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Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder. Advances in understanding the pathology have led to gene therapy and other treatments which are altering the natural course of the disease. These new treatments are having a tremendous impact on patients and their families. [ABSTRACT FROM AUTHOR]

The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration. Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug's approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Twin girls born at 30 weeks' gestation with spinal muscular atrophy (SMA) received onsasemnogene‐abeparvovec (OA) at 3.5 weeks of life. They had no treatment‐related adverse events, normal acquisition of motor milestones, and normal neurological examination at 19 months. Genotyping revealed 0 copies of SMN1 and a single, hybrid SMN2 gene containing the positive genetic modifier c.835‐44A>G. This was associated with full‐length SMN2 blood mRNA expression levels similar to a 2 copy SMA infant. The observed favorable outcomes are likely due to the genetic modifier combined with early drug administration enabled by prematurity. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletion and compound heterozygous mutations in survival motor neuron 1 (SMN1), with severity tied to the copy number of survival motor neuron 2 (SMN2). This study aimed to develop a rapid and comprehensive method for the diagnosis of SMA. A total of 292 children with clinically suspected SMA and 394 family members were detected by the amplification refractory mutation system polymerase chain reaction-capillary electrophoresis (ARMS-PCR-CE) method, which targeted 19 reported mutations, and the results were compared with those in multiplex ligation-dependent probe amplification (MLPA). Individuals with identified point mutations were further confirmed by SMN1 long-range PCR and Sanger sequencing. A total of 202 children with SMA, 272 carriers, and 212 normal individuals were identified in this study. No difference was found in the R-value distribution of exons 7 and 8 in SMN1 and SMN2 among these cohorts, with coefficients of variation consistently below 0.08. To detect exon 7 and 8 copy numbers in SMN1 and SMN2, the ARMS-PCR-CE results were concordant with those of MLPA. Approximately 4.95 % (10/202) of the study patients had compound heterozygous mutations. The ARMS-PCR-CE assay is a comprehensive, rapid, and accurate diagnostic method for SMA that simultaneously detects copy numbers of exons 7 and 8 in SMN1/SMN2, as well as 19 point mutations in SMN1 and 2 enhancers in SMN2. This approach can effectively reduce the time frame for diagnosis, facilitating early intervention and preventing birth defects. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by skeletal muscle weakness and atrophy. Patients with SMA types 1 and 2 develop severe disabilities conferring substantial patient and caregiver burden. Caregiver treatment characteristic preferences are useful for informing treatment choices and improving adherence. We aimed to identify drivers of SMA treatment preference from the perspective of caregivers of patients with SMA types 1 or 2 in the United States. We quantified the relative importance of different treatment characteristics and compared preferences for hypothetical treatment scenarios. Treatment attributes and attribute levels elicited were based on a literature search and interviews with caregivers and health care professionals. The most important treatment characteristics from the perspective of health care professionals and caregivers were identified and used in a survey to quantify relative importance for caregivers. Caregivers completed surveys regarding their preferences using swing weighting methodology. These results were used to estimate the relative value of four hypothetical SMA treatment scenarios exploring different modes of treatment administration. The swing weighting survey, completed by 20 caregivers, demonstrated that the attributes driving treatment preference were reduction in permanent ventilation needs and risk of severe adverse events, followed by treatment access (including cost coverage and availability), increased ability to sit without support, and less treatment administration burden. The hypothetical SMA treatment scenarios with the highest relative value offered an easier mode of administration, lowest risk of severe adverse events, less need of permanent ventilation, and highest ability of patients to feed and sit without support. Our findings suggest that caregivers prefer a treatment with reduced clinical burden and risk in which the cost is covered and treatment is available in the short term. These results can provide important contextual information for decision-makers and help promote patient-centered care for patients with SMA. [ABSTRACT FROM AUTHOR]

