The investigation included 70 people with genetically confirmed 5q SMA recruited from centres in Germany and Belgium, together with comparison groups of 31 patients with ALS, 31 with Alzheimer’s disease and 31 disease controls who had no evidence of neurodegeneration based on clinical evaluation, cerebrospinal fluid analysis and neuroimaging. SMA participants underwent repeated blood sampling and clinical assessment. The main follow-up points were 9–16 months and 22–26 months after baseline, while an exploratory cohort of eight Halle patients was sampled at approximately 50–58 months but had no corresponding baseline data. All 70 patients with SMA received nusinersen or risdiplam at follow-up: 45 received nusinersen and 25 received risdiplam. Because the study was retrospective, relied on available observations at each time point and had incomplete sampling at some visits, its longitudinal findings were considered exploratory rather than confirmatory.

Serum p-tau181 and p-tau217 were quantified with single-molecule array immunoassays, while neurofilament light chain was measured with a separate automated assay. Group differences were evaluated with multiple linear regression adjusted for age and sex, using SMA as the reference category. Concentrations of p-tau181 differed across the diagnostic groups in the overall model, with p less than 0.001. The adjusted coefficient for disease controls was −0.48, with a 95% confidence interval of −0.81 to −0.15, indicating lower p-tau181 in controls than in SMA. Levels were higher in ALS, with a coefficient of 0.99 and 95% confidence interval of 0.58 to 1.39, and in Alzheimer’s disease, with a coefficient of 0.56 and 95% confidence interval of 0.11 to 1.00. For p-tau217, no difference was detected between SMA and disease controls: the coefficient was −0.09, with a 95% confidence interval of −0.22 to 0.05. Levels of p-tau217 were higher in both ALS and Alzheimer’s disease than in SMA. The results show that the two phosphorylated tau species did not behave as interchangeable measures across these conditions.

Centre-specific analyses added nuance to the pooled comparisons. In the Ulm cohort, p-tau181 was lower in disease controls than in SMA, with a coefficient of −0.52 and 95% confidence interval of −0.73 to −0.31, but no clear difference was detected between SMA and either ALS or Alzheimer’s disease. In Leuven, the SMA-control difference was not detected, with a coefficient of −0.20 and 95% confidence interval of −0.56 to 0.17, while p-tau181 was higher in ALS and Alzheimer’s disease than in SMA. The Halle baseline group contained only two patients and was not statistically tested. For p-tau217, neither Ulm nor Leuven showed a clear SMA-control difference, although both cohorts had higher concentrations in ALS and Alzheimer’s disease than in SMA. These variations mean the overall diagnostic-group pattern should not be interpreted as a uniform, validated threshold for distinguishing SMA from other conditions.

Within-person comparisons produced the clearest longitudinal result. Among 56 patients with measurements at both baseline and follow-up 2, p-tau181 decreased by a median of 1.80 pg/mL, with an interquartile range of −5.90 to 2.10 pg/mL; the paired Wilcoxon signed-rank test gave p = 0.017. No relevant change was detected between baseline and follow-up 1 among 29 paired patients, when the median difference was 0.17 pg/mL, or between follow-up 1 and follow-up 2 among 28 paired patients, when it was 0.00 pg/mL. P-tau217 showed no relevant change at any interval. An unpaired analysis using all available samples at each time point did not detect significant differences among baseline, follow-up 1 and follow-up 2, showing how the conclusion depended on which patients could be paired. The eight-patient exploratory group had p-tau values within the upper range of earlier observations, but its size and lack of baseline samples prevented statistical testing or paired analysis.

Linear mixed-effects models, with repeated observations accounted for and estimates adjusted for age, sex and other applicable variables, linked both p-tau species to several clinical measures. Higher p-tau181 and p-tau217 concentrations were associated with higher Hammersmith Functional Motor Scale Expanded scores, higher Revised Upper Limb Module scores and higher forced vital capacity as a percentage of the predicted value; all corresponding false-discovery-rate-adjusted p values were below 0.001. In the Leuven risdiplam-treated subgroup, where the Motor Function Measure 32 was available, both biomarkers were also positively associated with total and domain scores, although those analyses were exploratory because they were restricted to one centre and a limited sample. Concentrations were lower with longer disease duration, and ambulatory participants had higher levels than non-ambulatory patients. Thus, higher circulating p-tau was linked to better preserved motor and respiratory function, rather than simply indicating more severe impairment.

Creatine kinase was positively associated with both p-tau181 and p-tau217, with false-discovery-rate-adjusted p values below 0.001, whereas neither biomarker showed a significant association with neurofilament light chain after correction for multiple testing. The authors considered this pattern consistent with the possibility that peripheral p-tau in SMA is more closely related to denervated or remodelling muscle than to ongoing neuroaxonal injury. They also proposed that p-tau181 and p-tau217 may capture different aspects of motor-neuron and muscle pathology. These interpretations remain mechanistic hypotheses, however, because the study did not directly measure tau release from tissue, analyse p-tau in cerebrospinal fluid alongside serum, or use imaging and electrophysiology to locate its biological source. The absence of an association with neurofilament light chain should therefore be viewed as an observed result within this cohort, not direct proof of a peripheral origin.

Exploratory multivariable regression models suggested a possible prognostic association while showing substantial uncertainty. Higher baseline p-tau181 was associated with a greater decline in the Hammersmith Functional Motor Scale Expanded by follow-up 2, with a coefficient of 1.79 and 95% confidence interval of 0.59 to 2.99. The corresponding estimate for p-tau217 was 1.60, with a 95% confidence interval of −0.13 to 3.33, indicating a less certain association. Neither biomarker was clearly associated with change in the Revised Upper Limb Module; in those exploratory models, male sex and older age accounted for more of the observed variation. Motor scores remained broadly stable during follow-up, and ceiling effects in adult SMA may have limited the sensitivity of upper-limb analyses. The p-tau181 association was therefore characterized as preliminary and hypothesis-generating, and it requires independent confirmation before it can be regarded as a prognostic marker.

The findings also raise questions about the interpretation of blood p-tau measurements in people with motor neuron disorders. Because p-tau181 was higher in SMA and ALS than in non-neurodegenerative controls, elevated circulating p-tau may occur without concurrent Alzheimer-type pathology. The comparison is strengthened by the study’s exclusion of ALS participants with positive or unknown amyloid-tau-neurodegeneration status and by the cerebrospinal-fluid biomarker criteria used to define the Alzheimer’s disease group. At the same time, the retrospective design, modest sample size, few time points, advanced disease stage in many participants, missing body-mass-index data and absence of paired cerebrospinal-fluid measurements limit how broadly the results can be generalized. Future studies involving earlier-stage SMA, more consistent serial sampling, cerebrospinal fluid and serum collected together, and imaging or electrophysiological measures would be needed to determine whether p-tau181 adds reliable value to clinical assessment or whether it mainly provides information about muscle-related processes in adult SMA.

Subject of Research: Serum phosphorylated tau biomarkers and clinical measures in 5q spinal muscular atrophy

Article Title: Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy

Article References: Stapf, C. D., Uzelac, Z., Iterbeke, L., Guthknecht, A., Barba, L., Strube, D., Kölsch, A., Kleeberg, K., Kendzierski, T., Roos, A., Steinacker, P., Abu-Rumeileh, S., Claeys, K. G., Weishaupt, J., Mensch, A., & Otto, M. (2026). Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy. Journal of Neurology, 273(11), Article 672. https://doi.org/10.1007/s00415-026-14194-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14194-1

Keywords: spinal muscular atrophy, p-tau181, p-tau217, blood biomarkers, motor function, muscle turnover, denervation, creatine kinase, longitudinal study, tau protein, Serum, levels

The scientific foundation for this transformation was laid in 1995, when a landmark study identified SMN1 as the disease-causing gene. The authors found that SMN1 was deleted in 98.7 percent of patients in a 229-person cohort and mutated in the remainder. Crucially, humans carry a nearly identical backup copy called SMN2, which differs by a single base-pair transition from C to T in exon seven. That single nucleotide inactivates an exonic splicing enhancer and introduces an exonic splicing silencer, causing roughly 90 percent of the protein produced from SMN2 to be truncated and degraded by cellular machinery. Because SMA severity is inversely related to the number of SMN2 copies a patient carries, this backup gene became the central target for drug development.

