RARE DISEASE
Nemaline myopathy
Nemaline myopathy
Nemaline myopathy
Synonyms: NEM, NM, Nemaline rod myopathy
Synonyms: NEM, NM, Nemaline rod myopathy
Synonyms: NEM, NM, Nemaline rod myopathy
Drug discovery
210
papers
On emerging therapies
Overview
Nemaline Myopathy is a genetically heterogeneous congenital myopathy characterized by skeletal muscle weakness, hypotonia, and pathognomonic nemaline bodies on muscle biopsy. Caused by mutations in NEB (50% of cases), ACTA1, TPM2/3, and other thin filament-associated genes, it presents across a severity spectrum from neonatal respiratory failure to mild adult-onset forms. Diagnosis combines clinical assessment, histopathology, and genetic testing. Common complications include respiratory insufficiency, dysphagia, and skeletal deformities [1][4][12].
Therapies
Supportive care: Noninvasive ventilation, gastrostomy for dysphagia, physical therapy, and scoliosis management [1][6][15].
Experimental approaches: Gene therapy (AAV vectors targeting ACTA1/NEB in preclinical models) and drug repurposing trials (L-tyrosine for bulbar function) [3][8][13][20].
No disease-modifying therapies approved [18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
210 drug discovery papers about Nemaline myopathy. Recent publications:
210 drug discovery papers about Nemaline myopathy. Recent publications:
categories:
Small molecules
small molecules
2026-08-22 | Efficacy of multimodality therapy for sporadic late onset nemaline myopathy and associated monoclonal gammopathy
ABSTRACT Sporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset disorder leading to muscle weakness, first reported in 1966. The disease is closely associated with plasma cell disorders, particularly monoclonal gammopathy (MG), but does not have a standardized treatment approach despite fatal outcome in several reported cases. In this report, a male patient diagnosed with SLONM-MGUS was treated using various modalities over several years, including intravenous immunoglobulin (IVIg) and monoclonal anti-CD 20 antibody, rituximab, and on progression, received a multi-modality treatment strategy with high-dose melphalan chemotherapy and autologous hematopoietic cell transplant (ASCT), followed by maintenance with immunomodulatory agent (IMiD), lenalidomide. He underwent ASCT in April 2018 (age 53) and, at the time of reporting (age 60), has maintained clinical benefit for more than seven years on lenalidomide maintenance. While prior therapies provided transient improvement, ASCT followed by maintenance therapy was associated with durable functional benefit. The study emphasizes the need to correctly diagnose this rare disorder and the potential benefit of multi-modality strategy including ASCT followed by lenalidomide maintenance in treating SLONM-MGUS and indicates that the disappearance of monoclonal protein is not always linked to neurological recovery. Our patient adds further evidence to the existing literature and demonstrates sequential clinical benefit from various modalities including IVIg, rituximab, ASCT, and IMiDs in this rare disorder.
2026-06-21 | Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.
2025-12-04 | Sporadic Late-Onset Nemaline Myopathy Associated with Multiple Myeloma: A Case Report.
Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired myopathy that is frequently associated with monoclonal gammopathy, most commonly monoclonal gammopathy of undetermined significance (MGUS). However, its association with overt multiple myeloma (MM) has been rarely reported. We present a case of SLONM associated with MM in which chemotherapy targeting the underlying MM led to mild-to-moderate improvement in muscle symptoms. This case underscores the potential pathogenic role of MM in SLONM and highlights the importance of treating underlying hematologic malignancies.
2025-11-13 | Sporadic late-onset nemaline myopathy with cardiomyopathy presenting as advanced heart failure despite autologous stem cell transplantation: a case report.
Nemaline myopathy is a rare neuromuscular disorder characterized by severe muscle weakness and dyskinesia, predominantly affecting skeletal muscles. Notably, significant cardiac involvement, especially in the sporadic late-onset subtype, is exceptionally uncommon. A 31-year-old female patient presented to our hospital with a 6-month history of chest tightness and progressive peripheral oedema for 10 days, superimposed on a 2-year course of proximal muscle weakness. Four months prior, she received a diagnosis of sporadic late-onset nemaline myopathy complicated by monoclonal gammopathy of uncertain significance, followed by autologous stem cell transplantation 2 months ago. The patient presented with advanced heart failure, characterized by dilated cardiac chambers and impaired ventricular systolic function, as evidenced by an echocardiographically derived left ventricular ejection fraction (LVEF) of 25%, an elevated pro-brain natriuretic peptide of 4673 pg/ml, and polyserosal effusions. Extensive late gadolinium enhancement in the ventricular walls on cardiac magnetic resonance imaging confirmed the suspected diagnosis of heart failure secondary to sporadic late-onset nemaline myopathy-related cardiomyopathy. Following active treatment with guideline-directed medical therapy for heart failure, the patient was discharged in an improved clinical condition, with her LVEF increasing to 57% at the 6-month follow-up. This case report highlights that sporadic late-onset nemaline myopathy may progress to severe cardiomyopathy and even heart failure, notwithstanding autologous stem cell support. Current evidence supports the application of standard heart failure medications as a rational therapeutic strategy.
2025-10-03 | Proteomic analysis of nemaline myopathy in infants reveals distinct common dysregulated proteins and cellular pathways
Background Nemaline myopathy is a rare congenital muscle disorder characterized by the presence of nemaline rods, protein aggregates, in muscle fibers. Pathogenic variants in several genes, most commonly NEB and ACTA1 , which encode thin filament proteins of the sarcomere, have been implicated in its etiology. Currently, there is no cure for nemaline myopathy, underscoring the need to identify disease-modifying targets for therapeutic development. Methods In this study, we employed quantitative nanoscale liquid chromatography–tandem mass spectrometry (LC-MS 3 ) with labeled protein analysis on muscle tissue from five normal controls and seven infants diagnosed with nemaline myopathy due to NEB or ACTA1 pathogenic variants. Results We identified and quantified 4,846 proteins across all samples, with 183 proteins showing significant dysregulation. Protein–protein interaction analysis revealed nine upregulated, muscle-specific proteins: NRAP, FBXO40, TRIM63, TRIM54, ALPK3, XIRP1, ANKRD2, LMOD2, and CSRP3. Further pathway analysis indicated upregulation of protein synthesis and proteasomal degradation processes, alongside downregulation of glycolysis. Notably, the dysregulated proteins and pathways were consistent across both genetic subtypes, suggesting shared molecular mechanisms underlying the disease. Conclusion This proteomic profiling study has identified key dysregulated proteins and pathways in infantile nemaline myopathy. These findings advance our understanding of the disease’s molecular basis and highlight candidate targets for future therapeutic intervention.
proteins
2023-01-26 | Exon skipping caused by splicing mutation in TNNT1 nemaline myopathy.
