VPSPr was first described in 2008 as a distinct entity among sporadic prion diseases, and fewer than 150 cases have been reported worldwide since then. Like all prion diseases, it is driven by the conversion of the normal, alpha-helix-rich cellular prion protein into a pathologic, beta-sheet-rich conformer known as PrP-Sc, which becomes insoluble and aggregates in the central nervous system. But VPSPr behaves differently from classic sporadic Creutzfeldt-Jakob disease (sCJD) in a crucial biochemical respect: the resistance of its abnormal prion protein to digestion by proteinase K is variable and significantly lower than in sCJD, producing a unique western blot profile. Its seeding activity is also reduced, which likely explains why the RT-QuIC assay in cerebrospinal fluid is negative in most cases.

That biochemical peculiarity has cascading diagnostic consequences. Neuroimaging with cranial MRI and FDG-PET is often inconclusive because the typical cortical or basal ganglia hyperintensities seen in classic prion disease are frequently absent. The 14-3-3 protein in cerebrospinal fluid, a common surrogate marker, often remains negative as well. Clinically, the disease course is considerably longer than sCJD, often lasting several years, and symptoms span extrapyramidal, psychiatric, cognitive, pyramidal and cerebellar domains. Which of these dominates depends strongly on the polymorphism at codon 129 of the PRNP gene, the same genetic modifier that shapes phenotypes in sCJD.

The research team, led by Anika Simonovska Serra and Ellen Gelpi, reviewed the published literature and found a consistent pattern. Methionine/methionine (MM) carriers, who average around 69 years at onset, more frequently present with extrapyramidal and cerebellar symptoms, and during disease progression most develop pyramidal signs suggestive of motor neuron disease, with a mean disease duration of roughly 46 months. Valine/valine (VV) carriers, who are younger on average at about 63.5 years, tend to present with cognitive and psychiatric symptoms overlapping with frontotemporal dementia, and later develop combined extrapyramidal and cerebellar features. Heterozygous MV carriers often begin with psychiatric and extrapyramidal symptoms but have the shortest average disease duration at around 22.5 months.

The first new case illustrates how bewildering the clinical picture can become. An 86-year-old woman with an MM genotype was referred for atypical parkinsonism with right-sided bradykinesia that did not respond to levodopa. She had experienced gait disturbance and frequent falls for seven years, along with memory problems and urinary incontinence. Examination revealed mild rigidity, postural instability, diffuse muscle weakness, dysarthria and a vertical gaze palsy, and a MoCA test confirmed significant cognitive impairment. Her cerebrospinal fluid showed normal 14-3-3 protein, a negative RT-QuIC assay and normal Alzheimer biomarkers. Brain MRI suggested normal pressure hydrocephalus, and because lumbar puncture temporarily alleviated some symptoms, a shunt was considered. Before surgery could happen, she deteriorated with personality changes, apathy, global aphasia and non-convulsive status epilepticus with myoclonus, and died after a total disease duration of roughly seven years.

Postmortem examination of her brain revealed a striking mixture of pathologies. Focal, mild spongiform change was present in the frontal and temporal cortex, basal ganglia and hippocampus, with the pre- and postcentral regions particularly affected, showing neuronal loss, gliosis and degeneration of the descending corticospinal tract. Immunohistochemistry for the disease-related prion protein revealed fleecy and freckled deposits over a faint synaptic staining pattern in cortical areas and the hippocampus, with focal intraneuronal granular deposits in the thalamus. Remarkably, the cerebellum was completely devoid of prion protein immunoreactivity, even after repeated staining with two different antibodies. Alongside the prion pathology, the team found abundant 4-repeat tau-positive grains consistent with argyrophilic grain disease at stage III, mild limbic-predominant age-related TDP-43 encephalopathy (LATE), mild Alzheimer disease neuropathologic changes, and diffuse small vessel disease. Western blot analysis of frozen cortical tissue confirmed the VPSPr signature: a 19 kDa prion protein fragment virtually devoid of the diglycosylated form, plus two additional truncated fragments, while the cerebellum was negative, matching the histology.

The second patient, a 69-year-old woman with a VV genotype, presented very differently. She developed subtle progressive cognitive decline from June 2021, and by late 2022 her memory impairment had worsened alongside prominent word-finding and naming difficulties and trouble following conversations. Brain MRI showed ventricular enlargement without cortical or basal ganglia hyperintensities, the EEG showed no triphasic waves, and the RT-QuIC assay was twice negative. Yet 14-3-3 protein in her cerebrospinal fluid was elevated on two measurements, raising clinical suspicion of CJD despite the atypical overall picture. She progressed to tetraplegia and dysphagia and died after about 3.5 years. Her autopsy showed the characteristic VPSPr morphology, including fleecy and freckled cortical deposits, granular deposits in large cholinergic neurons of the basal ganglia, and, in contrast to the first case, characteristic ill-defined coarse deposits, pseudo-plaques and microplaques in the cerebellar molecular layer. No additional protein aggregates were identified, making this a purer single-pathology case.

The contrast between the two cases highlights how the codon 129 polymorphism sculpts both clinical presentation and brain distribution of disease. The authors argue that detailed histotyping, as routinely performed for sCJD, could be useful in VPSPr as well: a laminar prion protein deposition pattern and intraneuronal granular deposits may suggest the valine genotype, while prominent involvement of the pyramidal system may predict methionine. Previous reports support these associations, with some MM patients presenting with motor neuron disease-like syndromes and neuropathological evidence of motor system involvement, including degeneration of the pyramidal tracts. The absence of cerebellar prion deposits in the first patient made the diagnosis particularly challenging, and the authors note that cerebellar sparing appears to be influenced by the presence of methionine at codon 129, with prior western blot data indicating that resistance to proteinase K digestion is lowest in VV cases and highest in MM cases.

Several deeper biological puzzles remain. The western blot pattern of VPSPr, with its characteristic low molecular weight 7 kDa fragment, resembles that seen in Gerstmann-Sträussler-Scheinker disease, an inherited prion protein amyloidosis, leading some researchers to propose that VPSPr represents the sporadic counterpart of that genetic disorder. Another striking discrepancy is that most VPSPr cases show only mild spongiform change despite severe neurological symptoms, which the authors attribute to the reduced seeding potency of the abnormal prion protein and to early toxic oligomer-mediated disruption of synaptic transmission, a process that can cripple neural circuits before neuronal loss becomes visible under the microscope. The team also cautions that the fleecy and freckled staining pattern of VPSPr can mimic nonspecific staining of beta-amyloid-related senile plaques in Alzheimer disease, although VPSPr microplaques lack classical amyloid characteristics and are negative for beta-amyloid, Congo red and thioflavin S.

For clinicians, the message is clear: VPSPr belongs in the differential diagnosis of rapidly progressive and atypically progressive neurological diseases, including cases within the frontotemporal lobar degeneration and motor neuron disease spectrum, especially in elderly patients whose biomarkers are inconclusive and who carry overlapping co-pathologies. As the population ages and mixed proteinopathies become increasingly common at autopsy, recognizing this rare prion disorder amid the noise of tau, TDP-43 and amyloid accumulation will remain one of neuropathology’s most demanding diagnostic challenges.

