Spinal Muscular Atrophy Research Articles

Effect of E134K pathogenic mutation of SMN protein on SMN-SmD1 interaction, with implication in spinal muscular atrophy: A molecular dynamics study

Spinal muscular atrophy (SMA) is a disease that results from mutations in the Survival of Motor Neuron (SMN) gene 1, leading to muscle atrophy due to motor neurons degeneration. SMN plays a crucial role in the assembly of spliceosomal small nuclear ribonucleoprotein complexes via binding to the arginine-glycine rich C-terminal tails of Sm proteins recognized by SMN Tudor domain. E134K Tudor mutation, cause of the more severe type I SMA, compromises the SMN-Sm interaction without a perturbation of the domain fold. By molecular dynamics simulations, we investigated the mechanism of Tudor-SmD1 interaction, and the effects on it of E134K mutation. It was observed that E134 is crucial to catch the positive dimethylated arginines (DMRs) of the SmD1 tail that, wrapping around the acidic Tudor surface, enters a central DMR into an aromatic cage. The flexible cage residue Y130 must be blocked from the wrapped tail to assure a stable binding.The charge inversion in E134K mutation causes the loss of a critical anchor point, disfavoring the tail wrapping and leaving Y130 free to swing, leading to DMR detachments and exposition of the C-terminal region of the tail. This could suggest new hypotheses regarding a possible autoimmune response by anti-Sm autoantibodies.

Beyond Motor Neurons in Spinal Muscular Atrophy: A Focus on Neuromuscular Junction.

5q-Spinal muscular atrophy (5q-SMA) is one of the most common neuromuscular diseases due to homozygous mutations in the SMN1 gene. This leads to a loss of function of the SMN1 gene, which in the end determines lower motor neuron degeneration. Since the generation of the first mouse models of SMA neuropathology, a complex degenerative involvement of the neuromuscular junction and peripheral axons of motor nerves, alongside lower motor neurons, has been described. The involvement of the neuromuscular junction in determining disease symptoms offers a possible parallel therapeutic target. This narrative review aims at providing an overview of the current knowledge about the pathogenesis and significance of neuromuscular junction dysfunction in SMA, circulating biomarkers, outcome measures and available or developing therapeutic approaches.

Androgen receptor post-translational modifications and their implications for pathology.

A major mechanism to modulate the biological activities of the androgen receptor (AR) involves a growing number of post-translational modifications (PTMs). In this review we summarise the current knowledge on the structural and functional impact of PTMs that affect this major transcription factor. Next, we discuss the cross-talk between these different PTMs and the presence of clusters of modified residues in the AR protein. Finally, we discuss the implications of these covalent modifications for the aetiology of diseases such as spinal and bulbar muscular atrophy (Kennedy's disease) and prostate cancer, and the perspectives for pharmacological intervention.

Relationship Between Hand Strength and Function in Duchenne Muscular Dystrophy and Spinal Muscular Atrophy: Implications for Clinical Trials.

Measurement of muscle strength and motor function is recommended in clinical trials of neuromuscular diseases, but the loss of hand strength at which motor function is impacted is not documented. To establish the relationship between hand strength and function, and to determine the strength threshold that differentiates normal and abnormal hand function in individuals with Duchenne Muscular Dystrophy (DMD) or Spinal Muscular Atrophy (SMA). Maximal handgrip and key pinch strength were measured with the MyoGrip and MyoPinch dynamometers, respectively. Hand function was assessed using the MoviPlate, the Motor Function Measure items for distal upper limb (MFM-D3-UL) and the Cochin Hand Function Scale (CHFS). Data from 168 participants (91 DMD and 77 SMA, age 6-31 years) were analyzed. Relationships between strength and function were significant (P < 0.001). Hand function was generally preserved when strength was above the strength threshold determined by Receiver-Operating Characteristic (ROC) analysis: For MFM-D3-UL, the calculated handgrip strength thresholds were 41 and 13% of the predicted strength for a healthy subject (% pred) and the key pinch strength thresholds were 42 and 26% pred for DMD and SMA, respectively. For the MoviPlate, handgrip strength thresholds were 11 and 8% pred and key pinch strength thresholds were 21 and 11% pred for DMD and SMA, respectively. For participants with sub-threshold strength, hand function scores decreased with decreasing strength. At equal % pred strength, individuals with SMA had better functional scores than those with DMD. Hand function is strength-dependent for most motor tasks. It declines only when strength falls below a disease-specific threshold. Therefore, therapies capable of maintaining strength above this threshold should preserve hand function.

