Collagen type VI is a microfibrillar collagen found throughout the extracellular matrices of skeletal muscle and connective tissue. It anchors muscle fibers to their surrounding scaffold, maintains the structural integrity and elasticity of blood vessels, skin, and joints, and interacts with integrins while regulating various growth factors. Three genes, COL6A1, COL6A2, and COL6A3, encode the alpha chains that assemble into the functional collagen VI network. When pathogenic variants disrupt this assembly, the result is a continuum of neuromuscular disorders known as collagen VI-related dystrophies. At the mild end sits Bethlem myopathy, historically described as an autosomal dominant condition, while the severe end is occupied by Ullrich congenital muscular dystrophy, a devastating disease that can arise from either recessive or dominant mutations depending on the molecular mechanism involved.

Ullrich congenital muscular dystrophy was first described by Otto Ullrich in 1930 and is estimated to affect roughly 0.13 per 100,000 people worldwide. Its presentation is famously paradoxical: early-onset generalized hypotonia and severe proximal joint contractures coexist with marked hyperlaxity of the distal joints, a combination that gives affected children a distinctive posture and unusual joint mobility at the fingers, wrists, and ankles. Most patients experience significant motor delays, and disease progression inexorably leads to restrictive respiratory failure, which remains the primary cause of illness and death within the first two decades of life. There is currently no curative treatment. Management depends on a proactive multidisciplinary approach built around supportive care, early respiratory monitoring, and intensive physical therapy to slow contracture progression and preserve whatever motor function remains.

The boy in this report was born at term after an uncomplicated pregnancy and normal spontaneous vaginal delivery, with birth weight, length, and head circumference all within normal limits. His parents are first cousins, a detail that would prove central to the diagnostic story. Abnormal neuromuscular features emerged within the first month of life, when clinicians noted dysmorphic features including low-set ears, a high-arched palate, and a low anterior hairline, alongside clenched fingers more pronounced on the right side and a congenital clubfoot deformity. These findings prompted longitudinal developmental follow-up, which revealed a significant global delay. At age three, the child cannot sit independently, though he can sit with support, and he remains nonverbal. Receptive language appears spared, as he responds consistently to simple commands and to his name, and social development is largely maintained with appropriate eye contact and social smiling.

Neurological examination showed generalized hypotonia affecting both the trunk and the limbs, with distal muscle weakness more pronounced than proximal weakness. Deep tendon reflexes were globally absent, yet there were no signs of lower motor neuron disease such as tongue atrophy or fasciculation, and no seizures or hearing and vision problems were reported. Given the combination of developmental delay, hypotonia, progressive joint contractures, and the consanguineous parentage, clinicians pursued a genetic cause early and turned to whole exome sequencing. The test uncovered the homozygous COL6A1 variant of uncertain significance. Serum creatine phosphokinase, a muscle enzyme that rises sharply in many muscular dystrophies, was measured twice and found to be entirely normal at 78 and 114 units per liter against a reference range of 0 to 190.

To characterize the neuromuscular phenotype further, the team performed nerve conduction studies and electromyography. Nerve conduction studies revealed decreased compound motor action potential amplitudes in several motor nerves; the response of the left median motor nerve was absent altogether, while the right median nerve showed reduced amplitude with decreased conduction velocity, though interpretation was limited by the child’s hand deformities and joint contractures. Electromyography showed normal spontaneous activity but early recruitment of small motor units in the left tibialis anterior muscle, a pattern the neurophysiologists interpreted as non-specific myopathic change. Brain magnetic resonance imaging, obtained as part of the developmental delay workup, showed prominence of the anterior horns of the lateral ventricles, widening of the Sylvian fissures, and a diffuse reduction in white matter volume, all described as non-specific findings.

The diagnostic reasoning hinged on excluding alternatives. Spinal muscular atrophy, a leading cause of the floppy infant, was considered but deemed highly unlikely given the absence of tongue fasciculations, intact receptive language, and myopathic rather than neurogenic changes on electromyography. Other congenital myopathies and muscular dystrophies were also weighed, but the normal creatine phosphokinase levels effectively ruled out most dystrophinopathies and alpha-dystroglycanopathies, which typically produce markedly elevated enzyme values. The distinct structural abnormalities, clenched fingers and clubfoot, further aligned the phenotype specifically with collagen VI deficiency rather than other central or peripheral causes of hypotonia, and the paradoxical pairing of distal hypermobility with progressive proximal contractures pointed squarely toward the Ullrich end of the collagen VI disease spectrum.

Genetically, the variant itself fits the known disease mechanism even though it lacks formal classification. Pathogenic missense variants affecting highly conserved residues within the triple-helical domains of collagen are well-established causes of Ullrich congenital muscular dystrophy, and similar novel homozygous COL6A1 missense variants, such as p.Gly556Val, have previously been identified as the direct cause of classic disease features in consanguineous families. Splice-site and non-coding variants in COL6A1 have likewise been shown to disrupt collagen VI formation even when initially designated as uncertain. One atypical feature complicates the picture: the child’s significant global developmental delay, particularly in expressive language, is unusual for collagen VI-related dystrophies, in which cognitive function is classically spared. The exome did not reveal any secondary genetic variants to explain the delay, so the authors suggest it may relate to the diffuse white matter reduction seen on MRI, or may be secondary to severe early motor impairment and limited environmental interaction, though an independent co-occurring cause cannot be excluded.

The case also carries public health significance beyond a single patient. Epidemiological data on collagen VI-related dystrophies in the Middle East remain remarkably scarce, and Arab populations, including those in Palestine, have high rates of consanguineous marriage, which substantially increases the incidence of rare autosomal recessive conditions. In this child, the first-cousin parentage directly enabled the expression of a homozygous mutation that would likely remain silent in a heterozygous carrier. Documenting such cases, the authors argue, expands the global mutational spectrum of COL6A1 and underscores the need for targeted genetic counseling and carrier screening in highly consanguineous communities, where recessive diagnoses cluster within extended families.

The report acknowledges its limitations honestly. Segregation analysis was not performed because parental genetic testing was unavailable, and no functional studies, such as muscle biopsy, collagen VI immunohistochemistry on skin biopsy, or fibroblast culture, were carried out, all of which would be needed to upgrade the variant from uncertain to pathogenic under strict American College of Medical Genetics and Genomics criteria. Muscle MRI, which can reveal characteristic patterns of fibro-fatty replacement in collagen VI-related dystrophies, was also not performed, largely because of resource constraints and the clinical risks of prolonged general anesthesia or deep sedation in a child with severe hypotonia. Even so, the strong genotype-phenotype correlation documented here provides exactly the kind of phenotypic evidence that geneticists need to reclassify variants of uncertain significance in the future. For families navigating the uncertainty of an unclassified genetic result, careful clinical description remains one of the most powerful diagnostic tools available, turning a single ambiguous line of sequence data into a meaningful answer about a child’s disease.