Background: Onasemnogene abeparvovec gene replacement therapy (GT) has changed the prognosis of patients with spinal muscular atrophy (SMA) with variable outcome regarding motor development in symptomatic patients. This pilot study evaluates acceptability, validity and clinical relevance of Inertial Measurement Units (IMU) to monitor spontaneous movement recovery in early onset SMA patients after GT. Methods: Clinical assessments including CHOPINTEND score (the gold standard motor score for infants with SMA) and IMU measurements were performed before (M0) and repeatedly after GT. Inertial data was recorded during a 25-min spontaneous movement task, the child lying on the back, without (10 min) and with a playset (15 min) wearing IMUs. Two commonly used parameters, norm acceleration 95th centile (||A||_95) and counts per minute (||A||_CPM) were computed for each wrist, elbow and foot sensors. Results: 23 SMA-patients were included (mean age at diagnosis 8 months [min 2, max 20], 19 SMA type 1, three type 2 and one presymptomatic) and 104 IMU-measurements were performed, all well accepted by families and 84/104 with a good child participation (evaluated with Brazelton scale). ||A||_95 and ||A||_CPM showed high internal consistency (without versus with a playset) with interclass correlation coefficient for the wrist sensors of 0.88 and 0.85 respectively and for the foot sensors of 0.93 and 0.91 respectively. ||A||_95 and ||A||_CPM were strongly correlated with CHOPINTEND (r for wrist sensors 0.74 and 0.67 respectively and for foot sensors 0.61 and 0.68 respectively, p-values < 0.001). ||A||_95 for the foot, the wrist, the elbow sensors and ||A||_CPM for the foot, the wrist, the elbow sensors increased significantly between baseline and the 12 months follow-up visit (respective p-values: 0.004, < 0.001, < 0.001, 0.006, < 0.001, < 0.001). Conclusion: IMUs were well accepted, consistent, concurrently valid, responsive and associated with unaided sitting acquisition especially for the elbow sensors. This study is the first reporting a large set of inertial sensor derived data after GT in SMA patients and paves the way for IMU-based follow-up of SMA patients after treatment. [ABSTRACT FROM AUTHOR]

Background: Oral function tests have been shown to reliably detect impaired bulbar function in adults with spinal muscular atrophy (SMA). Although not routinely recorded, it is known that persons with SMA are affected to varying degrees. Detecting differences in bite and tongue force, endurance, and maximum mouth opening has become particularly promising since the introduction of causal therapy for SMA. This study aimed to compare oral function among adult persons with SMA with different SMA types, walking abilities, and treatment status to a healthy control group. Methods: Data from oral function tests conducted on 58 persons with SMA and 45 healthy individuals were analyzed. Differences in oral function between SMA subgroups were pairwise tested and compared to the healthy control group using Wilcoxon rank sum tests. Results: In an overall comparison, three out of five oral function tests revealed lower values for the SMA group compared to the control group. Subgroup analyses indicated lower scores for most oral function tests in non-ambulatory, untreated patients with SMA type 2 compared to controls. Ambulatory, treated patients with SMA type 3 achieved strength and endurance values comparable to those of healthy individuals. Conclusions: The impairment of oral function varies across persons with SMA. Routine measurement of oral function is warranted to determine individual bulbar involvement stages. Further evaluation should be scheduled if indicators such as restricted maximum mouth opening arise. Trial registration DRKS, DRKS00015842. Registered 30 July 2019, https://drks.de/register/de/trial/DRKS00015842/preview. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) in children and adolescents with type 1 diabetes mellitus (T1DM) is a growing issue, with controversial data in the terms of prevalence and evaluation timelines. Currently, there are no clear standards for its early detection. Therefore, our aim was to assess the contribution of the Michigan neuropathy screening instrument (MNSI), lipid profile, serum neuron specific enolase (NSE), and serum heat shock protein 27 (HSP 27) to the prediction of DPN in children and adolescents with T1DM. Methods: In this case-control study, fifty children diagnosed with T1DM for at least five years were enrolled and evaluated through complete neurological examination, MNSI, and nerve conduction study (NCS). Additionally, HbA1c, lipid profile, serum NSE, and serum HSP 27 levels were measured for patients and controls. Results: The prevalence of DPN in our study was 24% by NCS, and electrophysiological changes showed a statistically significant lower conduction velocity for the posterior tibial and sural nerves, as well as a prolonged latency period for the common peroneal and sural nerves in neuropathic patients. In these patients, older age, earlier age of diabetes onset, longer disease duration, higher total cholesterol, triglycerides, low density lipoprotein cholesterol, HbA1c, serum NSE, and HSP27 levels were observed. The MNSI examination score ≥ 1.5 cutoff point had an area under the curve (AUC) of 0.955, with 75% sensitivity and 94.74% specificity, according to receiver operating characteristic curve analysis. However, the questionnaire's cutoff point of ≥ 5 had an AUC of 0.720, 75% sensitivity, and 63% specificity, with improved overall instrument performance when combining both scores. Regarding blood biomarkers, serum NSE had greater sensitivity and specificity in discriminating neuropathic patients than HSP27 (92% and 74% versus 75% and 71%, respectively). Regression analysis revealed a substantial dependency for MNSI and serum NSE in predicting DPN in patients. Conclusions: Despite limited research in pediatrics, MNSI and serum NSE are promising predictive tools for DPN in children and adolescents with T1DM, even when they are asymptomatic. Poor glycemic control and lipid profile changes may play a critical role in the development of DPN in these patients, despite conflicting results in various studies. [ABSTRACT FROM AUTHOR]