Subject of Research: Variably protease-sensitive prionopathy, a rare sporadic human prion disease, and its diagnostic challenges in the context of co-existing neurodegenerative pathologies

Article Title: Variably protease-sensitive prionopathy in the context of a complex proteinopathy: clinical and neuropathological challenges

Article References: Simonovska Serra, A., Vargiu, C. M., Klotz, S., Berger-Sieczkowski, E., Kreiter, M., Leoni, M., Guttmann-Lattmanig, A., Haider, L., Regelsberger, G., Parchi, P., & Gelpi, E. (2026). Variably protease-sensitive prionopathy in the context of a complex proteinopathy: clinical and neuropathological challenges. Frontiers in Neuroscience, 20, Article 1950078. https://doi.org/10.3389/fnins.2026.1950078

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1950078

Keywords: VPSPr, prion disease, Creutzfeldt-Jakob disease, PRNP codon 129, frontotemporal lobar degeneration, motor neuron disease, argyrophilic grain disease, LATE, TDP-43, western blot, neuropathology, proteinase K

Congenital dislocation of the knee is a rare malformation in which the knee joint is malformed or unstable from birth, often presenting as fixed hyperextension of the lower leg. The condition severely affects the quality of life of affected individuals and imposes a heavy burden on families and health systems. Its causes have long remained murky: clinicians have proposed contributions from genetic factors, atrophy of the quadriceps muscle, muscular nutritional imbalance, and mechanical or intrauterine factors. Because the etiology is heterogeneous, distinguishing isolated cases, which often respond well to conservative treatment, from syndromic cases, which carry a far grimmer outlook, is one of the central challenges in prenatal counseling. The new report demonstrates how genomic sequencing can draw that critical line before delivery.

The patient was a 34-year-old woman in her first pregnancy, conceived by artificial insemination, with no underlying disease and no family history of genetic disorders. Early screening had been reassuring: nuchal translucency measured at 12 weeks and 3 days was normal, and second-trimester serum screening at 17 weeks showed only a borderline risk for trisomy 21, at 1 in 790. The turning point came at 25 weeks of gestation, when ultrasound revealed polyhydramnios, an excess of amniotic fluid reflected by an amniotic fluid index of 20.1 centimeters, and a striking absence of observable fetal movements. Fetal akinesia, or lack of movement, is a red flag that frequently signals an underlying neuromuscular disorder.

The ultrasound findings were detailed and, in retrospect, characteristic. In the midsagittal view of the fetal face, the lower lip and chin lacked the normal S-shaped curve, with loss of the so-called reverse-S sign, and the mandibular facial angle measured 43 degrees, below the 50-degree diagnostic threshold for micrognathia, an abnormally small jaw. The limbs were fixed in abnormal postures: the upper arms were flexed across the chest with clenched fists, while the lower legs were crossed with both knees hyperextended. This combination of joint contractures, fixed limb positions, small jaw, and reduced movement pointed away from an isolated skeletal problem and toward a generalized neuromuscular process, prompting the team to recommend invasive genetic testing.

After genetic counseling, the researchers performed whole-exome sequencing on fetal cord blood. The analysis identified a heterozygous missense variant in the BICD2 gene, denoted c.1613A>G, which changes amino acid 538 from tyrosine to cysteine (p.Tyr538Cys). Critically, the variant was absent in both parents, indicating that it had arisen de novo in the fetus. Under the classification criteria of the American College of Medical Genetics and Genomics, the variant was graded as likely pathogenic on the basis of two pieces of evidence: PS2, reflecting de novo occurrence in a patient with the disease phenotype, and PM2, reflecting its absence from population databases. The variant sits in exon 5 of the gene, and testing confirmed the fetus was heterozygous while both parents carried the wild-type sequence.

Understanding why a defect in BICD2 can immobilize a fetus requires a look inside the cell. BICD2 is a cargo adaptor for dynein-1, the molecular motor that hauls freight along microtubule tracks toward the minus ends, generally toward the cell center. As an adaptor, BICD2 couples dynein to diverse cargoes, including RNA molecules, viral particles, and even nuclei, and it is crucial for coordinating motor proteins with their cargoes and regulatory proteins. The protein is built from three major coiled-coil segments with distinct jobs: dynein and its activator dynactin bind to the CC1 segment, the opposing motor kinesin binds to CC2, and known cargoes attach to the C-terminal CC3 segment. In neurons, which can extend over a meter in length, this transport system is nothing short of essential.

Mutations in BICD2 disrupt dynein-mediated transport, impair motor neuron function, and particularly affect the motor neurons of the lower limbs. The gene is the established cause of autosomal dominant spinal muscular atrophy with lower extremity predominance type 2, or SMALED2. The genotype-phenotype correlation for this disorder is relatively well mapped: de novo mutations tend to produce more severe disease, and variants in the CC2 region and the C-terminal cargo-binding region more often cause severe phenotypes. The p.Tyr538Cys change identified in this fetus lies squarely in the CC2 domain, the region that mediates binding of BICD2 to the kinesin motor KIF5B and participates in coordinating bidirectional transport. While the specific functional consequences of this exact variant have not yet been experimentally verified, its location in CC2, the precedent of pathogenic variants in the same region such as p.Arg501Pro, and the severity of the fetal phenotype together fit the established genotype-phenotype pattern of BICD2-related SMALED2.

The diagnosis was confirmed the hard way. Following multidisciplinary discussion, the family opted for termination of the pregnancy at 25 weeks via intra-amniotic instillation of ethacridine lactate. External examination and X-ray after the procedure confirmed the prenatal findings: bilateral flexion contractures of the upper limbs, thumbs held within the palms, the other four fingers clenched, crossed lower limbs, hyperextended knees, and micrognathia. Autopsy findings were consistent with both the prenatal ultrasound and the genetic diagnosis, closing the diagnostic loop and validating the ultrasound criteria that the team used to recognize the disorder in utero.

The report also maps out the differential diagnosis that prenatal specialists must navigate when they encounter fixed knee hyperextension. Congenital knee dislocation may be isolated or syndromic, and sequential scanning along the long axis of the limbs is used to detect the structural anomalies. Among the syndromic mimics are congenital myopathies caused by RYR1, NEB, and ACTA1 variants, with the RYR1- and NEB-related forms particularly important to exclude; prenatally these can show fetal hydrops, large cystic hygromas, and bilateral talipes. Larsen syndrome, caused by FLNB variants and inherited in autosomal dominant or recessive fashion, presents prenatally with multiple joint dislocations or anterior knee dislocation, spinal anomalies, and multisystem abnormalities. BICD2-related SMALED2, by contrast, lacks these features and follows autosomal dominant inheritance. The distinction matters enormously for prognosis: isolated congenital knee dislocation is treated conservatively with casting, orthoses, and gait training, with surgery reserved for refractory cases and the prognosis generally favorable, whereas syndromic cases carry poorer outcomes and often require surgery.

The authors argue that their case carries a practical message for fetal medicine. When ultrasound reveals micrognathia together with lower-limb postural abnormalities, fixed joint positions, reduced fetal movement, and polyhydramnios, BICD2-related SMALED2 should enter the differential diagnosis, and trio whole-exome sequencing, testing the fetus and both parents, should be performed as early as possible. By detailing the ultrasound features of congenital knee dislocation in a molecularly solved case, the report expands the prenatal phenotypic spectrum of BICD2-related disorders and underscores the diagnostic value of exome sequencing when fetal anomalies are detected before birth. For families, an early molecular answer transforms an unexplained set of ultrasound findings into a defined genetic diagnosis, enabling accurate recurrence-risk counseling, since a de novo variant carries a low but nonzero risk of recurrence, and allowing clinical management plans to be built on evidence rather than uncertainty.