Three FDA-approved disease-modifying therapies now anchor the treatment landscape. Nusinersen, marketed as Spinraza, is an antisense oligonucleotide that binds to a specific site within SMN2 pre-mRNA to promote inclusion of exon seven, restoring production of full-length SMN protein. Its development traced back to the discovery of an intronic splicing silencer called ISS-N1, and animal studies showed that blocking this element dramatically increased exon seven inclusion. The pivotal Phase 3 ENDEAR trial demonstrated significant improvement in infants with SMA Type 1, leading to accelerated FDA approval in 2016. Notably, in early 2026 the FDA approved a higher-dose regimen based on the DEVOTE study, with a safety profile consistent with more than a decade of clinical data.

Onasemnogene abeparvovec, known commercially as Zolgensma, takes a fundamentally different approach. It is a non-replicating adeno-associated virus serotype 9 vector that delivers a full-length SMN1 gene under the control of a hybrid promoter, capable of crossing the blood-brain barrier to reach spinal motor neurons after a single intravenous injection. A meta-analysis conducted four years after the drug’s release found mostly positive results, particularly in patients treated early in life, with motor milestone improvements that in many studies exceeded those achieved with nusinersen. A biodistribution study of post-mortem patient tissue confirmed vector genome presence throughout the central nervous system and in peripheral organs including skeletal muscle, heart, lung, and stomach.

Risdiplam, sold as Evrysdi, is the most recent addition and the first orally administered small-molecule SMN2 splicing modifier. The compound stabilizes the interaction between the 5-prime splice site on exon seven and the U1 small nuclear ribonucleoprotein, strengthening the splice site and reducing degradation. Unlike nusinersen, risdiplam crosses the blood-brain barrier because it does not bind to multi-drug resistant protein 1 and therefore cannot be pumped out of the central nervous system. A striking case study even documented prenatal therapy, with the drug administered orally to a mother carrying a confirmed SMA Type 1 fetus beginning at 32 weeks and 5 days of gestation; at 30 months of age, the child showed no manifestations of the disease. In a matching-adjusted indirect comparison, risdiplam-treated Type 1 patients showed a 78 percent reduction in mortality relative to historical nusinersen cohorts.

Despite these remarkable gains, the review emphasizes that the therapies are not curative. In 2024, approximately 75 percent of patients in the CureSMA database had received at least one disease-modifying therapy, yet only 47 percent of children and 19 percent of adults with SMA are ambulatory. Since the dawn of the therapy era, SMA mortality has dropped by nearly 80 percent, but 36 percent of patients still require some form of breathing support, and 89 percent of adults report that reaching new motor milestones remains their greatest unmet need. As patients live longer, a constellation of comorbidities has come into sharper focus, reshaping the clinical agenda.

Orthopedic complications illustrate this shift vividly. Between 60 and 90 percent of children with SMA develop scoliosis, which can complicate the intrathecal injections required for nusinersen and, if untreated, lead to chest deformities that further impair pulmonary function. Respiratory failure remains the leading cause of death, implicated in 72 percent of known SMA fatalities in a recent review. Gastrointestinal problems, including chronic constipation, dysphagia, and gastroesophageal reflux, are common, and eating difficulties can produce metabolic abnormalities such as glucose intolerance and insulin resistance. Cardiac irregularities, though less frequent, have been documented in infantile patients, ranging from congenital heart defects to cardiomyopathy.

The review also delves deeply into why motor neurons are selectively vulnerable to SMN deficiency, a question that remains only partially answered. SMN protein is best known for assembling small nuclear ribonucleoproteins, the complexes essential for recognizing splice sites and removing introns from pre-mRNA. Motor neurons harbor disproportionately high numbers of Cajal bodies, the nuclear structures where snRNP maturation is completed, likely reflecting their extraordinary demand for RNA metabolism to sustain constant electrical signaling. Low SMN reduces Cajal body numbers and, by extension, ribosome production. SMN also interacts with mRNA-binding proteins such as HuD, IMP1, and beta-actin that govern axonal transport and growth, and its deficiency disrupts neuromuscular junction maturation before symptoms even appear.

Looking forward, the authors survey a rich pipeline of alternative strategies. Induced pluripotent stem cells derived from patient skin fibroblasts have become powerful tools for drug screening and disease modeling, revealing pathways such as Fas ligand-mediated apoptosis and calcium dysregulation in cardiomyocytes. Gene editing approaches are particularly striking: a one-time base editing technique achieved an average of 87 percent permanent conversion of the disease-causing point mutation in mouse models with no detected off-target effects, while CRISPR-based prime editing of the ISS-N1 silencer sequence restored full-length SMN2 production in patient cells. Epidural spinal cord stimulation in a small cohort of adults produced a 40 percent increase in mean step length over four weeks, with benefits persisting even when the stimulator was switched off.

The review closes with a call for combination treatment strategies that build on existing therapies while addressing residual disease burden. Investigational agents such as apitegromab, a monoclonal antibody that blocks myostatin’s inhibition of skeletal muscle growth, are already being tested alongside approved drugs. The authors stress that SMA is fundamentally a multi-organ disease requiring multifactorial management, and that future research must ensure patients of all ages, including the growing population of adults living with the disease, are represented in treatment development. What began as a uniformly fatal diagnosis has become a chronic, manageable condition for many, but converting survival into truly restored function remains the defining challenge of the next decade.

Subject of Research: Disease-modifying therapies and future treatment directions for spinal muscular atrophy

Article Title: Spinal muscular atrophy in the disease-modifying therapy era: successes, limitations and future directions

Article References: Sexton, M. M., Crow, E. W., & Peng, C. A. (2026). Spinal muscular atrophy in the disease-modifying therapy era: successes, limitations and future directions. Frontiers in Molecular Medicine, 6, Article 1901311. https://doi.org/10.3389/fmmed.2026.1901311

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1901311

Keywords: spinal muscular atrophy, SMN1, SMN2, nusinersen, onasemnogene abeparvovec, risdiplam, gene therapy, motor neurons, antisense oligonucleotide, comorbidities, base editing, iPSCs

Mary Ellen Avery’s legacy provides the intellectual template for this kind of work. In the 1950s, Avery demonstrated that respiratory distress syndrome in premature newborns was caused by a deficiency of pulmonary surfactant, the lipoprotein mixture that keeps the tiny air sacs of the lung from collapsing with each breath. That insight, derived from careful basic science, eventually produced surfactant replacement therapy, one of the most consequential interventions in modern neonatology. The lesson embedded in her career is that a mechanistic discovery, pursued patiently over decades, can be converted into a system delivered to every infant who needs it. It is precisely that conversion, from knowledge to infrastructure, that the award celebrates.

Chung’s own work sits at the intersection of genetics, pediatrics, and public health. As a human geneticist who has led large-scale genomic medicine initiatives, she has focused on a question that sounds simple but is operationally formidable: which conditions should be looked for in every newborn, and how should the results be delivered to families in a way that changes outcomes rather than merely generating anxiety? The answer determines whether a diagnosis arrives in time to alter the course of a disease or only in time to explain it retrospectively.

The clearest recent example comes from spinal muscular atrophy, a genetic disorder that was, until recently, the leading inherited cause of infant mortality. SMA is caused by loss or mutation of the SMN1 gene, which produces a protein survival motor neurons require. Infants with the most severe form lose motor neurons progressively in the first months of life, and before effective therapy existed, most died of respiratory failure before their second birthday. The disease, however, has a crucial property that makes it an ideal target for newborn screening: intervention is dramatically more effective when it begins before symptoms appear, because motor neurons that have not yet been lost can be preserved.

The therapeutic landscape changed with the development of disease-modifying treatments, most prominently nusinersen, an antisense oligonucleotide that alters splicing of the related SMN2 gene so that it produces more functional survival motor neuron protein. The pivotal randomized trial published in the New England Journal of Medicine in 2017 showed that infants treated with nusinersen had significantly better motor-function outcomes than those receiving a sham control procedure. Suddenly, a fatal diagnosis became a treatable condition, but only if it was identified early enough. Screening became the bottleneck: without systematic detection at birth, infants would still present with established weakness, at which point the therapeutic window had narrowed.

Chung and colleagues addressed this directly in New York State, where a pilot study of population-based newborn screening for spinal muscular atrophy demonstrated that molecular screening could be integrated into existing public health infrastructure. The technical approach relies on detecting the homozygous deletion of SMN1 in dried blood spots, the same heel-prick specimens already collected from every newborn for dozens of metabolic and genetic conditions. The pilot study, published in Genetics in Medicine, established feasibility, laboratory workflow, and the clinical pathway connecting a positive screen to confirmatory testing and rapid treatment initiation. New York subsequently moved from pilot to universal screening, and the model has since been adopted across a growing number of states and countries.

