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The Revised upper limb module (RULM) has been increasingly used in clinical trials and in clinical settings. The aim of this study was to use the 'shift analysis' to assess the patterns of lost or gained abilities for each item on the RULM in an untreated cohort, stratified by SMA type, age, SMN2 copy number, and motor functional status. The analysis was performed on 222 12-month paired assessments from 129 individuals (115 assessment from type II and 107 from type III) who had at least two assessments at yearly intervals. There was a loss of one or more activities in 54% in type II and in 29% type III. A gain of one or more activities was found in 42% type II and in 22% type III. There were concomitant gains and losses in 27% in SMA II and in 9% in SMA III. Our results, measuring the number of abilities that are lost or gained, provide an additional method of detecting changes that can be used for the interpretation of the longitudinal data collected in treated SMA individuals.

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Down syndrome (DS), characterized by trisomy of chromosome 21, and spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, are individually recognized distinct entities. Their co-occurrence in clinical practice is rare and has not been extensively reported. We present a case of a three-month-old, female child who presented with respiratory failure necessitating intubation. Due to typical facial features and congenital heart disease, DS was confirmed with chromosomal analysis. However, subsequent recurrent chest and bloodstream infections, failure to extubate, and laboratory abnormalities raised the suspicion of accompanying immune disorder with DS. To investigate this, whole exome sequencing analysis was sent, and it revealed a homozygous pathogenic mutation in the SMA type 1 gene in the patient. This rare intersection of two unique genetic conditions presents diagnostic challenges due to overlapping clinical features like hypotonia and delay in motor skills, which can be progressive in both situations. Additionally, the clinical trajectory, therapeutic interventions, and outcomes are variable for both conditions and a lack of guidelines for the management of two concurrent genetic conditions, such as in our patient, can pose a challenge for clinicians. Hence, this case report underscores the importance of comprehensive clinical and diagnostic evaluation in individuals with syndromic features and the need for heightened vigilance for concurrent rare genetic conditions that add to the complexity of the disease and may impact clinical outcomes, management, and counseling for the family.

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Background: Biomarkers can be used to assess the severity of spinal muscular atrophy (5q SMA; SMA). Despite their potential, the relationship between biomarkers and clinical outcomes in SMA remains underexplored. This study aimed to assess the association among biomarkers, phenotypes, and motor milestones in Chinese patients diagnosed with SMA. Methods: We collected retrospective clinical and follow-up data of disease-modifying therapy (DMT)-naïve patients with SMA at our center from 2019 to 2021. Four biomarkers were included: survival motor neuron 2 (SMN2) copies, neuronal apoptosis inhibitory protein (NAIP) copies, full-length SMN2 (fl-SMN2), and F-actin bundling protein plastin 3 (PLS3) transcript levels. Data were analyzed and stratified according to SMA subtype. Results: Of the 123 patients, 30 were diagnosed with Type 1 (24.3%), 56 with Type 2 (45.5%), and 37 with Type 3 (30.1%). The mortality rate for Type 1 was 50%, with median survival times of 2 and 8 months for types 1a and 1b, respectively. All four biomarkers were correlated with disease severity. Notably, fl-SMN2 transcript levels increased with SMN2 copies and were higher in Type 2b than those in Type 2a (p = 0.028). Motor milestone deterioration was correlated with SMN2 copies, NAIP copies, and fl-SMN2 levels, while PLS3 levels were correlated with standing and walking function. Discussion: Our findings suggest that SMN2 copies contribute to survival and that fl-SMN2 may serve as a valuable biomarker for phenotypic variability in SMA Type 2 subtypes. These insights can guide future research and clinical management of SMA.

