球脊髄性筋萎縮症

Polyglutamine diseases are primarily age-dependent neurodegenerative disorders, but patient-based data also point to a broader, multisystem biology. Clinical, imaging, biochemical, and post-mortem studies support peripheral involvement across multiple organ systems in the onset and progression of Huntington's Disease, Spinal and Bulbar Muscular Atrophy, Dentatorubral-Pallidoluysian Atrophy, and six Spinocerebellar Ataxias. Various peripheral abnormalities often emerge before or alongside overt neurological symptoms, contribute to disability and mortality, and are only partly explained by deconditioning or medications. Current data support viewing polyglutamine diseases as systemic protein-misfolding syndromes with organ-selective vulnerability, where peripheral tissues both mirror and modify CNS pathology in humans. Here, we propose that integrated, longitudinal, multisystem phenotyping and targeted organ-directed interventions are essential components of future research investigations, clinical care, and trial design.

OBJECTIVES: To develop and validate a disease-specific patient-reported outcome (PRO) measure for spinal and bulbar muscular atrophy (SBMA). METHODS: A three-stage sequential design was adopted. Items were generated through qualitative interviews with patients with SBMA and expert review, refined using quantitative analyses, and evaluated for reliability and validity in independent cohorts from Japan and the United States. RESULTS: Interviews with 12 patients generated 234 candidate items, which were refined into a final 31-item SBMAPRO comprising five domains based on an online survey of 106 patients. Internal consistency across domains ranged from Cronbach's alpha values of 0.651 to 0.901. In the Japanese cohort, test-retest reliability yielded intraclass correlation coefficients of 0.941 for physical function, 0.877 for mental health, and 0.858 for social function. Construct validity was examined through correlations with disease-specific functional measurements and the 36-Item Short Form Survey (SF-36). The SBMAPRO correlated with the SBMA Functional Rating Scale ( r = -0.826, p <0.001) and with the SF-36 mental health ( r = -0.693, p <0.001) and social functioning ( r = -0.617, p <0.001) domains. In subscale analyses, the SBMAPRO social domain was associated with trunk-lower limb-related functional impairment ( r = -0.587, p < 0.001). Similar patterns were observed in the American cohort. CONCLUSION: The SBMAPRO demonstrated reliability and validity in Japanese and American cohorts. Associations between mental and social domains and trunk-lower limb dysfunction suggest that mobility impairment may contribute to psychological burden and restricted social participation in SBMA, indicating that this disease-specific PRO may complement clinician-rated measures.

Neurodegenerative diseases (NDDs) exhibit considerable molecular heterogeneity, making it difficult to pinpoint robust, disease-specific biomarkers. Although proteomic studies have deepened our understanding of individual disorders, systematic cross-disease comparisons with cross-platform validation remain scarce, especially for rare conditions like spinal and bulbar muscular atrophy (SBMA). To address this gap, we conducted a comparative plasma proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 264 participants across major neurodegenerative and related diagnostic groups, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), SBMA, and cognitively healthy controls. This unified framework allowed us to capture both disease-specific and shared protein signatures across neurodegenerative conditions. Candidate proteins were then validated in the UK Biobank (Olink Explore) and the Global Neurodegeneration Proteomics Consortium (SomaScan). Of 23 proteins assessed in the UK Biobank, four unique proteins (yielding six disease-protein associations) showed nominally significant and directionally concordant changes; of 20 proteins represented by 27 probes tested in the Global Neurodegeneration Proteomics Consortium, seven proteins reached nominal significance, all with full directional concordance across both cohorts. Notably, IGFBP2 was consistently elevated in AD and PD across independent datasets, pointing to shared metabolic dysregulation, while ADIPOQ showed parallel increases in the same conditions, reinforcing convergent shifts in energy metabolism. By contrast, CRTAC1 and COMP were selectively reduced in motor neuron diseases, suggesting disease-enriched alterations in extracellular matrix composition. Taken together, our findings provide a cross-disease, cross-platform framework for uncovering reproducible proteomic biomarkers and shed light on both overlapping and distinct molecular pathways in neurodegeneration.

Even in the risdiplam era, infants with SMA type 1 remain vulnerable to severe resistant infections because respiratory and bulbar weakness persist. Early cultures, susceptibility-guided antibiotics, airway-clearance measures, ventilatory support, and multidisciplinary PICU care are crucial to stabilize sepsis, prevent respiratory deterioration, and improve outcomes in this fragile population overall.

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by SMN1 mutations, leading to SMN protein deficiency and motor neuron loss. While progressive weakness, respiratory defects, and oral dysfunction are well-documented in patients, the underlying pathophysiology of breathing and bulbar deficits remains understudied in SMA animal models. METHODS: We evaluated breathing and oral function in the SMN∆7 mouse model of severe SMA. Respiratory parameters and chemoreflexes were assessed via whole-body plethysmography. To identify underlying structural changes, we performed histological analysis on lung tissue, the phrenic and hypoglossal nerves, and the muscles driving respiration and oral function. RESULTS: SMN∆7 mice exhibited baseline respiratory alterations and chemoreflex deficits. Histological analysis revealed reduced neuromuscular junction (NMJ) occupancy in respiratory and oral muscles, alongside axonal pathology in the phrenic and hypoglossal nerves and structural degradation in lung tissue. DISCUSSION: These data provide the first physiological and histological evidence of linked respiratory and oral dysfunction in the SMN∆7 mouse. Because these deficits closely approximate the clinical presentation seen in SMA patients, this model represents a valuable tool for testing therapies targeted at bulbar and respiratory failure.