Background: Children with spinal muscular atrophy (SMA) are at risk of low bone mineral density (BMD) and bone fragility. This study aims to assess lumbar spine BMD measured by quantitative computed tomography (QCT) and investigate influencing factors of low BMD in children with SMA without disease-modifying treatment. Methods: Demographic data, laboratory parameters, QCT data, and data on spinal radiographs were collected. A linear regression model was carried out to explore the correlations between BMD and its related factors. Results: Sixty-six patients with SMA who had complete records between July 2017 and July 2023 were analyzed, with SMA with a mean age of 5.4 years (range, 2.4–9.7 years), including type 1 in 14, type 2 in 37, and type 3 in 15. 28.8% of patients (19/66) were diagnosed with low BMD (Z-scores ≤ − 2), and the mean BMD Z-scores on QCT was − 1.5 ± 1.0. In our model, BMD Z-scores was associated with age (β=-0.153, p = 0.001). SMA phenotype and serum bone metabolism markers, such as serum phosphorus (P), alkaline phosphatase (ALP) and 25-Hydroxyvitamin D (25-OH-D) levels did not independently predict low BMD. ROC analysis showed that the age ≥ 6.3 years predicts a Z-scores ≤ -2.0 with a sensitivity of 68.4% and a specificity of 68.1%. Conclusions: Low BMD were highly prevalent in children with SMA without disease-modifying treatment in our centre. Regular monitoring of BMD is necessary for all types of SMA children, especially those aged ≥ 6.3 years. [ABSTRACT FROM AUTHOR]

Background: Therapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD. Methods: Longitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology. Results: Plasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF. Conclusions: Our data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD. [ABSTRACT FROM AUTHOR]

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. Plain Language Summary: 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 Scale–Expanded (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. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is the second most common fatal genetic disease in infancy. It is caused by deletion or intragenic pathogenic variants of the causative gene SMN1, which degenerates anterior horn motor neurons and leads to progressive myasthenia and muscle atrophy. Early treatment improves motor function and prognosis in patients with SMA, but drugs are expensive and do not cure the disease. Therefore, carrier screening seems to be the most effective way to prevent SMA birth defects. In this study, we genetically analyzed 1400 samples using multiplex ligation-dependent probe amplification (MLPA) and quantitative polymerase chain reaction (qPCR), and compared the consistency of the results. We randomly selected 44 samples with consistent MLPA and qPCR results for comprehensive SMA analysis (CASMA) using a long-read sequencing (LRS)-based approach. CASMA results showed 100% consistency, visually and intuitively explained the inconsistency between exons 7 and 8 copy numbers detected by MLPA in 13 samples. A total of 16 samples showed inconsistent MLPA and qPCR results for SMN1 exon 7. CASMA was performed on all samples and the results were consistent with those of resampling for MLPA and qPCR detection. CASMA also detected an additional intragenic variant c.-39A>G in a sample with two copies of SMN1 (RT02). Finally, we detected 23 SMA carriers, with an estimated carrier rate of 1/61 in this cohort. In addition, CASMA identified the "2 + 0" carrier status of SMN1 and SMN2 in a family by analyzing the genotypes of only three samples (parents and one sibling). CASMA has great advantages over MLPA and qPCR assays, and could become a powerful technical support for large-scale screening of SMA. [ABSTRACT FROM AUTHOR]