The TNNT1 gene encoding the slow skeletal muscle TnT has been identified as a causative gene for nemaline myopathy. TNNT1 nemaline myopathy is mainly characterized by neonatal-onset muscle weakness, pectus carinatum and respiratory insufficiency. Herein, we report on a Chinese girl with TNNT1 nemaline myopathy with mild clinical phenotypes without thoracic deformities or decreased respiratory function. Muscle biopsy showed moderate to marked type 1 fiber atrophy and nemaline rods. Next-generation sequencing identified the compound heterozygous c. 587dupA (p. D196Efs*41) and c. 387+5G>A mutations in the TNNT1 gene according to the transcript NM_003283.4. RNA sequencing revealed complete exon 9 skipping caused by the c. 387+5G>A mutation. Through quantitative PCR, we found that both the truncation c. 587dupA (p. D196Efs*41) and the splicing c. 387+5G>A mutations triggered nonsense-mediated mRNA decay (NMD). Western blotting showed the residual amount of the truncated TNNT1 protein by deletion of exon 9, which may ameliorate the disease to some extent.
2022-06-23 | Mob4-dependent STRIPAK involves the chaperonin TRiC to coordinate myofibril and microtubule network growth
Myofibrils of the skeletal muscle are comprised of sarcomeres that generate force by contraction when myosin-rich thick filaments slide past actin-based thin filaments. Surprisingly little is known about the molecular processes that guide sarcomere assembly in vivo, despite deficits within this process being a major cause of human disease. To overcome this knowledge gap, we undertook a forward genetic screen coupled with reverse genetics to identify genes required for vertebrate sarcomere assembly. In this screen, we identified a zebrafish mutant with a nonsense mutation in mob4. In Drosophila, mob4 has been reported to play a role in spindle focusing as well as neurite branching and in planarians mob4 was implemented in body size regulation. In contrast, zebrafish mob4geh mutants are characterised by an impaired actin biogenesis resulting in sarcomere defects. Whereas loss of mob4 leads to a reduction in the amount of myofibril, transgenic expression of mob4 triggers an increase. Further genetic analysis revealed the interaction of Mob4 with the actin-folding chaperonin TRiC, suggesting that Mob4 impacts on TRiC to control actin biogenesis and thus myofibril growth. Additionally, mob4geh features a defective microtubule network, which is in-line with tubulin being the second main folding substrate of TRiC. We also detected similar characteristics for strn3-deficient mutants, which confirmed Mob4 as a core component of STRIPAK and surprisingly implicates a role of the STRIPAK complex in sarcomerogenesis.
2021-10-06 | Structure of the thin filament in native skeletal muscles reveals its interaction with nebulin and two distinct conformations of myosin
Abstract Nebulin is a major structural protein of skeletal sarcomeres and is essential for proper assembly and contraction of skeletal muscle 1 . It stabilises and regulates the length of thin filaments, 2 but the structural mechanism remains nebulous. Using electron cryotomography and sub-tomogram averaging, we present the first structure of native nebulin bound to thin filaments within the A-band and I-band of intact sarcomeres. This in-situ reconstruction reveals unprecedented detail of interaction at pseudo-atomic resolution between nebulin and actin, providing the basis for understanding the structural and regulatory roles of nebulin. The position of nebulin on the thin filament indicates that there is no contact to tropomyosin or myosin, but an unexpected interaction with a troponin-T linker, possibly through two binding motifs on nebulin. In addition, our structure of myosin bound to the thin filaments reveals different conformations of the neck domain, both within the same sarcomere and when compared to purified structures, highlighting an inherent structural variability in muscle. We provide a complete description of cross-bridge formation on fully native, nebulin-containing thin filaments at near-atomic scale. Our structures establish the molecular basis for the role of nebulin as a thin filament “molecular ruler” and the impact of nemaline myopathies mutations that will aid future development of therapies.
2021-03-09 | Lmod3 promotes myoblast differentiation and proliferation via the AKT and ERK pathways.
Mutations in the Lmod3 gene have been identified as a genetic cause of nemaline myopathy. However, the mechanism underlying this disease and the function of Lmod3 remain largely unknown. In this study, we found that Lmod3 knockdown in C2C12 cells impaired myoblast differentiation, whereas enforced Lmod3 expression enhanced such differentiation. We also discovered that myoblast proliferation was promoted by Lmod3 overexpression but impeded by its knockdown. Additionally, knockdown of Lmod3 led to apoptosis in myoblasts. Concurrently, forced Lmod3 expression in C2C12 cells contributed to activation of the AKT and ERK pathways during myoblast differentiation and proliferation, respectively. Conversely, knockdown of Lmod3 in C2C12 cells produced the opposite results. Furthermore, administration of IGF-1, a booster of both AKT and ERK pathways, partially rescued the inhibitory effect of Lmod3 knockdown on both differentiation and proliferation of C2C12 cells. These results suggest that Lmod3 promotes differentiation and proliferation of myoblasts through the AKT and ERK pathways, respectively.
2020-09-15 | The molecular mechanism of muscle dysfunction associated with the R133W mutation in Tpm2.2.
