BackgroundFriedreich's ataxia (FRDA), a common hereditary ataxia with multisystem involvement, is caused by a biallelic GAA trinucleotide repeat expansion in the FXN gene, leading to reduced frataxin, mitochondrial dysfunction, and oxidative stress. This study evaluates cough effectiveness through voluntary peak cough flow (PCF).ObjectivesThe objective was to assess airway clearance dysfunction in individuals with FRDA by examining PCF and its relationship with pulmonary and oral strength, disease severity, and genetic factors.MethodsThis cross-sectional study, part of the Biomarkers in Friedreich's Ataxia observational study, involved 51 participants with molecularly proven FRDA undergoing respiratory testing, including spirometry, PCF, maximal respiratory pressures, sniff nasal inspiratory pressure, and lingual strength. Neurological impairment was assessed using the Modified Friedreich's Ataxia Rating Scale (mFARS) and Functional Staging for Ataxia.ResultsForty-seven participants completed PCF tests (31 female; mean age 22.60 years). Twenty-nine (61.7%) remained ambulant (mean mFARS 49.91). Seventeen (36.17%) had reduced PCF (<270 L/min). Lower PCF correlated with younger age, earlier disease onset, and decreased respiratory muscle strength. PCF showed strong associations with maximal inspiratory pressure (MIP), forced vital capacity (FVCpp), and maximal expiratory pressure (MEP). Multiple regression identified MIP and age of symptom onset as primary predictors.ConclusionsThe study demonstrates respiratory dysfunction in patients with FRDA, and shows that disease severity and muscle weakness affect airway clearance. PCF is a more direct and clinically meaningful indicator of cough effectiveness than FVCpp. Comprehensive respiratory evaluations, including muscle-strength testing, can identify individuals who may benefit from targeted interventions to prevent complications.

Neurodegeneration has traditionally been largely attributed to protein aggregation, yet ribonucleic acid (RNA) has emerged as an active driver of pathology. Expanded repeat RNAs, misregulated RNA-binding proteins, and aberrant RNA-protein interactions can directly or indirectly trigger neuronal dysfunction, although the distinction between the two mechanisms might, in some cases, be loose. RNA modulates prion-like aggregation, scaffolds liquid-liquid phase separation, and either promotes or inhibits protein assembly, depending on RNA sequence and structure. The aim of this review is to discuss our current understanding of RNA's dual role-as a facilitator of aggregation or as a potential therapeutic target-revealing new mechanistic insights into diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinocerebellar ataxias. We highlight RNA metabolism as a central determinant of neuronal vulnerability.

Spinocerebellar ataxia (SCA) is a group of progressive neurodegenerative diseases. These patients often suffer from pain with multiple etiologies. Our patient suffers from distressing neuropathic back pain, which was only marginally alleviated with high-dose conventional antineuropathic agents while suffering from the side effects. A course of scrambler therapy was prescribed, and sustained relief of neuropathic back pain was achieved for at least eight weeks after completion of scrambler therapy. This is the first case of neuropathic pain in SCA to be treated with scrambler therapy, to the best of our knowledge. Compared with usual daily scrambler therapy sessions, our patient received twice-daily sessions. The main takeaways from our case are that 1) scrambler therapy is a potential treatment for neuropathic pain in SCA patients; 2) it can treat neuropathic pain refractory to conventional antineuropathic agents with the added benefit of reducing the requirement as well as side effects associated with conventional antineuropathic agents; and 3) twice-daily sessions are a potential alternative to standard daily sessions with positive logistical implications.

A 12-year-old male neutered domestic shorthair cat was referred with severe polyphagia, polydipsia, polyuria, weight gain and signs of neurologic disease, including blindness, head tilt, and ataxia. Magnetic resonance imaging (MRI) identified a suprasellar mass consistent with a pituitary macroadenoma. Hypersomatotropism (HST) was diagnosed based on phenotypic changes compatible with acromegaly and an abnormally high serum insulin-like growth factor 1 (IGF-1) concentration (1253 ng/ml). Medical treatment with cabergoline monotherapy (10 μg/kg PO q24h) was prescribed. Progressive improvement of clinical signs was observed, accompanied by a gradual decrease in serum IGF-1 concentrations. Based on clinical and hormonal response, the dosing interval was sequentially extended to q48h and subsequently to q72h. By week 16 of treatment, signs of neurologic disease had resolved and serum IGF-1 concentrations decreased to values within the reference interval (749 ng/ml), while visual deficits persisted. By week 30, signs of neurologic disease remained absent, serum IGF-1 concentration was maintained within the reference interval, and diabetes mellitus did not develop. Cabergoline was well tolerated, with mild gastrointestinal signs reported early in the course of treatment.

Lethal-wasting (lew) is a spontaneous null mutation in the Syb1/Vamp1 gene encoding the vesicular SNARE protein synaptobrevin 1 (SYB1/VAMP1). Homozygous Syb1 lew/lew mice exhibit profound impairment in neuromuscular transmission and die around three weeks after birth. Pathogenic variants in human SYB1 are associated with a variety of disorders such as hereditary spastic ataxia and congenital myasthenic syndrome. Although Syb1 expression is highly enriched in neurons, it has also been reported in non-neuronal tissues, raising the possibility that non-neuronal defects contribute to the lethal phenotype. Here, we tested whether neuronal dysfunction is the primary cause of death in Syb1 lew/lew mice and whether the closely related isoform synaptobrevin 2 (Syb2/VAMP2) can substitute for Syb1functin in vivo . We show that neuron-specific expression of ECFP-Syb2 in Syb1 lew/lew mice fully rescues lethality in Syb1 lew/lew mice, restoring normal growth and motor function. Electrophysiological analyses demonstrate complete recovery of neuromuscular synaptic transmission, including spontaneous and evoked release as well as short-term plasticity. These findings establish that neuronal expression of ECFP-Syb2 is sufficient to prevent the lethal phenotype associated with Syb1 deficiency and demonstrate that Syb2 can functionally replace Syb1 at motor nerve terminals in vivo .

Mutations in Transglutaminase 6 (TG6) have been linked to a genetic form of spinocerebellar ataxia, namely SCA35. In recent years, several mutations associated with this disease have been identified. While some of them did not alter TG6 enzymatic activity, others induced a dominant-negative loss-of-function and altered subcellular localization. We previously observed that mutations identified in patients, which showed detrimental effects on neuronal viability in vitro, including mislocalization and activation of the unfolded protein response, were consistently characterized by a loss of TG6 enzymatic function. To investigate this effect in vivo, we re-derived Tgm6 knockout mice from the EMMA repository and performed behavioral characterization. We measured body weight and assessed motor performance using the rotarod, elevated beam/beam balance test, and ladder test, beginning at 1 month of age and continuing through 16 months of age. Here, we report that TG6 loss-of-function impairs motor coordination in male mice, suggesting a sex-specific function for this enzyme.

Spinocerebellar ataxia (SCA)-50 is a recently reported rare subtype. We describe the first case of SCA-50 from the Indian subcontinent. A 22-year-old man presented with progressive cerebellar ataxia over 2 years, along with oculomotor abnormalities and imaging findings indicating mild cerebellar atrophy. Genetic testing revealed an NPTX1 gene mutation, which correlates with SCA-50. Its unique pathogenesis distinguishes it from other SCA subtypes.