Spinal Muscular Atrophy Research Articles

Health information literacy among children with spinal muscular atrophy and their caregivers

BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that leads to multiple organ dysfunction. The advent of disease-modifying treatments makes the early diagnosis of SMA critical. Health information literacy is vital for obtaining, understanding, screening, and using health information. Considering the importance of early diagnosis and the challenges in obtaining accurate information on patients with SMA, this cross-sectional study assessed health information literacy among children with SMA and their caregivers in China.MethodsInterviews with the caregivers of 10 patients with SMA were conducted by neurologists specializing in SMA. A questionnaire for evaluating the level of health information literacy was further developed among 145 children with SMA aged 10.0–120.0 months, with the average age of 81.9 months, and their caregivers. Parameters, such as the age at the onset of the first symptom and time from recognition of the first symptom to diagnosis, were examined. Health information literacy was measured using four dimensions: cognition, search, evaluation, and application.ResultsThe average time from the first symptom to first medical consultation was 4.8 months, and that from the first symptom to diagnosis was 10.8 months. There is a significant delay from the onset of the initial symptoms to a definitive diagnosis. Thirty-five (24%) patients had poor while 26 (18%) had high health information literacy. The overall score for health information literacy was 69; the scores for health information cognition and application were 90 and 84, respectively. The scores for evaluation (61) and search (57) were low. Medical personnel were considered the most professional and credible sources of information. Additionally, search engines and patient organizations were the other two most important sources of health literacy.ConclusionPatients with SMA and their caregivers had low levels of health information literacy. SMA information visibility and standardization need to be improved. Medical personnel with experience in the diagnosis and treatment of SMA and media should aim to share knowledge and increase the quality of life of those with SMA.

Oximetry and carbon dioxide screening for ventilatory requirements in children with spinal muscular atrophy type 1-3

IntroductionDespite disease modifying treatments (DMT), assisted ventilation is commonly required in children with Spinal Muscular Atrophy (SMA). Guidelines suggest screening with oximetry and transcutaneous carbon dioxide (TcCO2) for sleep disordered breathing (SDB). AimTo determine the utility of pulse oximetry and TcCO2 as a screen for SDB and the need for Non-Invasive Ventilation (NIV) in children with SMA type 1–3. MethodsA prospective cohort study was conducted in Queensland, Australia. Full diagnostic PSG was completed in DMT naïve children with SMA. Pulse oximetry and TcCO2 were extracted from PSG. Apnoea-hypopnoea indices (AHI) criteria were applied to PSG results to define the need for NIV. Abnormal was defined as: ≤3 months of age [mo] AHI≥10 events/hour; >3mo AHI ≥5 events/hour. Receiver operating characteristic curves were calculated for abnormal PSG and pulse oximetry/TcCO2 variables, and diagnostic statistics were calculated. ResultsForty-seven untreated children with SMA were recruited (type 1 n = 13; 2 n = 21; 3 n = 13) ranging from 0.2 to 18.8 years old (median 4.9 years). Oxygen desaturation index ≥4 % (ODI4) ≥20events/hour had sensitivity 82.6 % (95 % CI 61.2–95.0) and specificity of 58.3 % (95 % CI 36.6–77.9). TcCO2 alone and combinations of oximetry/TcCO2 had low diagnostic ability. The same methodology was applied to 36 children who were treated (type 1 n = 7; type 2 n = 17; type n = 12) and oximetry±TcCO2 had low diagnostic ability. ConclusionODI4 ≥20events/hour can predict the need for NIV in untreated children with SMA. TcCO2 monitoring does not improve the PPV. If normal however, children may still require a diagnostic PSG. Neither oximetry nor TcCO2 monitoring were useful screening tests in the children treated with DMT.

Cost-Effectiveness Analysis of Newborn Screening for Spinal Muscular Atrophy in Italy.