Subject of Research: A novel COL6A1 gene variant associated with Ullrich congenital muscular dystrophy in a child with congenital hypotonia

Article Title: Unclassified COL6A1 Variant in a Child With Congenital Hypotonia: A Case Report

Article References: Nofal, K., Ghaith, H. M. A., Barghouthi, H. A., Shahrori, M., Darraj, B., & Hetta, A. A. (2026). Unclassified COL6A1 Variant in a Child With Congenital Hypotonia: A Case Report. Clinical Case Reports, 14(10), Article e73765. https://doi.org/10.1002/ccr3.73765

Image Credits: AI Generated

DOI: 10.1002/ccr3.73765

Keywords: COL6A1, Ullrich congenital muscular dystrophy, collagen VI-related dystrophies, congenital hypotonia, whole exome sequencing, variant of uncertain significance, consanguinity, neuromuscular disorders, genetic diagnosis, ClinVar, muscle weakness, rare disease

The therapeutic armamentarium at the center of the article acts at different levels of the pathogenic cascade. The neonatal Fc receptor antagonists efgartigimod alfa and rozanolixizumab promote the degradation of circulating pathogenic IgG antibodies, giving them a rapid onset of action and a favorable safety profile. Ravulizumab, a long-acting terminal C5 complement inhibitor, acts downstream by preventing formation of the membrane attack complex and complement-mediated injury at the postsynaptic membrane; the CHAMPION MG trial confirmed rapid and lasting improvement in acetylcholine receptor antibody-positive generalized myasthenia gravis with maintenance dosing every eight weeks. Rituximab, by contrast, acts upstream by depleting CD20-positive B cells and may provide long-term immunosuppressive effect; in the RINOMAX randomized trial, rituximab given within twelve months of diagnosis increased the probability of achieving minimal disease manifestations and reduced the need for rescue treatment compared with placebo.

The Athens team retrospectively described seven purposively selected adults managed between February 2025 and July 2026, distinguishing therapies that had actually been administered from those merely planned at the data cutoff. Treatment selection was guided by disease severity, corticosteroid-related risks, presence of thymoma, comorbidities, peripheral venous access, vaccination requirements and the need for rapid improvement or sustained disease management. During the study period, efgartigimod alfa and rozanolixizumab were the only FcRn antagonists and ravulizumab the only C5 complement inhibitor commercially available in Greece, a practical constraint that shaped the pathways. Follow-up under the targeted strategy ranged from one to twelve months, and no treatment-related side effects, relevant infections or rescue therapies for worsening disease were recorded.

Three of the cases involved recent-onset disease, defined as diagnosis within the preceding twelve months. A 72-year-old man with a four-month history and advanced chronic glaucoma, for which corticosteroid escalation was contraindicated, received four cycles of efgartigimod alfa as a rapidly acting bridging therapy; prednisolone was halved from 15 to 7.5 milligrams per day while clinical stability was maintained, and rituximab was planned as the longer-term non-steroidal strategy. A 71-year-old man with recently diagnosed early-stage prostate cancer and hypertension received two cycles of rozanolixizumab, whose subcutaneous route was clinically practical, with prednisolone reduced from 15 to 12.5 milligrams per day while he completed the vaccinations required before planned rituximab. A 59-year-old man with type 2 diabetes and cardiovascular comorbidities worsened by steroids received a single efgartigimod cycle and reached a Myasthenia Gravis Activities of Daily Living score of 0, with prednisolone reduced from 20 to 17.5 milligrams per day.

A fourth profile involved very-late-onset disease, defined as onset at age 65 or older. An 80-year-old man with two months of predominantly bulbar dysfunction requiring a nasogastric tube received prednisolone, intravenous immunoglobulin and two rituximab infusions of 500 milligrams each, achieving enough improvement to remove the tube. Because dysarthria and dysphagia persisted and his peripheral venous access was poor, rozanolixizumab was initiated nine weeks after the second rituximab infusion as continuing, symptom-guided FcRn inhibition with the practical advantage of subcutaneous administration. After four cycles with intercycle intervals of three to six weeks determined by clinical need, his status improved from class IIIB to IIB, prednisolone fell from 10 to 7.5 milligrams per day, and immunophenotyping six months after rituximab showed CD19-positive cells at 0.5 percent, confirming sustained B-cell depletion.

Two thymoma-associated cases illustrate the bridging logic most vividly. A 46-year-old woman referred eighteen months after diagnosis with severe ocular-cervical-bulbar weakness received prednisolone, intravenous immunoglobulin, plasma exchange and four weekly rituximab infusions, yet disabling neck flexor weakness, nasal speech and dysarthria persisted. Efgartigimod was started eleven months after the rituximab course; after three cycles at seven-week intervals, prednisolone was reduced from 20 to 10 milligrams per day, and ravulizumab was intended as long-term therapy once required vaccinations were completed. A 48-year-old woman whose thymoma was removed incidentally, and who also carried a history of HPV-associated cervical adenocarcinoma, had poor venous access that precluded further plasma exchange; two efgartigimod cycles improved her from class IVB to IIA with an MG-ADL score of 1, while meningococcal vaccination proceeded toward planned ravulizumab. The choice is supported by growing real-world evidence, including an Italian multicenter ravulizumab cohort of 14 thymoma patients showing greater early Quantitative Myasthenia Gravis response in this subgroup, and a separate cohort of 23 patients confirming complement inhibitor effectiveness in thymoma-associated disease.

The seventh case involved chronic, corticosteroid-dependent disease with prominent ocular relapse. A 71-year-old man with a seven-year history had achieved pharmacological remission on mycophenolate mofetil and low-dose alternate-day prednisolone, then developed an unprovoked ocular-bulbar relapse with severe bilateral ptosis and diplopia. Prednisolone was raised to 25 milligrams per day, and symptom recurrence during tapering indicated inadequate control despite mycophenolate. Three efgartigimod cycles improved his MG-ADL score from 7 to 2 and his class from IIIB to IIB, but residual ptosis tended to recur as each cycle approached, precluding steroid reduction. Ravulizumab was therefore planned for sustained control, a rationale reinforced by a post hoc analysis of CHAMPION MG showing benefit across individual MG-ADL items, with particularly notable improvements in ocular symptoms including eyelid ptosis and diplopia.

The article also highlights practical pharmacology that determines sequencing. Clinically meaningful improvement with efgartigimod may appear as early as one week after the first administration, with maximal benefit generally around week four, while rozanolixizumab improvement has been detected from day eight, the first post-baseline assessment. FcRn antagonists require no pre-treatment vaccinations, allowing immediate initiation, whereas C5 complement inhibition demands meningococcal vaccination against serogroups A, C, W, Y and B completed at least two weeks before the first ravulizumab dose, with antibacterial prophylaxis required if treatment must begin sooner. This vaccination delay is precisely why FcRn antagonists served as immediately available bridging therapies in the thymoma and relapsing cases. For planned rituximab transitions, the team uses an interval of at least two to three weeks after the last FcRn dose, reflecting efgartigimod pharmacokinetics and serum IgG recovery preferably above 5 grams per liter, while stressing that no evidence-based interval has been established.

A subtle pharmacokinetic consideration runs through the discussion: because FcRn inhibition enhances IgG catabolism and ravulizumab is an IgG-based monoclonal antibody, FcRn blockade increases ravulizumab clearance, which is why the pathways were sequential rather than concomitant. Japanese clinicians have recently reported two refractory patients treated with combined subcutaneous efgartigimod and zilucoplan, a macrocyclic peptide C5 inhibitor that, not being an IgG antibody, escapes FcRn-mediated catabolism; zilucoplan was not commercially available in Greece during the study period. The authors are candid about limitations, including the retrospective single-center design, very small and heterogeneous sample, potential selection bias and the fact that several planned transitions had not yet been implemented, making the observations descriptive and hypothesis-generating rather than proof of comparative efficacy. Still, the seven pathways assign distinct but complementary clinical roles to each agent, rapid IgG reduction, long-term B-cell depletion and sustained terminal complement inhibition, and argue that treatment sequence should be tailored to disease phenotype, therapeutic objective, comorbidities, vaccination requirements and route of administration, with prospective studies needed to establish optimal intervals and biomarkers capable of guiding individualized selection.