Assessing the Swallowing Function in Children with Spinal Muscular Atrophy: An Easily Accessible and Objective Multidimensional Approach.

Spinal muscular atrophy (SMA), a genetic neuromuscular disease caused by lack of survival of motor neuron (SMN) protein, is characterized by muscular atrophy and respiratory and bulbar dysfunction. While swallowing disorders are common, they remain poorly studied. Our study aimed to explore 1) intraoral pressure measurements with the Iowa Oral Performance Instrument system and the reliability of a Swallowing Function Assessment Questionnaire (SFAQ) in healthy controls, and 2) evaluate their use as swallowing function biomarkers and the evolution of swallowing function over time in children with SMA. We recruited 53 healthy children and 27 SMA patients all treated with SMN gene modulator therapy. Participants completed the SFAQ and underwent at least one measurement of maximal oral pressures (lingual, labial, and masseter). Mean oral normalized pressure index were lower (all sites p < 0.001) and mean SFAQ scores were higher (p < 0.001) in patients compared with healthy controls. Pressure evolution over 1 year in SMA patients for all three oral sites did not show significant differences. SFAQ scores correlated negatively with oral pressures at all three sites in patients. Both tools provided new insights on the oral and pharyngeal phase of swallowing in SMA patients. In SMA patients, muscle strength in certain crucial anatomical regions during swallowing is weaker than in healthy children.

Nusinersen effectiveness and safety in pediatric patients with 5q-spinal muscular atrophy: a multi-center disease registry in China

ObjectiveTo evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients.MethodsUsing a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results.ResultsAs of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4–5.4) and 4.1 (2.8–5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7–3.1) and 2.3 (1.2–3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5–5.3) and 4.3 (2.6–6.0) in HFMSE, and 2.1 (1.2–3.0) and 1.5 (0.0–3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae.ConclusionsThese data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance.

Role of senataxin in R-loop-mediated neurodegeneration.

Senataxin is an RNA:DNA helicase that plays an important role in the resolution of RNA:DNA hybrids (R-loops) formed during transcription. R-loops are involved in the regulation of biological processes such as immunoglobulin class switching, gene expression and DNA repair. Excessive accumulation of R-loops results in DNA damage and loss of genomic integrity. Senataxin is critical for maintaining optimal levels of R-loops to prevent DNA damage and acts as a genome guardian. Within the nucleus, senataxin interacts with various RNA processing factors and DNA damage response and repair proteins. Senataxin interactors include survival motor neuron and zinc finger protein 1, with whom it co-localizes in sub-nuclear bodies. Despite its ubiquitous expression, mutations in senataxin specifically affect neurons and result in distinct neurodegenerative diseases such as amyotrophic lateral sclerosis type 4 and ataxia with oculomotor apraxia type 2, which are attributed to the gain-of-function and the loss-of-function mutations in senataxin, respectively. In addition, low levels of senataxin (loss-of-function) in spinal muscular atrophy result in the accumulation of R-loops causing DNA damage and motor neuron degeneration. Senataxin may play multiple functions in diverse cellular processes; however, its emerging role in R-loop resolution and maintenance of genomic integrity is gaining attention in the field of neurodegenerative diseases. In this review, we highlight the role of senataxin in R-loop resolution and its potential as a therapeutic target to treat neurodegenerative diseases.

Engineered Branaplam Aptamers Exploit Structural Elements from Natural Riboswitches.

Drug candidates that fail in clinical trials for efficacy reasons might still have favorable safety and bioavailability characteristics that could be exploited. A failed drug candidate could be repurposed if a receptor, such as an aptamer, were created that binds the compound with high specificity. Branaplam is a small molecule that was previously in development to treat spinal muscular atrophy and Huntington's disease. Here, we report the development of a small (48-nucleotide) RNA aptamer for branaplam with a dissociation constant of ∼150 nM. Starting with a combinatorial RNA pool integrating the secondary and tertiary structural scaffold of a Guanine-I riboswitch aptamer interspersed with regions of random sequence, in vitro selection yielded aptamer candidates for branaplam. Reselection and rational design were employed to improve binding of a representative branaplam aptamer candidate. A resulting variant retains the pseudoknot and two of the paired elements (P2 and P3) from the scaffold but lacks the enclosing paired element (P1) that is essential for the function of the natural Guanine-I riboswitch aptamer. A second combinatorial RNA pool based on the scaffold for TPP (thiamin pyrophosphate) riboswitches also yielded a candidate offering additional opportunities for branaplam aptamer development.