Background: The introduction of newborn screening (NBS) for spinal muscular atrophy (SMA) has increased the early diagnosis of 5q-associated SMA in presymptomatic and symptomatic preterm infants. National and international recommendations for treating preterms and newborns < 38 weeks of gestational age are unavailable. Our retrospective multicentre study aimed to evaluate the postnatal clinical course of preterm infants with 5q-associated SMA diagnosed since the implementation of NBS in Germany in 2021 and to summarize the German experience regarding the decision-making process for available treatment regimens for preterm infants with ≤ 3 survival of motor neuron 2 (SMN2) copies. Results: Twelve preterm infants with 5q-associated SMA and a mean gestational age of 34.0 weeks (range: 26.1–36.8) and birth weight of 2022 g (range: 645–3370) were reported from 8/20 German SMA NBS follow-up centers using a pseudonymized questionnaire. Confirmatory diagnosis, including SMN2 copy number, was completed on average on postnatal day 13. All patients had a biallelic deletion of exon 7 or exons 7 and 8 of the survival of motor neuron 1 (SMN1) gene, with SMN2 copy numbers of two in 10 patients and three in two patients. The neonatal course was complicated by respiratory distress due to prematurity (n = 2), sepsis (n = 2), and jaundice (n = 2). At birth, 11 preterm infants (91.6%) were presymptomatic. However, the neurological status of one patient deteriorated at five weeks of age (postconceptional age of 41.8 weeks) prior to the start of treatment. Disease-modifying treatments were initiated in all patients at a mean postconceptional age of 38.8 weeks, with the majority receiving onasemnogene abeparvovec (83.3%, including 2 patients with prior risdiplam bridge therapy). Notably, consensus among participating experts from German neuromuscular centers resulted in 83.3% of patients receiving disease-modifying treatment at term. Conclusions: Premature infants with SMA require interdisciplinary care in close collaboration with the neuromuscular center. SMA NBS facilitates early initiation of disease-modifying therapy, ideally during the presymptomatic phase, which significantly influences the prognosis of the newborn. [ABSTRACT FROM AUTHOR]

Introduction: Duchenne muscular dystrophy is a genetic X-linked recessive disorder. This condition is characterized by progressive loss of muscle tissue. Thus, it results in deterioration and inability to perform basic motor skills such as independent movement or breathing. Due to progressive muscle weakness, patients with advanced stages of DMD require mechanical ventilation, feeding, and rehabilitation. Furthermore, alterations in cardiac muscle lead to cardiomyopathy. Despite advanced supportive treatment, DMD is a fatal disease. Purpose: The aim of the paper is to present, using a case study description, the current standards of treatment for patients with Duchenne muscular dystrophy as well as the current state of knowledge and new discoveries regarding this medical condition. Material and methods The patient's medical records were analyzed and available literature in PubMed was reviewed to write this article using the keywords: „Duchenne muscular dystrophy"; „cardiomyopathy"; „mechanical ventilation"; „gene therapy"; Conclusions Early detection of respiratory and circulatory insufficiency improves the patient's quality of life. Many patients with an advanced stage of Duchenne muscular dystrophy need specialized treatment, for example, in the intensive care unit. Therefore there is an urgent need for new treatment methods, such as gene therapies, which can slow down or break the course of the disease. New discoveries and the implementation of new treatment standards can enhance the quality of life for patients and extend their lifespans. [ABSTRACT FROM AUTHOR]