Subject of Research: Prenatal genetic diagnosis of congenital knee dislocation caused by a BICD2 gene variant

Article Title: Case Report: Prenatal diagnosis of congenital knee dislocation caused by BICD2 gene variant

Article References: Ge, X., Li, W., Wei, H., & Liu, M. (2026). Case Report: Prenatal diagnosis of congenital knee dislocation caused by BICD2 gene variant. Frontiers in Genetics, 17, Article 1938741. https://doi.org/10.3389/fgene.2026.1938741

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1938741

Keywords: BICD2, congenital knee dislocation, prenatal ultrasound, whole-exome sequencing, SMALED2, micrognathia, dynein, motor neuron disease, fetal akinesia, genetic counseling, ACMG criteria, polyhydramnios

The research team, led by investigators at the University of Illinois at Chicago and the University of California, San Diego, took advantage of a rare and powerful resource: postmortem spinal cords from sporadic ALS patients whose clinical phenotypes had been carefully characterized during life by a single neurologist. Rather than studying a mixed patient population, the investigators deliberately selected the extremes of the clinical spectrum. Six patients had shown predominantly upper motor neuron signs at disease onset, including spasticity, hyperreflexia, pathological reflexes, and loss of fine skilled movements. Seven others had presented with predominantly lower motor neuron signs, marked by weakness, atrophy, and fasciculations. Thirteen neurologically healthy control spinal cords completed the comparison set.

The logic of this design is elegant. Upper motor neurons are the long projection neurons whose cell bodies sit in the motor cortex and whose axons descend through the brainstem, cross at the level of the pyramids, and form the lateral corticospinal tract, the great white-matter highway that carries commands to the lower motor neurons of the spinal cord. Because those axons are bundled together in a discrete tract, the lateral columns of the spinal cord offer the most direct window into upper motor neuron degeneration, something that is nearly impossible to assess by counting neurons in the cortex or by quantifying protein aggregates in brain tissue. If the clinical signs of upper motor neuron dysfunction truly reflect degeneration of this tract, then the tract should look profoundly damaged in patients with upper motor neuron-predominant disease and relatively spared in those with lower motor neuron-predominant disease.

That is precisely what the team found. Using Luxol Fast Blue-Periodic Acid Schiff staining to visualize myelin, the fatty insulation that wraps axons, the researchers documented severe, unmistakable myelin loss in the lateral corticospinal tract at all three spinal cord levels examined, cervical, thoracic, and lumbar, in every single one of the six upper motor neuron-predominant patients. In striking contrast, the lateral tracts of the lower motor neuron-predominant patients looked essentially indistinguishable from those of healthy controls at every level. The correlation between clinical phenotype and pathology followed an almost all-or-none pattern, providing the kind of clinicopathological validation that has been largely absent since Charcot’s era, when histological techniques were rudimentary by modern standards.

Myelin loss, however, was only the beginning of the story. The team developed a quantitative method to measure axon size distributions, generating frequency histograms of thousands of axons stained for neurofilament heavy chain, a core structural protein of the axonal skeleton. Previous studies had suggested that large-diameter axons, which originate from the giant Betz cells of the primary motor cortex and constitute the longest fibers in the corticospinal tract, are selectively lost in ALS. The new data extend that picture dramatically: axons of every caliber, from the smallest fibers measuring roughly 3.2 micrometers to the largest at about 16.4 micrometers, were significantly depleted in the upper motor neuron-predominant group, and the loss was consistently worse than in the lower motor neuron-predominant group at all three spinal levels. Sensory axons in the dorsal columns, examined as an internal comparison, were largely preserved, underscoring the specificity of the motor tract degeneration.

The most consequential observation emerged when the researchers compared axon loss between the cervical and lumbar segments of the cord. Because corticospinal axons travel from the brain downward, the lumbar cord represents the distal, far end of these extraordinarily long projections, while the cervical cord lies closer to their origin. In the upper motor neuron-predominant patients, axonal loss across all size ranges was significantly more pronounced in the lumbar cord than in the cervical cord, a rostrocaudal gradient that was absent in the lower motor neuron-predominant group. This length-dependent pattern is the anatomical signature of a dying-back process, the same phenomenon long recognized in peripheral neuropathies, where degeneration begins at the distant tips of long nerves and progresses proximally, producing the familiar stocking-glove pattern of sensory loss.

Woven through the degenerating tract, the researchers identified a striking inflammatory landscape. Foamy microglia, the brain’s resident immune cells swollen with lipid droplets after engulfing myelin and axonal debris, accumulated in large numbers precisely within the regions of most severe myelin and axon loss in the upper motor neuron-predominant cords. Quantification of Iba1-positive cells confirmed that these round, lipid-laden phagocytes were significantly increased at all three spinal levels compared with both the lower motor neuron-predominant group and controls. Notably, reactive astrocytes labeled by GFAP showed no comparable differences, and no foamy microglia were found in the sensory dorsal columns. The tight spatial coupling between foamy microgliosis and tract degeneration suggests an intimate glio-axonal interaction in upper motor neuron degeneration, although the study cannot determine whether these immune cells are drivers of the damage or simply the cleanup crew arriving after the collapse.

The study also delivered a surprise about TDP-43, the misfolded RNA-binding protein whose translocation from the nucleus to the cytoplasm is considered the pathological signature of ALS. While phosphorylated TDP-43 aggregates were rarely or never observed within the lateral corticospinal tract, a finding independently confirmed across three laboratories, total TDP-43 was measurably increased inside the axons of both the lateral and ventral corticospinal tracts when the protein was colocalized with phosphorylated neurofilament markers. Fibril-like axonal TDP-43 was also detected in the ventral horn gray matter, but the sensory axons of the dorsal columns showed no such elevation. This compartment-specific dysregulation hints that TDP-43 may behave differently in axons than in cell bodies, and differently in upper versus lower motor neurons, opening a new dimension for mechanistic studies.

The authors are careful to distinguish pattern from mechanism. Dying back, in their framing, is a descriptive term for distal-to-proximal degeneration, not a claim that sick axons are killing their neurons. Indeed, they argue, the most likely cause is a proximal failure within the neuron itself, probably in the cell body, that manifests first in the most distant axonal territory. Emerging evidence supports this view: when TDP-43 escapes the nucleus, it causes loss of function in transcripts such as STMN2, which maintains axon integrity, and UNC13A, which supports neuromuscular junction function, so a nuclear defect can silently starve the far reaches of an axon long before the cell body itself shows damage. The competing dying-forward hypothesis, which posits toxic antegrade spread from the motor cortex, remains speculative and has been criticized for its inability to explain the heterogeneity of ALS motor phenotypes.

The clinical implications are significant. Because upper motor neuron-predominant patients often survive longer, the extent of corticospinal tract destruction observed here was unexpectedly severe, suggesting a prolonged preclinical phase of slow but relentless degeneration. The findings also indicate that upper motor neuron degeneration progresses along two independent axes, one defined by the site of symptom onset and another by the relative balance of upper versus lower motor neuron involvement, with lumbar-projecting axons degenerating even in patients whose disease began in the bulbar region. For a field whose therapeutic pipeline has been dominated by neuron-centric strategies, this work makes a forceful case that the axon, its myelin sheath, and the foamy microglia that attend its demise deserve equal attention, and that length-dependent vulnerability may be a unifying principle across both tiers of the motor system in ALS.