A decision-analytic model assessed the cost effectiveness of newborn screening from the National Health Service perspective in 400,000 newborns. Newborn screening enabling early identification and presymptomatic treatment of SMA was compared with no newborn screening, symptomatic diagnosis, and treatment. Transition probabilities between health states were estimated from clinical trial data. Higher-functioning health states were associated with increased survival, higher utility values, and lower costs. Long-term survival and utilities were extrapolated from scientific literature. Health care costs were collected from official Italian sources. A lifetime time horizon was applied, and costs and outcomes were discounted at an annual rate of 3%. Deterministic and probabilistic sensitivity analyses were conducted. Newborn screening followed by presymptomatic treatment yielded 324 incremental life-years, 390 incremental quality-adjusted life-years, and reduced costs by €1,513,375 over a lifetime time horizon compared with no newborn screening. Thus, newborn screening was less costly and more effective than no newborn screening. Newborn screening has a 100% probability of being cost effective, assuming a willingness-to-pay threshold of >€40,000. Newborn screening followed by presymptomatic SMA treatment is cost effective from the Italian National Health Service perspective.

A preliminary study on the effects of long-term robot suit exercise training on gait function and quality of life in patients with spinal and bulbar muscular atrophy

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.

AMEsobreRuedas Early Powered Mobility in Children with Spinal Muscular Atrophy Type I: Protocol of a Randomized Controlled Trial.

Background: Young children with spinal muscular atrophy type 1 (SMA1) have limited independent mobility and participation that may lead to cognitive development delays. Implementing early powered mobility in interventions may help them to learn self-initiated movement, play, and having fun to participate in natural settings. The aim of this study is to evaluate the effectiveness of an early power mobility intervention for increasing participation, functional ability, and quality of life in young children with SMA1. Methods: AMEsobreRuedas is a randomized waiting list controlled clinical trial. A sample of 24 children (10 months-5 years old, with SMA1) will be randomly allocated to two groups. The experimental group will perform a family-centered intervention with powered mobility for 16 weeks in their natural environment: a 12-week-structured program three times a week; and a 4-week follow-up with free use of the powered mobility device. The control group (waiting list) will keep their routine and will receive the same intervention after the experimental group. Five assessments will be carried out at baseline and weeks 4, 8, 12, and 16. Primary outcomes are participation (YC-PEM); functional ability (PEDI-CAT); and quality of life (PedsQL-Neuromuscular module). Results: It is expected that this study will provide further knowledge about the positive impact of powered mobility for the analyzed variables. Moreover, family engagement in the intervention and establishment of functional goals may help to add valuable information about real needs in future research. Conclusions: Early powered mobility could increase the opportunities for children with SMA1 to learn to move independently and participate in their natural environment.

Newborn Screening for Spinal Muscular Atrophy: Variations in Practice and Early Management of Infants with Spinal Muscular Atrophy in the United States.

In the United States (U.S.), newborn screening (NBS) for spinal muscular atrophy (SMA) is implemented by individual states. There is likely variation in the practice patterns of state NBS programs and among the providers caring for newborns with SMA. This is a prospective, descriptive, observational study that seeks to quantify and describe practice patterns and heterogeneities in state NBS programs and provider practices in the U.S. We surveyed U.S. state NBS programs and care providers of newborns with SMA. Thirty states and 41 practitioners responded. NBS program practices vary by state. Most (74%) state programs provide results to both primary care and specialist providers and also defer confirmatory SMA testing to those providers. Two states had relatively high rates of false-positive or inclusive results. The total birth prevalence of SMA was 1:13,862. Most providers were in tertiary care centers (90%) and were child neurologists (81%) and/or had fellowship training in Neuromuscular Medicine or Electromyography (76%). All providers see new referrals in less than a week, but many do not initiate treatment until >3 weeks of age (39%), with most commonly reported delays related to insurance processes. Most (81%) prefer onasemnogene abeparvovec-xioi (OA) as the treatment of choice, mainly due to perceived efficacy and the route/frequency of administration. NBS practice patterns in the U.S. vary by state but overall yielded the predicted birth prevalence of positive results. Providers evaluate these newborns urgently, but many do not initiate therapy until after 3 weeks of age. Treatment delays are mainly related to insurance processes.