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OBJECTIVE: We describe outcomes following onasemnogene abeparvovec monotherapy for patients with ≥four survival motor neuron 2 (SMN2) gene copies in RESTORE, a noninterventional spinal muscular atrophy patient registry. METHODS: We evaluated baseline characteristics, motor milestone achievement, post-treatment motor function, use of ventilatory/nutritional support, and adverse events as of December 22, 2022. RESULTS: At data cutoff, 19 patients in RESTORE had ≥four SMN2 copies and were treated with onasemnogene abeparvovec monotherapy (n=12 [63.2%] four copies; n=7 [36.8%] >four copies). All patients were identified by newborn screening and were reported as asymptomatic at diagnosis. Median age at onasemnogene abeparvovec administration was 3.0 months. Median time from treatment to last recorded visit was 15.4 months, with a range of post-treatment follow-up of 0.03-39.4 months. All 12 children who were assessed for motor development achieved new milestones, including standing alone (n=2) and walking alone (n=5). Five children reported one or more treatment-emergent adverse events (one Grade 3 or greater). No deaths or use of ventilatory/nutritional support were reported. CONCLUSIONS: Real-world findings from the RESTORE registry indicate that patients with ≥four SMN2 gene copies treated with onasemnogene abeparvovec monotherapy demonstrated improvements in motor function. Adverse events experienced by these patients were consistent with previously reported findings.

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Spinal muscular atrophy is no longer a leading cause of inherited infant death in the United States. Since 2016, three genetic therapies have been approved for the treatment of spinal muscular atrophy. Each therapy has been well studied with robust data for both safety and efficacy. However, there are no head-to-head comparator studies to inform clinical decision making. Thus, treatment selection, timing, and combination therapy is largely up to clinician preference and insurance policies. As the natural history of spinal muscular atrophy continues to change, more data is needed to assist in evidence-based and cost-effective clinical decision making.

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INTRODUCTION/AIMS: Nusinersen intrathecal administration can be challenging in spinal muscular atrophy (SMA) adults. We aimed to determine if the ultrasound (US)-assistance reduces the number of needle attempts and needle redirections needed for intrathecal drug administration and its impact on the procedure time, the incidence of adverse events (AEs), and patient satisfaction in these patients. METHODS: Fifty-eight patients aged 18 years and older scheduled for intrathecal nusinersen injection were enrolled and randomized (1:1 ratio) into Group 1 (nusinersen infusion with US-assisted technique) or Group 2 (nusinersen infusion with landmark-based technique). The number of attempts, number of redirections, periprocedural time, AEs and patient satisfaction were reported. Continuous variables were compared with the Student t-test or Wilcoxon rank sum test. Categorical variables were evaluated with the Chi-square test or Fisher's exact test in case of expected frequencies <5. The p-values <.05 were considered statistically significant. RESULTS: There were no statistical differences in the number of attempts, AEs, or patient satisfaction between the two groups. The number of needle redirections was significantly lower in the ultrasound group versus landmark-based group (p < .05) in both the overall group of patients and in the subgroup with difficult spines. The periprocedural time was about 40 seconds longer in US-group versus landmark-based group (p < .05). DISCUSSION: In SMA adults, US assistance reduces the number of needle redirections needed for intrathecal drug administration. These results suggest that the US assistance may be advantageous for nusinersen therapy to reduce the therapeutic burden of intrathecal infusion.

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BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) as the second most common neurodegenerative disorder in childhood is characterized by the deficiency of survival of motor neuron (SMN) protein leading predominantly to degeneration of alpha motor neurons and consequently to progressive muscle weakness and atrophy. Besides some biomarkers like SMN2 copy number therapeutic biomarkers for SMA with known relevance for neuromuscular transmission are lacking. Here, we examined the potential of Thrombospondin-4 (TSP4) to serve as a cerebrospinal fluid (CSF) biomarker, which may also indicate treatment response. METHODS: We used untargeted proteomic analyses to determine biomarkers in CSF samples derived from pediatric pre-symptomatic (n = 6) and symptomatic (n = 4) SMA patients. The identified biomarker TSP4 was then validated in additional 68 CSF samples (9 adult and 24 pediatric SMA patients, 5 adult and 13 pediatric non-disease controls in addition to 17 pediatric disease controls) by enzyme-linked immunosorbent assay (ELISA) as an additional analytical approach. RESULTS: Untargeted proteomic analyses of CSF identified a dysregulation of TSP4 and revealed a difference between pre-symptomatic SMA patients and patients identified after the onset of first symptoms. Subsequent ELISA-analyses showed that TSP4 is decreased in pediatric but not adult SMA patients. CSF of pediatric patients with other neurological disorders demonstrated no alteration of TSP4 levels. Furthermore, CSF TSP4 levels of pediatric SMA patients increased after first dose of Nusinersen. CONCLUSIONS: We found that TSP4 levels are exclusively reduced in CSF of pediatric SMA patients and increase after treatment, leading us to the hypothesis that TSP4 could serve as a CSF biomarker with the potential to monitor treatment response in pediatric SMA patients. Moreover, TSP4 enable to distinguish pre-symptomatic and symptomatic patients suggesting a potential to serve as a stratification marker.