The same logic has been extended to Duchenne muscular dystrophy, another severe neuromuscular condition in which early identification may enable earlier access to emerging therapies. A two-year pilot study of newborn screening for Duchenne in New York, reported in Annals of Clinical and Translational Neurology, evaluated the performance of screening for elevated creatine kinase and confirmatory genetic testing in dried blood spots. These pilots illustrate a recurring pattern in Chung’s career: rigorous, unglamorous implementation science that determines whether a screening concept can actually function at population scale, with acceptable rates of false positives, clear follow-up protocols, and equitable reach across diverse communities.

Chung’s most ambitious project in this space is the GUARDIAN study, a genomic newborn screening program conducted in New York that screened tens of thousands of infants for hundreds of genetic conditions, many of which are actionable in early childhood. Unlike traditional newborn screening, which targets a fixed panel of biochemical markers, genomic screening reads the infant’s DNA directly, allowing a single platform to detect conditions ranging from metabolic disorders to hearing loss to cardiac arrhythmia syndromes. The study received in-kind contributions from GeneDx and Illumina, and its results are shaping the debate over how much genetic information should be gathered at birth and how families should be counseled about findings that range from urgently actionable to uncertain.

The GUARDIAN study also raises the ethical and logistical questions that any system of universal early care must confront. Screening an entire population inevitably identifies infants with variants of uncertain significance, conditions that may never cause symptoms, and incidental findings unrelated to the reason for testing. The design of the program, with defined gene panels focused on childhood-onset, actionable conditions, reflects an attempt to balance the promise of early intervention against the risks of overdiagnosis and medicalization of healthy infancy. Chung’s framing of the work, as building systems of care rather than simply tests, emphasizes that a screen is only as valuable as the clinical pathway behind it: confirmatory diagnostics, genetic counseling, treatment access, and long-term follow-up.

The deeper argument of the Avery Award lecture is historical and structural. Medicine tends to organize itself around the sick patient who arrives at the clinic, but the greatest gains in pediatric health have come from systems that reach children before illness declares itself: vaccination schedules, congenital hypothyroidism screening, hearing screening, pulse oximetry for critical congenital heart disease, and now genomic screening. Each of these required decades of persistence, coalition-building among scientists, public health officials, advocacy groups, and families, and a willingness to demonstrate value through pilot data before universal implementation. Chung’s career, from her leadership in identifying the genetic basis of conditions to her role in designing and executing population screening programs, exemplifies the long gestational period that careers in physician science often require before the birth of innovation reaches patients. In honoring that journey, the Society for Pediatric Research signals to the next generation of pediatrician-scientists that the highest-impact work may not be a single discovery but the patient construction of systems that ensure every child, starting at birth, benefits from what medicine already knows.

Subject of Research: Newborn screening and systems of early pediatric care, including genomic screening for treatable genetic conditions

Article Title: The journey to establishing systems of care for all children, starting at birth: the Society for Pediatric Research’s 2026 Mary Ellen Avery award

Article References: Chung, W. K. (2026). The journey to establishing systems of care for all children, starting at birth: the Society for Pediatric Research’s 2026 Mary Ellen Avery award. Pediatric Research. https://doi.org/10.1038/s41390-026-05580-6

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05580-6

Keywords: newborn screening, spinal muscular atrophy, Mary Ellen Avery, Wendy Chung, GUARDIAN study, genomic medicine, nusinersen, Duchenne muscular dystrophy, pediatric research, public health, SMN1, early intervention

The technical backdrop to their argument is a field advancing on multiple fronts simultaneously. A review by Pan and colleagues, published in the same journal, traces how CRISPR-Cas9 and its increasingly refined descendants, including base editing, prime editing, and AI-guided RNA design, are converging with cell and vector engineering to offer potentially curative options for children with rare monogenic diseases. Base editing chemically converts one DNA letter into another without cutting both strands of the double helix, while prime editing allows more precise insertions and deletions with fewer unwanted byproducts. Machine learning tools are accelerating the design of RNA molecules and delivery vehicles, shortening development timelines that once stretched over decades.

The clinical results are no longer theoretical. Several gene therapy products now carry approval from the Food and Drug Administration or the European Medicines Agency for pediatric indications, and dozens more sit in active clinical trials. Diseases once uniformly fatal or progressively disabling, such as spinal muscular atrophy and metachromatic leukodystrophy, now have potentially curative options. The commentary describes this as an inflection point, but one whose promise is fragile, because access for children today and development of new therapies tomorrow hinge on coverage decisions made in insurance boardrooms as much as in laboratories.

Price is the most visible obstacle. Atidarsagene autotemcel, marketed as Lenmeldy, is a one-time therapy for metachromatic leukodystrophy with a list price of 4.25 million dollars, making it among the most expensive medicines ever approved. Onasemnogene abeparvovec, sold as Zolgensma, is a single infusion for spinal muscular atrophy priced near 2.1 million dollars. Exagamglogene autotemcel, known as Casgevy, the first CRISPR-edited cell therapy approved for sickle cell disease, and lovotibeglogene autotemcel, or Lyfgenia, a lentiviral-edited counterpart, list in a similar range. These figures dwarf the cost of conventional orphan drugs and raise immediate questions about affordability for health plans serving children.

Yet the authors caution against reading these prices as simple profiteering. The costs reflect the genuine expense of manufacturing an individualized cell or gene product, a process that involves harvesting a patient’s own cells, engineering them in specialized facilities, performing quality control, and returning them to the patient, all under regulatory scrutiny. Independent health economic assessments have judged several of these therapies cost-effective when measured against the lifetime value of a one-time cure compared with years or decades of standard care, which for conditions like sickle cell disease includes repeated hospitalizations, transfusions, and pain crises. From that perspective, a multimillion-dollar price tag can represent a bargain over a lifetime, even as it creates an acute budget shock for any single insurer.

This tension between long-term value and short-term affordability lies at the heart of the coverage problem. A child treated at age three may remain enrolled with a health plan for only a few years before the family changes jobs or coverage, meaning the insurer that pays for the cure may never capture the savings from avoided care. Economists describe this as a mismatch between who pays and who benefits, and it gives payers a rational incentive to delay or deny coverage in the hope that someone else will bear the cost. For families, the consequence is that access can depend on the accident of which insurance plan covers a child in a given year.

The commentary also examines the frontier of ultra-rare disease, where the economics become even more difficult. Landmark cases such as patient-specific in vivo gene editing for a rare genetic condition and patient-customized oligonucleotide therapy, each developed for a single individual, have demonstrated that bespoke treatments are technically feasible. But therapies designed for one or a handful of patients will never recoup their development costs through sales, no matter how high the price. The authors point to proposed funding approaches for N-of-1 trials of individualized gene-targeted therapies and to efforts to overcome barriers to commercially pre-viable gene and cell therapies for rare and ultra-rare diseases as signs that researchers and policymakers are searching for models that do not depend on conventional market returns.

Regulatory innovation is moving in parallel. The FDA has launched a framework for accelerating the development of individualized therapies for ultra-rare diseases, an acknowledgment that the agency’s traditional pathways were designed for drugs manufactured at scale rather than treatments built for one patient. On the payment side, the Centers for Medicare and Medicaid Services have expanded access to gene therapies through innovative state agreements, and proposals for a national benefit for cell and gene therapies have been advanced in health policy forums. These arrangements, including outcome-based contracts in which manufacturers receive full payment only if a therapy works as promised, represent early attempts to spread risk between manufacturers, payers, and the public.

For the pediatric community, the stakes are unusually high because timing matters in a way it does not in adult medicine. Many of the conditions targeted by gene editing are progressive, and the therapies work best, or only, when administered before irreversible organ damage occurs. Newborn screening programs increasingly identify affected infants in the first days of life, creating a narrow window in which regulatory approval, insurance authorization, manufacturing capacity, and clinical delivery must all align. A delay of months in coverage negotiation can convert a curative intervention into a palliative one, which is why the authors frame payment policy as an integral component of the therapy itself rather than an administrative afterthought.

The commentary closes with a call to build the policy environment deliberately rather than reactively. The authors argue that without coordinated action on coverage, reimbursement, and financing, the remarkable science described by Pan and colleagues will reach only a fraction of the children who could benefit, and that uncertain payment prospects may deter investment in therapies for the rarest conditions of all. The tools of molecular biology have, in their telling, largely been proven; the rulebook that determines who can use them is still being written, and the next chapter will be drafted not by geneticists but by policymakers, insurers, and the families advocating for their children.