Our Journey from Individual Efforts to Nationwide Support: Implementing Newborn Screening for Spinal Muscular Atrophy in Serbia.

Innovative treatments for spinal muscular atrophy (SMA) yield the utmost advantages only within the presymptomatic phase, underlining the significance of newborn screening (NBS). We aimed to establish statewide NBS for SMA in Serbia. Our stepwise implementation process involved technical validation of a screening assay, collaboration with patient organizations and medical professionals, a feasibility study, and negotiation with public health representatives. Over 12,000 newborns were tested during the 17-month feasibility study, revealing two unrelated SMA infants and one older sibling. All three children received therapeutic interventions during the presymptomatic phase and have shown no signs of SMA. No false-negative results were found among the negative test results. As frontrunners in this field in Serbia, we established screening and diagnostic algorithms and follow-up protocols and raised awareness among stakeholders about the importance of early disease detection, leading to the incorporation of NBS for SMA into the national program on 15 September 2023. Since then, 54,393 newborns have been tested, identifying six SMA cases and enabling timely treatment. Our study demonstrates that effective collaborations between academia, non-profit organizations, and industry are crucial in bringing innovative healthcare initiatives to fruition, and highlights the potential of NBS to revolutionize healthcare outcomes for presymptomatic SMA infants and their families.

Systematic Review of Presymptomatic Treatment for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) causes the degeneration of motor neurons in the spinal cord. Treatments including nusinersen, risdiplam, and onasemnogene abeparvovec have been shown to be effective in reducing symptoms, with recent studies suggesting greater effectiveness when treatment is initiated in the presymptomatic stage. This systematic review synthesises findings from prospective studies of presymptomatic treatment for 5q SMA published up to December 2023. The review identified three single-arm interventional studies of presymptomatic treatment (NURTURE, RAINBOWFISH, and SPR1NT), six observational studies comparing presymptomatic or screened cohorts versus symptomatic cohorts, and twelve follow-up studies of screened cohorts only (i.e., babies identified via newborn screening for SMA). Babies with three SMN2 copies met most motor milestones in the NURTURE study of nusinersen and in the SPR1NT study of onasemnogene abeparvovec. Babies with two SMN2 copies in these two studies met most motor milestones but with some delays, and some required ventilatory or feeding support. The RAINBOWFISH study of risdiplam is ongoing. Naïve comparisons of presymptomatic treatment in SPR1NT, versus untreated or symptomatic treatment cohorts, suggested improved outcomes in patients treated presymptomatically. Comparative observational studies supported the finding that presymptomatic treatment, and early treatment following screening, may improve outcomes compared with treatment at the symptomatic stage. Further research should assess the long-term clinical outcomes and cost-effectiveness of presymptomatic treatment for SMA.

Safety of risdiplam in spinal muscular atrophy patients after short-term treatment with nusinersen.

Following the approval of risdiplam, there are more possibilities for disease-modifying therapy (DMT) in children with spinal muscular atrophy (SMA). Non-treatment-naïve subjects with SMA involved in the JEWELFISH study, designed to evaluate the safety and tolerability of risdiplam, were required to undergo a washout period before receiving risdiplam. This study aims to investigate the safety of administering risdiplam in patients within 90 days of receiving treatment with nusinersen. Data were collected on SMA patients who had undergone treatment with nusinersen, and who then received risdiplam within 90 days of their last dose of nusinersen, including demographic characteristics, information on treatment with nusinersen and risdiplam, adverse events, and laboratory assessments in a follow-up period of 90 days, presented as median (range). A total of 15 children with SMA were reported, including 8 males and 7 females. The median number of doses of previous nusinersen treatment received was 8 (6-17) doses, and the median age at first risdiplam treatment was 4.3 (1.9-11.2) years. Specifically, 8 children received risdiplam 30 days or less after their most recent nusinersen treatment, 2 at 31-60 days after nusinersen, and 5 at 61-89 days post-nusinersen. Adverse events of pyrexia, pneumonia, vomiting and rash were reported in 4 patients. Our study showed good safety data on patients who received risdiplam following nusinersen within the washout period of 90 days. This supplements the JEWELFISH study in the era of DMT, providing additional guidance for clinicians, but additional data from other centers is needed.