Subject of Research: Distal axonopathy of upper motor neurons in amyotrophic lateral sclerosis

Article Title: Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy (“dying back”): a clinical-neuropathological study

Article References: Liu, J., Ong, K., Meng, A., Stokin, G. B., Loeb, J. A., Ravits, J., & Song, F. (2026). Lateral sclerosis in amyotrophic lateral sclerosis is an upper motor neuron distal axonopathy (“dying back”): a clinical-neuropathological study. Acta Neuropathologica, 152(1), Article 48. https://doi.org/10.1007/s00401-026-03072-9

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03072-9

Keywords: amyotrophic lateral sclerosis, lateral sclerosis, corticospinal tract, upper motor neuron, dying back axonopathy, myelin loss, TDP-43, foamy microglia, neuroinflammation, axonal degeneration, spinal cord pathology, motor neuron disease

Dyskeratosis congenita is a paradigmatic telomere biology disorder. Patients typically present with the classical triad of abnormal skin pigmentation, nail dystrophy and oral leukoplakia, but the most dangerous manifestations are systemic: progressive bone marrow failure, pulmonary fibrosis, liver disease and a markedly elevated risk of malignancy. The condition arises when telomeres, the repetitive DNA-protein caps at the ends of chromosomes, are maintained inadequately. Because telomeres shorten with every round of cell division, tissues that rely on continual stem cell replenishment are hit hardest, which explains the premature-ageing character of the disease. Genetically, dyskeratosis congenita is heterogeneous, with pathogenic variants identified in genes encoding components of the telomerase enzyme and its associated factors, including DKC1, TERT, TERC, NOP10, TINF2 and, since the landmark 2008 study by Vulliamy and colleagues in Proceedings of the National Academy of Sciences, NHP2.

NHP2 occupies a fascinating position at the intersection of two essential cellular machines. It is one of the four core proteins of H/ACA ribonucleoprotein particles, the small nucleolar complexes responsible for pseudouridylation, the isomerisation of uridine residues in ribosomal RNA and small nuclear RNAs. Remarkably, the same H/ACA architecture is also found in the telomerase RNA component, where the H/ACA domain serves as the binding platform that recruits NHP2, NOP10, GAR1 and dyskerin to the telomerase ribonucleoprotein. Structural work published in 2024 by Ghanim and colleagues in Nature Communications resolved the human telomerase H/ACA ribonucleoprotein at near-atomic resolution, showing precisely how these proteins cradle the RNA scaffold. When NHP2 is defective, both ribosome biogenesis and telomere maintenance are compromised, and recent biochemical studies, including work by Malinski and colleagues in Human Molecular Genetics in 2023, have demonstrated that pathological NHP2 variants destabilise the protein, impair H/ACA ribonucleoprotein complex formation and reduce telomerase activity.

Against this molecular backdrop, the clinical picture in the Norwegian family is striking. The affected individuals developed progressive muscular atrophy, and the central question the team set out to answer was whether the muscle degeneration reflected a myopathic process, in which the muscle fibres themselves fail, or a neurogenic process, in which the loss of innervation from motor neurons or peripheral axons causes the fibres to waste away secondarily. This distinction matters enormously for diagnosis, prognosis and any future therapeutic strategy, yet it can be difficult to establish in rare multisystem disorders where muscle involvement has not previously been characterised. Prior case reports, such as a 2025 description in Clinical Dysmorphology of a patient with novel phenotypic features of NHP2-related disease and a 2023 report in QJM of idiopathic non-cirrhotic portal hypertension in an NHP2-mutant patient, had already hinted that the clinical spectrum of NHP2 mutations extends well beyond the classical triad, but detailed neuromuscular pathology had remained largely undocumented.

The pathological evidence assembled by the Oslo team points decisively toward a neurogenic mechanism. In neurogenic atrophy, muscle biopsy reveals characteristic patterns that reflect the loss of axonal input: groups of small, angulated atrophic fibres scattered through the tissue, fibre type grouping as denervated fibres are reinnervated by surviving motor axons and adopt the histochemical profile of their new neighbours, and, in advanced disease, groups of atrophic fibres clustered together as entire motor units fail. These features stand in contrast to the rounded fibre hypertrophy, necrosis, regeneration and fibrofatty replacement that typify primary muscle disease. The authors’ neuropathological evaluation of the biopsies, combined with imaging and clinical neurophysiological assessment by specialists in rare neurological and congenital neuromuscular disorders at Oslo University Hospital, allowed them to localise the lesion to the motor neuron or its axon rather than to the muscle fibre membrane or the contractile apparatus.

That conclusion carries particular weight in light of what is known about long-term denervation. Studies of chronically denervated human muscle, notably the work of Kern and colleagues published in the Journal of Neuropathology and Experimental Neurology in 2004, have shown that prolonged loss of innervation causes degeneration not only of the contractile machinery but also of the excitation-contraction coupling apparatus, and that this degeneration can be partially reversed by functional electrical stimulation. In other words, once the nerve supply is lost, the muscle undergoes a stereotyped secondary degeneration that can masquerade as intrinsic muscle disease if the biopsy is interpreted in isolation. Recognising the neurogenic signature in NHP2-related dyskeratosis congenita therefore reframes the muscle wasting as a problem of the nervous system, opening the possibility that the same telomere-driven stem cell exhaustion that depletes the bone marrow may also be depleting the motor neuron pool or degrading the long peripheral axons that are among the most metabolically demanding cells in the body.

The molecular half of the study connects this pathology to the underlying genetics. Using whole-exome sequencing performed at the Norwegian High-Throughput Sequencing Centre, together with transcriptomic analysis, the researchers identified the NHP2 variant segregating with disease in the family and characterised its downstream consequences. Bioinformatics analyses supported the in vitro work conducted in the laboratory of Hilde Loge Nilsen at Akershus University Hospital and the University of Oslo, where the team examined how the mutant protein affects H/ACA ribonucleoprotein assembly and telomerase function. The convergence of clinical genetics, molecular cell biology and neuropathology in a single investigation is what distinguishes this report: rather than simply adding a phenotype to a gene, the authors trace a mechanistic pathway from a defective RNA-modifying and telomere-maintenance protein through to a specific pattern of tissue destruction that can be recognised under the microscope.

The broader significance of the finding lies in what it suggests about the vulnerability of the neuromuscular system to telomere failure. Motor neurons are among the longest-lived and largest cells in the human body, with axons extending up to a metre in length, and they are generally considered post-mitotic, which raises the question of how a telomere maintenance defect damages them. Several non-mutually-exclusive mechanisms are plausible. Telomere dysfunction triggers DNA damage signalling at chromosome ends, a process characterised by Takai, Smogorzewska and de Lange in Current Biology in 2003, and such damage responses can induce cell death or dysfunction even in non-dividing cells. Alternatively, the pseudouridylation defects caused by impaired H/ACA ribonucleoproteins could perturb ribosome biogenesis and translation quality in a way that selectively stresses neurons with extreme axonal maintenance demands. The disease is also increasingly discussed alongside motor neuron disorders, and the journal’s own subject indexing places this article within the categories of motor neuron disease, amyotrophic lateral sclerosis and neuromuscular disease, reflecting the nosological neighbourhood the finding occupies.

For clinicians, the practical message is that unexplained neurogenic muscle atrophy, particularly when accompanied by subtle features of premature ageing, cytopenias, pulmonary or hepatic fibrosis, or a family history suggestive of telomere disease, should prompt consideration of dyskeratosis congenita and testing of telomere biology genes including NHP2. Conversely, patients with known NHP2 mutations should be monitored for neuromuscular symptoms, since the atrophy documented in this family appears to be a genuine and characteristic manifestation of the disease rather than an incidental finding. Whole-body muscle MRI, whose diagnostic utility in non-5q spinal muscular atrophies was reviewed by Berling and colleagues in Neurology Genetics in 2026, may prove valuable in defining the distribution of involvement and distinguishing neurogenic patterns across the expanding family of telomere-related neuromuscular phenotypes.