Subject of Research: Insurance coverage and reimbursement policy for pediatric gene and cell therapies

Article Title: Editing the rulebook: building the policy environment for children to access gene therapy

Article References: Pulcini, C. D., Chua, K.-P., Conti, R. M., On behalf of the Pediatric Policy Council, Keller, D., Montez, K., Ragavan, M., Lorch, S., Plax, K., Cheng, T., Geme, J. S., Lakshmanan, A., & Mariani, T. J. (2026). Editing the rulebook: building the policy environment for children to access gene therapy. Pediatric Research. https://doi.org/10.1038/s41390-026-05588-y

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05588-y

Keywords: gene therapy, CRISPR, pediatrics, health policy, insurance coverage, drug pricing, rare disease, sickle cell disease, spinal muscular atrophy, reimbursement, base editing, ultra-rare disease

The biology behind spinal muscular atrophy explains why this region has long frustrated diagnosticians. The disease is caused by loss or mutation of the SMN1 gene, which encodes a protein essential for the survival of motor neurons. Humans, however, carry a nearly identical backup copy called SMN2, distinguished by a single nucleotide change at position c.840 in exon 7. That one base difference alters how SMN2 pre-messenger RNA is spliced, so most SMN2 transcripts are translated into a truncated, unstable protein that is rapidly degraded. Each SMN2 copy produces only about ten percent of the functional protein generated by SMN1, and the proportion varies across tissues. Because the two genes are more than ninety-nine percent identical, distinguishing them requires reading across the entire roughly 28.5-kilobase locus, something short-read sequencing struggles to accomplish reliably.

Traditional testing reflects these limitations. Quantitative PCR can detect homozygous deletions of SMN1 exons 7 and 8, the molecular signature of most SMA cases, but it cannot report precise copy numbers or identify point mutations. Multiplex ligation-dependent probe amplification, or MLPA, reliably measures SMN1 and SMN2 copy numbers and detects exon rearrangements, yet it cannot resolve haplotypes or sequence-level variants. Neither method can determine whether a person with two SMN1 copies carries both on one chromosome or one on each, a distinction that matters enormously for reproductive risk. A so-called 2+0 silent carrier, with both copies on a single chromosome, appears normal on standard screening but faces the same one-in-four chance of having an affected child as a classic 1+1 carrier when paired with another carrier.

Single-molecule real-time sequencing sidesteps these obstacles through sheer read length. In the new study, researchers at Zhangzhou Municipal Hospital extracted genomic DNA from peripheral blood, amplified the full-length SMN1 and SMN2 genes together with their downstream regions using long-range PCR, and ligated the amplicons into dumbbell-shaped SMRTbell libraries. These libraries were sequenced on a Sequel II CNDx platform in circular consensus sequencing mode for thirty hours, generating high-fidelity reads that span the entire locus. Because each read covers the whole gene, the c.840 site unambiguously labels each molecule as SMN1 or SMN2, allowing the software to count copies of each gene separately and scan for point mutations at the same time. The technology carries no GC bias and handles the highly repetitive sequence architecture of this region that defeats shorter reads.

The clinical validation was striking. Among the 771 screened individuals, SMRT sequencing and qPCR produced fully concordant results in one hundred percent of samples. The most common genotype was two copies each of SMN1 and SMN2, found in 55.25 percent of participants, followed by a 2:1 ratio in 29.44 percent. Two SMN1 copies were present in 91.18 percent of the cohort, but the distribution revealed important outliers: 2.33 percent of individuals carried only one SMN1 copy and were classified as deletion carriers, yielding a carrier frequency of 2.33 percent, consistent with previously reported rates of 1.2 to 2.2 percent in Chinese populations. More provocatively, 6.36 percent carried three SMN1 copies and one individual carried four, indicating that at least two SMN1 genes sit on a single chromosome in these people, a configuration that standard qPCR cannot distinguish from the benign two-copies-on-two-chromosomes arrangement.

That finding carries direct reproductive consequences. Individuals with elevated SMN1 copy numbers may be silent carriers whose risk is invisible to conventional screening, since qPCR reports only total copy number without allele distribution. The study authors note that definitive assignment of 2+0 status still requires family-based haplotype phasing and pedigree analysis, which lay beyond the scope of the current work. Even so, the results underscore a hidden reservoir of reproductive risk in the general population. With roughly one in fifty people in many populations carrying an SMN1 deletion, and couples who are both carriers facing a one-in-four chance of an affected child in each pregnancy, carrier screening has become a public health priority, and the accuracy of that screening depends entirely on the resolution of the underlying technology.

The study also catalogued the distribution of SMN2, the modifier gene that shapes disease severity. Two copies of SMN2 were the most common configuration at 57.59 percent, one copy accounted for 33.07 percent, and small fractions of individuals carried three or four copies. Notably, 6.10 percent of the screened population carried homozygous SMN2 deletions, a genotype that is not itself disease-causing but eliminates the compensatory buffer that SMN2 provides. Because SMN2 copy number is inversely related to clinical severity in SMA patients, knowing a patient’s SMN2 count helps predict disease course and informs treatment decisions, particularly now that disease-modifying therapies exist for a condition that was, until recently, essentially untreatable.

Four qPCR-confirmed SMA patients served as independent validation cases, and their stories illustrate both the technology’s power and the disease’s variability. Patient 1, a 16-year-old female with severe scoliosis who first showed hand tremors at twelve months, had zero copies of SMN1 and three copies of SMN2 confirmed by all three methods, consistent with SMA type II. Patient 2, a 12-year-old male unable to walk independently at seventeen months, showed the same molecular profile with profound proximal weakness and absent reflexes, also diagnosed as type II. Patient 3, a 17-year-old male with flexion contractures, generalized hypotonia, and complete lower limb paralysis, carried zero SMN1 copies and three SMN2 copies but was classified as type I. Patient 4, a three-month-old male with hypotonia since birth, had zero SMN1 copies and two SMN2 copies, with electromyography revealing nerve fiber damage across multiple limbs, confirming type I disease. No pathogenic point mutations were detected in any patient.

The discordance among patients sharing three SMN2 copies is scientifically telling. Three of the four patients carried the same SMN2 count yet spanned two clinical types, echoing a large analysis of 1,627 SMA patients with three SMN2 copies in which fifteen percent had type I disease, fifty-four percent type II, and thirty-one percent type III. The relationship between copy number and severity is clearly not a simple inverse correlation; even among patients with four or five SMN2 copies, one and five percent respectively still develop type I disease. Whether different SMN2 variants possess distinct functional properties, or whether modifying mutations within SMN2 influence its compensatory capacity, remains an open question that the authors flag for future investigation.

The study’s limitations are candidly acknowledged. Point mutations in SMN1 account for roughly two percent of SMA carrier alleles, yet none were detected in this cohort, a result that may reflect their genuine rarity or a sample size insufficient to capture such infrequent events. Larger-scale studies will be needed to validate the technology’s performance on rare genotypes. Nevertheless, the trajectory is clear: SMA genetic testing has evolved from single-site detection toward whole-gene, haplotype-level analysis, and long-read sequencing has already matured into clinical practice for other monogenic disorders such as thalassemia and congenital adrenal hyperplasia. With its ability to resolve copy numbers, haplotypes, and point mutations in a single assay across one of the human genome’s most treacherous paralogous regions, single-molecule real-time sequencing appears poised to become a cornerstone of SMA diagnosis, carrier screening, and genetic counseling, potentially catching silent carriers that today’s methods routinely miss.

Subject of Research: Clinical application of single-molecule real-time long-read sequencing for spinal muscular atrophy diagnosis and carrier screening

Article Title: Clinical Practice of Single‐Molecule Real‐Time Sequencing in the Diagnosis of Spinal Muscular Atrophy

Article References: Wei, H., Zheng, Y.-W., Zhang, N.-K., Gao, T.-L., Zheng, J.-X., Li, T.-Y., & Hong, S.-R. (2026). Clinical Practice of Single‐Molecule Real‐Time Sequencing in the Diagnosis of Spinal Muscular Atrophy. Molecular Genetics & Genomic Medicine, 14(10), Article e70314. https://doi.org/10.1002/mgg3.70314

Image Credits: AI Generated

DOI: 10.1002/mgg3.70314

Keywords: spinal muscular atrophy, SMRT sequencing, SMN1, SMN2, long-read sequencing, carrier screening, genetic diagnosis, copy number variation, qPCR, MLPA, motor neuron disease, genetic counseling

The research, led by Vanessa Campes Dannenberg and Maria L. Castro-Codesal of the University of Alberta, together with colleagues at the Hospital for Sick Children in Toronto and the Alberta Children’s Hospital in Calgary, examined the medical records of 115 children and young people with neuromuscular disorders who were recommended for home non-invasive ventilation, or NIV, between 2010 and 2023. Most of the participants were male, with a median age of 11.8 years at the time of ventilation initiation. The most common diagnoses were Duchenne muscular dystrophy, accounting for 39 percent of the cohort, congenital muscular dystrophies at 19 percent, and spinal muscular atrophy at 14 percent. Nearly every child in the study carried at least one additional chronic condition, with a median of four comorbidities per patient, underscoring how medically complex this population is.