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BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce. METHODS: A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up. RESULTS: Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1-12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients. CONCLUSIONS: Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.

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Introduction: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS. Methods: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH). Results: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH. Conclusion: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.

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BACKGROUND: The motor neuron survival protein performs numerous cellular functions; hence, spinal muscular atrophy (SMA) is considered to be a multi-organ disease with possible sensory system damage. The controversy surrounding the presence of sensory disturbances, prompted us to conduct standard electrophysiological studies and assess the sensory thresholds for different modalities in adults with SMA types 2 and 3. The study group consisted of 44 adult SMA patients (types 2 and 3). All patients underwent neurological examination using the Hammersmith Functional Motor Scale - Expanded (HFMSE). Standard sensory electrophysiological studies in the ulnar nerve and the estimation of vibratory, temperature, and warm- and cold-induced pain thresholds with temperature dispersion assessment were performed using quantitative sensory testing (QST). RESULTS: The most repeatable result was the high amplitude of the sensory nerve action potentials (SNAP) in SMA patients compared to controls. This was higher in type 2 patients compared to type 3a and 3b patients and patients with low HFSME scores. Patients with SMA, especially type 3b presented a longer sensory latency and slower conduction velocity than did controls. Cold pain threshold was higher and warm dispersion larger in SMA. The vibratory limit was higher in patients with high HFSME scores. CONCLUSIONS: A high SNAP amplitude suggests sensory fibre hyperactivity, which may be based on overactivation of metabolic pathways as an adaptive mechanism in response to SMN protein deficiency with additionally coexisting small C- and A-delta fibre damage. SMA patients seem to have a concomitant, mild demyelinating process present at the early SMA stage.

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Objective To analyze the muscle trophism and expression of interleukin-6 in the biceps brachii muscle of rats with incomplete cervical spinal cord injury treated with neuromuscular electrical stimulation (NMES). Methods Adult rats underwent C5-C7 spinal cord hemisection and a 5-week NMES protocol. Trophism of the biceps brachii was assessed using muscle weight/body weight ratio and histological analysis. Interleukin-6 expression from biceps brachii was measured using the enzyme-linked immunosorbent assay technique. Results Preservation of the biceps brachii muscle trophism was found in the NMES treated group, along with prevention of the reduction of interleukin-6 levels. Conclusion Spinal cord injury causes muscle atrophy and decreases interleukin-6 levels. These alterations are partially prevented by NMES. The results suggest a possible NMES action mechanism and underscore the clinical use of this therapeutic tool.