The study, approved by the Regional Ethics Committee of Norway and conducted with informed consent from the participating family under the Declaration of Helsinki, exemplifies the kind of deep phenotyping that rare disease research increasingly demands. By combining genetic sequencing, molecular cell biology, electron microscopy, radiology and clinical neurology, the Oslo consortium has turned a single family’s illness into a general lesson about how defects in the cell’s RNA-processing and telomere-maintenance machinery can manifest as degeneration of the motor system. As the clinical spectrum of NHP2-related dyskeratosis congenita continues to expand, this pathological and molecular roadmap will help clinicians recognise the neuromuscular face of the disease earlier, and it gives researchers a concrete model in which to test whether protecting motor neurons or their axons can slow the devastating muscle wasting that telomere failure can ultimately inflict.

Subject of Research: Neurogenic muscular atrophy caused by NHP2 mutations in dyskeratosis congenita

Article Title: Neurogenic muscular atrophy in NHP2-related dyskeratosis congenita in a family: pathological and molecular insights

Article References: Misceo, D., Lirussi, L., Antal, E.-A., Sikiric, A., Ørstavik, K., Bjørnstad, P. M., Sundaram, A. Y. M., Elkamil, A. I., Esbensen, Q. Y., Bøker, T., Brorson, S. H., Hoddevik, E. H., Nilsen, H. L., Frengen, E., & Strømme, P. (2026). Neurogenic muscular atrophy in NHP2-related dyskeratosis congenita in a family: pathological and molecular insights. Acta Neuropathologica, 152(1), Article 45. https://doi.org/10.1007/s00401-026-03088-1

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03088-1

Keywords: dyskeratosis congenita, NHP2, telomerase, telomere biology, neurogenic atrophy, motor neuron disease, H/ACA ribonucleoprotein, muscle pathology, whole-exome sequencing, rare disease, neuromuscular disorder, pseudouridylation

The research, led by José Castro and Mamede de Carvalho at the Hospital de Santa Maria and the Universidade de Lisboa, drew on one of the largest single-centre ALS cohorts ever assembled for this purpose: 1,486 patients contributing 2,968 serial phrenic nerve conduction studies. In this test, a small electrical stimulus is applied over the nerve in the neck, and electrodes record the compound muscle action potential, the summed electrical response of the diaphragm. Because the diaphragm cannot voluntarily influence the evoked signal, the amplitude is, by design, effort-independent. The investigators expressed each amplitude as a percentage of an age- and sex-predicted normative value and asked a deceptively simple question: does this number forecast when a patient will need breathing support, above and beyond the established clinical measures?

The answer, delivered through a pre-registered analysis plan lodged publicly on the Open Science Framework, was emphatic. Using cause-specific Cox proportional hazards models with death treated as a competing risk, the team found that each 10 percent decrease in predicted phrenic amplitude was associated with a 22 percent higher hazard of starting non-invasive ventilation, with an adjusted hazard ratio of 1.22 and a 95 percent confidence interval of 1.16 to 1.27. The statistical weight of the association was extraordinary: a likelihood-ratio chi-square of 77.6, corresponding to a p-value of roughly ten to the minus eighteenth. In a field where biomarker candidates routinely collapse on replication, a signal of this magnitude in nearly three thousand serial measurements commands attention.

Perhaps the most clinically useful finding is the temporal structure of the prediction. The association was concentrated in the near term: within the first year of follow-up, the hazard ratio climbed to 1.31 per 10 percent decrement, before attenuating in later intervals. This makes physiological sense. The phrenic compound muscle action potential reflects the number and integrity of functioning motor units in the diaphragm, so a low or rapidly falling amplitude signals that the respiratory motor pool is approaching a functional threshold. Once that threshold is crossed, ventilatory decline accelerates. For clinicians, the message is that the nerve test is not a distant oracle but a near-term alarm, precisely the window in which the timing of ventilation matters most for survival and quality of life.

The quantitative gains over existing practice were substantial. Adding phrenic amplitude to a clinical model built on forced vital capacity and the revised ALS Functional Rating Scale, the standard severity instrument that incorporates respiratory items, improved discrimination by an optimism-corrected increment of 0.055, with a bootstrap-validated confidence interval of 0.034 to 0.073. That may sound modest, but in prognostic modelling, where incremental improvements of this size are considered meaningful, it represents a genuine advance. More striking is the absolute risk translation: patients whose phrenic amplitude fell below the age- and sex-adjusted normal threshold had approximately double the twelve-month risk of requiring ventilation, 62 percent versus 29 percent. A single bedside-adjacent measurement effectively stratifies patients into two very different futures.

To capture the dynamic nature of the disease, the team also deployed a Bayesian joint longitudinal-survival model, a sophisticated statistical architecture that links repeated measurements over time to the hazard of the clinical event. This analysis separated two distinct prognostic signals: the current amplitude itself, carrying a hazard ratio of 1.57 per 10 percent decrement, and the rate of decline of that amplitude, carrying an independent hazard ratio of 1.30. In other words, both where the diaphragm’s electrical output stands today and how fast it is eroding contribute independent information. This dual signal mirrors the logic clinicians apply intuitively to forced vital capacity, but here it operates on a measurement that no amount of weakness elsewhere in the body can distort.

The problem the study solves is well documented in the ALS literature. Forced vital capacity depends on bulbar competence to seal the mouthpiece, on respiratory muscle strength to generate flow, and on cognitive capacity to follow instructions. Slow vital capacity has been proposed as a gentler alternative, and supine measurements add sensitivity to diaphragmatic weakness, but all remain effort-dependent to some degree. Recent work from the same Lisbon group showed that cognitive dysfunction is associated with an underestimation of respiratory function on these tests, meaning the very patients whose breathing is deteriorating may appear deceptively stable. Guidelines from the European Academy of Neurology and its predecessors have long acknowledged the difficulty of timing ventilation, and the randomised trial by Bourke and colleagues that established the survival benefit of non-invasive ventilation relied on thresholds that cooperative patients can demonstrate but severely affected ones cannot.

The phrenic nerve conduction study itself is not new. It has been studied as a prognostic marker in ALS since at least 2009, when Pinto, Turkman and colleagues showed its value in predicting respiratory insufficiency, and the Lisbon group has since published normative data establishing age- and sex-referenced amplitude thresholds. What distinguishes the new work is scale, rigour and statistical ambition. The pre-registered plan, the competing-risk framework, the bootstrap validation, the time-dependent discrimination analyses and the joint modelling collectively meet the standards set by the TRIPOD reporting guidelines for clinical prediction models. The authors also positioned the measurement as a candidate outcome for clinical trials, where an objective, effort-independent readout of respiratory motor unit loss could serve as a sensitive endpoint for drugs targeting motor neuron degeneration.

Important caveats remain, and the authors state them plainly. The cohort is single-centre, and although it is large, the amplitude values were expressed against normative data derived from the same investigative tradition, raising the possibility of centre-specific calibration. External validation in independent cohorts, ideally spanning different health systems and ethnicities, is required before the marker can be embedded in guidelines, and the models will need recalibration to local populations. The association also attenuates beyond the first year, so the marker complements rather than replaces longitudinal clinical assessment. And while the test involves a mild electrical stimulus that most patients tolerate well, it is still an invasive neurophysiological procedure compared with a spirometry manoeuvre, which shapes how it might be deployed in routine monitoring.