Ghost muscle fibres reconstituted with myosin heads labeled with the fluorescent probe 1,5-IAEDANS were used for analysis of muscle fibre dysfunction associated with the R133W mutation in β-tropomyosin (Tpm2.2). By using polarized microscopy, we showed that at high Ca2+ the R133W mutation in both αβ-Tpm heterodimers and ββ-Tpm homodimers decreases the amount of the myosin heads strongly bound to F-actin and the number of switched-on actin monomers, with this effect being stronger for ββ-Tpm. This mutation also inhibits the shifting of the R133W-Tpm strands towards the open position and the efficiency of the cross-bridge work. At low Ca2+, the amount of the strongly bound myosin heads is lower for R133W-Tpms than for WT-Tpms which may contribute to a low myofilament Ca2+-sensitivity of the R133W-Tpms. It is concluded that freezing of the mutant αβ- or ββ-Tpm close to the blocked position inhibits the strong binding of the cross-bridges and the switching on of actin monomers which may be the reason for muscle weakness associated with the R133W mutation in β-tropomyosin. The use of reagents that activate myosin may be appropriate to restore muscle function in patients with the R133W mutation.
antibodies
2026-09-16 | Myeloma-Associated Sporadic Late-Onset Nemaline Myopathy, Successfully Treated with Daratumumab Based Induction and Autologous Stem Cell Transplantation: A Case Report.
Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired myopathy often associated with monoclonal gammopathy. We report a 48-year-old man presenting with progressive proximal and truncal muscle weakness in whom SLONM associated with smoldering myeloma was highly suspected. He received daratumumab, lenalidomide, and dexamethasone followed by high-dose melphalan with autologous stem cell transplantation and posttransplant therapy. Treatment resulted in marked improvement in muscle strength and performance status. The patient achieved minimal residual disease negativity and has remained relapse-free for 5 years. This case highlights the potential efficacy of daratumumab-based therapy followed by transplantation in SLONM associated with plasma cell dyscrasia. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2026-09-13 | 294th ENMC international workshop: Diagnosis and management of paraproteinemic myopathies focusing on sporadic late-onset nemaline myopathy (SLONM) and light-chain (AL) amyloid myopathy. 27th -29th March 2026, Hoofddorp, The Netherlands.
Paraproteinemic myopathies are rare but potentially treatable disorders caused by pathogenic monoclonal proteins, yet diagnosis is often delayed because of nonspecific clinical manifestations and the lack of standardized diagnostic approaches. The 294th ENMC International Workshop convened 21 experts from 12 countries and two patient representatives to establish international consensus on their diagnosis and management. The workshop reviewed current evidence on sporadic late-onset nemaline myopathy (SLONM), light-chain (AL) amyloid myopathy, vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS), and scleromyxedema-associated myopathy. Clinical red flags include age at symptom onset ≥40 years, subacute proximal and/or axial weakness, normal or mildly elevated creatine kinase levels (except in VAMMGAS), dysphagia, weight loss, systemic manifestations, and poor response to conventional immunotherapy. Consensus diagnostic criteria for SLONM and a diagnostic algorithm for paraproteinemic myopathies were established. Routine Congo red staining of muscle biopsies, particularly in patients with monoclonal protein, was recommended. The workshop endorsed replacing SLONM-MGUS with SLONM-MP to reflect the pathogenic role of the monoclonal protein and recommended plasma cell-directed therapy as the cornerstone of treatment for SLONM-MP and AL amyloid myopathy. These recommendations provide the first international consensus framework for the diagnosis and management of paraproteinemic myopathies and establish priorities for future collaborative research.
2026-05-12 | Nemaline Myopathy in Systemic Lupus Erythematosus
Sporadic late-onset nemaline myopathy (SLONM) is a rare muscle disorder that can be treated or may pose a potential threat to life. It usually manifests in the later stages of life and is characterized by the accumulation of nemaline rods within muscle fibers. The pathophysiology of this disease is still not fully understood, with some evidence suggesting that autoimmune responses and hematological neoplasia may be involved. Herein, a case of SLONM associated with systemic lupus erythematosus is presented, which showed a favorable response to immunotherapy. Cite this article as: Cui R, Luan X, Dai S. Nemaline myopathy in systemic lupus erythematosus. Eur J Rheumatol. 2026, 13(2), 0048, doi:10.5152/eurjrheum.2026.25045.
2026-03-21 | Skeletal and Cardiac Myopathy with Acquired Factor X Deficiency in a Patient with Monoclonal Gammopathy of Clinical Significance: A Rare Case Report
Monoclonal gammopathies include several types of plasma cell proliferative disorders, which might be benign to malignant. Monoclonal Gammopathy of Clinical Significance (MGCS) refers to small plasma cell clones that cause organ damage without meeting criteria for multiple myeloma. The common MGCS syndromes include renal, neurologic and cutaneous, while there is evidence of haematological and multi-organ involvement. MGCS-associated myopathy is a rare presentation, including amyloid light chain amyloidosis and sporadic late-onset nemaline myopathy. MGCS presenting solely with myopathy may lead to misdiagnosis with other common causes of myopathies, delaying management. The condition being rare, it lacks standardised guidelines on management, while data from certain reports suggest treating monoclonal gammopathy for optimal results. This article presents a case of a 57-year-old man with progressive thigh pain, ecchymoses, and proximal muscle weakness for four months. MRI showed muscle oedema, and autoantibody positivity initially suggested immune-mediated myositis. However, recurrent bleeding with deranged coagulation revealed acquired factor X deficiency. Further evaluation demonstrated elevated lambda light chains, abnormal kappa/lambda ratio, and 5% clonal plasma cells on bone marrow biopsy. Cardiac imaging revealed infiltrative cardiomyopathy without amyloidosis. These findings confirmed MGCS with multisystem involvement (myopathy, cardiomyopathy, and coagulopathy). The patient improved on daratumumab, bortezomib, cyclophosphamide, and dexamethasone. This case illustrates the diagnostic challenge of MGCS, which may mimic autoimmune myositis. Awareness of such atypical presentations is crucial, as therapy is guided by organ injury rather than tumour burden. Early recognition and clone-directed treatment are essential to preserve organ function.
2026-01-04 | Monoclonal Gammopathy - the common denominator of sporadic late-onset nemaline myopathy and paraproteinemic neuropathy.