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Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations or deletions in the survival motoneuron 1 (SMN1) gene, resulting in deficiency of the SMN protein that is essential for motoneuron function. Smn depletion in mice disturbs axonal RNA transport and translation, thereby contributing to axon growth impairment, muscle denervation, and motoneuron degeneration. However, the mechanisms whereby Smn loss causes axonal defects remain unclear. RNA localization and translation in axons are controlled by RNA-binding proteins (RBP) and we recently observed that the neuronal RBP Ptbp2 modulates axon growth in motoneurons. Here, we identify Smn as an interactor of Ptbp2 in the cytosolic compartments of motoneurons. We show that the expression level of Ptbp2 is reduced in axons but not in the somata of Smn-depleted motoneurons. This is accompanied by reduced synthesis of the RBP hnRNP R in axons. Re-expression of Ptbp2 in axons compensates for the deficiency of Smn and rescues the defects in axon elongation and growth cone maturation observed in Smn-deficient motoneurons. Our data suggest that Ptbp2 and Smn are components of cytosolic mRNP particles, contributing to the precise spatial and temporal control of protein synthesis within axons and axon terminals.

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INTRODUCTION: Nusinersen clinical trials have limited data on adolescents and adults with 5q-associated spinal muscular atrophy (SMA). We conducted a systematic literature review (SLR) and meta-analysis to assess effectiveness of nusinersen in adolescents and adults with SMA in clinical practice. METHODS: Our search included papers published 12/23/2016 through 07/01/2022 with ≥ 5 individuals ≥ 13 years of age and with ≥ 6 months' data on ≥ 1 selected motor function outcomes [Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), and Six-Minute Walk Test (6MWT)]. For meta-analysis, effect sizes were pooled using random-effects models. To understand treatment effects by disease severity, subgroup meta-analysis by SMA type and ambulatory status was conducted. RESULTS: Fourteen publications including 539 patients followed up to 24 months met inclusion criteria for the SLR. Patients were age 13-72 years and most (99%) had SMA Type II or III. Modest improvement or stability in motor function was consistently observed at the group level. Significant mean increases from baseline were observed in HFMSE [2.3 points (95% CI 1.3-3.3)] with 32.1% (21.7-44.6) of patients demonstrating a clinically meaningful increase (≥ 3 points) at 18 months. Significant increases in RULM were consistently found, with a mean increase of 1.1 points (0.7-1.4) and 38.3% (30.3-47.1) showing a clinically meaningful improvement (≥ 2 points) at 14 months. Among ambulatory patients, there was a significant increase in mean 6MWT distance of 25.0 m (8.9-41.2) with 50.9% (33.4-68.2) demonstrating a clinically meaningful improvement (≥ 30 m) at 14 months. The increases in HFMSE were greater for less severely affected patients, whereas more severely affected patients showed greater improvement in RULM. CONCLUSIONS: Findings provide consolidated evidence that nusinersen is effective in improving or stabilizing motor function in many adolescents and adults with a broad spectrum of SMA.

Motor neurons are specialized cells in the brain and spinal cord that control the function of muscles. People with spinal muscular atrophy (SMA) do not make enough survival motor neuron (SMN) protein, which motor neurons need to function. As a result, people with SMA experience decreased muscle function that gets worse over time. Nusinersen is a drug that increases the amount of SMN protein made in the brain and spinal cord. However, most clinical trials of nusinersen have been in infants and children with SMA. Less is known about the effects of nusinersen in teenagers and adults with SMA who may have less severe but still progressive forms of the disease. In this manuscript, we first conducted a thorough review and analysis of research published by investigators who treated teenagers and adults with nusinersen for up to 24 months. We then used an additional analysis, called a meta-analysis, that allowed us to combine the information from several articles, so that we could better understand whether nusinersen helped these patients. We looked at 3 tests that investigators used to see how nusinersen affected patients' motor function. The Hammersmith Functional Motor Scale­Expanded (HFMSE) assesses upper and lower limb motor function; the Revised Upper Limb Module (RULM) evaluates upper limb function; and the Six-Minute Walk Test (6MWT) measures the maximum distance a person can walk in 6 minutes. Our study showed that nusinersen can improve motor function or prevent motor function from getting worse in many teenagers and adults with SMA.