Even with those qualifications, the implications are considerable. Respiratory failure remains the dominant cause of death in ALS, and the window for initiating ventilation comfortably, with time for adjustment, education and psychological preparation, is narrow and easy to miss when the usual yardsticks falter. An effort-independent electrical signature of the diaphragm’s remaining motor units, measured in a clinic room in minutes, that roughly doubles the predicted twelve-month risk when abnormal, offers a way to keep that window open for the patients who need it most, including those who can no longer perform the breathing manoeuvres their own care depends on. As disease-modifying therapies multiply and trials search for responsive endpoints, the humble phrenic nerve, stimulated and recorded for decades in neurophysiology labs, may be poised to become one of the most consequential numbers on the ALS chart.

Subject of Research: Phrenic nerve conduction studies as prognostic biomarkers of respiratory failure in amyotrophic lateral sclerosis

Article Title: Phrenic nerve amplitude as an effort-independent prognostic biomarker of respiratory failure in amyotrophic lateral sclerosis

Article References: Castro, J., Sá, V., Lopes, D., Alves, I., Oliveira Santos, M., & de Carvalho, M. (2026). Phrenic nerve amplitude as an effort-independent prognostic biomarker of respiratory failure in amyotrophic lateral sclerosis. Journal of Neurology, 273(10), Article 574. https://doi.org/10.1007/s00415-026-14125-0

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14125-0

Keywords: amyotrophic lateral sclerosis, phrenic nerve, nerve conduction studies, non-invasive ventilation, respiratory failure, prognosis, biomarkers, forced vital capacity, diaphragm, neurophysiology, motor neuron disease, ALSFRS-R

ALS is the most common form of motor neuron disease, a progressive neurodegenerative disorder that typically claims lives through respiratory failure within two to five years of diagnosis. While the search for disease-modifying therapies continues, multidisciplinary care has become a cornerstone of improving quality of life. Within that care landscape, metabolism and nutrition have emerged as critical determinants of disease progression. Hypermetabolism, appetite loss, and malnutrition affect up to half of people living with ALS and are associated with faster functional decline and earlier death. Studies consistently show that loss of weight and fat mass predict poorer outcomes, whereas a higher body mass index is linked to slower progression.

The energy imbalance that drives this decline arises through multiple, often co-existing mechanisms. Skeletal muscle and mitochondrial dysfunction can elevate energy expenditure, while swallowing difficulties, upper-limb weakness, and reduced appetite simultaneously cut intake. Qualitative research has also documented substantial psychological and behavioural barriers that patients, carers, and healthcare professionals face when trying to adopt high-calorie diets. Despite growing recognition of these problems, clinicians have lacked clear guidance on how to identify emerging energy imbalance and translate it into individualized nutritional targets, and dietitians report considerable uncertainty about how best to calculate and adjust energy requirements for this population.

To address both questions at once, the Australian team designed a prospective case-control and within-case comparison study. Participants with ALS attended baseline anthropometric and metabolic assessments and were invited back for repeat visits every three to four months, accumulating 1794 participant-months of follow-up across 120 patients with two or more visits. Body composition was measured with whole-body air displacement plethysmography using a BOD POD system, and resting energy expenditure was assessed by indirect calorimetry under a canopy hood. Functional capacity was tracked with the revised ALS Functional Rating Scale, and the rate of functional decline was calculated as the monthly loss of points since symptom onset.

The researchers classified patients by their percentage weight change during the first six months after study inclusion, adapting the Global Leadership Initiative on Malnutrition criteria. Forty-nine participants were classed as Weight Gain, with a mean gain of 2.76 kilograms; 36 as Stable Weight, with a mean loss of 2.13 kilograms; and 35 as Weight Loss, averaging a striking 7.54-kilogram drop, or about 10 percent of body weight. Crucially, baseline body weight, body mass index, fat mass, fat-free mass, and measured resting energy expenditure were comparable across the three groups, meaning the classification itself, rather than pre-existing differences, marked the dividing line between diverging trajectories.

What followed the six-month landmark was stark. Using joint longitudinal-survival models that account for informative dropout associated with death, the team showed that patients in the Weight Loss group continued to lose body weight, body mass index, fat mass, and fat-free mass at the steepest rates, and their ALS Functional Rating Scale scores declined significantly faster than those of the other groups. Survival analysis told an even grimmer story: median survival from the landmark visit was 12.2 months for the Weight Loss group, compared with 26.8 months for Stable Weight and 31.8 months for Weight Gain. After sex adjustment, early weight loss carried an approximately five-fold higher mortality hazard relative to the Weight Gain reference group, with a hazard ratio of 4.78 and a confidence interval of 2.68 to 8.53.

The pattern of tissue loss carried its own diagnostic weight. Because body weight and fat mass declined in parallel, the authors argue that the weight loss reflects sustained negative energy balance rather than being attributable solely to loss of muscle mass. In the joint models adjusted for age and sex, higher longitudinal body weight showed the strongest anthropometric association with lower mortality risk, with a standardized hazard ratio of 0.42, while higher fat mass conferred a modest but significant protective association, with a standardized hazard ratio of 0.63. Patients with early weight loss also had lower respiratory and bulbar subscores at baseline and a faster rate of functional decline, consistent with computational modelling indicating that site of onset, respiratory function, and progression rate predispose patients to severe weight loss.

The second half of the study examined whether any of the predictive energy equations proposed for use in ALS could have anticipated these trajectories. In a nested cohort of 82 patients with three-day food diaries and repeat assessments, the researchers compared reported energy intake with equation-derived estimated energy requirements. Concordance was defined as alignment between the intake-to-requirement ratio and the observed weight-change category within a plus-or-minus 10 percent range, consistent with Australian dietary standards. The results were sobering: overall concordance ranged from just 17.3 percent for the Mifflin-St Jeor five-year equation to 32.1 percent for the best-performing model. No equation performed consistently across all weight-change groups.

Some equations failed in instructive ways. An ideal-body-weight-based approach using a body mass index target of 30, adapted from work by Nakamura and colleagues, showed the greatest concordance among patients who lost weight, correctly classifying 60 percent of them, but it generated excessively high energy targets for those who were weight-stable or gaining. Conversely, an equation assuming increased resting energy expenditure produced requirement estimates below reported intake across all groups, which would have suggested adequate or even excessive intake in patients who went on to lose weight. Sex-adjusted equations such as Harris-Benedict and Mifflin-St Jeor fared somewhat better in patients with mild weight loss of up to 5 percent. The authors conclude that no single equation should be applied universally, and that estimates derived at a single time point should never be interpreted in isolation.

The study’s implications point toward serial monitoring and phenotype-informed dietetic care rather than formula-driven prescription. Because weight loss may reflect, rather than cause, a more aggressive disease course, the observational design cannot establish causation, and randomized trials will be needed to determine whether stabilizing weight improves outcomes. Trials of high-calorie diets have shown promise in some patients, particularly those with faster-progressing disease, but results have been inconsistent, possibly reflecting differences in disease stage, metabolic phenotype, or the macronutrient composition of the interventions. Evidence of impaired metabolic flexibility, glucose intolerance, and altered lipid metabolism in ALS suggests that substrate utilization may matter as much as total calories, and observational studies linking higher fat intake with longer survival hint that dietary composition could be tailored to metabolic profile. The Sheffield-led OptiCALS randomized trial is currently testing whether an individualized high-calorie dietary intervention improves functional and nutritional outcomes. In the meantime, the message from Brisbane is clear: weigh patients early, weigh them often, and treat a five percent drop in six months as the clinical alarm it truly is.