Subject of Research: Neurology

Article Title: Individualized sequencing of targeted immunotherapies in generalized myasthenia gravis across distinct patient profiles

Article References: Zouvelou, V., Tzavella, D., Strataki, E., & Vakrakou, A. G. (2026). Individualized sequencing of targeted immunotherapies in generalized myasthenia gravis across distinct patient profiles. Frontiers in Neurology, 17, Article 1989043. https://doi.org/10.3389/fneur.2026.1989043

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1989043

Keywords: myasthenia gravis, immunotherapy, FcRn antagonists, rituximab, ravulizumab, neuromuscular disorders, targeted therapy, Individualized, sequencing, targeted, immunotherapies, generalized

That blind spot is the post-operative patient. Fernández argues that in patients with poorly controlled gMG who undergo urgent abdominal surgery—say, emergency laparotomy for perforated diverticulitis—myasthenic or cholinergic crisis is too often treated as a diagnosis of exclusion rather than a condition demanding immediate priority intervention once clinically suspected. In practice, respiratory failure in this population is frequently labeled as multifactorial, attributed to sepsis, fluid overload, or post-operative deconditioning, rather than recognized as myasthenic crisis. The problem, she stresses, is not uncertainty about whether crisis belongs in the differential diagnosis; it is diagnostic ambiguity that delays crisis-specific therapy while clinicians sequentially rule out competing explanations.

The immunological logic behind the risk is layered. Immunosuppression can mask both clinical and septic signs, blunting the early warning signals that would normally trigger suspicion. Infection itself can drive autoantibody production, with single-cell immune profiling studies showing that neutrophils promote myasthenia gravis exacerbation through secretion of B-cell activating factor (BAFF). Prolonged fasting around surgery creates nutritional deficits, including hypophosphatemia, which directly impairs diaphragmatic contractility and is further aggravated by refeeding syndrome. Sepsis-related oxidative stress adds yet another hit, damaging the motor endplate where antibodies are already compromising signal transmission. Each mechanism compounds the others, and none announces itself clearly in a sedated, ventilated patient.

The confounders specific to the post-operative setting are formidable. Sedation and pain mask the oculobulbar signs—ptosis, diplopia, bulbar weakness—that typically herald a myasthenic crisis. Post-operative ileus introduces uncertainty about whether orally administered pyridostigmine is even being absorbed, complicating the distinction between myasthenic crisis, in which antibody-mediated weakness predominates, and cholinergic crisis, caused by excess anticholinesterase medication. And the growing number of patients maintained on biologic therapy raises a thorny question: does plasma exchange (PLEX) remain appropriate as first-line rescue in someone already receiving an FcRn antagonist or other biologic agent?

Fernández also challenges a widespread assumption embedded in the literature the review cites: that oculobulbar findings will accompany or precede respiratory failure, prompting early suspicion of crisis. In her clinical experience, myasthenic crisis in the critically ill post-operative patient can present as isolated hypercapnic respiratory failure with no oculobulbar signs at all. In an intubated patient on mechanical ventilation, cooperation-dependent pulmonary function testing is simply not feasible. Her proposed solution is bedside diaphragmatic ultrasonography, a rapid, repeatable tool that can support or exclude the suspicion of crisis without delaying management, and she argues it deserves explicit consideration in future guidance on crisis recognition in post-operative intensive care units.

At the heart of the commentary lies what Fernández calls the central clinical dilemma: the sequencing of exclusion versus treatment. The instinctive pattern—rule out fluid overload, uncontrolled sepsis, cholinergic excess, and mechanical or pulmonary causes before committing to crisis-specific immunotherapy—may be exactly backwards. Pure fluid overload rarely accounts on its own for the need for intubation; one would expect a response to diuretics and non-invasive ventilation, together with a distinct lung ultrasound pattern such as that described in the BLUE protocol. Moreover, the two mechanisms are not mutually exclusive, since respiratory muscle weakness can amplify even mild fluid overload. In a patient with poorly controlled gMG on biologic therapy and acute hypercapnic respiratory failure of neuromuscular pattern in the early post-operative period, the pretest probability of crisis is high enough that treatment should start in parallel with, not subordinate to, the exclusion of alternative diagnoses.

The emerging evidence base for acting quickly is thin but consistent. A systematic review by Tang and colleagues describes improvement with efgartigimod across 20 patients with myasthenic crisis, and a prospective case series by Song and colleagues reports ventilator weaning within a mean of 10.4 days. Adding weight to the argument for early intervention, absence of myasthenia gravis-specific immunosuppressive treatment at intensive care unit admission has been independently associated with prolonged weaning in a WEAN Safe analysis of ventilation outcomes. Together, Fernández contends, these findings support initiating specific treatment without delay, even while acknowledging that efgartigimod’s crisis evidence remains limited to case series rather than randomized trials.

The question of PLEX versus FcRn antagonism in patients already on biologic therapy, Fernández argues, deserves nuance rather than a blanket recommendation. Efgartigimod itself, by inhibiting FcRn, non-specifically reduces circulating IgG, which may also accelerate clearance of IgG-based therapeutic monoclonal antibodies—so it should not be assumed that efgartigimod better preserves concomitant biologic therapy than PLEX does. Biologic agents in gMG are also mechanistically heterogeneous. For B-cell-depleting agents such as rituximab, PLEX matters most shortly after infusion; once B-cell depletion is established, the pharmacodynamic effect may persist even as circulating drug levels fall. Complement inhibitors such as eculizumab and ravulizumab, by contrast, depend on continuous plasma concentrations, so lowering circulating levels—whether by PLEX or by FcRn inhibition—could more directly compromise their efficacy. Her commentary proposes a decision framework weighing hemodynamic and coagulation status, sepsis control, renal and volume status, and the specific biologic agent, since no single dimension alone determines the safest rescue choice.

Looking ahead, Fernández calls on future guidance to address three priorities explicitly: recognition of myasthenic crisis in patients whose post-operative respiratory failure is otherwise labeled multifactorial after urgent abdominal surgery; the role of diaphragmatic ultrasonography in atypical presentations lacking oculobulbar signs; and individualization of rescue therapy by biologic agent, mechanism, and timing, without implying superiority of any single modality in myasthenic crisis. As more patients with difficult-to-control gMG are maintained on biologic therapy, the population of immunosuppressed surgical patients facing this diagnostic minefield is set to grow, making the commentary’s message—that crisis should be treated in parallel with exclusion, not after it—one that intensive care and neurology teams alike cannot afford to ignore.

Subject of Research: Efgartigimod therapy and myasthenic crisis recognition in generalized myasthenia gravis

Article Title: Commentary: Efgartigimod for generalized myasthenia gravis: a comprehensive review of clinical evidence and future perspectives

Article References: Fernández, A. B. (2026). Commentary: Efgartigimod for generalized myasthenia gravis: a comprehensive review of clinical evidence and future perspectives. Frontiers in Neurology, 17, Article 1975630. https://doi.org/10.3389/fneur.2026.1975630

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1975630

Keywords: efgartigimod, generalized myasthenia gravis, myasthenic crisis, FcRn antagonist, plasma exchange, diaphragmatic ultrasonography, post-operative respiratory failure, neuromuscular disorders, Commentary, generalized, myasthenia, gravis

FSHD is among the most common hereditary neuromuscular disorders, affecting roughly 5 in 100,000 people worldwide. Unlike Duchenne muscular dystrophy, it does not shorten life expectancy, but its progressive nature exacts a heavy toll. The disease stems from a genetic error on chromosome 4: a contraction of D4Z4 macrosatellite repeats causes hypomethylation of the region, allowing sporadic expression of DUX4, a transcription factor normally silent in mature skeletal muscle. DUX4 switches on germline and early stem cell genes that should never be active in adult muscle, disrupting cellular homeostasis and triggering inflammation and apoptosis. The result is a progressive, asymmetric loss of muscle mass that typically begins in the face, shoulder girdle, and upper arms, later spreading to the trunk and lower limbs. Severity varies enormously: up to 30 percent of genetic carriers report no symptoms, while approximately 20 percent become wheelchair-dependent.

