マリネスコ・シェーグレン症候群

Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency that leads to progressive neurodegeneration and cardiomyopathy. Effective disease-modifying therapies remain limited. Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.

The clinical assessment of spinocerebellar ataxia type 3 (SCA3) is hindered by subjective factors and inter-rater variability. This study utilizes a previously validated wearable plantar pressure insole system established in our prior work to build a multiscenario digital balance detection framework, and assesses its efficacy in differentiating SCA3 patients from healthy individuals and in evaluating disease severity. The study involved 74 SCA3 patients and 45 healthy controls, who were equipped with custom-developed plantar force sensors to perform standing tasks with eyes open (EO) and eyes closed (EC). Center of pressure (COP) variables were analyzed to determine their correlation with clinical characteristics and their discriminative capability. An XGBoost model was employed to classify disease severity, with SHAP analysis providing enhanced interpretability. COP variables derived from EC tasks demonstrated superior performance in terms of area under the curve, accuracy, sensitivity, and specificity compared to those from EO tasks. Significant correlations were identified between COP variables, such as the eyes closed, left side sway velocity (EC-L velocity) SD, and clinical scores (r > 0.4). The model achieved an accuracy of 87% in classifying disease severity, with SHAP analysis highlighting key variables and interactions. COP variables offer a robust, multidimensional measure of motor dysfunction.

BACKGROUND: Marinesco-Sjögren syndrome (MSS) is a rare and disabling genetic disorder caused primarily by pathogenic variants in the SIL1 gene. SIL1 functions as a nucleotide exchange factor for the molecular chaperone BiP within the endoplasmic reticulum (ER), which is essential for protein folding. This study aims to characterize a novel SIL1 compound heterozygous pathogenic mutation and investigate its disease-causing mechanism. METHODS: We determined a novel SIL1 compound heterozygous mutation information using whole exome sequencing and Sanger sequencing. RNA-seq, RT-qPCR and Western blot were employed to assess the impact of mutations on SIL1 RNA and protein levels. Immunofluorescence was used to monitor localization changes at the cellular level. Structural prediction and coimmunoprecipitation were utilized to investigate the effects of mutations on protein interactions. RESULTS: We identified a 6-year-old girl with MSS carrying novel compound heterozygous variants in the SIL1 gene (c.570_572delCAA (p. Asn190del) and c.740C>T (p. Ala247Val)). Subsequent functional experiments revealed that the mutations show a reduction in SIL1 mRNA and protein levels. Structural prediction and coimmunoprecipitation indicate that the compound variants may be associated with the development of MSS by weakening SIL1-BiP binding. CONCLUSIONS: These findings expand the SIL1 variant spectrum and provide preliminary functional evidence that the identified variants may affect SIL1 abundance and SIL1-BiP interaction, supporting their relevance to the MSS phenotype in this family.

BACKGROUND: The clinimetric properties of the Patient-Reported Outcome Measure of Ataxia (PROM-Ataxia) have only been partially explored. This study aimed to investigate its convergent validity, responsiveness, and minimal clinically important difference (MCID), as well as its discriminative ability at the earliest disease stages in different types of spinocerebellar ataxia (SCA). METHODS: Baseline and 1 year PROM-Ataxia data were obtained from three single-center cohort studies involving ataxic and pre-ataxic SCA1, SCA3, and SCA7 mutation carriers and healthy controls. Spearman correlations were assessed between PROM-Ataxia scores and the Scale for the Assessment and Rating of Ataxia, Inventory of Non-Ataxia Signs, SCA Functional Index, Cerebellar Cognitive Affective Syndrome Scale, 5-level EuroQoL 5-Dimensional Visual Analogue Scale, Patient Health Questionnaire-9, Unified Huntington Disease Rating Scale Part IV, and the Activities of Daily Living subscale of the Friedreich Ataxia Rating Scale. Responsiveness was evaluated using standardized response means (SRM), and MCIDs through anchor-based and distribution-based approaches. RESULTS: Seventy-six mutation carriers (20 SCA1, 40 SCA3, 16 SCA7) were included at baseline, with 68 completing the 1-year follow-up visit. PROM-Ataxia scores correlated moderately to strongly with other measures (ρ=0.46-0.89, p<0.001) and differentiated pre-ataxic individuals from healthy controls (p<0.001). Over one year, PROM-Ataxia demonstrated a gradual average increase (+ 3.9, p=0.048) with considerable between-subject variability of change (SD=22.0) and low responsiveness (SRM=0.17). The MCID of the PROM-Ataxia total score was estimated at 9.8-12.7. CONCLUSION: PROM-Ataxia already distinguishes pre-ataxic SCA mutation carriers from healthy controls in physical, ADL, and mental health domains, and demonstrates strong convergent validity. Although responsiveness at the group level was somewhat limited because of large interindividual variability, 1 year follow-up scores adequately reflected the individual patient's global impression of change.

The differential diagnosis of dizziness is broad and can include both vestibular and autonomic pathology. Vestibular dizziness is typically described as a sensation of movement (e.g. the world is spinning) while dizziness related to autonomic dysfunction is typically described as symptoms of orthostatic intolerance (e.g. postural lightheadedness). It is important to differentiate the type of dizziness to guide proper diagnostic and therapeutic workup. We describe the case of a young patient evaluated in the autonomic clinic for dizziness, ultimately found to have a rare cerebellar neurodegenerative disorder. A 23-year-old female with a past medical history of migraine without aura presented in autonomic clinic with a four-month history of slow, progressive onset of vestibular dizziness. Neurological exam was notable for downbeat nystagmus, but no appendicular or truncal ataxia was appreciated. Subsequent vestibular evaluation was consistent with central vestibular dysfunction. Magnetic resonance imaging (MRI) of the brain with and without contrast was notable for severe cerebellar atrophy. The patient subsequently underwent genetic testing which demonstrated a pathogenic and likely pathogenic variant in the Anoctamin 10 (ANO10) gene, which is seen in Autosomal Recessive Spinocerebellar Ataxia, Autosomal Recessive Type 10 (SCAR10). To our knowledge, this case represents the first reported instance of SCAR10 presenting with the sole neurologic exam finding of downbeat nystagmus without cerebellar ataxia. Additionally, the finding of severe cerebellar atrophy seen on MRI, without gait or limb ataxia on exam is an interesting clinicoradiological dissociation. This case suggests that nystagmus may represent an early disease marker, even in the absence of clinical ataxia in patients with SCAR10.