Sporadic late-onset nemaline myopathy (SLONM) is an acquired adult-onset myopathy characterized by subacute proximal weakness and nemaline rods in muscle. Although SLONM frequently occurs with monoclonal gammopathy of undetermined significance (MGUS), the coexistence with other MGUS-related disorders has not been reported. We describe three patients with SLONM and paraproteinemic neuropathy, showing sensory involvement and variable motor deficits, from mild non-progressive disease to a severe form with bulbar complications. Muscle histology revealed a significant number of fibres with nemaline rods and also frequent mitochondrial abnormalities, while nerve pathology demonstrated granular endoneurial deposits consistent with immune-complex-mediated neuropathy. One untreated patient remained stable, whereas the other two progressive, immunosuppressive-refractory cases improved with anti-plasma cell therapy. These cases illustrate a previously unreported co-occurrence of SLONM and MGUS-associated neuropathy. Despite differing clinical courses, shared pathology suggests common mechanisms, with mitochondrial abnormalities as a possibly under-recognized feature. Muscle and nerve biopsy including electronmicroscopic analysis is crucial for accurate diagnosis, and clone-directed therapy may provide benefit.
gene therapies
2026-09-25 | KLHL40 gene replacement therapy in severe nemaline myopathy improves survival and skeletal muscle function in a preclinical mouse model
Nemaline myopathy is a severe inherited skeletal muscle disorder characterized by profound muscle weakness, impaired mobility, and early mortality in severe cases. Despite the devastating clinical burden, no disease-modifying therapies are currently available. Nemaline myopathy-causing genes either encode sarcomeric structural proteins or regulators of sarcomeric protein stability, resulting in primary defects in sarcomere structure and function. Recessive mutations in KLHL40 cause one of the most severe forms of nemaline myopathy, frequently resulting in perinatal lethality. Given its loss-of-function mechanism, KLHL40-associated nemaline myopathy is an attractive candidate for gene replacement therapy. We therefore evaluated the therapeutic potential of systemic AAV9-mediated KLHL40 gene replacement in a mouse model of severe nemaline myopathy. A single systemic administration of an AAV9 vector encoding human KLHL40 during early disease produced durable rescue of survival, skeletal muscle pathology, motor performance, and contractile function in KLHL40-deficient mice. Therapeutic benefit was accompanied by restoration of sarcomere organization and normalization of myofiber size without detectable long-term histopathological abnormalities in major organs. Collectively, our findings provide a strong preclinical foundation for developing AAV9-mediated KLHL40 gene replacement as a treatment for severe KLHL40-associated nemaline myopathy.
2026-09-05 | Diagnostic Reappraisal after 12-Year Follow-up of Pediatric Myopathy with Heterozygous NEB Variants and Dystrophy-Like Progression
Background: Mutations in the NEB gene are the most frequent genetic cause of autosomal recessive nemaline myopathy, a clinically heterogeneous congenital myopathy.In pediatric myopathy, longitudinal observation is essential because the evolving phenotype may challenge an initially plausible molecular interpretation and reveal features requiring diagnostic reappraisal.Case presentation: This report describes a 12-year clinical-genetic trajectory in a child with congenital-onset myopathy, persistent hyperCKemia, two heterozygous NEB variants, and later dystrophy-like progression.Clinical exome sequencing performed at 5 years of age identified two heterozygous NEB variants: the canonical splice-site variant c.10872+1G>C and the missense variant c.11333T>C (p.Ile3778Thr).The patient achieved independent ambulation at 20 months but later developed progressive weakness, Gowers' sign, scapular winging, distal muscle wasting, and progressive functional decline, ultimately losing independent ambulation at 12 years.Cardiac and respiratory assessments remained normal during follow-up.Conclusions: This report describes a 12-year clinical-genetic trajectory in a child with congenital-onset myopathy, persistent hyperCKemia, two heterozygous NEB variants of unresolved phase, and later dystrophy-like progression.The longitudinal course highlights the importance of cautious interpretation of exome findings and supports ongoing diagnostic reappraisal when evolving features broaden the neuromuscular differential diagnosis.(
2026-06-24 | Kbtbd13 knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6.
Nemaline myopathy type 6 (NEM6) is a rare neuromuscular disorder caused by pathogenic variants in the Kelch repeat and BTB domain-containing 13 (KBTBD13) gene. Patients experience muscle weakness, excessive fatigue, and impaired muscle relaxation that affect their daily activities related to abnormal protein aggregation in muscle cells and a predominance of slow-twitch myofibers, and no specific therapies are available. Here, we studied a clinically relevant Kbtbd13:p.Arg408Cys knockin mouse model to elucidate the molecular changes driving disease pathogenesis through measurements of muscle contractility, single myofiber assays, super-resolution microscopy, and x-ray diffraction. Kbtbd13:p.Arg408Cys knockin mice closely phenocopied human NEM6 pathology at the morphological, functional, and transcriptional levels, with the p.Arg408Cys variant causing mislocalization of KBTBD13 in the muscle sarcomere, associated with disease onset between 1 and 3 months of age, plateauing by 9 months, and with little progression at 18 months. As a potential therapeutic approach, we knocked down Kbtbd13 using short hairpin RNA against Kbtbd13 delivered intramuscularly via an adeno-associated virus 9 vector at either the prephenotype (1-month-old) or peak-phenotype (3- or 7-month-old) stages. A single treatment at the prephenotype stage prevented the development of impaired relaxation kinetics, nemaline rod aggregation, and slow-twitch myofiber predominance at 3 months of age. A single treatment at 3 months of age, after onset of disease, restored muscle morphology, contractility, and muscle-relaxation kinetics over 6 months. These data provide insights into NEM6 pathogenesis and suggest that Kbtbd13 knockdown might be a promising therapeutic strategy for patients with NEM6.
2026-06-19 | Congenital ACTA1-associated homozygous nemaline myopathy: case report
Nemaline myopathies are a heterogeneous group of congenital structural myopathies characterized by rod-shaped inclusions in the sarcoplasm and/or nuclei of muscle fibers. Pathogenic variants in the ACTA1 gene represent the second most frequent cause of nemaline myopathies, with 90 % exhibiting autosomal dominant inheritance. Homozygous pathogenic variants typically are manifested by severe infantile phenotype 2B, whereas the phenotypic spectrum of mild and moderate forms has yet to be systematically categorized. This article presents an 8-year-old patient with homozygous actinopathy (NM_001100.4(ACTA1):c.661GC (p.Val221Leu)) corresponding to the typical phenotype of congenital myopathy-2A. Distinctive features of this case were the presence of distal hand joint hypermobility, rimmed vacuolar changes on histological analysis, and abnormal white matter signal intensity on neuroimaging. Magnetic resonance pattern of fatty infiltration and edematous changes in the pelvic girdle and lower extremity muscles were also presented. Combined inheritance of pathogenic homozygous variants in the COQ8A gene (formerly ADCK3) (NM_020247.5(COQ8A):c.1189GA (p.Val397Met)) required differential diagnosis with primary coenzyme Q10 deficiency, which may involve skeletal muscle pathology.