The pathological picture is more complex than simple muscle wasting. Quantitative MRI reveals fatty infiltration two to three times greater than in age-matched controls, along with STIR hyperintensity lesions—pockets of edema interpreted as signs of active inflammation. Muscle biopsies from STIR-positive regions show mononuclear cell infiltrates, elevated expression of major histocompatibility complex I, and greater collagen deposition, indicating fibrosis. Oxidative stress compounds the damage: transcriptomic analyses show upregulation of TNFα pathway genes, FSHD myoblasts display increased susceptibility to oxidative injury, and patients carry a reduced ratio of reduced to oxidized glutathione in their blood. Critically, these radiological features—fatty infiltration, lesion burden, and shrinking muscle volume—are the most sensitive markers of progression, detectable within a single year, while functional scores often lag behind.

Weakness in FSHD exceeds what muscle loss alone can explain. Individuals consistently show reductions in maximal voluntary contraction force of more than 40 percent compared with controls, and even after correcting for fatty infiltration, specific force—the force per unit of contractile cross-sectional area—remains reduced by over 30 percent. Yet isolated single muscle fibers from the same patients generate nearly normal specific force. This paradox points the finger away from the contractile machinery itself and toward collective impairments: MRI-based estimates of contractile area likely overstate true fiber area because they cannot distinguish fibrosis, edema, and interstitial cells from contractile tissue. Emerging evidence also implicates defective excitation–contraction coupling. Meta-analyses reveal downregulation of genes associated with neuromuscular junction architecture, single-fiber electromyography shows abnormal transmission correlated with disease duration, sarcolemmal reorganization increases the distance between the sarcolemma and the nearest myofibril—potentially disrupting the T-tubule network—and muscle excitability studies reveal partial depolarization of the resting membrane potential, which could inactivate voltage-gated sodium channels and attenuate calcium release from the sarcoplasmic reticulum.

Against this backdrop, the review defines high-load resistance training precisely: programs using loads of 70 to 90 percent of one-repetition maximum, or the 4 to 12 repetition maximum range, which meta-analyses show are most effective at simultaneously increasing muscle mass and maximal strength. The authors emphasize that while lighter loads produce comparable hypertrophy when volume is matched, higher loads yield greater strength gains. Optimal prescription involves at least four sets per muscle group per week—ideally ten or more for maximizing hypertrophy—rest intervals of one to two minutes between sets, a minimum frequency of two weekly bouts, and progressive overload, in which loads are increased over time to maintain the targeted repetition range at near-maximal effort.

The acute responses to such training are well characterized in healthy populations. A single bout causes rapid neuromuscular fatigue, myofibrillar disruption visible under electron microscopy, mild swelling lasting up to 48 hours, soreness persisting for days, and elevated serum creatine kinase. Plasma cytokines such as IL-6, IL-1ra, MCP-1, and G-CSF rise transiently, and severe disruption is followed by mononuclear cell infiltration—collectively termed exercise-induced muscle damage. Crucially, these responses are normal remodeling processes, not signs of intolerance. Healthy individuals recover within days and are protected against comparable damage in subsequent bouts, a phenomenon known as the repeated bout effect. Meanwhile, anabolic signaling through MAPK pathways and mTORC1 drives muscle protein synthesis that remains elevated beyond 48 hours, while protein degradation returns to baseline—the cumulative imbalance producing net accretion of contractile protein.

Long-term, the benefits are substantial. Twelve to 24 weeks of high-load resistance training typically increases one-repetition maximum by 20 to 50 percent, with early gains driven primarily by neural adaptations—increased motor unit recruitment and discharge rate within the first two to four weeks—before morphological hypertrophy of roughly 5 to 20 percent becomes detectable. Strength gains translate into improved gait speed, chair stand performance, and balance, the very capacities that underpin independence. Equally relevant to FSHD, evidence from other populations shows that resistance training reduces fatty infiltration in older and overweight adults, attenuates chronic low-grade inflammation as measured by C-reactive protein, reduces oxidative stress markers in metabolic conditions, and—strikingly—alters inflammatory gene expression and reduces interstitial fibrosis in myositis, an autoimmune myopathy that shares mononuclear infiltration, fatty infiltration, fibrosis, and muscle fiber regeneration with FSHD.

So where did the caution come from? The review traces much of the dogma to two influential studies. Over 50 years ago, Johnson and Braddom reported that most members of an FSHD family were weaker in their dominant arm—the one used habitually—and concluded that extensive use, including resistance training, accelerates disease progression. But the conclusions were never substantiated by statistical analysis, and the methods were described only vaguely. Brouwer and colleagues later found statistically significant side-to-side differences in just 3 of 10 strength tests, with small numerical differences relative to large standard deviations. Subsequent studies across 102 individuals with FSHD found no effect of handedness on weakness patterns, and a case report in monozygotic twins reached the same conclusion. The overwork weakness hypothesis, in other words, does not withstand replication.

The recommendation to avoid loads above 30 percent of one-repetition maximum fares no better. Several resistance training studies have included individuals with FSHD who repeatedly lifted loads well above that threshold, and all reported the training was well tolerated, with most showing moderate improvements in strength and function. On eccentric contractions, the review notes that submaximal eccentric actions—inevitable in daily activities like sitting down—are demonstrably safe, and the only study to test maximal eccentric contractions found that individuals with myopathic disease showed slightly attenuated signs of exercise-induced muscle damage compared with healthy controls, whose creatine kinase rose significantly more three days post-exercise. Though limited to two individuals with FSHD, the study gives no indication of heightened vulnerability. Persistent soreness, the authors add, is the expected response of any untrained person beginning training—not evidence of disease provocation—and clinicians should avoid language that reinforces a sense of fragility, which fuels fear and exercise avoidance.

The most cited study on the topic, published by van der Kooi and colleagues in 2004, trained 19 individuals with FSHD for 52 weeks and is frequently invoked as proof that resistance training offers no benefit. Yet the review highlights critical limitations: the program started with 10RM loads progressing toward 5RM—below the high-load definition—lacked a healthy positive control group, and produced a 37 percent increase in elbow flexion one-repetition maximum that has been overshadowed by emphasis on its negative findings. No available study has adequately addressed whether high-load training affects the major pathological features of FSHD, considered the disease’s inherent asymmetry, or employed gold-standard whole-body MRI to track fibrosis, fatty infiltration, and muscle mass. Until such trials are conducted, the authors conclude, patients and clinicians will remain without answers about an intervention that is accessible, inexpensive, and likely low-risk—one that could delay the mobility decline and loss of independence that define advanced FSHD.

Subject of Research: FSHD

Article Title: High-load resistance training and FSHD: harmful mixture or a silver bullet combination?