Ubiquitination Insight from Spinal Muscular Atrophy-From Pathogenesis to Therapy: A Muscle Perspective.

Spinal muscular atrophy (SMA) is one of the most frequent causes of death in childhood. The disease's molecular basis is deletion or mutations in the SMN1 gene, which produces reduced survival motor neuron protein (SMN) levels. As a result, there is spinal motor neuron degeneration and a large increase in muscle atrophy, in which the ubiquitin-proteasome system (UPS) plays a significant role. In humans, a paralogue of SMN1, SMN2 encodes the truncated protein SMNΔ7. Structural differences between SMN and SMNΔ7 affect the interaction of the proteins with UPS and decrease the stability of the truncated protein. SMN loss affects the general ubiquitination process by lowering the levels of UBA1, one of the main enzymes in the ubiquitination process. We discuss how SMN loss affects both SMN stability and the general ubiquitination process, and how the proteins involved in ubiquitination could be used as future targets for SMA treatment.

Burden of rare genetic disorders in India: twenty-two years’ experience of a tertiary centre

BackgroundRare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India.ResultsOverall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29–13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study.ConclusionThe present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Impact of Disease Severity and Disease-Modifying Therapies on Myostatin Levels in SMA Patients.

Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels' correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients' age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials.

Timing of SMN replacement therapies in mouse models of spinal muscular atrophy: a systematic review and meta-analysis.

Mutations in the Survival of Motor Neuron 1 gene lead to a loss of survival motor neuron protein in patients with spinal muscular atrophy. Revolutionary advances in gene therapy have led to survival motor neuron-replacement therapies that significantly prolong life expectancy and improve neuromuscular function. However, accumulating evidence suggests that the timing of survival motor neuron-replacement therapies is a critical determinant of success. We performed a systematic review and meta-analysis of all pre-clinical studies testing survival motor neuron replacement therapies in mouse models of spinal muscular atrophy to assess the impact of timing of delivery on therapeutic effectiveness. We incorporated four databases in this pre-registered study (PROSPERO 2020 CRD42020200180): EMBASE, PubMed, Scopus and Web of Science. Inclusion criteria were; primary research article, a measure of survival analysis, use of survival motor neuron mouse model and evaluation of survival motor neuron-targeting therapy. Exclusion criteria included; use of therapies not known to directly target survival motor neuron, genetic manipulations and/or lack of appropriate controls. We screened papers using the SyRF platform. The main outcome we assessed was survival in treated groups compared to untreated groups. We performed meta-analysis of survival using median survival ratio and the random effects model and measured heterogeneity using the I 2 statistic. Subgroup analyses were performed to assess treatment efficacy based on timing of intervention (embryonic delivery, day of birth, postnatal day 2 and postnatal day 3 or later) and treatment type. If detailed in the studies, body weight compared to untreated spinal muscular atrophy models and motor neuron number were included as secondary outcomes for meta-analysis. 3469 studies were initially identified, with 78 ultimately included. Survival motor neuron-replacement therapies significantly affected survival in favour of treatment by a factor of 1.20 (95% CI 1.10-1.30, P < 0.001) with high heterogeneity (I 2 = 95%). Timing of treatment was a significant source of heterogeneity (P < 0.01), with earlier treatment having a greater impact on survival. When stratified by type of treatment, earlier treatment continued to have the strongest effect with viral vector replacement therapy and antisense oligonucleotide therapy. Secondary outcome measures of body weight and spinal motor neuron counts were also positively associated with early treatment. Earlier delivery of survival motor neuron replacement therapies is therefore a key determinant of treatment efficacy in spinal muscular atrophy.