Health-related quality of life of adults with spinal muscular atrophy: insights from a nationwide patient registry in Germany.

Spinal muscular atrophy (SMA) is a rare, autosomal-recessive disease characterized by progressive muscular atrophy and weakness resulting in substantial disability and short life expectancy. The objective of this cross-sectional study was to assess health-related quality of life (HRQoL) of adults with SMA in Germany in the era of disease-modifying therapy. Adults with SMA were recruited via the German national TREAT-NMD SMA patient registry. HRQoL was measured using the EQ-5D-5L, the Health Utilities Index Mark III (HUI), and the Short Form (36) Health Survey (SF-36). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). A total of 82 adults with SMA (mean age: 42years, 51% female) self-completed the study questionnaire. The mean EQ-5D-5L utility was estimated at 0.5135 (range across subgroups: 0.31-0.99), mean EQ-VAS at 69.71 (64.67-90.00), mean HUI-derived utility at 0.3171 ( - 0.02-0.96), mean SF-6D utility at 0.6308 (0.58-0.65), and mean SF-36 Physical Component Summary and Mental Health Component Summary scores at 33.78 (9.92-53.10) and 53.49 (21.02-72.25), respectively. We show that adults with SMA experience considerable impairment across a wide range of health dimensions, including mobility, dexterity, pain, and emotional well-being. However, our results exhibit non-trivial variability across clinical subgroups and HRQoL measures. These data contribute to our understanding of the subjective impact of living with a severely debilitating neuromuscular disease, such as SMA.

Recent Advance in Disease Modifying Therapies for Spinal Muscular Atrophy

Abstract Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease characterized by progressive weakness and atrophy of skeletal muscles. With homozygous survival motor neuron 1 (SMN1) gene mutation, all SMA patients have at least one copy of the SMN2 gene, which provides an opportunity for drug targeting to enhance SMN expression. Current three disease modifying drugs, including nusinersen, onasemnogene abeparvovec, and risdiplam, have demonstrated impressive effectiveness in SMA treatment. Nusinersen is an antisense oligonucleotide targeting SMN2 pre-messenger RNA (mRNA) to modify alternative splicing and is effective in SMA children and adults, administrating via intermittent intrathecal injection. Onasemnogene abeparvovec is an adeno-associated viral vector carrying human SMN1 gene, featuring intravenous injection once in a lifetime for SMA patients less than 2 years of the age. Risdiplam is a small molecule also targeting SMN2 pre-mRNA and is effective in SMA children and adults with administration via oral intake once per day. Patients with SMA should receive these disease modifying therapies as soon as possible to not only stabilize disease progression, but potentially obtain neurological improvement. The development in these therapies has benefited patients with SMA and will potentially provide insight in future drug discovery for other neurodegenerative diseases.

Brazilian version of the Hammersmith Functional Motor Scale Expanded: cross-cultural adaptation and validation.

The Hammersmith Functional Motor Scale Expanded (HFMSE) has been widely used to assess the motor function of patients with spinal muscular atrophy (SMA) older than 2 years, with the ability to sit and/or walk. To translate, cross-culturally adapt and validate the HFMSE to Brazilian Portuguese. The translation process and cross-cultural adaptation followed international guidelines recommendations. The reliability and applicability of the Brazilian version consisted of the application of the HFMSE (in Brazilian Portuguese) to 20 patients with types 2 and 3 SMA. Two examiners assessed the participants for interrater reliability, through the analysis of Kappa reliability agreement (k) and intraclass correlation coefficient (ICC). The HFMSE was successfully translated and cross culturally adapted to Brazilian Portuguese. Twenty participants with types 2 and 3 SMA were enrolled in the study (type 2 = 6; type 3 = 14). The ICC for the total score showed very high reliability (ICC =1.00), and the reliability of each of the items individually was considered excellent (Kappa > 0.80). The Brazilian version of the HFMSE proved to be valid and reliable for the evaluation of SMA patients older than 2 years with the ability to sit and/or walk.