Subject of Research: Prognostic value of early weight loss and the performance of predictive energy equations in amyotrophic lateral sclerosis

Article Title: Early weight loss predicts poorer prognosis and highlights limitations of predictive energy equations in amyotrophic lateral sclerosis

Article References: Sewell-Green, A. R., Capstick, R., Holdom, C. J., Matthews-Rensch, K., Cameron, J., McCombe, P. A., Henderson, R. D., Ngo, S. T., & Steyn, F. J. (2026). Early weight loss predicts poorer prognosis and highlights limitations of predictive energy equations in amyotrophic lateral sclerosis. Journal of Neurology, 273(10), Article 575. https://doi.org/10.1007/s00415-026-14093-5

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14093-5

Keywords: amyotrophic lateral sclerosis, weight loss, prognosis, energy balance, predictive energy equations, malnutrition, hypermetabolism, body composition, nutrition, motor neuron disease, survival, dietetic care

The research, led by a team at Hubei University of Chinese Medicine and Hubei Provincial Hospital of Traditional Chinese Medicine in Wuhan, examined whether baseline sleep quality, measured with the Pittsburgh Sleep Quality Index, was associated with a composite endpoint combining tracheostomy or death from any cause, whichever came first. The PSQI is a widely used self-report questionnaire that scores sleep quality across seven domains, including sleep duration, sleep disturbances, sleep latency, daytime dysfunction, and use of sleep medication, with total scores ranging from zero to 21 and higher values indicating worse sleep.

The investigators drew on a non-public institutional ALS registry to identify patients treated between January 2019 and May 2022. In total, 268 patients with ALS were included in the analysis, and 115 of them experienced the composite endpoint event during follow-up. The cohort was divided into three groups according to PSQI score: 117 patients scored between 0 and 5, indicating no clinically significant sleep disturbance; 92 patients scored between 6 and 10, reflecting mild disturbance; and 59 patients scored between 11 and 21, indicating moderate-to-severe sleep disturbance.

The statistical architecture of the study was deliberately thorough. Kaplan-Meier curves were used to visualize differences in endpoint-free survival across the PSQI categories, and the separation between groups was statistically significant, with a log-rank P value below 0.001. Restricted cubic spline analyses then probed the shape of the relationship between continuous PSQI scores and risk, revealing an overall increasing association with no significant evidence of non-linearity. In other words, the risk appeared to climb steadily as sleep quality worsened, rather than jumping abruptly at any particular threshold.

The centerpiece of the analysis was a multivariable Cox proportional hazards model that adjusted for an unusually comprehensive set of potential confounders: age, sex, household income, site of disease onset, forced vital capacity, total score on the revised ALS Functional Rating Scale, disease progression rate, body mass index, serum albumin, and Hamilton depression rating scale score. In this fully adjusted model, each one-point increase in PSQI score was associated with a 13 percent higher risk of tracheostomy or death, with a hazard ratio of 1.13 and a 95 percent confidence interval of 1.07 to 1.20, a result that reached statistical significance at P less than 0.001.

When patients were categorized by severity of sleep disturbance, a striking pattern emerged. Compared with patients who had no sleep disturbance, those with moderate-to-severe disturbance had a significantly higher risk of the composite endpoint, with a hazard ratio of 2.65 and a 95 percent confidence interval of 1.55 to 4.53. Mild sleep disturbance, by contrast, was not significantly associated with increased risk. This dose-response-like pattern, in which only the more severe category showed a robust signal, suggests that the association is not simply an artifact of minor, transient sleep complaints but is concentrated among patients whose sleep is substantially disrupted.

Subgroup analyses extended the picture across strata of household income, age, disease progression rate, sex, site of onset, body mass index, and albumin levels. Notably, the researchers observed significant interactions for household income and disease progression rate, indicating that the strength of the association between sleep quality and outcomes may vary depending on these patient characteristics. Sensitivity analyses were also performed to test the robustness of the findings, and the authors report that the core association held across the models they examined.

Why might poor sleep track with worse outcomes in a neurodegenerative disease that destroys motor neurons? The authors themselves urge caution on interpretation, and their reasoning is worth unpacking. Sleep disturbance in ALS is rarely an isolated complaint. It can be driven by nocturnal respiratory dysfunction, as weakening respiratory muscles lead to hypoventilation during sleep, fragmented rest, morning headaches, and daytime fatigue. It can also reflect muscle cramps, spasticity, pain, drooling, depression, and anxiety, all of which become more common as the disease advances. In this sense, the PSQI may partly function as a proxy for unmeasured nocturnal respiratory impairment or for overall disease burden rather than as an independent causal factor.

This caveat shapes the study’s practical implications. The authors explicitly state that the observational data should not be interpreted as evidence that improving sleep quality will causally improve ALS outcomes. Treating sleep problems may well improve comfort and quality of life, and clinicians already recognize the importance of screening for respiratory insufficiency and initiating noninvasive ventilation when indicated, but the new findings do not establish that sleep interventions will change the trajectory of the disease itself. What the data do support, according to the authors, is the incorporation of systematic sleep assessment into prognostic risk stratification for ALS, so that a simple questionnaire score can help clinicians identify patients who may warrant closer monitoring.

The study also highlights a broader shift in how ALS research is approaching prognosis. Traditional predictors such as site of onset, forced vital capacity, and the rate of functional decline remain the backbone of clinical staging, but researchers are increasingly probing whether patient-reported measures, nutritional markers, and psychological factors add incremental predictive value. By adjusting for depression with the Hamilton depression rating scale and for a wide range of clinical variables, the Chinese team attempted to isolate the contribution of sleep quality specifically, and the persistence of the association after such extensive adjustment lends weight to the finding, even within the limits of a single-center retrospective design.

Several limitations deserve mention when weighing the results. The cohort comprised 268 patients from one institution in Wuhan, and retrospective registry data are inherently vulnerable to measurement error and missing information. The PSQI is a subjective instrument, and objective measures such as polysomnography were not used to characterize sleep-disordered breathing directly. Residual confounding by unmeasured variables, particularly detailed nocturnal respiratory physiology, remains possible, and the authors acknowledge this directly. The composite endpoint of tracheostomy or all-cause death, while clinically meaningful, also blends different events whose timing may be influenced by patient and family decisions about invasive ventilation.

Nevertheless, the signal is compelling enough to merit follow-up. A 13 percent increase in risk per PSQI point, and a nearly threefold elevation among patients with moderate-to-severe sleep disturbance, represents one of the larger effect sizes reported for a patient-reported measure in ALS prognostication. If prospective studies in other populations confirm the association and clarify the mechanisms, sleep assessment could become a routine, low-cost component of ALS care, flagging patients whose nighttime symptoms may be the first audible warning of respiratory decline. For now, the study stands as a reminder that in a devastating disease, even the quiet hours of the night carry information that clinicians cannot afford to ignore.

Subject of Research: The association between sleep quality measured by the Pittsburgh Sleep Quality Index and the risk of tracheostomy or death in patients with amyotrophic lateral sclerosis

Article Title: Association between PSQI and composite endpoints in ALS patients: a retrospective cohort study from China

Article References: Jiang, Q., Jiang, R., Kong, W., Yang, D., Zhu, Q., Wu, M., Wan, S., Cai, F., Xu, D., & Zhou, J. (2026). Association between PSQI and composite endpoints in ALS patients: a retrospective cohort study from China. BMC Medicine. https://doi.org/10.1186/s12916-026-05263-3

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05263-3

Keywords: amyotrophic lateral sclerosis, sleep quality, Pittsburgh Sleep Quality Index, sleep disturbance, prognosis, retrospective cohort study, tracheostomy, all-cause mortality, motor neuron disease, Cox regression, noninvasive ventilation, BMC Medicine

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 clinical picture of FOSMN is as distinctive as it is devastating. Patients typically notice unilateral facial tingling or numbness, followed by progressive weakness that advances over a span of two to six years, eventually encompassing the entire face, scalp, and upper limbs. Bulbar symptoms, including difficulty swallowing and speaking, often emerge within six years of onset. A hallmark feature is atrophy of the temporal and masseter muscles, the muscles of chewing, which can give the face a hollowed appearance. Both sensory and motor deficits follow a strict rostro-caudal trajectory, marching downward from the head toward the hands, with profound muscle wasting documented as late as ten years after the first symptoms. Lower motor neuron signs, particularly muscle atrophy, are present in every documented case.