Background: Literature-based discovery (LBD) aims to help researchers to identify relations between concepts which are worthy of further investigation by text-mining the biomedical literature. While the LBD literature is rich and the field is considered mature, standard practice in the evaluation of LBD methods is methodologically poor and has not progressed on par with the domain. The lack of properly designed and decent-sized benchmark dataset hinders the progress of the field and its development into applications usable by biomedical experts. Results: This work presents a method for mining past discoveries from the biomedical literature. It leverages the impact made by a discovery, using descriptive statistics to detect surges in the prevalence of a relation across time. The validity of the method is tested against a baseline representing the state-of-the-art "time-sliced" method. Conclusions: This method allows the collection of a large amount of time-stamped discoveries. These can be used for LBD evaluation, alleviating the long-standing issue of inadequate evaluation. It might also pave the way for more fine-grained LBD methods, which could exploit the diversity of these past discoveries to train supervised models. Finally the dataset (or some future version of it inspired by our method) could be used as a methodological tool for systematic reviews. We provide an online exploration tool in this perspective, available at https://brainmend.adaptcentre.ie/. [ABSTRACT FROM AUTHOR]

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 diseasemodifying 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and objectives: Several recent clinical studies have indicated that vamorolone is comparable in effectiveness to glucocorticosteroids for treating Duchenne muscular dystrophy (DMD). However, there is a lack of extensive data regarding the efficacy and safety of various doses of vamorolone. We conducted a study to evaluate the efficacy of different doses of vamorolone in boys with DMD, and compare the safety of vamorolone vs. glucocorticosteroids, prednisone or deflazacort in boys with DMD. Methods: We performed systematic searches of the PubMed, Embase, and Cochrane Library databases for vamorolone, glucocorticosteroids, prednisone or deflazacort in boys with DMD. We assessed statistical heterogeneity across trials based on the Newcastle Ottawa scale (NOS) tool test and I 2 values, and mean differences were pooled using the random-effects model. We used traditional meta-analysis to evaluate efficacy and safety of vamorolone 6.0 mg/ kg/d vs. vamorolone 2.0 mg/kg/d and vamorolone vs. prednisone. A network meta-analysis was applied to estimated the safety of vamorolone in comparison to glucocorticosteroids, prednisone and deflazacort. Our meta-analysis were performed using Revman 5.4 software, and our network meta-analysis were performed using Stata/MP 18.0. Results: In the meta-analysis, a total of 193 patients were analyzed across four clinical trials (97 patients receiving vamorolone 2 mg/kg per day; 96 patients receiving vamorolone 2 mg/kg per day). We observed that there were statistically significant differences in boys with DMD between vamorolone 6.0 mg/kg/d and vamorolone 2.0 mg/kg/d in TTSTANDV (MD = 0.03, 95%CI = 0.00-0.06, p = 0.04), TTRWV (MD = 0.13, 95%CI = 0.08-0.19, p < 0.01), 6MWT (MD = 24.54, 95%CI = 4.46-44.82, p = 0.02), TTCLIMBV (MD = 0.04, 95%CI = 0.01-0.06, p = 0.009), no significant difference in BMI z score (MD = 0.09, 95%CI = -0.03- 0.20, p = 0.13). Indirect comparisons derived from network meta-analysis did not show significant differences among vamorolone, glucocorticosteroids, prednisone and deflazacort in BMI z score. Conclusion: Our findings implied that boys with DMD who took vamorolone 6 mg/kg daily instead of 2 mg/kg daily may be safer and have superior motor function. However, more large sample randomized controlled trials are needed to confirm our results. Systematic Review Registration: This systematic review and meta-analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (registration number: CRD42024562916). [ABSTRACT FROM AUTHOR]

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The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches. [ABSTRACT FROM AUTHOR]

Precision Medicine (PM) is a transformative clinical medicine strategy that aims to revolutionize healthcare by leveraging biological information and biomarkers. In the context of maternal and neonatal health, PM enables personalized care from preconception through the postnatal period. Qatar has emerged as a key player in PM research, with dedicated programs driving advancements and translating cutting-edge research into clinical applications. This article delves into neonatal and maternal health in Qatar, emphasizing PM programs and initiatives that have been implemented. It also features noteworthy clinical cases that demonstrate the effectiveness of precision interventions. Furthermore, the article highlights the role of pharmacogenomics in addressing various maternal health conditions. The review further explores potential advancements in the application of PM in maternal and neonatal healthcare in Qatar. Article highlights Precision Medicine (PM) uses biological, lifestyle and environmental information including biomarkers for personalized care from preconception through the postnatal period. Qatar has become a significant player in PM research, with dedicated programs translating advanced research into clinical practice. Qatar's PM programs, including premarital genetic screening, newborn screening and reproductive medicine demonstrate significant progress and commitment. The article emphasizes the role of pharmacogenomics (PGx) in addressing maternal and neonatal health conditions. Anticipated integration of advanced multi-omics technologies and AI-driven predictive models into clinical practice. Continued evolution of pharmacogenomics to optimize drug therapies for pregnant women and neonates. Future efforts will focus on personalized interventions and improved healthcare outcomes for mothers and newborns in Qatar. [ABSTRACT FROM AUTHOR]