Analysis of the efficacy and adverse effects of nusinersen in the treatment of children with spinal muscular atrophy in China.

This study was based on a retrospective clinical observational cohort study of a two-center application of nusinersen in China to evaluate the clinical efficacy and adverse effects of nusinersen in the treatment of SMA (spinal muscular atrophy) Types 1-3. Clinical data from children with clinically and genetically confirmed 5qSMA from a double center in western China (the Second Affiliated Hospital of Xi'an Jiaotong University and the Second Hospital of West China of Sichuan University). All children were younger than 18 years of age. Patients were assessed for motor function and underwent blood and fluid tests before each nusinersen injection. At 14-month follow-up, 100% of children had improved their HFMSE (Hammersmith Functional Motor Scale Expanded) score, 83.6% had improved their CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) score, and 66.6% had improved their RULM (Revised Upper Limb Module) score by ≥3 points from baseline, and their 6MWT (6-min walk test) was 216.00±52.08m longer than at baseline. The age of the child at the start of treatment was negatively correlated with the clinical efficacy of nusinersen; the younger the child, the better the response to treatment. No significant adverse effects affecting the treatment and quality of life of the child were observed during the treatment of SMA with nusinersen. This study concluded that nusinersen is clinically beneficial for children with SMA in western China, with mild adverse effects.

Evaluating the Novel Use of Unmanned Video Objective Structured Clinical Examination Stations in Pediatric Resident Training: Results and Insights

Abstract Background: Objective structured clinical examination (OSCE) is vital in assessing medical trainees’ clinical competence. Unlike the traditional resource-intensive OSCE, video-based OSCE has advantages like asynchronous assessment and more immediate feedback. However, their applicability and effectiveness in pediatric residency training are less explored. This study aims to evaluate the feasibility and outcomes of using unmanned video OSCE stations in pediatric residency training. Materials and Methods: A cross-sectional study was conducted with 79 pediatric residents participating in OSCE mock stations. Video clips showing real-life clinical scenarios were played. Residents then responded electronically to scenario-related multiple-choice questions. Descriptive statistics were employed to analyze residents’ responses to multiple-choice questions. Results: In a study of 79 physicians, the majority were female (63.3%) and under 34 years old (62%), with most receiving their training outside Riyadh (79.7%). Their clinical understanding, assessed through a nonmanned OSCE video, varied: 16.5% accurately diagnosed spinal muscular atrophy in infants, while 48.1% correctly identified laryngomalacia in 2-month-olds. The average knowledge score was 2.89 out of 7, with a standard deviation of 1.19. Notably, 43% answered three scenarios correctly. Analysis showed no significant correlation between the physicians’ gender, age, or training location and their knowledge scores, indicating diverse expertise levels irrespective of these demographic factors. Conclusion: Unmanned video OSCE stations show promise in enhancing pediatric residency training assessments by providing instant feedback and streamlining the evaluation process. However, challenges and the need for targeted interventions should be considered. Future research should focus on refining technology integration and assessing long-term impacts on residents’ clinical skills and patient care outcomes. Ensuring the privacy and security of video recordings is essential in this technologically evolving landscape.