The central question was deceptively simple: when three different sets of polysomnography-based criteria are applied to the same overnight sleep study, do they identify the same children as needing breathing support? The team compared the 2023 guidelines from the American College of Chest Physicians, known as CHEST, against the traditional American Academy of Sleep Medicine, or AASM, definitions of moderate-to-severe obstructive sleep apnea and nocturnal hypoventilation, and against a new set of REM-related criteria proposed by the authors themselves. The CHEST criteria, drawn from a European Respiratory Society statement on pediatric long-term ventilation, flag children whose end-tidal or transcutaneous carbon dioxide exceeds 50 mmHg for at least 2 percent of total sleep time, or rises by 10 mmHg above their waking baseline, or whose oxygen saturation drops below 90 percent for at least 2 percent of sleep time or five continuous minutes.

Those thresholds matter because they are far more sensitive than the older AASM definitions, which require carbon dioxide to exceed 50 mmHg for a full 25 percent of total sleep time before labeling a child as hypoventilating. The results were striking. Only 9 percent of the children met the AASM-based hypoventilation criterion, while the CHEST guidelines identified 25 percent, and the REM-related criteria caught 12 percent. For nocturnal hypoxemia, for which the AASM framework offers no initiation criterion at all, the CHEST guidelines identified 22 percent of the cohort and the REM-related criteria 15 percent. In total, 71 percent of the children met at least one NIV initiation criterion across the three criteria sets, but a meaningful minority were visible only through the newer lenses.

Agreement between the criteria sets, measured with kappa statistics, told a nuanced story. Overall agreement between the CHEST and REM-related criteria was moderate, with a kappa of 0.71, and agreement on nocturnal hypoxemia between those two sets was similarly moderate at 0.69. The strongest agreement, a kappa of 0.86, emerged between the CHEST and AASM criteria on the apnea-hypopnea index, which is unsurprising given that both frameworks use similar thresholds of five or more respiratory events per hour. The divergence, in other words, was not about counting apneas and hypopneas. It was about the slow, silent buildup of carbon dioxide and the dips in oxygen that occur without any discrete respiratory event, particularly during the muscle atonia of REM sleep.

That physiology is the heart of the study’s argument. In children with neuromuscular weakness, breathing during REM sleep depends heavily on the diaphragm, because the intercostal and upper airway muscles lose their tone in that stage. When the diaphragm is also weak, carbon dioxide accumulates and oxygen levels fall, often without producing a single scored apnea. As the disease progresses, these abnormalities spread into non-REM sleep and eventually into wakefulness, culminating in chronic respiratory failure. The authors’ proposed REM-related criteria were designed to capture this earliest phase, and the analysis showed that an additional 11 percent of children met REM-related indications that the AASM-based criteria missed entirely. Thirteen percent of the cohort, twelve children, met no AASM-based criteria at all but satisfied at least one CHEST and one REM-related criterion.

The study also looked at what happened after ventilation began. Ninety-six percent of the children, 111 in total, successfully started NIV, and 73 percent of them sustained the therapy for six to twelve months, the window the researchers chose to avoid the acclimatization period when adherence is typically unstable. Adherence was respectable: children used the machine for a median of six hours per night, and on a median of 60 percent of nights they managed more than four hours of use. Clinician-documented reports from routine visits described improvements in general health in 34 percent of children, better sleep quality in 36 percent, and improved breathing during sleep in 25 percent. Most children avoided emergency department visits, ward admissions, and intensive care during the follow-up period.

Notably, the study found no significant differences in lung function before and after NIV initiation in any of the criteria groups, and no differences in adherence or clinical outcomes between groups. The authors attribute this largely to the substantial overlap among the three groups, since most children met the apnea-hypopnea thresholds common to all criteria sets. They also caution that NIV does not reverse the decline in lung function driven by the underlying disease; at best, it slows the trajectory, and changes are influenced by disease-modifying therapies and the natural history of each disorder. Only about half of the cohort could perform lung function testing that met American Thoracic Society technical standards, further limiting those comparisons.

The findings carry real weight for clinical practice. Earlier work in children with Duchenne muscular dystrophy had already suggested that disease-specific criteria could prompt ventilation for an additional 22 percent of children compared with standard AASM definitions. This study extends that insight to a broader neuromuscular population and adds a physiological rationale: many children show REM-related hypoventilation or hypoxemia with a normal apnea-hypopnea index, and the CHEST guidelines, by lowering the carbon dioxide threshold and adding an explicit hypoxemia criterion, are built to detect exactly that pattern. This matters especially for conditions such as myotonic dystrophy, in which discrete respiratory events are less common but carbon dioxide retention can still be dangerous.

The researchers acknowledge the limits of their retrospective design, their reliance on chart documentation, and the overlap that prevented subgroup comparisons. They also note that future studies may be difficult to conduct, because withholding ventilation until advanced hypoventilation develops would now be ethically questionable. Still, their conclusion is clear and forward-looking: guidelines for children with neuromuscular disease should integrate disease-specific and sleep-stage-specific polysomnographic criteria, watching REM sleep closely for the first signs of failure. Caught early, supported by a mask and a machine at home, these children may avoid the steepest part of the respiratory decline that has long defined their prognosis.

Subject of Research: Polysomnographic criteria for initiating non-invasive ventilation in children with neuromuscular diseases

Article Title: Establishing polysomnographic criteria for initiation of non-invasive ventilation in children with neuromuscular diseases

Article References: Dannenberg, V. C., Amin, R., Anagnostopoulos, G., Adeleye, A., Bendiak, G. N., Kolski, H., & Castro-Codesal, M. L. (2026). Establishing polysomnographic criteria for initiation of non-invasive ventilation in children with neuromuscular diseases. Journal of Clinical Sleep Medicine, 22(1), Article 117. https://doi.org/10.1007/s44470-026-00102-x

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00102-x

Keywords: neuromuscular disease, non-invasive ventilation, polysomnography, REM sleep, sleep-disordered breathing, nocturnal hypoventilation, Duchenne muscular dystrophy, spinal muscular atrophy, pediatric sleep medicine, CHEST guidelines, AASM criteria, nocturnal hypoxemia

The study, published in the journal Advances in Therapy, drew on the Komodo Health Research Database, one of the largest longitudinal healthcare claims datasets in the country, covering approximately 330 million individuals across commercial insurance, Medicare, and Medicaid programs. Researchers led by Walter Toro Jimenez of Novartis Pharmaceuticals Corporation, together with colleagues at Analysis Group, examined claims recorded between January 2016 and October 2024 to reconstruct how patients with spinal muscular atrophy actually move through the therapeutic landscape. Because the data capture routine clinical care rather than the carefully controlled conditions of a clinical trial, the findings offer a rare window into how the promise of these therapies is being translated into everyday practice.

The biology underlying the disease explains why treatment has evolved so rapidly. Spinal muscular atrophy results from homozygous deletions or mutations in the SMN1 gene, which deprives the body of survival motor neuron protein and triggers the progressive degeneration of motor neurons in the spinal cord. A second gene, SMN2, produces small amounts of the same protein, and the severity of disease generally tracks with how much functional protein the SMN2 copies can generate. All three approved therapies work by increasing the output of that backup gene, but they do so through strikingly different mechanisms. Nusinersen, approved in 2016, is an antisense oligonucleotide injected into the spinal canal that corrects the splicing of SMN2 transcripts. Risdiplam, approved in 2020, is an oral small molecule that achieves the same splicing modulation through daily dosing. Onasemnogene abeparvovec, approved in 2019 as an intravenous infusion for children under two, delivers a functional copy of the SMN1 gene directly into cells using a viral vector, effectively replacing the missing genetic instructions in a single administration.

The clearest signal in the new analysis comes from the youngest patients. Among 257 children who initiated their first disease-modifying therapy at age two or younger during 2022 through 2024, a period after newborn screening had become widely available across most of the United States, 64.6 percent began with onasemnogene abeparvovec, 24.9 percent with risdiplam, and only 10.5 percent with nusinersen. The contrast with the immediate post-approval era is stark. An earlier study using a different claims database covering January 2017 through March 2021 found that just 16.2 percent of children under two received the gene therapy, while 83.8 percent received nusinersen. The researchers attribute the reversal largely to newborn screening, which was introduced in the US in 2018 and now identifies affected infants before symptoms appear, allowing treatment to begin at the stage when clinical trials have shown the greatest benefit.