Diagnosis has traditionally rested on electrophysiology rather than imaging. A prolonged or absent blink reflex is a key clinical hallmark, while needle electromyography reveals neurogenic denervation and reinnervation across cranial, cervical, and thoracic levels. Sensory nerve conduction studies typically show reduced amplitudes in the upper limbs. Conventional brain MRI, cerebrospinal fluid analysis, and laboratory work are generally unremarkable, although scans may occasionally show atrophy of the tongue or spinal cord. The main differential diagnoses include bulbar-onset amyotrophic lateral sclerosis, which is purely motor and lacks the facial sensory loss characteristic of FOSMN, as well as Bickerstaff brainstem encephalitis and Miller Fisher syndrome, which are distinguished by their acute, postinfectious course, eye movement palsies, and ataxia, in sharp contrast to the slow neurodegenerative progression of FOSMN.

What causes FOSMN remains unknown, but growing evidence points to an intriguing overlap with two better-known neurodegenerative conditions: amyotrophic lateral sclerosis and frontotemporal dementia. The motor features of FOSMN, with bulbar weakness and muscle atrophy, resemble ALS, while a subset of patients develops cognitive deficits and behavioral changes reminiscent of frontotemporal dementia. Genetic studies have strengthened this connection, identifying mutations in ALS-associated genes including SOD1, TARDBP, and SQSTM1 in some patients. Postmortem examinations have revealed significant atrophy of the trigeminal nerve roots, degenerative changes in both the sensory and motor nuclei of the trigeminal nerve, and substantial loss of anterior horn cells, the spinal motor neurons that control voluntary movement. Yet no accepted diagnostic criteria exist, and the fundamental question of whether FOSMN is neurodegenerative or immune-mediated remains open.

To probe the disease in living patients, the Ulm team, led by Angela Rosenbohm with Hans-Peter Müller and Jan Kassubek as senior authors, recruited six consecutive patients with clinically confirmed FOSMN, four men and two women aged 48 to 84 years, who presented to their department between 2016 and 2026. Given that only about one hundred cases exist worldwide, even a group of six represents a substantial cohort for this condition. The patients were compared with thirty age- and sex-matched healthy controls, all free of neurological, psychiatric, or major medical illness and without gross brain pathology on conventional MRI. The study was approved by the Ethics Committee of the University of Ulm and conducted in accordance with the Declaration of Helsinki, with written informed consent from all participants.

The researchers deployed two complementary, unbiased analysis techniques on data acquired from a 1.5 Tesla scanner. The first, atlas-based volumetry, processed T1-weighted structural images by segmenting them into gray matter, white matter, and cerebrospinal fluid compartments, normalizing them into standard Montreal Neurological Institute space, and measuring volumes of predefined brain regions using the LONI Probabilistic Brain Atlas. All results were standardized to the mean intracranial volume of the controls. The second technique, diffusion tensor imaging combined with whole brain-based spatial statistics, probed the microstructure of white matter tracts by measuring fractional anisotropy, a metric that reflects the directional organization of water diffusion and therefore the integrity of nerve fiber bundles. Statistical comparisons used the Welch test with false discovery rate correction and a cluster-size threshold to guard against spurious findings.

The volumetric results were striking. At the group level, FOSMN patients showed significant global brain atrophy, but the most pronounced volume loss was localized to the medulla oblongata, the lowermost portion of the brainstem that houses the nuclei of the trigeminal nerve and the medial lemniscus, a major sensory pathway. The insula, a deep cortical region involved in integrating bodily sensations, showed the next highest degree of shrinkage. Across the cerebral lobes, gray matter was generally more affected than white matter. This combination of widespread cerebral volume loss with a focal brainstem emphasis is anatomically plausible for a disorder that attacks the cranial nerves governing facial sensation and the bulbar muscles controlling speech and swallowing.

The diffusion imaging results added a second layer of insight. Fractional anisotropy was significantly reduced in the right frontal lobe and, bilaterally, along the superior and inferior longitudinal fasciculi, two major association pathways. The superior longitudinal fasciculus forms a large arcuate bundle connecting the frontal lobes with the parietal and temporal regions, while the inferior longitudinal fasciculus is an occipitotemporal projection system. Notably, the corticospinal tract, the primary motor pathway whose degeneration is the classic imaging signature of ALS, showed no significant involvement. The affected tracts are polymodal integration highways, and their disruption mirrors patterns previously described in frontotemporal lobar degeneration, aligning with the clinical and genetic overlap between FOSMN and that spectrum of disease. Interestingly, while direct connections to the face area of the somatosensory cortex did not fall within the significant clusters, trigeminal nerve disorders such as trigeminal neuralgia have previously been linked to microstructural alterations along the superior longitudinal fasciculus.

The authors are careful about the limitations. Six patients cannot settle every question, and diffusion tensor imaging cannot establish the directionality of tract changes, so the findings do not explain the characteristic rostro-caudal march of symptoms. Only one patient in the cohort showed upper motor neuron signs, so corticospinal tract involvement in more motor-dominant cases remains to be tested. Nor can MRI resolve whether the underlying process is neurodegenerative or immune-mediated. Yet the consistency of the volumetric and microstructural findings, obtained with standardized protocols on a single scanner, constitutes a genuine advance: for the first time, routine-looking scans have yielded an objective, in vivo neuroanatomical pattern for a disease whose biology has been almost entirely inferred from case reports and autopsies.

The clinical profiles of the six patients underscore the severity of the condition. Three presented with facial numbness, one with oropharyngeal dysphagia, one with weakness of the masticatory muscles, and one with forearm weakness. Swallowing impairment was confirmed by fiberoptic endoscopic evaluation in five patients, and two required feeding tubes placed directly into the stomach. Two patients developed upper-limb paresis a mean of 48 months after diagnosis, with intervals ranging from 12 to 84 months. The mean follow-up was just over four years. The team emphasizes that future progress will require multicenter studies with standardized clinical and neuroimaging assessments, ideally incorporating spinal cord imaging and longitudinal measurements that track how the brain changes as individual symptoms progress. Such phenotype-neuroimaging correlations, they argue, are the key to finally understanding what drives this enigmatic disorder, and potentially to distinguishing it earlier from the ALS-like and inflammatory conditions it so often mimics.

Subject of Research: Neuroimaging signatures of facial onset sensory and motor neuronopathy (FOSMN)

Article Title: Neuroimaging signatures of facial onset sensory and motor neuronopathy (FOSMN)

Article References: Rosenbohm, A., Herrera-Angeles, F., Huppertz, H.-J., Haeusler, K. G., Weishaupt, J. H., Müller, H.-P., & Kassubek, J. (2026). Neuroimaging signatures of facial onset sensory and motor neuronopathy (FOSMN). Journal of Neurology, 273(10), Article 639. https://doi.org/10.1007/s00415-026-14174-5

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14174-5

Keywords: FOSMN, neuroimaging, diffusion tensor imaging, atlas-based volumetry, motor neuron disease, amyotrophic lateral sclerosis, frontotemporal dementia, medulla oblongata, white matter tracts, brainstem, rare disease, MRI

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