A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia

Cytochrome-c oxidase (COX) is part of the mitochondrial complex IV (CIV). COX deficiency is usually associated with tRNA variants, and less frequently with variants in COX assembly factors. Mutations in COX subunits encoded by mitochondrial DNA and nuclear DNA are rare, likely because most of them are associated to very severe phenotypes with early lethality. COX18, an assembly factor of CIV, has long been analyzed as a potential cause of mitochondrial disease. To date, only one patient has been identified carrying a homozygous missense variant in COX18, associated with neonatal encephalo-cardiomyopathy and axonal sensory neuropathy. Here, we describe a 40-year-old patient, asymptomatic until 7 months of age, who presented with progressive muscle weakness resembling spinal muscle atrophy type-2, associated with oculofacial apraxia and dysarthric speech. Electrophysiology analysis highlighted a severe sensory-motor neuropathy. Muscle biopsy showed striking and diffuse decreases of COX staining and a substantial reduction of CIV activity. Muscle biopsy showed no ragged-red fibers, although ultrastructural mitochondrial alterations were evident. A novel homozygous variant (c.598G>A), located in the last nucleotide of exon 3, was detected in COX18 by whole-exome sequencing, which affected the splicing donor site, as demonstrated by cDNA-seq. The patient fibroblasts express a truncated form of COX18 (COX18Δ112-240) capable of assembling CIV and CIV-involving supercomplexes. However, CIV activity was decreased. COX18 full-length (COX18-fl) overexpression partially rescued CIV activity in the patient fibroblasts. The rescue of the null CIV activity in COX18-KO-HEK293 cells by overexpressing of COX18Δ112-240 was significantly lower than in cells with COX18-fl. In addition, cox-18 downregulation in C. elegans resulted in slow growth and, diminished reduced motility phenotypes and as well as severe fragmentation of the mitochondrial network. Our case expands the phenotypes associated with COX18 variants and supports the pathogenic role of COX18 as the cause of a severe encephaloneuropathy syndrome.

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing datasets.

Spinal muscular atrophy (SMA) is a genetic disorder that causes progressive degeneration of lower motor neurons and the subsequent loss of muscle function throughout the body. It is the second most common recessive disorder in individuals of European descent and is present in all populations. Accurate tools exist for diagnosing SMA from genome sequencing data. However, there are no publicly available tools for GRCh38-aligned data from panel or exome sequencing assays which continue to be used as first line tests for neuromuscular disorders. This deficiency creates a critical gap in our ability to diagnose SMA in large existing rare disease cohorts, as well as newly sequenced exome and panel datasets. We therefore developed and extensively validated a new tool - SMA Finder - that can diagnose SMA not only in genome, but also exome and panel sequencing samples aligned to GRCh37, GRCh38, or T2T-CHM13. It works by evaluating aligned reads that overlap the c.840 position of SMN1 and SMN2 in order to detect the most common molecular causes of SMA. We applied SMA Finder to 16,626 exomes and 3,911 genomes from heterogeneous rare disease cohorts sequenced at the Broad Institute Center for Mendelian Genomics as well as 1,157 exomes and 8,762 panel sequencing samples from Tartu University Hospital. SMA Finder correctly identified all 16 known SMA cases and reported nine novel diagnoses which have since been confirmed by clinical testing, with another four novel diagnoses undergoing validation. Notably, out of the 29 total SMA positive cases, 23 had an initial clinical diagnosis of muscular dystrophy, congenital myasthenic syndrome, or myopathy. This underscored the frequency with which SMA can be misdiagnosed as other neuromuscular disorders and confirmed the utility of using SMA Finder to reanalyze phenotypically diverse neuromuscular disease cohorts. Finally, we evaluated SMA Finder on 198,868 individuals that had both exome and genome sequencing data within the UK Biobank (UKBB) and found that SMA Finder's overall false positive rate was less than 1 / 200,000 exome samples, and its positive predictive value (PPV) was 97%. We also observed 100% concordance between UKBB exome and genome calls. This analysis showed that, even though it is located within a segmental duplication, the most common causal variant for SMA can be detected with comparable accuracy to monogenic disease variants in non-repetitive regions. Additionally, the high PPV demonstrated by SMA Finder, the existence of treatment options for SMA in which early diagnosis is imperative for therapeutic benefit, as well as widespread availability of clinical confirmatory testing for SMA, warrants the addition of SMN1 to the ACMG list of genes with reportable secondary findings after genome and exome sequencing.

Integrated Approaches and Practical Recommendations in Patient Care Identified with 5q Spinal Muscular Atrophy through Newborn Screening.

In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and skeletal deformities. Recognizing the pre-symptomatic phases supported by screening and confirmatory genetic tests is crucial for early diagnosis. This work addresses key considerations in implementing 5q-SMA screening within the Brazilian National Newborn Screening Program and explores Brazil's unique challenges and opportunities, including genetic tests, time-to-patient referral to specialized centers, program follow-up, and treatment algorithms. We aim to guide healthcare professionals and policymakers, facilitating global discussions, including Latin American countries, and knowledge-sharing on this critical subject to improve the care for newborns identified with 5q SMA.