Equally revealing is what happens after the first treatment. Children who started with the gene therapy were the least likely to add a second therapy type: only 12.0 percent of them did so, compared with 20.3 percent of those who began with risdiplam and 55.6 percent of those who began with nusinersen. Among the subset of 209 children with the most severe, type 1 form of the disease, the pattern held, with 8.3 percent of gene therapy recipients adding a second therapy versus 60.9 percent of nusinersen recipients and 18.5 percent of risdiplam recipients. The implication is that a single gene replacement appears to satisfy treatment needs for most infants, whereas patients on the chronic, repeat-dosing therapies more often end up adding or switching to another modality, most frequently the gene therapy itself.

To understand sequencing across the full age spectrum, the researchers assembled a second cohort of 341 patients with types 1 through 3 of the disease who received at least two different therapy types between May 2019, when at least two options became available, and October 2024. This group was markedly older, with a mean age of 15.4 years at the start of their first recorded therapy, and reflected an era when nusinersen was the only option: 75.4 percent of them began with the antisense oligonucleotide, 15.2 percent with risdiplam, and 9.4 percent with the gene therapy. Within this cohort, risdiplam was the most common second treatment, received by 76.2 percent of patients, followed by nusinersen at 13.2 percent and the gene therapy at 10.6 percent. Only five patients, or 1.5 percent, progressed to a third therapy type. The median interval between the first and second treatments was 18.9 months, though the timing varied by starting therapy, from 21.7 months for nusinersen starters to 13.2 months for those who began with risdiplam.

The picture changes again when the analysis is restricted to the 44 children who received multiple therapies and began treatment at age two or younger during 2022 through 2024, the true newborn screening generation. In this group, first treatments were distributed far more evenly, with 36.4 percent starting on the gene therapy, 34.1 percent on nusinersen, and 29.5 percent on risdiplam. When these children did move to a second therapy, the gene therapy dominated: 52.3 percent received onasemnogene abeparvovec as their second treatment, 45.5 percent received risdiplam, and just 2.3 percent received nusinersen. All of the children who had started on risdiplam, and most of those who had started on nusinersen, went on to receive the gene therapy. The median time from first to second treatment in this young cohort was 13.4 months, and the researchers suggest that some patients may have received the oral or injectable therapies as a bridge while awaiting gene therapy, while others switched because of the demonstrated value of gene replacement in previously treated patients.

The data also expose the growing complexity of managing a disease that now has multiple viable treatment pathways. A 2023 community survey cited in the study reported that 47.4 percent of children with spinal muscular atrophy had received more than one therapy type, with families and physicians citing reasons that included wanting a different treatment, physician recommendation, the desire to pursue every available option, and loss of motor function. The claims analysis adds a further wrinkle: among young children treated with multiple therapies, 20.0 percent of those who started on nusinersen and 38.5 percent of those who started on risdiplam later received the same therapy again after initiating a second one. Whether this reflects concurrent use, re-initiation after a gap, or something else cannot be determined from claims data alone, but the authors note that it points to increasing treatment complexity and burden for patients and caregivers alike.

The study has important caveats, which the authors acknowledge candidly. Claims databases lack the clinical measures, such as motor function scores, disease severity, and genetic modifiers like SMN2 copy number, that would allow researchers to connect treatment sequencing to outcomes. The specific reasons behind any switch, whether efficacy concerns, adverse effects, or issues of access and insurance coverage, are invisible in billing records. Disease type itself had to be inferred from an established algorithm based on age at diagnosis and patterns of clinical activity, raising the possibility of misclassification, particularly among pre-symptomatic infants identified by screening in whom distinguishing clinical features have not yet emerged. Birth-year service dates are masked for privacy, which forced the exclusion of the small fraction of patients, 5.2 percent, who received multiple therapy types in their first year of life, and small subgroup sizes limit the precision of some estimates.

Even with those limitations, the analysis stands as the first large-scale, real-world description of how patients with spinal muscular atrophy navigate an era of multiple disease-modifying options, and its message is unambiguous: newborn screening has reshaped the field, gene replacement therapy now anchors early treatment, and sequential multi-therapy strategies have become an ordinary feature of care rather than an exception. The landscape is still shifting. In 2025, regulators approved an intrathecal formulation of onasemnogene abeparvovec for patients aged two and older, meaning that for the first time all three therapeutic modalities are available across the full age range. Future studies, the authors write, will need to examine treatment sequencing across that broader population, control for the confounding factors that claims data cannot capture, and, most critically, link sequencing strategies to long-term clinical outcomes as the therapeutic story of this once untreatable disease continues to unfold.

Subject of Research: Real-world treatment sequencing patterns among patients with spinal muscular atrophy receiving multiple disease-modifying therapies

Article Title: Real-World Treatment Patterns in Patients with Spinal Muscular Atrophy Receiving Multiple Disease-Modifying Therapies

Article References: Toro Jimenez, W., Yang, M., Song, W., Ye, D., Lemus Wirtz, E., Meehan, J., & Reyna, S. (2026). Real-World Treatment Patterns in Patients with Spinal Muscular Atrophy Receiving Multiple Disease-Modifying Therapies. Advances in Therapy. https://doi.org/10.1007/s12325-026-03710-4

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03710-4

Keywords: spinal muscular atrophy, onasemnogene abeparvovec, nusinersen, risdiplam, gene therapy, newborn screening, disease-modifying therapy, treatment patterns, SMN1, SMN2, motor neuron disease, real-world evidence

The letter responds to a study by Dannenberg and colleagues, published earlier in the same journal, that set out to establish polysomnographic criteria for starting non-invasive ventilation in children with neuromuscular disease. That original investigation addressed a genuine gap. For decades, clinicians have relied on a patchwork of guidelines, expert consensus, and institutional habit when interpreting sleep studies in this population, and the thresholds used to declare a sleep study abnormal have varied widely between centers. Any serious attempt to standardize those thresholds therefore deserves attention, and the letter writers acknowledge the value of the effort even as they probe its foundations.

Polysomnography, the overnight sleep test at the center of this debate, records a remarkable array of physiological signals: brain electrical activity through electroencephalography, eye movements that mark rapid eye movement sleep, muscle tone at the chin and limbs, airflow at the nose and mouth, respiratory effort through chest and abdominal belts, and blood oxygen saturation through pulse oximetry, alongside carbon dioxide measurement where available. In healthy children, breathing during sleep is remarkably stable, particularly in non-REM stages. In children with weakened respiratory muscles, however, the physiology changes in characteristic ways, and understanding those changes is essential to understanding why the criteria debate matters so much.

The key vulnerability lies in REM sleep. During REM, the body’s skeletal muscles, with the exception of the diaphragm and the extraocular muscles, lose their tone as part of the brainstem’s protective mechanism that prevents sleepers from acting out dreams. In a child whose intercostal muscles and accessory breathing muscles are already weakened by conditions such as Duchenne muscular dystrophy or spinal muscular atrophy, this REM-related muscle atonia can leave the diaphragm working alone against the resistance of a floppy chest wall. The result is shallow, inefficient breathing confined to REM periods, with oxygen saturation drifting downward and carbon dioxide accumulating, often without any dramatic apneas to catch an automated scoring algorithm’s attention. This pattern, sometimes called REM-related hypoventilation, is typically the earliest sleep-breathing abnormality in progressive neuromuscular disease.

Because the earliest abnormalities are subtle and stage-specific, the choice of polysomnographic thresholds carries enormous weight. Should the trigger for considering ventilation be a certain number of oxygen desaturations per hour, a defined percentage of sleep time spent below a saturation cutoff, an elevated transcutaneous or end-tidal carbon dioxide level, or some combination of these? Each option has methodological trade-offs. Desaturation indices borrowed from adult obstructive sleep apnea practice may miss the slow, sustained gas exchange deterioration typical of neuromuscular disease, where the abnormality is hypoventilation rather than discrete apneic events. Carbon dioxide measures, though more directly relevant to hypoventilation, are technically finicky in children, prone to signal drift and displacement, and not uniformly available across sleep laboratories.

These technical uncertainties form one strand of the letter’s argument. The authors raise methodological considerations about how criteria derived from a particular patient population and a particular set of recording practices can be generalized. Reference values for pediatric sleep studies differ by age, and children with neuromuscular disease span a wide developmental range, from toddlers with congenital myopathies to adolescents with advanced dystrophinopathies. A single threshold applied across that spectrum risks misclassifying both the youngest patients, whose normal physiology differs from school-age children, and those with slowly versus rapidly progressive conditions, whose trajectories of respiratory decline follow very different clocks.