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INTRODUCTION/AIMS: Available studies on scoliosis surgery in spinal muscular atrophy (SMA) have focused on the primary outcome of the procedure-the correction of the curve-whereas research focusing on secondary outcomes is scarce. We aimed to investigate postsurgical changes in respiratory function, motor function, weight, pain, and satisfaction. METHODS: We retrospectively reviewed the clinical notes of 32 disease-modifying treatment-naïve patients (26 SMA2, 6 nonambulant SMA3). We also performed investigator-developed phone interviews and conducted a focus group with families on postsurgical satisfaction. RESULTS: Mean annual rate of forced vital capacity percent decline improved in SMA2: -3.2% postsurgery versus -6.9% presurgery (p < .001), with similar trajectories in SMA3. Gross motor functional scores (Hammersmith Functional Motor Scale) available in 12/32 dropped immediately after surgery: median loss of 6.5 points, with relatively spared upper limb function. Weight z-scores postsurgery dropped in 16/32, requiring food supplements (5/16); one/16 lost >5% of total weight requiring gastrostomy. Postsurgical pain was frequently reported, especially hip pain (13/32). Overall, 10/10 patients/parents participating in the phone interview rated the procedure as very successful for posture and physical appearance. Nonetheless, 7/10 reported postsurgical pain, reduced mobility, and unmet care needs. The seven patients/parents attending the focus group highlighted lack of intensive physiotherapy programs, occupational therapy assistance, and psychological support as postsurgical unmet care needs. DISCUSSION: This study reports a positive impact of scoliosis surgery on respiratory function and overall satisfaction with posture and physical appearance. The observed negative impact on the other outcomes highlights the importance of multidisciplinary approaches to improve postoperative management.

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AIM: The availability of disease-modifying therapies and newborn screening programs for spinal muscular atrophy (SMA) has generated an urgent need for reliable prognostic biomarkers to classify patients according to disease severity. We aim to identify cerebrospinal fluid (CSF) prognostic protein biomarkers in CSF samples of SMA patients collected at baseline (T0), and to describe proteomic profile changes and biological pathways influenced by nusinersen before the sixth nusinersen infusion (T302). METHODS: In this multicenter retrospective longitudinal study, we employed an untargeted liquid chromatography mass spectrometry (LC-MS)-based proteomic approach on CSF samples collected from 61 SMA patients treated with nusinersen (SMA1 n=19, SMA2 n=19, SMA3 n=23) at T0 at T302. The Random Forest (RF) machine learning algorithm and pathway enrichment analysis were applied for analysis. RESULTS: The RF algorithm, applied to the protein expression profile of naïve patients, revealed several proteins that could classify the different types of SMA according to their differential abundance at T0. Analysis of changes in proteomic profiles identified a total of 147 differentially expressed proteins after nusinersen treatment in SMA1, 135 in SMA2, and 289 in SMA3. Overall, nusinersen-induced changes on proteomic profile were consistent with i) common effects observed in allSMA types (i.e. regulation of axonogenesis), and ii) disease severity-specific changes, namely regulation of glucose metabolism in SMA1, of coagulation processes in SMA2, and of complement cascade in SMA3. CONCLUSIONS: This untargeted LC-MS proteomic profiling in the CSF of SMA patients revealed differences in protein expression in naïve patients and showed nusinersen-related modulation in several biological processes after 10 months of treatment. Further confirmatory studies are needed to validate these results in larger number of patients and over abroader timeframe.

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Background and aim: Muscular atrophy is one of the most common age-related conditions characterized by the deterioration of skeletal muscle structures and impaired functions. It is associated with cellular senescence and chronic inflammation, which impair the function of muscle stem cells. Bazi Bushen (BZBS) is a patent compound Chinese medicine that has been shown to have anti-aging effects in various animal models. In this study, we investigated the effects and mechanisms of BZBS on muscular atrophy in naturally aged mice. Experimental procedure: A muscular atrophy model of naturally aged mice (18 months) was employed with administration of BZBS (2 g/kg/d, 1 g/kg/d) and nicotinamide mononucleotide (NMN, 200 mg/kg/d). After six months of drug administration, muscle weight loss, muscle function and muscle histopathology were measured to evaluate the therapeutic effect of BZBS. The expression of cellular senescence, inflammatory and satellite cell-related factors were used to assess the effects of BZBS in inhibiting cellular senescence, reducing inflammation and improving muscle atrophy. Results and conclusion: Compared with age matched natural aging mice, we found that BZBS improved muscle strength, mass, and morphology by reducing senescent cells, inflammatory cytokines, and intermyofiber fibrosis in aged muscle tissues. We also found that BZBS prevented the reduction of Pax7 positive stem cells and stimulated the activation and differentiation into myocytes. Our results suggest that BZBS might be a promising intervention in senile muscular atrophy.