Quality considerations and major pitfalls for high throughput DNA-based newborn screening for severe combined immunodeficiency and spinal muscular atrophy

Quality considerations and major pitfalls for high throughput DNA-based newborn screening for severe combined immunodeficiency and spinal muscular atrophy

Measurement properties of the EQ-5D-Y-3L, PedsQL 4.0, and PROMIS-25 Profile v2.0 in pediatric patients with spinal muscular atrophy

ObjectiveThe objective of this study was to examine the psychometric properties of the EQ-5D-Y-3 L, Patient Reported Outcomes Measurement System 25-item version profile v2.0 (PROMIS-25), and Pediatric Quality of Life Inventory™ version 4.0 Generic Core Scale (PedsQL 4.0) in Chinese pediatric patients with spinal muscular atrophy (SMA).MethodsThe data used in this study were obtained via a web-based cross-sectional survey. Parents of pediatric patients with SMA completed the proxy-reported EQ-5D-Y-3 L, PedsQL 4.0, and PROMIS-25 measures. Information about socioeconomic and health status was also obtained. The ceiling and floor effects, factorial structure, convergent validity, and known-group validity of the three measures were assessed.ResultsThree hundred and sixty-three parents of children aged from 5 to 12 completed the questionnaires. Strong floor effects were observed for the physical function components of the PROMIS-25 (41.3%) and PedsQL 4.0 (67.8%). For EQ-5D-Y-3 L, 84.6% of the respondents reported having “a lot of” problems with the dimensions “walking” and “looking after myself.” Minimal ceiling or floor effects were observed for the EQ-5D-Y-3 L index value. The confirmatory factor analysis supported a six-factor structure for the PROMIS-25, but did not support a four-factor structure for the PedsQL 4.0. All hypothesized correlations of the dimensions among the three measures were confirmed, with coefficients ranging from 0.28 to 0.68. Analysis of variance showed that EQ-5D-Y-3 L demonstrated better known-group validity than the other two measures in 14 out of 16 comparisons.ConclusionsThe EQ-5D-Y-3 L showed better discriminant power than the other two measures. The physical health dimensions of all three measures showed the significant floor effects. These findings provide valuable insights into the effectiveness of these measures at capturing and quantifying the impact of SMA on patients’ health-related quality of life.

Reproductive genetic carrier screening in pregnancy: improving health outcomes and expanding access.

Reproductive genetic carrier screening (RGCS) serves to screen couples for their risk of having children affected by monogenic conditions. The included conditions are mostly autosomal recessive or X-linked with infantile orearly-childhood onset. Cystic fibrosis, spinal muscular atrophy, and hemoglobinopathies are now recommended by the American College of Obstetricians and Gynecologists (ACOG) for universal screening. Recommendations for further RGCS remain ethnicity based. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors in recent years have recommended universal expanded-panel RGCS and moving towards a more equitable approach. ACOG guidelines state that offering RGCS is an acceptable option, however it has not provided clear guidance on standard of care. Positive results on RGCS can significantly impact reproductive plans for couples, including pursuing invitro fertilization with preimplantation genetic testing, prenatal genetic testing, specific fetal orneonatal treatment, or adoption. RGCS is a superior approach compared to ethnicity-based carrier screening and moves away from single race-based medical practice. We urge the obstetrics and gynecology societies to adopt the guidelines for RGCS put forward by multiple societies and help reduce systemic inequalities in medicine in our new genetic age. Having national societies such as ACOG and theSociety for Maternal-Fetal Medicine officially recommend and endorse RGCS would bolster insurance coverage and financial support by employers for RGCS. The future of comprehensive reproductive care in the age of genomic medicine entails expanding access so patients and families can make the reproductive options that best fit their needs.

Insights into spinal muscular atrophy from molecular biomarkers.

Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness. It is one of the most common genetic causes of mortality among infants aged less than 2 years. Biomarker research is currently receiving more attention, and new candidate biomarkers are constantly being discovered. This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons. We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy, which are classified as either specific or non-specific biomarkers. This review provides new insights into the pathogenesis of spinal muscular atrophy, the mechanism of biomarkers in response to drug-modified therapies, the selection of biomarker candidates, and would promote the development of future research. Furthermore, the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.