The clinical considerations the authors emphasize are equally important. Polysomnography captures a single night, a snapshot that may not represent a child’s typical sleep, particularly in an unfamiliar laboratory environment where the first-night effect can suppress REM sleep and mask the very abnormalities clinicians are hunting for. A child whose REM time is curtailed on the study night may appear deceptively normal. Conversely, transient illness, nasal congestion, or anxiety can exaggerate abnormalities. Serial monitoring, careful correlation with daytime symptoms such as morning headaches, excessive sleepiness, poor school performance, and frequent nocturnal awakenings, and attention to trends over time may matter as much as any single numeric cutoff.

The stakes of getting these criteria right extend well beyond the sleep laboratory. Long-term non-invasive ventilation reshapes family life. Research on children with neuromuscular diseases who use ventilators, including work by Johannsen and colleagues cited in the letter, has examined the impact of long-term ventilator use on health-related quality of life and the mental health of affected children and their families, highlighting the need for a revised perspective on how these burdens are weighed. Initiating ventilation is not merely a technical prescription; it commits families to nightly routines, equipment maintenance, and an enduring reminder of disease progression. Criteria that are too permissive risk imposing these burdens without benefit, while criteria that are too restrictive risk depriving children of an intervention that, when appropriately timed, can improve sleep quality, daytime functioning, and potentially survival.

The letter also underscores a broader lesson about how evidence accumulates in pediatric sleep medicine. Large randomized trials are difficult to conduct in rare diseases, and much practice has been built on observational data and expert opinion. Studies that attempt to formalize criteria, such as the Dannenberg investigation, are valuable precisely because they make the reasoning explicit and testable. Letters such as that from Munir and colleagues serve as the peer community’s quality control, pressing authors on methodology, generalizability, and clinical applicability. This dialectic, proposal followed by critique followed by refinement, is how a field gradually converges on standards that clinicians can trust and families can understand.

For clinicians caring for children with neuromuscular disease, the practical message is one of calibrated vigilance. Sleep studies should be interpreted with awareness of REM physiology, age-appropriate norms, and the limitations of single-night testing, and the decision to start ventilation should integrate polysomnographic findings with symptoms, lung function trends, and family circumstances. For researchers, the exchange highlights the need for longitudinal studies that follow children from before ventilation is initiated, tracking which criteria best predict benefit, and for harmonization of carbon dioxide measurement and scoring practices across laboratories. The Islamabad authors’ contribution, though brief in the letter format, helps keep a consequential debate honest: the numbers on a sleep report are only as meaningful as the physiology, methodology, and human context behind them. As non-invasive ventilation becomes an ever more central therapy for children with weakened breathing muscles, refining the criteria that govern its initiation is not an academic exercise but a question with lifelong consequences for the children and families at its center.

Subject of Research: Polysomnographic criteria for initiating non-invasive ventilation in children with neuromuscular diseases

Article Title: Methodological and clinical considerations for polysomnographic criteria guiding non-invasive ventilation initiation in pediatric neuromuscular diseases

Article References: Munir, A. B., Imran, H., & Faraz, N. (2026). Methodological and clinical considerations for polysomnographic criteria guiding non-invasive ventilation initiation in pediatric neuromuscular diseases. Journal of Clinical Sleep Medicine, 22(1), Article 143. https://doi.org/10.1007/s44470-026-00166-9

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00166-9

Keywords: polysomnography, non-invasive ventilation, pediatric neuromuscular disease, sleep-disordered breathing, REM-related hypoventilation, Duchenne muscular dystrophy, spinal muscular atrophy, nocturnal hypoventilation, carbon dioxide monitoring, sleep medicine, clinical criteria, ventilator initiation

The study, published open access in Cellular and Molecular Life Sciences, describes these cytoplasmic SMN condensates as S-bodies. Under stress conditions such as osmotic challenge, oxidative stress induced by arsenite, or reducing stress induced by dithiothreitol, human lung fibroblasts responded within minutes by assembling these structures along microtubules. Live-cell imaging of cells stably expressing a fluorescently tagged SMN showed that the process is strikingly fast and reversible: when mechanical stress was applied, condensates appeared within seconds, and when osmotic stress was lifted, the assemblies reorganized over the course of recovery. The researchers used indirect immunofluorescence, fluorescence in situ hybridization, and super-resolution STORM microscopy to map the molecular composition and dynamics of these bodies in detail.

What makes S-bodies particularly intriguing is their selectivity. The team showed that they exclude G3BP1, a defining marker of classical stress granules, demonstrating that S-bodies are not simply another flavor of generic stress condensate. Instead, they specifically sequester UsnRNPs that have been mislocalized to the cytoplasm by stress. The assembly of S-bodies also proved independent of ongoing UsnRNP biogenesis: blocking translation with cycloheximide or transcription with NVP2 did not prevent their formation, indicating that the condensation machinery responds to the physical state of the cell rather than to the flux of newly made spliceosomal components.

The recovery phase revealed a second, equally elegant act. As stressed cells returned to normal conditions, the S-bodies did not simply dissolve. Instead, they underwent a microtubule-dependent reorganization into split condensates containing both SMN and CLNS1A, a protein known from the PRMT5 complex that acts earlier in the UsnRNP assembly pathway. The researchers named these dual-compartment structures Janus bodies, after the two-faced Roman god, because they bridge two distinct stages of the assembly line. Within these Janus bodies, SMN colocalized with its interaction partners Gemin2 and DDX20, with methylated Sm proteins, and with the hypermethylated cap structures of UsnRNAs, suggesting that the condensates serve as processing hubs where captured UsnRNPs are evaluated and cleared.

To understand the biophysical basis of this behavior, the authors draw on the concept of liquid-liquid phase separation, or LLPS, the process by which mixtures of proteins and RNAs demix into dense condensates within the cell. Nuclear SMN is already known to condense in Cajal bodies, where it promotes late maturation steps of the spliceosomal machinery. The new work extends this principle to the cytoplasm and assigns it a protective function: rather than participating in assembly, cytoplasmic SMN condensation acts as a buffer, physically sequestering misplaced UsnRNPs so that they cannot interfere with cytoplasmic processes or form aberrant aggregates. The biphasic nature of the response, first sequestration in S-bodies and then resolution through Janus bodies, provides a complete lifecycle for the stress response.

The most clinically resonant finding concerns spinal muscular atrophy, or SMA, a devastating neuromuscular disease caused by loss or deficiency of functional SMN. SMA arises because humans carry a duplicated SMN gene, SMN2, which produces predominantly a truncated protein, SMND7, that lacks exon 7 and is unstable. In cellular models of the disease, including mouse embryonic fibroblasts carrying a humanized SMN2 allele, the researchers found that S-bodies failed to assemble and that cytoplasmic UsnRNPs were not cleared after stress. This failure identifies an impaired tolerance to molecular crowding as a previously unrecognized hallmark of SMA, extending the disease picture beyond the well-established defects in UsnRNP biogenesis and motor neuron survival.

Importantly, the team tested whether pharmacological intervention could restore this protective function. Risdiplam, a small molecule approved for the treatment of SMA that splices SMN2 transcripts productively, was applied to the humanized mouse embryonic fibroblasts. Western blot analysis confirmed that a 24-hour treatment restored SMN expression levels in these cells, raising the possibility that reconstituting sufficient SMN protein also reconstitutes the cytoplasmic condensation response. While the study focuses on cellular models rather than patient neurons, the result suggests that some benefits of SMN-restoring therapies may include the reestablishment of this stress-buffering quality control system, a hypothesis that will require testing in disease-relevant contexts.

The work also reframes how scientists think about the relationship between condensates and the cytoskeleton. The dependence of both S-body maintenance and the transition to Janus bodies on microtubules indicates that phase separation and cytoskeletal transport are not parallel, independent systems but are mechanistically coupled. Microtubules appear to provide the tracks along which the condensates organize, mature, and redistribute during recovery. This coupling may ensure that captured UsnRNPs are routed to specific cellular locations for processing rather than being scattered randomly through the cytoplasm, adding a layer of spatial control to what might otherwise be a simple sequestration mechanism.

Broader implications reach into several active areas of cell biology. The finding that distinct stressors, including osmotic, oxidative, reducing, and mechanical stress, all trigger S-body formation suggests a general response to conditions that perturb molecular crowding. Because UsnRNPs contain uridine-rich small nuclear RNAs, their cytoplasmic accumulation could in principle seed unwanted RNA interactions, and the S-body system may represent an evolved safeguard against such molecular misbehavior. The study also connects to the growing literature on membraneless organelles, stress granules, processing bodies, and U bodies, positioning S-bodies as a distinct member of this family with a dedicated cargo and a defined lifecycle.