2025-07-01 | Left-Atrial Angiogram With Transthoracic Echocardiogram-Guided Mitral Transcatheter Edge-to-Edge Repair: A Patient With Tracheostomy and Severe Venous Tortuosity
A 35-year-old woman with low body mass index (14 kg/m2) with a background of nemaline myopathy, chronic hypoxic respiratory failure with left pneumonectomy, tracheostomy, and severe scoliosis with Harrington rod placement presented with severe mitral regurgitation with New York Heart Association (NYHA) Class III symptoms. Her transthoracic echocardiogram (TTE) showed left ventricular ejection fraction of 66%, myxomatous mitral valve (MV) with severe regurgitation, moderate tricuspid regurgitation, and right ventricular systolic pressure of 34 mm Hg.
other
2025-11-22 | Sporadic late-onset nemaline myopathy (SLONM): Data from a case series and literature review of 144 patients.
Sporadic Late-Onset Nemaline Myopathy (SLONM) is an acquired myopathy presenting in adulthood with progressive proximal and axial muscle weakness. A substantial proportion of cases are associated with monoclonal gammopathy of undetermined significance (MGUS), referred to as SLONM-MGUS, suggesting a potential immune-mediated pathogenesis. Although the presence of MGUS has clinical and therapeutic implications, its exact role in disease severity and progression remains unclear. We aimed to characterize clinical, pathological, and prognostic differences between SLONM-MGUS and SLONM without MGUS (SLONM-noMGUS). We conducted a systematic review of SLONM case series published over the past 25 years, supplemented by a single-center case series of five additional patients from our institution (Sant'Andrea Hospital, Rome). Eligible subjects included adult patients diagnosed with SLONM based on clinical features and muscle biopsy demonstrating nemaline rods. Data on demographics, laboratory parameters, histopathological findings, treatments and outcomes were extracted and compared between SLONM-MGUS and SLONM-noMGUS cohorts. Of the 144 patients analyzed, 47 % were classified as SLONM-MGUS. These patients exhibited more severe clinical manifestations, including increased respiratory involvement (p = 0.006). Histopathologically, SLONM-MGUS revealed more prominent nemaline rods (p = 0.032), often accompanied by cytoplasmic bodies and lobulated fibers, and frequently required repeat muscle biopsies for diagnosis (p = 0.0285). Inflammatory infiltrates were less frequent in SLONM-MGUS (p = 0.0176). Functional outcomes were significantly worse in this group, with reduced likelihood of full recovery (p = 0.013) and higher rates of non-ambulatory status (p = 0.01). Patients receiving dual or more treatment regimens, particularly those including IVIg and/or autologous stem cell transplantation (ASCT), had more favorable outcomes. These findings indicate that SLONM-MGUS represents a more severe phenotype of SLONM with distinct clinico-pathological features and poorer prognosis. Notably, combined treatment regimens, including IVIg and/or ASCT, were associated with improved outcomes, highlighting the importance of early recognition and aggressive therapeutic strategies in selected patients.
2024-03-17 | Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy
Abstract Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.
2023-05-08 | NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.
Nemaline myopathy (NM) is a rare neuromuscular disorder associated with congenital or childhood-onset of skeletal muscle weakness and hypotonia, which results in limited motor function. NM is a genetic disorder and mutations in 12 genes are known to contribute to autosomal dominant or recessive forms of the disease. Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients. Because of the large size of the NEB gene and lack of mutational hot spots, developing therapies that can benefit a wide group of patients is challenging. Although there are several promising therapies under investigation, there is no cure for NM. Therefore, targeting disease modifiers that can stabilize or improve skeletal muscle function may represent alternative therapeutic strategies. Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM. We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish. Our findings suggest that Nrap is a disease modifier that affects skeletal muscle structure and function in NM; thus, therapeutic targeting of Nrap in nebulin-related NM and related diseases may be beneficial for patients.
2022-01-28 | A case of sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance: long-term observation of neurological symptoms after autologous stem-cell transplantation.
A 47-year-old woman presented with progressive limb weakness. A neurological examination revealed proximal dominant symmetrical muscle weakness in her limbs, and electromyography revealed complex repetitive discharges and short motor unit potentials with positive sharp waves in the biceps. We observed early recruitment in the quadriceps, and laboratory tests revealed normal creatine kinase. Serum protein electrophoresis showed monoclonal IgG-lambda, but the bone marrow aspiration specimen was normal. A muscle biopsy revealed nemaline rod accumulations in the muscle fibers; based on the results, we diagnosed the patient with sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS). We administered repeated intravenous immunoglobulin, but her limb weakness continued, and she developed a restrictive ventilatory defect. The patient received melphalan, followed by autologous stem-cell transplantation (ASCT). Her upper extremity strength and respiratory capability improved within one year after ASCT; however, it was not until six years after ASCT that her atrophied lower extremities strengthened. A discrepancy in the timeline of treatment response between the upper or respiratory muscles and the atrophied lower limb was characteristic in the patient, suggesting that the efficacy of ASCT on SLONM-MGUS should be evaluated in the long term, especially in severely atrophied muscles. In addition, this case showed that ASCT for SLOMN-MGUS is an effective treatment option in Asian populations.