Disruptions in normal development and the emergence of health conditions often result from the malfunction of vital genes in the human body. Decades of scientific research have focused on techniques to modify or substitute defective genes with healthy alternatives, marking a new era in disease treatment, prevention and cure. Recent strides in science and technology have reshaped our understanding of disorders, medication development and treatment recommendations, with human gene and cell therapy at the forefront of this transformative shift. Its primary objective is the modification of genes or adjustment of cell behaviour for therapeutic purposes. In this review, we focus on the latest advances in gene and cell therapy for treating human genetic diseases, with a particular emphasis on FDA and EMA‐approved therapies and the evolving landscape of genome editing. We examine the current state of innovative gene editing technologies, particularly the CRISPR‐Cas systems. As we explore the progress, ethical considerations and prospects of these innovations, we gain insight into their potential to revolutionize the treatment of genetic diseases, along with a discussion of the challenges associated with their regulatory pathways. This review traces the origins and evolution of these therapies, from conceptual ideas to practical clinical applications, marking a significant milestone in the field of medical science. [ABSTRACT FROM AUTHOR]

Copyright of Revista Medica del IMSS is the property of Direccion de Prestaciones Medicas - IMSS and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: The long‐term favorable safety profile of nusinersen provides an opportunity to consider a higher dose. We report on the relationships between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy. Methods: The analyses used data from the CS3A and ENDEAR studies of nusinersen in participants with infantile‐onset spinal muscular atrophy (SMA). Steady‐state CSF trough (Ctrough) levels, plasma phosphorylated neurofilament heavy chain (pNF‐H) levels, body weight, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores were selected as parameters of interest. A validated population pharmacokinetic (PK) model was applied to predict the nusinersen CSF Ctrough. PK/pharmacodynamic (PK/PD) models used nusinersen CSF Ctrough measurements, which were time‐matched with CHOP INTEND scores. Results: Higher nusinersen CSF exposure was associated with a greater decrease in pNF‐H levels and greater efficacy, as measured by change in the CHOP INTEND score from baseline. These findings indicate a dose–response relationship between CSF nusinersen levels and treatment response. The higher dose is predicted to lead to approximately a 2.4‐fold increase in nusinersen CSF levels with fewer loading doses. PK/PD modeling indicates that a higher concentration of nusinersen may predict an additional 5‐point increase in CHOP INTEND score beyond that observed with 12 mg. Interpretation: Our data indicate that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy when compared with the currently approved 12‐mg dose. The efficacy, safety, and PK of a higher nusinersen dose are currently under investigation in the ongoing phase 2/3 DEVOTE study (NCT04089566). [ABSTRACT FROM AUTHOR]

Background: This prospective study investigates the pattern of pareses in 5q-associated spinal muscular atrophy (SMA) to identify disease-specific characteristics and potential differences from amyotrophic lateral sclerosis (ALS) and spinobulbar muscular atrophy (SBMA). Detailed knowledge about pareses patterns in SMA facilitates differential diagnosis and supports therapeutic monitoring. Methods: Between January 2021, and June 2021, 66 SMA patients (59.1% male, aged 33.6 ± 15.2 years) were included in the study. Most patients had SMA type II (n = 28) or SMA type III (n = 28), seven patients had SMA type I, and three patients had SMA type IV. We analyzed the pattern of pareses using the UK Medical Research Council (MRC) scoring system. Results: In both, upper and lower limbs muscle weakness was less pronounced in distal (upper limbs: MRC median 3.0 (interquartile range 1.5–3.5); lower limbs: 1.5 (0.5–3.0)) compared to proximal muscle groups (upper limbs: 2.0 (1.5–2.6); p < 0.001; lower limbs: 0.5 (0.5–1.5); p < 0.001). Thenar muscles were stronger than other small hand muscles (3.0 (2.0–3.5) vs 3.0 (1.5–3.5); p = 0.004). Muscles had more strength in upper (2.3 (1.5–3.1)) compared to lower limbs (1.1 (0.5–2.3); p < 0.001) and in flexors compared to extensors. Conclusion: We identified a specific pattern of muscle paresis in SMA which is different from the pattern of paresis in ALS and SBMA. As a rule of thumb, the pattern of pareses is similar, but not identical to ALS in distal, but different in proximal muscle groups. [ABSTRACT FROM AUTHOR]