For the SMA research community, the identification of condensation defects as a disease phenotype opens new avenues for biomarker development and therapeutic evaluation. If the ability to form S-bodies and clear cytoplasmic UsnRNPs correlates with clinical outcomes, assays based on this cellular response could complement existing measures of SMN protein levels. More fundamentally, the work exemplifies how a protein famous for one role, nuclear assembly of the splicing machinery, can moonlight in an entirely different compartment under stress, and how the failure of that second role may contribute to disease. As the field of biomolecular condensates matures, studies like this one demonstrate that these droplets are not curiosities of physical chemistry but essential, regulated, and clinically relevant machines of cellular housekeeping.

Subject of Research: Stress-induced cytoplasmic SMN condensates that sequester and clear mislocalized UsnRNPs and their failure in spinal muscular atrophy

Article Title: Biphasic SMN condensates safeguard stress-induced cytoplasmic mislocalization of splicing RNPs

Article References: Riedel, Y. L., Dressler, J., Schilling, M. T., & Gruss, O. J. (2026). Biphasic SMN condensates safeguard stress-induced cytoplasmic mislocalization of splicing RNPs. Cellular and Molecular Life Sciences, 83(1), Article 350. https://doi.org/10.1007/s00018-026-06459-9

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06459-9

Keywords: SMN, spinal muscular atrophy, UsnRNP, liquid-liquid phase separation, stress granules, microtubules, Cajal bodies, CLNS1A, spliceosome, Risdiplam, molecular crowding, condensates

The research, led by Melissa Bowerman of Keele University’s School of Medicine together with colleagues at the University of Hertfordshire and the Wolfson Centre for Inherited Neuromuscular Disease, builds on earlier work from the same laboratory that combined bioinformatics with drug repositioning strategies to identify compounds capable of correcting metabolic defects in SMA. Rather than starting from scratch with novel molecules, the team deliberately focused on drugs that are already approved for human use, an approach that could shorten the path from bench to bedside considerably. The three candidates that emerged—pioglitazone, a thiazolidinedione used to treat type 2 diabetes; melatonin, a hormone that regulates circadian rhythms; and insulin, the classic metabolic hormone—each target a different facet of cellular energy handling.

The experimental system at the heart of the study is the Smn2B/- mouse, a well-established model of SMA that carries a deletion of the mouse Smn gene alongside a human SMN2 transgene. This model recapitulates many features of the human disease, including motor dysfunction, muscle atrophy, shortened lifespan and systemic metabolic abnormalities. The researchers treated these mice with each of the three compounds and assessed a battery of behavioural, molecular and histological endpoints. Alongside the mouse work, they used the nematode worm Caenorhabditis elegans as a complementary in vivo platform, allowing rapid evaluation of the compounds’ effects in a second organism with conserved metabolic pathways.

The results, the team reports, were encouraging across the board, albeit to different degrees for each compound. All three drugs improved various pathological features in the SMA mice and worms, including survival, body weight, motor function, muscle size, the health of the spinal cord and the accumulation of lipids in the liver. Hepatic steatosis—the abnormal build-up of fat in liver tissue—is one of the metabolic pathologies increasingly recognised in SMA patients and models, and its improvement following treatment suggests that the compounds were acting on genuine disease-relevant biology rather than producing non-specific effects. Improvements in muscle size and spinal cord health point to benefits that extend beyond the liver into tissues central to neuromuscular function.

Of the three interventions, melatonin produced the most significant effect on survival, the endpoint that carries the greatest weight in preclinical SMA research. This finding is particularly striking because melatonin is not typically thought of as a metabolic drug; its best-known role is as a circadian signal produced by the pineal gland. Yet the study found that melatonin’s activity in SMA mice extended across several tissues, influencing molecular effectors involved in circadian rhythm regulation, glucose metabolism, mitochondrial biogenesis and the browning of white adipose tissue. Browning—the conversion of energy-storing white fat into energy-burning beige or brown fat—is a process with profound implications for systemic energy balance, and its disruption has been implicated in the metabolic dysfunction seen in SMA.

The involvement of mitochondria is another thread worth unpacking. Mitochondria are the power plants of the cell, and their biogenesis—the generation of new mitochondrial material—is governed by molecular pathways that respond to metabolic stress. In SMA, mitochondrial defects have been observed in multiple tissues, and the ability of melatonin to influence mitochondrial biogenesis suggests a mechanism by which the hormone could restore cellular energy capacity in vulnerable tissues such as muscle and liver. Similarly, its effects on glucose metabolism echo the insulin resistance and dyslipidaemia documented in SMA patients, abnormalities that current disease-modifying therapies do not adequately address.

That last point is crucial to understanding why the study matters. The last several years have seen a remarkable transformation in SMA care, with the arrival of nusinersen, an antisense oligonucleotide that modifies SMN2 splicing; onasemnogene abeparvovec, a gene therapy that delivers a functional copy of the SMN1 gene; and risdiplam, an oral SMN2 splicing modifier. These therapies have delivered dramatic gains in survival and motor function, particularly when treatment begins early. Yet they share a common limitation: they are designed to raise SMN levels, primarily benefiting the neuromuscular system, and they leave the peripheral and metabolic pathologies of the disease largely untouched. Patients treated with these drugs still exhibit metabolic abnormalities, and the peripheral tissues—skeletal muscle, liver, pancreas and adipose tissue—remain sites of ongoing dysfunction. The new study argues that this therapeutic gap is precisely where metabolism-targeted interventions could make a difference.

The concept of SMA as a metabolic disease is grounded in the biology of SMN itself. Although the protein is best known for its role in the assembly of spliceosomal ribonucleoproteins, its loss produces detectable abnormalities in tissues far removed from the motor neuron. Insulin resistance, hepatic steatosis, dyslipidaemia and circadian disruption have all been documented in SMA, and these abnormalities are not merely consequences of immobility; they appear to arise from cell-autonomous metabolic defects. Reframing SMA pathology from a neurocentric to a metabolic perspective, as the authors put it, reveals a disease landscape in which energy handling goes wrong in parallel with, and possibly contributes to, neuromuscular degeneration. On this view, correcting metabolic dysfunction is not an afterthought but a legitimate therapeutic goal in its own right.

The translational appeal of the approach lies in the fact that all three compounds are already commercially approved. Pioglitazone is prescribed worldwide for type 2 diabetes and has a well-characterised safety profile, although its use is associated with weight gain and, in some patients, concerns about fluid retention and fracture risk. Melatonin is available over the counter in many countries and is generally well tolerated. Insulin, of course, is a mainstay of diabetes management, though its use in non-diabetic patients would require careful dosing and monitoring. The authors are careful to note that the study was conducted in mouse and worm models, and that the doses, timing and combinations used in animals may not translate directly to humans. Clinical trials would be needed to establish whether these interventions, alone or in combination with existing SMN-restoring therapies, can deliver measurable benefits in patients. Nevertheless, the fact that the compounds are approved means that safety data already exist, potentially accelerating the design of early-phase studies.

The broader significance of the work may lie in the shift it represents in how the field thinks about combination therapy for SMA. Just as oncology moved from single-agent treatments to rational multi-drug regimens that attack different vulnerabilities simultaneously, neuromuscular medicine may be heading toward pairing SMN-restoring therapies with second-generation treatments aimed at specific non-neurological pathologies. The findings position metabolism, as the authors conclude, at the forefront of targets for SMA treatments and provide a strong rationale for exploring metabolism-targeted second-generation therapies to complement currently approved disease-modifying treatments. For a disease that was once considered untreatable, and which now has effective but incomplete therapies, the prospect of adding metabolic correction to the therapeutic arsenal represents a meaningful step forward—one that could matter most for the patients whose peripheral symptoms persist despite the most advanced neuromuscular interventions available today.

Subject of Research: Testing commercially approved metabolism-targeting drugs in a mouse model of spinal muscular atrophy

Article Title: Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes

Article References: Çetin, Ö., McCallion, E., Hoolachan, J. M., Sutton, E. R., Cook, J., Al-Mozani, Y., Dhoowooah, A., Varughese, M. S., Velandia Dorta, L. F., Koomson, J., Rashid, S., Pacheco-Torres, P., Dimitriadi, M., & Bowerman, M. (2026). Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06461-1

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06461-1

Keywords: spinal muscular atrophy, metabolism, melatonin, pioglitazone, insulin, Smn2B/- mice, drug repositioning, mitochondrial biogenesis, hepatic steatosis, circadian rhythm, adipose tissue browning, combination therapy