Article References: Meinhold, M., & Hornberger, T. A. (2026). High-load resistance training and FSHD: harmful mixture or a silver bullet combination?. Journal of Neurology, 273(10), Article 605. https://doi.org/10.1007/s00415-026-14148-7

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14148-7

Keywords: FSHD, resistance training, muscular dystrophy, exercise science, neuromuscular disorders, DUX4, muscle physiology, High-load, resistance, training, harmful, mixture

The research team, led by Jenny Linnea Victoria Lindroos of the University of Bergen and the Norwegian Institute of Public Health, exploited a unique strength of the Nordic healthcare infrastructure: mandatory national registers that record every birth, every hospital contact, and every prescription dispensed at a pharmacy. By harmonizing and pooling data from the Norwegian medical birth register covering 1999 to 2023 and its Swedish counterpart covering 1994 to 2022, and linking these records individually through each mother’s national identity number, the investigators assembled a cohort of 339 pregnancies among women with confirmed myasthenia gravis, drawn from more than 2.5 million births. The diagnosis itself was verified through multiple routes, including hospital diagnoses coded under the International Classification of Diseases and repeated fills of pyridostigmine, the standard symptomatic treatment, with validation studies in Norway showing a positive predictive value of 99 percent for the register-based diagnosis.

The methodological innovation at the heart of the study was group-based multi-trajectory modeling, an unsupervised statistical clustering technique that can follow several medication classes simultaneously across repeated time windows. Rather than imposing predefined categories such as early versus late pregnancy, the model let the data speak, dividing the timeline into four pre-pregnancy quarters, three trimesters, and two postpartum periods, and estimating how each pregnancy’s use of symptomatic drugs, oral corticosteroids, and non-steroidal immunosuppressants evolved together. The algorithm tested three, four, and five latent groups, ultimately settling on a four-group solution that balanced statistical fit, measured by an entropy of 0.92 and posterior probabilities between 95 and 99.6 percent, against clinical interpretability and privacy constraints that ruled out groups smaller than ten pregnancies.

Among the 339 pregnancies, 201, or roughly 59 percent, involved at least one fill of a myasthenia gravis medication during the year before pregnancy or during pregnancy itself, while 138 women, about 41 percent, filled no myasthenia gravis prescriptions at all across that entire window. The four trajectories that emerged were named for their defining patterns: Intermittent users, the largest group at 20.9 percent of the cohort; Persistent symptomatic-only users at 19.8 percent; Immunosuppressant plus symptomatic users at 10.3 percent; and Immunosuppressant-only users at 8.3 percent. The two largest groups relied exclusively on symptomatic medications such as pyridostigmine but differed sharply in consistency. Persistent symptomatic-only users refilled their prescriptions in 75 to 88 percent of every time period, averaging two fills per period, whereas Intermittent users filled prescriptions in only 21 to 28 percent of pre-pregnancy periods and just 13 percent during the second trimester. The average dispensed pyridostigmine dose told the same story, at 269 milligrams per day for the persistent group versus 159 for the intermittent group.

The immunosuppressant groups displayed more complex dynamics. Immunosuppressant plus symptomatic users carried the heaviest treatment burden, purchasing pyridostigmine at an average of 450 milligrams per day during the first trimester and prednisolone at roughly 16 milligrams per day, double the dose seen in the immunosuppressant-only group. Strikingly, their use of non-steroidal immunosuppressant therapy, chiefly azathioprine, fell steeply after conception, from around 60 percent filling prescriptions before pregnancy to only 20 percent in the third trimester. The authors interpret this drop as a deliberate attempt to avoid fetal drug exposure, though they cannot exclude improvement in disease activity, side effects, or pregnancy-related vomiting as contributing causes. In contrast, Immunosuppressant-only users maintained a remarkably stable prednisolone trajectory of about 8 milligrams per day throughout the entire study period, below the 10-milligram threshold generally considered safe in pregnancy, and rarely needed symptomatic medications at all.

Safety signals in the dispensing data were reassuring in several respects. Known teratogenic drugs, specifically methotrexate, mycophenolate mofetil, and cyclophosphamide, were never dispensed later than nine to twelve months before pregnancy, indicating that clinicians and patients successfully cleared these hazardous agents well before conception. Tacrolimus was never refilled during pregnancy, and prednisolone was the only oral corticosteroid used throughout. Biologics such as rituximab appeared only in pre-pregnancy and postpartum windows, and plasma exchange was confined to the pre-pregnancy period. Azathioprine, considered acceptably safe based on observational and animal data, was the dominant non-steroidal immunosuppressant, and its use actually rose during the final nine months before conception among the heaviest treatment group, a pattern the authors read as evidence of preconception treatment optimization.

Hospital contact patterns added a crucial clinical dimension to the medication trajectories. Overall, myasthenia gravis admissions were infrequent, but they clustered conspicuously in one group: 23 percent of Immunosuppressant plus symptomatic users were admitted for myasthenia gravis during pregnancy, and 26 percent had at least one such admission before pregnancy, with 71 percent requiring myasthenia gravis outpatient visits. This same group also showed the highest body mass index, more diabetes and gestational hypertension, and, tellingly, the lowest use of preconception folic acid supplementation, with fewer than five women taking it. Combined with the observation that 23 percent of these women had no specialist outpatient contact at all in the year before pregnancy, the authors argue that many of these pregnancies were likely unplanned and not preceded by neurological counseling, a gap with tangible consequences given that this group also frequently stopped immunosuppression during gestation.

By contrast, the Non-users, who made up 41 percent of the cohort, almost never required myasthenia gravis admissions during pregnancy or postpartum and rarely initiated treatment after delivery, consistent with stable remission or minimal disease manifestation. The Immunosuppressant-only users presented a paradox: minimal myasthenia gravis hospital contacts but frequent non-myasthenia specialist care, likely reflecting the known associations of corticosteroid exposure with hypertension, hyperglycemia, infections, preeclampsia, and preterm birth, alongside a high rate of autoimmune comorbidity at 39 percent and assisted reproductive technology conception in 21 percent of the group. Notably, the trajectory groups aligned closely with the Myasthenia Gravis Foundation of America Post-intervention Status classification, suggesting that dispensing records alone can proxy disease severity classes without requiring clinical examination data.

The study’s limitations deserve honest framing. Infusion therapies such as rituximab, administered in hospitals rather than pharmacies, were invisible to the prescription registers in Sweden and in Norway before 2022, and the drug’s long-lasting immunosuppressive effect may partly explain the large Persistent symptomatic-only group, particularly its Swedish predominance. Spontaneous and induced abortions could not be included because birth registers incompletely capture them, meaning the findings generalize best to pregnancies progressing to birth, and severe cases may be underrepresented. The authors also lacked antibody status, thymectomy history, and formal severity scores. Even so, the cohort’s population basis, prospective data capture, and cross-national harmonization make it an unusually robust evidence base.

The practical message for clinicians is unambiguous. Most women with myasthenia gravis enter pregnancy with no, low, or stable medication use and remain on predictable trajectories, but the minority who combine immunosuppressants with symptomatic therapy face the highest risk of disease exacerbation, hospitalization, and abrupt treatment discontinuation precisely when stability matters most. The authors conclude that identifying these trajectory subgroups, which likely represent distinct disease courses in relation to pregnancy, could enable individualized care pathways, and that preemptive discussions about reproductive plans should be routine when treating women of childbearing age with myasthenia gravis. For a disease whose course in pregnancy has long been described as unpredictable, this register-based cartography of real-world drug use turns a page: the unpredictability, it turns out, has structure, and that structure can now be named, measured, and planned around.