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Objective.To evaluate electrical impedance myography (EIM) in conjunction with machine learning (ML) to detect infantile spinal muscular atrophy (SMA) and disease progression.Approach. Twenty-six infants with SMA and twenty-seven healthy infants had been enrolled and assessed with EIM as part of the NeuroNEXT SMA biomarker study. We applied a variety of modern, supervised ML approaches to this data, first seeking to differentiate healthy from SMA muscle, and then, using the best method, to track SMA progression.Main Results.Several of the ML algorithms worked well, but linear discriminant analysis (LDA) achieved 88.6% accuracy on subject muscles studied. This contrasts with a maximum of 60% accuracy that could be achieved using the single or multifrequency assessment approaches available at the time. LDA scores were also able to track progression effectively, although a multifrequency reactance-based measure also performed very well in this context.Significance.EIM enhanced with ML promises to be effective for providing effective diagnosis and tracking children and adults with SMA treated with currently available therapies. The normative trends identified here may also inform future applications of the technology in very young children. The basic analyses applied here could also likely be applied to other neuromuscular disorders characterized by muscle atrophy.

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The impact of disease-modifying therapy ranges from cure to no impact with a wide range of intermediates. In cases where the intermediate group reaches a plateau after the acquisition of some muscle strength, it is necessary to set a functional level appropriate for increased motor power and establish a long-term exercise plan to maintain it. As the disease status stabilizes and the life span increases, early nonsurgical interventions are required, such as using a standing frame to prevent joint contracture, applying a spinal brace at the early stage of scoliosis, and maintaining sitting postures that exaggerate lumbar lordosis. In cases where scoliosis and hip displacement occur and progress even after conservative managements are implemented, early referral to surgery should be considered. Oromotor activity and swallowing function are influenced not only by the effects of disease-modifying drugs, but also by post-birth experience and training. Therefore, although the feeding tube cannot be removed, it is necessary to make efforts to simulate the infant feeding development while maintaining partial oral feeding. Since the application period of non-invasive ventilators has increased, it has become more important to prevent long-term complications such as facial abrasion, skin allergy, orthodontic deformities, and maxillary flattening caused by the interface. Dual ventilator mode or interface can also be utilized.

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Spinal and bulbar muscular atrophy (SBMA) progressively impairs gait function, resulting in the need for patients to use a wheelchair approximately 20 years after onset. No reports have investigated the effects of long-term exercise training using the Hybrid Assisted Limb (HAL) in patients with multiple SBMA. This study investigated the effects of long-term exercise training using HAL in patients with SBMA and its effects on the quality of life (QoL). Six courses of HAL treatment were administered to three males with SBMA, and leuprorelin was administered to each patient. Each course had a 4-5 week duration, during which the treatment was performed nine times, with a rest period of at least 2 months between each course. A 2-minute walk test (2MWT) and a 10-m walk test (10MWT) were performed to measure gait ability, and a blood test to measure the serum creatine kinase (CK) and creatinine (CRE) levels was performed before and after each course of treatment. We evaluated QoL using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). The average 2MWT distance improved over 2 years (p = 0.038), and the 10MWT showed neither improvement nor decline. No increase or decrease in serum CK or CRE levels was observed. There were no significant changes in the SF-36 physical, mental, or social summary scores. In combination with leuprorelin therapy, robot-assisted training using HAL maintained gait ability and QoL in patients with SBMA for 2 years.

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Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.