2020-12-22 | Sporadic late-onset nemaline myopathy: a case report of a treatable cause of cardiac failure
Abstract Background Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired, adult-onset myopathy, characterized by proximal muscle weakness and the pathognomonic feature of nemaline rods in muscle fibres. Sporadic late-onset nemaline myopathy is associated with cardiac pathology in case reports and small case series, but the severity of cardiac disease is generally mild and rarely requires specific treatment. This case report describes severe heart failure as an early feature of SLONM, which responded to specific treatments, and highlights SLONM as a potentially reversible cause of heart failure. Case summary A 65-year-old woman presented with progressive muscle weakness and a dramatic loss of muscle bulk in her thighs, followed by progressive effort breathlessness over an 18-month period. She required a wheelchair to ambulate. A diagnosis of SLONM was made on histopathological assessment of a muscle biopsy along with electron microscopy. An echocardiogram showed a severely dilated and impaired left ventricle. She was treated with standard heart failure medications and autologous stem cell transplantation, which resulted in improvement of both her cardiac and muscle function, and allowed her to walk again and resume near-normal functional performance status. Discussion Cardiomyopathy can be a relatively early and life-threatening feature of SLONM and even in severe cases can be effectively treated with standard heart failure medications and autologous stem cell transplantation.
small molecules
2026-08-22 | Efficacy of multimodality therapy for sporadic late onset nemaline myopathy and associated monoclonal gammopathy
ABSTRACT Sporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset disorder leading to muscle weakness, first reported in 1966. The disease is closely associated with plasma cell disorders, particularly monoclonal gammopathy (MG), but does not have a standardized treatment approach despite fatal outcome in several reported cases. In this report, a male patient diagnosed with SLONM-MGUS was treated using various modalities over several years, including intravenous immunoglobulin (IVIg) and monoclonal anti-CD 20 antibody, rituximab, and on progression, received a multi-modality treatment strategy with high-dose melphalan chemotherapy and autologous hematopoietic cell transplant (ASCT), followed by maintenance with immunomodulatory agent (IMiD), lenalidomide. He underwent ASCT in April 2018 (age 53) and, at the time of reporting (age 60), has maintained clinical benefit for more than seven years on lenalidomide maintenance. While prior therapies provided transient improvement, ASCT followed by maintenance therapy was associated with durable functional benefit. The study emphasizes the need to correctly diagnose this rare disorder and the potential benefit of multi-modality strategy including ASCT followed by lenalidomide maintenance in treating SLONM-MGUS and indicates that the disappearance of monoclonal protein is not always linked to neurological recovery. Our patient adds further evidence to the existing literature and demonstrates sequential clinical benefit from various modalities including IVIg, rituximab, ASCT, and IMiDs in this rare disorder.
2026-06-21 | Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.
2025-12-04 | Sporadic Late-Onset Nemaline Myopathy Associated with Multiple Myeloma: A Case Report.
Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired myopathy that is frequently associated with monoclonal gammopathy, most commonly monoclonal gammopathy of undetermined significance (MGUS). However, its association with overt multiple myeloma (MM) has been rarely reported. We present a case of SLONM associated with MM in which chemotherapy targeting the underlying MM led to mild-to-moderate improvement in muscle symptoms. This case underscores the potential pathogenic role of MM in SLONM and highlights the importance of treating underlying hematologic malignancies.
2025-11-13 | Sporadic late-onset nemaline myopathy with cardiomyopathy presenting as advanced heart failure despite autologous stem cell transplantation: a case report.
Nemaline myopathy is a rare neuromuscular disorder characterized by severe muscle weakness and dyskinesia, predominantly affecting skeletal muscles. Notably, significant cardiac involvement, especially in the sporadic late-onset subtype, is exceptionally uncommon. A 31-year-old female patient presented to our hospital with a 6-month history of chest tightness and progressive peripheral oedema for 10 days, superimposed on a 2-year course of proximal muscle weakness. Four months prior, she received a diagnosis of sporadic late-onset nemaline myopathy complicated by monoclonal gammopathy of uncertain significance, followed by autologous stem cell transplantation 2 months ago. The patient presented with advanced heart failure, characterized by dilated cardiac chambers and impaired ventricular systolic function, as evidenced by an echocardiographically derived left ventricular ejection fraction (LVEF) of 25%, an elevated pro-brain natriuretic peptide of 4673 pg/ml, and polyserosal effusions. Extensive late gadolinium enhancement in the ventricular walls on cardiac magnetic resonance imaging confirmed the suspected diagnosis of heart failure secondary to sporadic late-onset nemaline myopathy-related cardiomyopathy. Following active treatment with guideline-directed medical therapy for heart failure, the patient was discharged in an improved clinical condition, with her LVEF increasing to 57% at the 6-month follow-up. This case report highlights that sporadic late-onset nemaline myopathy may progress to severe cardiomyopathy and even heart failure, notwithstanding autologous stem cell support. Current evidence supports the application of standard heart failure medications as a rational therapeutic strategy.
2025-10-03 | Proteomic analysis of nemaline myopathy in infants reveals distinct common dysregulated proteins and cellular pathways
Background Nemaline myopathy is a rare congenital muscle disorder characterized by the presence of nemaline rods, protein aggregates, in muscle fibers. Pathogenic variants in several genes, most commonly NEB and ACTA1 , which encode thin filament proteins of the sarcomere, have been implicated in its etiology. Currently, there is no cure for nemaline myopathy, underscoring the need to identify disease-modifying targets for therapeutic development. Methods In this study, we employed quantitative nanoscale liquid chromatography–tandem mass spectrometry (LC-MS 3 ) with labeled protein analysis on muscle tissue from five normal controls and seven infants diagnosed with nemaline myopathy due to NEB or ACTA1 pathogenic variants. Results We identified and quantified 4,846 proteins across all samples, with 183 proteins showing significant dysregulation. Protein–protein interaction analysis revealed nine upregulated, muscle-specific proteins: NRAP, FBXO40, TRIM63, TRIM54, ALPK3, XIRP1, ANKRD2, LMOD2, and CSRP3. Further pathway analysis indicated upregulation of protein synthesis and proteasomal degradation processes, alongside downregulation of glycolysis. Notably, the dysregulated proteins and pathways were consistent across both genetic subtypes, suggesting shared molecular mechanisms underlying the disease. Conclusion This proteomic profiling study has identified key dysregulated proteins and pathways in infantile nemaline myopathy. These findings advance our understanding of the disease’s molecular basis and highlight candidate targets for future therapeutic intervention.
proteins
2023-01-26 | Exon skipping caused by splicing mutation in TNNT1 nemaline myopathy.