Subject of Research: Medication use trajectories during pregnancy in women with myasthenia gravis

Article Title: Medication use trajectories in myasthenia gravis pregnancies: a population-based drug utilization study

Article References: Lindroos, J. L. V., Gilhus, N. E., Brauner, S., Bjørk, M.-H., Midelfart-Hoff, J., Cesta, C. E., Furu, K., & Cohen, J. M. (2026). Medication use trajectories in myasthenia gravis pregnancies: a population-based drug utilization study. Journal of Neurology, 273(10), Article 572. https://doi.org/10.1007/s00415-026-14115-2

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14115-2

Keywords: myasthenia gravis, pregnancy, pharmacoepidemiology, pyridostigmine, prednisolone, azathioprine, immunosuppression, trajectory modeling, Nordic registers, autoimmune disease, neuromuscular disorders, maternal health

The genetic roots of FSHD lie in a region of chromosome 4 called D4Z4, a stretch of repeated DNA sequences that normally keeps a gene called DUX4 silenced. In FSHD1, which accounts for about 95 percent of cases, these repeats contract to between one and ten units instead of the usual eleven or more, allowing DUX4 to be aberrantly expressed in muscle tissue. DUX4 is a transcription factor that wreaks havoc once activated, driving oxidative stress, impaired muscle regeneration, and the activation of innate immune and antiviral pathways. The shorter the residual repeat array, the more DUX4 is released and, generally, the earlier and more severe the disease. But this relationship is far from complete. Even relatives carrying identical D4Z4 contractions can differ dramatically in severity, a gap that has long suggested the involvement of additional modifiers, whether genetic, epigenetic, environmental, or immunological.

That immunology might matter in FSHD is not an entirely new idea. Muscle biopsies from patients frequently show inflammatory infiltrates dominated by CD8-positive T lymphocytes and macrophages, and magnetic resonance imaging reveals muscle edema during active phases of the disease. Transcriptomic studies have documented upregulation of interferon signaling and cytokine-related genes in FSHD tissues, and DUX4 itself can induce the expression of inflammatory mediators. Isolated case reports have also described patients with both FSHD and autoimmune conditions such as myasthenia gravis or inflammatory myopathies. What remained unknown was whether these co-occurrences were coincidental or whether autoimmune disease systematically shapes the course of the muscular dystrophy.

To answer that question, the Nice team analyzed 299 adults with genetically confirmed FSHD1, all evaluated between 2017 and 2025, for whom complete demographic, clinical, and genetic data were available. Each patient was classified using the Comprehensive Clinical Evaluation Form, a standardized tool that sorts patients into four categories: category A for the typical facial and scapular phenotype, category B for incomplete weakness limited to the scapular or facial muscles, category C for pauci-symptomatic or asymptomatic carriers, and category D for atypical presentations. Autoimmune diagnoses were only accepted when confirmed by the relevant specialist, with strict criteria applied for conditions such as Sjögren’s syndrome, which required fulfillment of the 2016 ACR/EULAR classification criteria with positive anti-SSA or anti-SSB antibodies.

The results were striking. Eighty-two patients, or 27.4 percent of the cohort, had at least one autoimmune disease, and fourteen of them carried two. In total, 96 autoimmune conditions spanning fourteen distinct diagnoses were recorded. Hashimoto’s thyroiditis was the most common, affecting 32 patients, followed by autoimmune diabetes in 16, atopic dermatitis in 12, myasthenia gravis in 10, and primary biliary cholangitis and psoriasis in 7 each. When the researchers compared these counts with published prevalence estimates from the general population, several conditions stood out as dramatically overrepresented. Myasthenia gravis appeared roughly 167 times more often than expected, primary biliary cholangitis about 106 times, autoimmune diabetes nearly 43 times, idiopathic inflammatory myositis about 72 times, and Sjögren’s syndrome more than 16 times. By contrast, common inflammatory skin disorders such as atopic dermatitis and psoriasis were not enriched, suggesting that the association involves specific autoimmune mechanisms rather than a generalized tendency toward inflammation.

The clinical implications were equally compelling. Patients with autoimmune comorbidities were older at examination, with a mean age of 56.3 years compared with 51.2 years, and had a later disease onset, at 38.4 years versus 33.7 years. More intriguingly, despite carrying significantly larger D4Z4 repeat arrays, 7.18 repeat units on average versus 6.53, which should ordinarily predict a milder disease, these patients scored significantly worse on the FSHD severity scale, 7.98 versus 6.56. The distribution of phenotypes also shifted: autoimmune patients were far more likely to fall into category D, the atypical group, at 30.5 percent versus 8.3 percent of non-autoimmune patients, and less likely to show the classical category A presentation. Within categories A and B, autoimmune patients again had significantly higher severity scores.

To test whether autoimmunity was an independent driver of severity rather than a byproduct of age or genetic background, the researchers built a multivariable linear regression model incorporating age, sex, disease duration, D4Z4 repeat number, and autoimmune status. The genetic effect held firm: each additional repeat unit was associated with a decrease in severity score of nearly one point, with a beta coefficient of minus 0.96, while each additional year of disease duration added 0.11 points. But the autoimmune signal was even more pronounced. After adjusting for every other variable, the presence of an autoimmune disease added an average of 2.12 points to the severity score, an effect that was highly statistically significant. Notably, there was no interaction between autoimmune status and repeat number, meaning the autoimmune penalty appeared to operate in parallel with, rather than through, the primary genetic defect.

Perhaps the most provocative finding concerns the subgroup of patients carrying seven to ten D4Z4 repeat units, the larger residual arrays conventionally associated with milder disease. Autoimmune disease was substantially more frequent in this group, affecting 36.1 percent of patients with seven to ten repeats compared with just 16.2 percent of those with shorter alleles, and 73 of the 96 recorded autoimmune conditions occurred in the larger-repeat subgroup. The authors propose a conceptual model in which the relative contribution of disease modifiers depends on repeat size. In patients with short alleles, below seven repeats, the primary genetic contraction dominates the clinical picture. In those with larger alleles, however, secondary factors, including autoimmune disease, unrelated genetic disorders, hormones, telomere shortening, aging, and immunosenescence, may play a proportionally greater role in shaping phenotype and severity. This could explain why patients with seemingly mild genetics sometimes develop serious disease, and why the seven-to-ten repeat range appears repeatedly as a hotspot for modifier effects in this and previous studies from the same group.

The biological mechanisms linking autoimmunity and FSHD severity remain speculative but plausible. Chronic muscle injury in FSHD may release intracellular antigens and pro-inflammatory mediators that fuel immune activation, while systemic autoimmune inflammation could in turn exacerbate muscle dysfunction, impair regeneration, or interact with the epigenetic regulation of the D4Z4 locus itself. The later disease onset observed in autoimmune patients hints that an age-related pro-inflammatory state, compounded by immunosenescence, may gradually tip the balance in genetically susceptible individuals. The authors are careful to note that their study is retrospective and single-center, that referral bias may have inflated the detection of autoimmune comorbidities in a national neuromuscular center, and that several rare conditions were represented by too few cases for firm conclusions. Still, the message for clinical practice is clear: systematically screening FSHD patients for autoimmune disease could refine prognosis and, if future longitudinal studies confirm causality, open the door to immune-targeted therapies for a subgroup of patients whose disease severity is being quietly amplified by their own immune systems.