Clinically relevant mouse models of severe spinal muscular atrophy with respiratory distress type 1.

Spinal Muscular Atrophy with Respiratory Distress (SMARD1) is a lethal infantile disease, characterized by the loss of motor neurons leading to muscular atrophy, diaphragmatic paralysis, and weakness in the trunk and limbs. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause a wide spectrum of motor neuron disease. Though mutations in IGHMBP2 are mostly associated with SMARD1, milder alleles cause the axonal neuropathy, Charcot-Marie-Tooth disease type 2S (CMT2S), and some null alleles are potentially a risk factor for sudden infant death syndrome (SIDS). Variant heterogeneity studied using an allelic series can be informative in order to create a broad spectrum of models that better exhibit the human variation. We previously identified the nmd2J mouse model of SMARD1, as well as two milder CMT2S mouse models. Here, we used CRISPR-Cas9 genome editing to create three new, more severe Ighmbp2 mouse models of SMARD1, including a null allele, a deletion of C495 (C495del) and a deletion of L362 (L362del). Phenotypic characterization of the IGHMBP2L362del homozygous mutants and IGHMBP2C495del homozygous mutants respectively show a more severe disease presentation than the previous nmd2J model. The IGHMBP2L362del mutants lack a clear denervation in the diaphragm while the IGHMBP2C495del mutants display a neurogenic diaphragmatic phenotype as observed in SMARD1 patients. Characterization of the Ighmbp2-null model indicated neo-natal lethality (median lifespan = 0.5days). These novel strains expand the spectrum of SMARD1 models to better reflect the clinical continuum observed in the human patients with various IGHMBP2 recessive mutations.

Ensuring continuity and development of spinal muscular atrophy treatment in Poland

Ensuring continuity and development of spinal muscular atrophy treatment in Poland

Hereditary sensory autonomic neuropathy type VI in the age of genetic testing

AbstractBackgroundHereditary sensory and autonomic neuropathy type VI (HSAN VI) is a rare recessive genetic disorder caused by mutations in the human dystonin (DST) gene. We report a novel homozygous alternate transcript mutation in the DST gene causing a severe neonatal form of HSAN VI.Patient DescriptionThis baby boy was born with severe hypotonia, respiratory distress, dysmorphic features, and bilateral club feet. Imaging, karyotyping, Prader–Willi assay, spinal muscular atrophy genetic panel and myotonic dystrophy genetic panel were all negative. A comprehensive neuropathy panel detected a homozygous pathogenic variant in the DST gene—alternate transcript NM_015546.4:c.1357G&gt;A (p.Trp4525*). Nerve conduction studies revealed mixed axonal and demyelinating sensorimotor neuropathy, suggesting the possibility of motor involvement in severe forms of this rare condition. The infant ultimately developed sepsis and died from cardiorespiratory arrest. Neuropathological findings of focal and mild spinal nerve axonal degeneration were nonspecific.ConclusionCollective analysis of these patients would help to further characterize the spectrum of disease pathology and could provide insight into the neurophysiology and neuropathology of this rare condition.