Background: An increasing number of clinical trials for new therapeutic strategies are underway or being considered for dystrophinopathy. Having detailed data on the natural progression of this condition is crucial for assessing the effectiveness of new drugs. However, there's a lack of data regarding the long-term data on the natural course and how it's managed in China. In this study, we offer a comprehensive overview of clinical and molecular findings, as well as treatment outcomes in the Chinese population. Methods: Institutional data on all patients with dystrophinopathy from August 2011 to August 2021 were retrospectively reviewed. The data included geographic distribution, age at diagnosis, molecular findings, and treatment options, such as corticosteroids, cardiac interventions, and clinical outcomes. Results: In total, 2097 patients with dystrophinopathy, including 1703 cases of Duchenne muscular dystrophy (DMD), 311 cases of Becker muscular dystrophy (BMD), 46 cases of intermediate muscular dystrophy (IMD), and 37 cases categorized as "pending" (individuals with an undetermined phenotype), were registered in the Children's Hospital of Fudan University database for dystrophinopathy from August 2011 to August 2021. The spectrum of identified variants included exonic deletions (66.6%), exonic duplications (10.7%), nonsense variants (10.3%), splice-site variants (4.5%), small deletions (3.5%), small insertions/duplications (1.8%), and missense variants (0.9%). Four deep intronic variants and two inversion variants were identified. Regarding treatment, glucocorticoids were administered to 54.4% of DMD patients and 39.1% of IMD patients. The median age at loss of ambulation was 2.5 years later in DMD patients who received glucocorticoid treatment. Overall, one cardiac medicine at least was prescribed to 7.4% of DMD patients, 8.3% of IMD patients, and 2.6% of BMD patients. Additionally, ventilator support was required by four DMD patients. Eligibility for exon skipping therapy was found in 55.3% of DMD patients, with 12.9%, 10%, and 9.6% of these patients being eligible for skipping exons 51, 53, and 45, respectively. Conclusions: This is one of the largest studies to have evaluated the natural history of dystrophinopathy in China, which is particularly conducive to the recruitment of eligible patients for clinical trials and the provision of real-world data to support drug development. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy (SMA) is a neurodegenerative disorder. Although prior studies have investigated the metabolomes of SMA in various contexts, there is a gap in research on cerebrospinal fluid (CSF) metabolomics compared to healthy controls. CSF metabolomics can provide insights into central nervous system function and patient outcomes. This study aims to investigate CSF metabolite profiles in untreated SMA patients to enhance our understanding of SMA metabolic dysregulation. Methods: This case control study included 15 SMA patients and 14 control subjects. CSF samples were collected, and untargeted metabolomics was conducted to detect metabolites in SMA and control groups. Results: A total of 118 metabolites abundance were significantly changed between the SMA and control groups. Of those, 27 metabolites with variable importance for the projection (VIP) ≥ 1.5 were identified. The top 5 differential metabolites were N-acetylneuraminic acid (VIP = 2.38, Fold change = 0.43, P = 5.49 × 10–5), 2,3-dihydroxyindole (VIP = 2.33, Fold change = 0.39, P = 1.81 × 10–4), lumichrome (VIP = 2.30, Fold change = 0.48, P = 7.90 × 10–5), arachidic acid (VIP = 2.23, Fold change = 10.79, P = 6.50 × 10–6), and 10-hydroxydecanoic acid (VIP = 2.23, Fold change = 0.60, P = 1.44 × 10–4). Cluster analysis demonstrated that the differentially metabolites predominantly clustered within two main categories: protein and amino acid metabolism, and lipid metabolism. Conclusions: The findings highlight the complexity of SMA, with widespread effects on multiple metabolic pathways, particularly in amino acid and lipid metabolism. N-acetylneuraminic acid may be a potential treatment for functional improvement in SMA. The exact mechanisms and potential therapeutic targets associated with metabolic dysregulation in SMA require further investigation. [ABSTRACT FROM AUTHOR]