Subject of Research: The association between autoimmune comorbidities and clinical severity in facioscapulohumeral muscular dystrophy type 1

Article Title: Autoimmune Comorbidities as Modifiers of Phenotypic Heterogeneity in Facioscapulohumeral Dystrophy

Article References: Pini, J., Tammam, G., Ezaru, A., Gambella, M., Sanson, B., Villa, L., Cavalli, M., Ioncea, M.-B., Puma, A., & Sacconi, S. (2026). Autoimmune Comorbidities as Modifiers of Phenotypic Heterogeneity in Facioscapulohumeral Dystrophy. Annals of Clinical and Translational Neurology, Article acn3.70529. https://doi.org/10.1002/acn3.70529

Image Credits: AI Generated

DOI: 10.1002/acn3.70529

Keywords: FSHD, muscular dystrophy, autoimmune disease, DUX4, D4Z4, myasthenia gravis, Hashimoto's thyroiditis, disease modifiers, genetics, inflammation, clinical severity, neuromuscular disorders

Myopathies — diseases that primarily affect skeletal muscle — represent one of the most heterogeneous diagnostic challenges in clinical genetics. They can arise from defects in hundreds of different genes, spanning structural muscle proteins, ion channels, metabolic enzymes, mitochondrial machinery and RNA-processing factors. Clinical presentations overlap heavily: a patient with progressive weakness may ultimately turn out to have a dystrophinopathy, a metabolic myopathy, a congenital myopathy or an inflammatory condition with a genetic underpinning. This heterogeneity has long forced diagnostic laboratories to choose between narrowly targeted gene panels, which are cheap but blind to anything outside their curated gene list, and exome sequencing, which captures the protein-coding portion of the genome but systematically misses variants buried in introns, regulatory regions and structural rearrangements.

The study was conducted within PFMG2025, a national program piloted by the French Genomic Medicine Initiative to bring genome sequencing into routine clinical practice for rare diseases. Between July 2020 and October 2024, patients with myopathies who remained genetically undiagnosed after prior testing underwent genome sequencing at two designated clinical laboratories: SeqOIA in Paris and AURAGEN in Lyon. The retrospective analysis drew on clinical, paraclinical and genetic data collected across these platforms, making it one of the largest real-world assessments of genome sequencing for muscle disease conducted at a national scale. Crucially, the sequencing was performed as part of ordinary clinical care, not as a research protocol, which means the results reflect what health systems can realistically achieve rather than what is possible only under ideal laboratory conditions.

The headline result is deceptively simple: among 265 families, genome sequencing produced a conclusive molecular diagnosis — variants classified as likely pathogenic or pathogenic under American College of Medical Genetics and Genomics criteria — in 68 cases, a diagnostic yield of 26 percent. That figure might appear modest until it is placed in context. Every one of these patients had already passed through the existing diagnostic cascade, including, for many, gene panels and exome sequencing specifically designed to catch myopathy genes. A 26 percent yield in this heavily pre-tested population demonstrates that genome sequencing is not merely a marginal upgrade over existing methods; it reaches diagnostic territory that those methods structurally cannot access.

The technical reasons for this advantage lie in the fundamental differences between sequencing strategies. Gene panels and exome approaches rely on capture-based enrichment, which selectively amplifies exons — the roughly one to two percent of the genome that encodes proteins — before sequencing. Deep intronic regions, where pathogenic variants can disrupt splicing by creating cryptic exon insertion sites, are largely invisible to these methods unless specifically probed. Copy-number variants, complex rearrangements and variants in poorly captured exons are also systematically underdetected. Whole-genome sequencing, by contrast, reads across the entire genome uniformly, without capture bias, allowing laboratories to detect deep intronic splice-altering variants, exon-level deletions and duplications, and other non-coding pathogenic mechanisms in a single assay. This breadth proved decisive in the French cohort: the authors report that genome sequencing was necessary for the resolution of 20.5 percent of all cases with conclusive or candidate findings, because the responsible variants would not have been detectable using other established techniques.

Beyond the confirmed diagnoses, the study highlights the more nuanced contribution of variants of uncertain significance. When the researchers considered candidate VUS findings that nonetheless raised a strong diagnostic hypothesis — for example, variants in genes consistent with the patient’s clinical presentation, or variants whose pathogenicity is supported by emerging functional evidence but which do not yet meet formal ACMG criteria for pathogenicity — the effective diagnostic yield rose to 44 percent. In clinical practice, such findings are not endpoint diagnoses, but they can reshape patient management, guide surveillance for known complications, inform reproductive counseling, and direct families toward research studies and, increasingly, toward gene-specific clinical trials. As gene-specific therapies for neuromuscular diseases multiply, the difference between a confirmed diagnosis and a strong hypothesis is shrinking in practical importance, because both can determine eligibility for intervention.

The identification of deep intronic variants deserves particular emphasis, because these discoveries are rewriting the known architecture of neuromuscular disease. Pathogenic changes located thousands of base pairs away from the nearest exon were long considered unfindable at diagnostic scale, yet they are now recognized as substantial contributors to myopathies — most famously in dystrophinopathies, where deep intronic pseud exon activation accounts for a meaningful fraction of patients who previously tested negative on exons-focused assays. In the French cohort, the ability of genome sequencing to elucidate these complex variants, and to uncover previously undescribed pathogenic mechanisms, accounted for a large share of the diagnoses that panel and exome sequencing had missed. The authors argue that this capacity underscores the complex nature of neuromuscular genetic disorders and demonstrates how genome sequencing can deliver a genetic diagnosis within routine clinical practice rather than in specialized research settings.

The PFMG2025 program itself is a case study in how to operationalize genomic medicine at national scale. Funded by the French government through the National Research Agency under the Programme d’Investissements d’Avenir, the initiative connects a dense network of neuromuscular reference centers — spanning hospitals from Paris to Marseille, Lyon, Bordeaux, Grenoble and beyond — with centralized sequencing and analysis platforms. Clinicians across the FILNEMUS network prescribed genome sequencing for patients with suggestive phenotypes, encoded clinical information in standardized HPO terms, and returned findings through structured counseling pathways. This architecture allowed the study to capture the full diversity of myopathy subtypes and patient ages, from infants with congenital presentations to adults with slowly progressive weakness, and to measure performance in the messy reality of clinical medicine rather than in a curated cohort.

For patients and families, the practical consequences of a molecular diagnosis are difficult to overstate. A confirmed genetic cause ends the diagnostic odyssey — often a decade or more of investigations — and replaces uncertainty with a named condition that carries a defined natural history, evidence-based surveillance recommendations and, increasingly, targeted treatment options. Genetic diagnoses also ripple across families, enabling cascade testing of relatives, precise reproductive risk assessment and prenatal or preimplantation diagnostic options. In neuromuscular medicine specifically, the therapeutic landscape is changing rapidly: therapies for spinal muscular atrophy have transformed that disease’s trajectory, and gene-targeted approaches for Duchenne muscular dystrophy, limb-girdle muscular dystrophies and metabolic myopathies are advancing through trials. Every one of these interventions depends on knowing the exact gene involved — which makes the diagnostic yield of genome sequencing a direct determinant of who can access emerging treatments.

The French results add to a growing international consensus that the era of sequential, gene-limited testing is ending. Health systems that still route patients through panels first, then exomes, then genomes only after years of delay, are paying for repeated negative tests while withholding the one assay capable of detecting the full spectrum of pathogenic variation. The PFMG2025 findings — a 26 percent conclusive yield in a pre-tested myopathy population, rising to 44 percent with strong candidate findings, and more than one in five resolved cases achievable only through genome sequencing — make a data-driven argument for moving genome sequencing forward in the diagnostic pathway for muscle disease. As sequencing costs continue to fall and analysis pipelines for non-coding and structural variants mature, the question facing clinicians and payers is shifting from whether to adopt genome sequencing to how quickly the diagnostic cascade can be reorganized around it.