Orphan diseases in children: experience in the use of oedematous enteral nutrition

Introduction. Increased protein and energy requirements, as well as intoxication symptoms in patients with malignant neoplasms (MN), spinal muscular atrophy (SMA) and cystic fibrosis (CF) determine the need to use specialized protein detoxification nutrition in their diet.Aim. To evaluate the tolerability and clinical efficacy of the domestic specialized food product of dietary therapeutic and dietary preventive nutrition Protein detoxification cocktail NUTRIO (liquid mixture) in children with orphan diseases, over 2 years old. Materials and methods. We observed 18 children with rare diseases, aged from 2 years 11 months to 16 years. 6 children had a confirmed diagnosis of MN, 10 – SMA, 2 – CF. All children received the NUTRIO Detox Protein Cocktail twice a day: children aged 3 to 7 years old – ½ serving (100 ml), and aged 8 to 16 years – 1 serving (200 ml). The observation period was 1 month.Results. It was found that all patients (100% of patients) highly rated the taste of the product. There were no refusals from the product. No allergic, dyspeptic or other side effects were noted during the observation period. All patients showed positive dynamics of nutritional status, an increase in the level of total protein and albumin in the blood, a decrease in markers of intoxication and inflammation, an improvement in the quality of life, increased endurance, physical activity and an improvement in the psycho-emotional background.Discussion. The results we obtained correlate well with the authors’ data on the clinical efficacy, safety and significant economic benefits of using this diet.Conclusions. The use of the domestic specialized food product of dietary therapeutic and dietary preventive nutrition Protein detoxification cocktail NUTRIO in diet therapy of children with malignant neoplasms, SMA and CF is effective for correcting their nutritional status and improving the quality of life.

Central neurodegeneration in Kennedy’s disease accompanies peripheral motor dysfunction

Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease (KD), is a rare hereditary neuromuscular disorder demonstrating commonalities with amyotrophic lateral sclerosis (ALS). The current study aimed to define functional and central nervous system abnormalities associated with SBMA pathology, their interaction, and to identify novel clinical markers for quantifying disease activity. 27 study participants (12 SBMA; 8 ALS; 7 Control) were recruited. SBMA patients underwent comprehensive motor and sensory functional assessments, and neurophysiological testing. All participants underwent whole-brain structural and diffusion MRI. SBMA patients demonstrated marked peripheral motor and sensory abnormalities across clinical assessments. Increased abnormalities on neurological examination were significantly associated with increased disease duration in SBMA patients (R2 = 0.85, p < 0.01). Widespread juxtacortical axonal degeneration of corticospinal white matter tracts were detected in SBMA patients (premotor; motor; somatosensory; p < 0.05), relative to controls. Increased axial diffusivity was significantly correlated with total neuropathy score in SBMA patients across left premotor (R2 = 0.59, p < 0.01), motor (R2 = 0.63, p < 0.01), and somatosensory (R2 = 0.61, p < 0.01) tracts. The present series has identified involvement of motor and sensory brain regions in SBMA, associated with disease duration and increasing severity of peripheral neuropathy. Quantification of annualized brain MRI together with Total Neuropathy Score may represent a novel approach for clinical monitoring.

Nusinersen Improves Motor Function in Type 2 and 3 Spinal Muscular Atrophy Patients across Time.

Spinal muscular atrophy (SMA) is a genetic disorder primarily caused by mutations in the SMN1 gene, leading to motor neuron degeneration and muscle atrophy, affecting multiple organ systems. Nusinersen treatment targets gene expression and is expected to enhance the motor function of voluntary muscles in the limbs and trunk. Motor skills can be assessed through specific scales like the Revised Upper Limb Module Scale (RULM) and Hammersmith Functional Motor Scale Expanded (HFMSE). This study aims to evaluate the influence of nusinersen on the motor skills of patients with SMA Type 2 and 3 using real-world data collected over 54 months. A prospective longitudinal study was conducted on 37 SMA patients treated with nusinersen, analyzing data with R statistical software. The outcomes revealed significant improvements in motor functions, particularly in SMA Type 3 patients with higher RULM and HFSME scores. Additionally, GEE analysis identified time, type, age, and exon deletions as essential predictors of motor score improvements. The extended observation period is both a major strength and a limitation of this research, as the dropout rates could present challenges in interpretation. Variability in responses, influenced by genetic background, SMA type, and onset age, highlights the need for personalized treatment approaches.

Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency

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, 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.