The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual's genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner's fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies. [ABSTRACT FROM AUTHOR]

Gene therapy has made considerable strides in recent years. More than 4000 protein-coding genes have been implicated in more than 6000 genetic diseases; next-generation sequencing has dramatically revolutionized the diagnosis of genetic diseases. Most genetic diseases are considered very rare or ultrarare, defined here as having fewer than 1:100,000 cases, but only one of the 12 approved gene therapies (excluding RNA therapies) targets an ultrarare disease. This article explores three gene supplementation therapy approaches suitable for various rare genetic diseases: lentiviral vector-modified autologous CD34+ hematopoietic stem cell transplantation, systemic delivery of adeno-associated virus (AAV) vectors to the liver, and local AAV delivery to the cerebrospinal fluid and brain. Together with RNA therapies, we propose a potential business model for these gene therapies. [ABSTRACT FROM AUTHOR]

Due to the imperfect development of the brain and the varied biological, environmental, and experiential elements that arise during childhood and adolescence, paediatric neuropsychology differs from adult neuropsychology. According to current theories, certain brain regions have a reciprocal effect on various neuro functioning systems, which, in turn, affects the child's ability to think and perceive. The interaction of functioning systems most likely affects the child's behavioural, psychological, and cognitive manifestation of a childhood condition. These days, parents worry about their children doing well in school. A variety of intelligence scores are utilised to evaluate children's cognitive abilities. Intelligence research is important since it sheds light on the individual's qualities, shortcomings, and special talents. Currently, a large number of standardised tests are used since intelligence is seen as a measurable commodity. When diagnosing dyslexia, attention-deficit/hyperactivity disorder, autism spectrum disorders, intellectual disability, and other problems in the paediatric population, intelligence scales play a critical role. It is vital to recognise that every exam has a unique set of constraints. This paper explores the benefits and drawbacks of the currently utilised intelligence measures while offering an overview of each. The goal of this evaluation is to make it easier to analyse different intelligence measures and decide which ones are applicable for what circumstances and needs. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is an intractable neuromuscular disorder primarily caused by homozygous deletions in exon 7 of the SMN1 gene. Early diagnosis and prompt treatment of patients with SMA have a significant impact on prognosis, and several therapies have recently been developed. Current SMA screening tests require a significant turnaround time to identify patients with suspected SMA, due both to the interval between the birth of a newborn and the collection of blood for newborn mass screening and the difficulty in distinguishing between SMN1 and SMN2, a paralog gene that requires testing in specialized laboratories. The aim of this study was therefore to develop a novel SMA screening assay that can be rapidly performed in ordinary hospitals and clinics to overcome these issues. We designed over 100 combinations of forward and reverse primers with 3′ ends targeting SMN1-specific sites around exon 7, and evaluated their specificity and amplification efficiency by quantitative PCR to identify the best primer pair. Furthermore, we performed a single-stranded tag hybridization assay after PCR. To evaluate the accuracy and practicality of the newly developed assay, we analyzed saliva specimens from five patients with SMA and two SMA carriers collected in an outpatient clinic and DNA specimens from three patients with SMA and four SMA carriers from a biobank, together with those from healthy individuals. DNA and raw saliva specimens from all patients with SMA demonstrated a biallelic loss of SMN1, whereas those from carriers and healthy individuals did not. The results of 50 independent experiments were consistent for all samples. The assay could be completed within one hour. This simple and convenient new screening tool has the potential to allow patients with SMA to receive disease-modifying therapies within a shorter timeframe. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Behcet Uz Children's Hospital is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]