Subject of Research: Diagnostic yield of whole-genome sequencing compared with gene-panel and exome sequencing in genetically unresolved myopathies

Article Title: Genome sequencing improves diagnostic outcomes over panel and exome sequencings in myopathies: findings from the French PFMG2025 initiative

Article References: Verebi, C., Maino, A., Metay, C., Nectoux, J., Leturcq, F., Michel, L., Menassa, R., Pion, E., Cossee, M., Gorokhova, S., Krahn, M., Ramond, F., Fauré, J., Hersent, C., Malfatti, E., FILNEMUS PFMG2025 Consortium, Audic, F., Authier, F.-J., Barnerias, C., … Stojkovic, T. (2026). Genome sequencing improves diagnostic outcomes over panel and exome sequencings in myopathies: findings from the French PFMG2025 initiative. Genome Medicine. https://doi.org/10.1186/s13073-026-01769-w

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01769-w

Keywords: genome sequencing, myopathy, diagnostic yield, PFMG2025, exome sequencing, gene panel, neuromuscular disorders, deep intronic variants, genomic medicine, France, rare disease diagnosis, variants of uncertain significance

Congenital myopathies are a heterogeneous family of disorders that typically announce themselves in early childhood with floppiness and generalised muscle weakness, most prominently in the muscles closest to the trunk. Severity spans an enormous range: the most affected infants are born with respiratory insufficiency and swallowing difficulties, while milder cases may only become apparent in adolescence or adulthood. Birth prevalence has been estimated at roughly 15 per 100,000 live births, and more than 40 different genes have been implicated, although about one in five patients still lack a confirmed genetic diagnosis. Despite this genetic diversity, the underlying cellular defects converge on a handful of mechanisms, including disturbed calcium handling in muscle fibres, abnormal sarcomeric proteins, and defects in membrane trafficking and cytoskeletal organisation.

It is precisely this convergence that made salbutamol an attractive candidate. As a β2-adrenergic agonist, the drug exerts anabolic effects on skeletal muscle, increasing protein synthesis, reducing protein degradation, and shifting myosin heavy chain expression from slow type I fibres towards fast type IIa fibres. Many congenital myopathies share type 1 fibre predominance and muscle fibre atrophy, so a drug that counteracts these features could plausibly help patients regardless of which faulty gene they carry. Earlier open-label studies in Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy hinted at short-term gains, but placebo-controlled trials failed to show sustained benefit, and a small pilot in core myopathies was too limited in design to be conclusive.

The new trial, known as COMPIS, was designed to settle the question with far greater rigour. Led by researchers at Queen Silvia’s Children’s Hospital in Gothenburg, with nationwide recruitment through paediatric neuromuscular centres in Stockholm, Lund/Malmö and Uppsala, the study enrolled 18 participants aged 6 to 30 with genetically verified congenital myopathies. Crucially, the cohort included both children who could walk and those who could not, and baseline functional severity ranged from severely impaired to mildly affected. Genetic causes included variants in RYR1, ACTA1, NEB, SELENON, TPM2, TPM3 and MYBPC1, reflecting the true diversity of clinical practice rather than a narrowly selected subgroup.

The crossover design meant every participant served as their own control. After a screening visit, participants were randomised to receive either 24 weeks of daily oral salbutamol added to standard of care, or standard of care alone, followed by a four-week washout and then the alternate treatment. Because participants and treating physicians inevitably knew which treatment was being given, the investigators masked the physiotherapists and occupational therapists who performed all functional assessments, ensuring that outcome measurement remained objective. The primary endpoint was the Motor Function Measure-32, a validated 32-task assessment of gross and fine motor function scored out of 96 points.

The results were unambiguous. During salbutamol treatment, the mean MFM-32 total score rose by 3.72 points, compared with an essentially flat 0.11 points during standard care alone, yielding an adjusted mean difference of 3.61 points in favour of the drug. That margin exceeds previously established thresholds for clinically meaningful change in congenital-onset neuromuscular disorders. Improvements were concentrated in the domains most affected by the disease, namely standing and transfers, and axial and proximal motor function. Dominant hand grip strength also increased significantly, and muscle strength measured by hand-held myometry trended upwards across all tested muscle groups.

Perhaps most striking were the gains in respiratory and ambulatory function. Seated forced vital capacity, a key indicator of breathing capacity, increased by 0.20 litres relative to control, a difference the authors consider particularly important because respiratory insufficiency is a common and morbid manifestation of congenital myopathies even when limb function appears stable. Among the 11 ambulatory participants, six-minute walking distance improved by an estimated 38 metres, and the time needed to rise from lying on the floor fell by 1.6 seconds, corresponding on log-scale analysis to a 9 percent increase in walking distance and a 23 percent reduction in rise time. For families, such gains translate into greater independence and delayed reliance on assistive devices and home adaptations.

Safety and tolerability were reassuring. Only two adverse events occurred during salbutamol treatment, neither clearly related to the drug, and there were no serious adverse events. Six participants experienced mild, expected pharmacological side effects, chiefly transient palpitations and one case of tremor, which resolved within one to two weeks in nearly all cases. No arrhythmias or clinically relevant electrocardiographic abnormalities emerged, blood pressure and heart rate stayed within normal ranges, and no participant discontinued treatment. Notably, every single participant chose to continue taking salbutamol after the study ended. Five participants gained a clinically significant amount of weight during treatment, reporting increased appetite, but statistical adjustment for weight change did not alter the findings.

The authors are careful to acknowledge limitations. The sample of 18 participants, while a triumph of recruitment in such a rare disease, was too small to detect differences in response by genotype, age or sex, and the open-label nature means patient-reported outcomes could be influenced by expectation. Longer-term studies will be needed to determine whether the benefits persist. Nevertheless, the trial stands as the first randomised, controlled, blinded-endpoint study of salbutamol in this population, and its implications reach beyond congenital myopathies. At a time when gene therapies for these disorders have stumbled, one trial was halted after treatment-related deaths, salbutamol offers a low-cost, globally marketed alternative that could be deployed now under multidisciplinary neuromuscular care, with baseline cardiac evaluation and monitoring. The researchers also emphasise a broader lesson: as repurposed medicines enter clinical practice, preserving the affordability and worldwide availability of generic drugs will be essential to ensuring equitable access for the patients who need them.

Subject of Research: A randomised crossover trial of oral salbutamol for motor function and muscle strength in congenital myopathies

Article Title: Effects of oral salbutamol treatment on motor function and muscle strength in congenital myopathies (COMPIS): a single-centre, randomised, open-label, blinded-endpoint, crossover trial in Sweden

Article References: Michael, E., Staaf, P., Gudmundsson, M., Klanac, B., Weichbrodt, J., Edofsson, U., Thuestad, I. J., Sejersen, T., Imberg, H., & Darin, N. (2026). Effects of oral salbutamol treatment on motor function and muscle strength in congenital myopathies (COMPIS): a single-centre, randomised, open-label, blinded-endpoint, crossover trial in Sweden. eClinicalMedicine, Article 104186. https://doi.org/10.1016/j.eclinm.2026.104186

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104186

Keywords: congenital myopathies, salbutamol, drug repurposing, neuromuscular disorders, randomised crossover trial, muscle strength, motor function, respiratory function, RYR1, pediatric neurology, eClinicalMedicine, rare disease