrophy. This review synthesizes recent advances in miRNA dysregulation across all nine PolyQ diseases, focusing on studies published since 2019. We examine how specific miRNAs modulate core pathogenic cascades-including mutant protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, and apoptosis-and then link these molecular events to disease-relevant motor, cognitive, and psychiatric phenotypes. The review highlights therapeutic progress, including the preclinical efficacy of adeno-associated virus (AAV)-delivered artificial miRNAs and emerging exosome-based platforms that target mutant transcripts such as HTT, ATXN1, ATXN3, and ATXN7. AAV5-miHTT has advanced to a first-in-human trial for Huntington's disease (NCT04120493)-a key milestone in clinical translation. Circulating miRNAs in plasma and cerebrospinal fluid show diagnostic potential as minimally invasive, stage-specific biomarkers, but challenges persist in normalization, cross-biofluid concordance, and clinical validation. Despite substantial progress, translational barriers remain-including off-target effects, delivery optimization, immunogenicity, and patient heterogeneity. Overcoming these barriers will require integrative approaches that combine single-cell transcriptomics, engineered delivery systems, machine learning, and longitudinally phenotyped clinical cohorts. This review integrates mechanistic insights, biomarker discovery, and therapeutic development to move miRNA-based strategies toward disease-modifying interventions for PolyQ disorders.

BACKGROUND AND PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset X-linked neuromuscular disorder associated with progressive weakness, sensory involvement and impaired mobility. Falls appear frequent in SBMA, but their real-world frequency and circumstances have not been systematically described. This study investigated the frequency, context and perceived causes of falls and near-falls in adults with SBMA. METHODS: A cross-sectional survey was conducted in adults with genetically confirmed SBMA attending a UK specialist clinic. Participants completed a modified Falls Events Questionnaire, reporting fall and near-fall frequency over the previous 12 months and describing up to three events of each type. Participant-level analyses described prevalence and frequency, while event-level analyses descriptively summarised circumstances. RESULTS: Of 83 questionnaires distributed, 61 were returned (73.5%). 55 participants (90%) reported at least 1 fall and 42 (69%) reported falls at least monthly; 51 (84%) reported at least one near-fall. The 55 fallers described 153 fall events (up to three per participant). At event level, most occurred indoors (58%) and during walking, reaching/bending or turning. Participants most commonly attributed falls to muscle weakness (44%), tripping (18%) and loss of balance (17%). Bruising and sprain/strain were common, while fractures were rare (2%). The 51 participants reporting near-falls described 153 events; walking was the most common activity at the time of the near-fall, and grabbing a stable surface was the most commonly reported strategy used to avert a fall. DISCUSSION: Falls and near-falls were frequently reported in this SBMA cohort and commonly occurred during everyday mobility tasks. Participants most often attributed events to weakness, loss of balance and tripping. These descriptive findings support greater clinical attention to falls in SBMA and may inform assessment and rehabilitation priorities, while prospective studies are needed to establish mechanisms and intervention effectiveness.

Spinal muscular atrophy (SMA) Type 1 in infants with two SMN2 copies is characterised by rapid motor neuron loss and a historically fatal course if untreated; however, nationwide real-world comparative data evaluating screening efficacy remain scarce. This nationwide retrospective, multicentre study evaluated the real-world impact of Turkey's national newborn screening (NBS) program on clinical outcomes in a high-risk population-of infants with genetically confirmed SMA and two SMN2 copies-treated with nusinersen. Patients were classified into a historical symptomatic cohort diagnosed before NBS implementation (pre-NBS, n = 162) and an NBS cohort identified through screening (n = 96); all received nusinersen. Outcomes included survival, respiratory and nutritional independence, and acquisition of WHO-defined motor milestones. Motor function was evaluated using the Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) scale. The NBS program markedly reduced the mean age at diagnosis and treatment initiation. Mortality was 6.3% in the NBS cohort compared with 30.9% in the pre-NBS group (p < 0.001). CHOP-INTEND scores at baseline were higher in the NBS cohort. Sustained motor gains were confirmed in both cohorts, though the NBS cohort maintained superior function throughout follow-up; 48.3% of NBS-identified infants achieved independent walking, compared with only 8.6% in the pre-NBS group. Preservation of bulbar and respiratory function was superior in the NBS cohort, whereas the pre-NBS group demonstrated progressive decline. NBS program fundamentally altered the clinical trajectory of SMA Type 1 in infants with two SMN2 copies in the present cohort. Pre-symptomatic treatment in the NBS cohort supports sustained motor development and preserves bulbar and respiratory functions, underscoring the importance of minimising delays between birth, diagnosis, and treatment initiation.

Spinal and bulbar muscular atrophy and Parkinson's disease rarely coexist. We describe a male patient presenting with parkinsonism, hyposmia, with DAT-SPECT deficits, responsive to dopaminergic therapy, preceding recognition of SBMA confirmed genetically. Dopamine agonist-associated dropped head syndrome unmasked underlying lower motor neuronopathy, highlighting diagnostic pitfalls and overlap between synucleinopathy and polyglutamine disease.