The TNNT1 gene encoding the slow skeletal muscle TnT has been identified as a causative gene for nemaline myopathy. TNNT1 nemaline myopathy is mainly characterized by neonatal-onset muscle weakness, pectus carinatum and respiratory insufficiency. Herein, we report on a Chinese girl with TNNT1 nemaline myopathy with mild clinical phenotypes without thoracic deformities or decreased respiratory function. Muscle biopsy showed moderate to marked type 1 fiber atrophy and nemaline rods. Next-generation sequencing identified the compound heterozygous c. 587dupA (p. D196Efs*41) and c. 387+5G>A mutations in the TNNT1 gene according to the transcript NM_003283.4. RNA sequencing revealed complete exon 9 skipping caused by the c. 387+5G>A mutation. Through quantitative PCR, we found that both the truncation c. 587dupA (p. D196Efs*41) and the splicing c. 387+5G>A mutations triggered nonsense-mediated mRNA decay (NMD). Western blotting showed the residual amount of the truncated TNNT1 protein by deletion of exon 9, which may ameliorate the disease to some extent.
2022-06-23 | Mob4-dependent STRIPAK involves the chaperonin TRiC to coordinate myofibril and microtubule network growth
Myofibrils of the skeletal muscle are comprised of sarcomeres that generate force by contraction when myosin-rich thick filaments slide past actin-based thin filaments. Surprisingly little is known about the molecular processes that guide sarcomere assembly in vivo, despite deficits within this process being a major cause of human disease. To overcome this knowledge gap, we undertook a forward genetic screen coupled with reverse genetics to identify genes required for vertebrate sarcomere assembly. In this screen, we identified a zebrafish mutant with a nonsense mutation in mob4. In Drosophila, mob4 has been reported to play a role in spindle focusing as well as neurite branching and in planarians mob4 was implemented in body size regulation. In contrast, zebrafish mob4geh mutants are characterised by an impaired actin biogenesis resulting in sarcomere defects. Whereas loss of mob4 leads to a reduction in the amount of myofibril, transgenic expression of mob4 triggers an increase. Further genetic analysis revealed the interaction of Mob4 with the actin-folding chaperonin TRiC, suggesting that Mob4 impacts on TRiC to control actin biogenesis and thus myofibril growth. Additionally, mob4geh features a defective microtubule network, which is in-line with tubulin being the second main folding substrate of TRiC. We also detected similar characteristics for strn3-deficient mutants, which confirmed Mob4 as a core component of STRIPAK and surprisingly implicates a role of the STRIPAK complex in sarcomerogenesis.
2021-10-06 | Structure of the thin filament in native skeletal muscles reveals its interaction with nebulin and two distinct conformations of myosin
Abstract Nebulin is a major structural protein of skeletal sarcomeres and is essential for proper assembly and contraction of skeletal muscle 1 . It stabilises and regulates the length of thin filaments, 2 but the structural mechanism remains nebulous. Using electron cryotomography and sub-tomogram averaging, we present the first structure of native nebulin bound to thin filaments within the A-band and I-band of intact sarcomeres. This in-situ reconstruction reveals unprecedented detail of interaction at pseudo-atomic resolution between nebulin and actin, providing the basis for understanding the structural and regulatory roles of nebulin. The position of nebulin on the thin filament indicates that there is no contact to tropomyosin or myosin, but an unexpected interaction with a troponin-T linker, possibly through two binding motifs on nebulin. In addition, our structure of myosin bound to the thin filaments reveals different conformations of the neck domain, both within the same sarcomere and when compared to purified structures, highlighting an inherent structural variability in muscle. We provide a complete description of cross-bridge formation on fully native, nebulin-containing thin filaments at near-atomic scale. Our structures establish the molecular basis for the role of nebulin as a thin filament “molecular ruler” and the impact of nemaline myopathies mutations that will aid future development of therapies.
2021-03-09 | Lmod3 promotes myoblast differentiation and proliferation via the AKT and ERK pathways.
Mutations in the Lmod3 gene have been identified as a genetic cause of nemaline myopathy. However, the mechanism underlying this disease and the function of Lmod3 remain largely unknown. In this study, we found that Lmod3 knockdown in C2C12 cells impaired myoblast differentiation, whereas enforced Lmod3 expression enhanced such differentiation. We also discovered that myoblast proliferation was promoted by Lmod3 overexpression but impeded by its knockdown. Additionally, knockdown of Lmod3 led to apoptosis in myoblasts. Concurrently, forced Lmod3 expression in C2C12 cells contributed to activation of the AKT and ERK pathways during myoblast differentiation and proliferation, respectively. Conversely, knockdown of Lmod3 in C2C12 cells produced the opposite results. Furthermore, administration of IGF-1, a booster of both AKT and ERK pathways, partially rescued the inhibitory effect of Lmod3 knockdown on both differentiation and proliferation of C2C12 cells. These results suggest that Lmod3 promotes differentiation and proliferation of myoblasts through the AKT and ERK pathways, respectively.
2020-09-15 | The molecular mechanism of muscle dysfunction associated with the R133W mutation in Tpm2.2.
Ghost muscle fibres reconstituted with myosin heads labeled with the fluorescent probe 1,5-IAEDANS were used for analysis of muscle fibre dysfunction associated with the R133W mutation in β-tropomyosin (Tpm2.2). By using polarized microscopy, we showed that at high Ca2+ the R133W mutation in both αβ-Tpm heterodimers and ββ-Tpm homodimers decreases the amount of the myosin heads strongly bound to F-actin and the number of switched-on actin monomers, with this effect being stronger for ββ-Tpm. This mutation also inhibits the shifting of the R133W-Tpm strands towards the open position and the efficiency of the cross-bridge work. At low Ca2+, the amount of the strongly bound myosin heads is lower for R133W-Tpms than for WT-Tpms which may contribute to a low myofilament Ca2+-sensitivity of the R133W-Tpms. It is concluded that freezing of the mutant αβ- or ββ-Tpm close to the blocked position inhibits the strong binding of the cross-bridges and the switching on of actin monomers which may be the reason for muscle weakness associated with the R133W mutation in β-tropomyosin. The use of reagents that activate myosin may be appropriate to restore muscle function in patients with the R133W mutation.
antibodies
2026-09-16 | Myeloma-Associated Sporadic Late-Onset Nemaline Myopathy, Successfully Treated with Daratumumab Based Induction and Autologous Stem Cell Transplantation: A Case Report.
Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired myopathy often associated with monoclonal gammopathy. We report a 48-year-old man presenting with progressive proximal and truncal muscle weakness in whom SLONM associated with smoldering myeloma was highly suspected. He received daratumumab, lenalidomide, and dexamethasone followed by high-dose melphalan with autologous stem cell transplantation and posttransplant therapy. Treatment resulted in marked improvement in muscle strength and performance status. The patient achieved minimal residual disease negativity and has remained relapse-free for 5 years. This case highlights the potential efficacy of daratumumab-based therapy followed by transplantation in SLONM associated with plasma cell dyscrasia. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2026-09-13 | 294th ENMC international workshop: Diagnosis and management of paraproteinemic myopathies focusing on sporadic late-onset nemaline myopathy (SLONM) and light-chain (AL) amyloid myopathy. 27th -29th March 2026, Hoofddorp, The Netherlands.
Paraproteinemic myopathies are rare but potentially treatable disorders caused by pathogenic monoclonal proteins, yet diagnosis is often delayed because of nonspecific clinical manifestations and the lack of standardized diagnostic approaches. The 294th ENMC International Workshop convened 21 experts from 12 countries and two patient representatives to establish international consensus on their diagnosis and management. The workshop reviewed current evidence on sporadic late-onset nemaline myopathy (SLONM), light-chain (AL) amyloid myopathy, vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS), and scleromyxedema-associated myopathy. Clinical red flags include age at symptom onset ≥40 years, subacute proximal and/or axial weakness, normal or mildly elevated creatine kinase levels (except in VAMMGAS), dysphagia, weight loss, systemic manifestations, and poor response to conventional immunotherapy. Consensus diagnostic criteria for SLONM and a diagnostic algorithm for paraproteinemic myopathies were established. Routine Congo red staining of muscle biopsies, particularly in patients with monoclonal protein, was recommended. The workshop endorsed replacing SLONM-MGUS with SLONM-MP to reflect the pathogenic role of the monoclonal protein and recommended plasma cell-directed therapy as the cornerstone of treatment for SLONM-MP and AL amyloid myopathy. These recommendations provide the first international consensus framework for the diagnosis and management of paraproteinemic myopathies and establish priorities for future collaborative research.
2026-05-12 | Nemaline Myopathy in Systemic Lupus Erythematosus
Sporadic late-onset nemaline myopathy (SLONM) is a rare muscle disorder that can be treated or may pose a potential threat to life. It usually manifests in the later stages of life and is characterized by the accumulation of nemaline rods within muscle fibers. The pathophysiology of this disease is still not fully understood, with some evidence suggesting that autoimmune responses and hematological neoplasia may be involved. Herein, a case of SLONM associated with systemic lupus erythematosus is presented, which showed a favorable response to immunotherapy. Cite this article as: Cui R, Luan X, Dai S. Nemaline myopathy in systemic lupus erythematosus. Eur J Rheumatol. 2026, 13(2), 0048, doi:10.5152/eurjrheum.2026.25045.
2026-03-21 | Skeletal and Cardiac Myopathy with Acquired Factor X Deficiency in a Patient with Monoclonal Gammopathy of Clinical Significance: A Rare Case Report
Monoclonal gammopathies include several types of plasma cell proliferative disorders, which might be benign to malignant. Monoclonal Gammopathy of Clinical Significance (MGCS) refers to small plasma cell clones that cause organ damage without meeting criteria for multiple myeloma. The common MGCS syndromes include renal, neurologic and cutaneous, while there is evidence of haematological and multi-organ involvement. MGCS-associated myopathy is a rare presentation, including amyloid light chain amyloidosis and sporadic late-onset nemaline myopathy. MGCS presenting solely with myopathy may lead to misdiagnosis with other common causes of myopathies, delaying management. The condition being rare, it lacks standardised guidelines on management, while data from certain reports suggest treating monoclonal gammopathy for optimal results. This article presents a case of a 57-year-old man with progressive thigh pain, ecchymoses, and proximal muscle weakness for four months. MRI showed muscle oedema, and autoantibody positivity initially suggested immune-mediated myositis. However, recurrent bleeding with deranged coagulation revealed acquired factor X deficiency. Further evaluation demonstrated elevated lambda light chains, abnormal kappa/lambda ratio, and 5% clonal plasma cells on bone marrow biopsy. Cardiac imaging revealed infiltrative cardiomyopathy without amyloidosis. These findings confirmed MGCS with multisystem involvement (myopathy, cardiomyopathy, and coagulopathy). The patient improved on daratumumab, bortezomib, cyclophosphamide, and dexamethasone. This case illustrates the diagnostic challenge of MGCS, which may mimic autoimmune myositis. Awareness of such atypical presentations is crucial, as therapy is guided by organ injury rather than tumour burden. Early recognition and clone-directed treatment are essential to preserve organ function.
2026-01-04 | Monoclonal Gammopathy - the common denominator of sporadic late-onset nemaline myopathy and paraproteinemic neuropathy.
Sporadic late-onset nemaline myopathy (SLONM) is an acquired adult-onset myopathy characterized by subacute proximal weakness and nemaline rods in muscle. Although SLONM frequently occurs with monoclonal gammopathy of undetermined significance (MGUS), the coexistence with other MGUS-related disorders has not been reported. We describe three patients with SLONM and paraproteinemic neuropathy, showing sensory involvement and variable motor deficits, from mild non-progressive disease to a severe form with bulbar complications. Muscle histology revealed a significant number of fibres with nemaline rods and also frequent mitochondrial abnormalities, while nerve pathology demonstrated granular endoneurial deposits consistent with immune-complex-mediated neuropathy. One untreated patient remained stable, whereas the other two progressive, immunosuppressive-refractory cases improved with anti-plasma cell therapy. These cases illustrate a previously unreported co-occurrence of SLONM and MGUS-associated neuropathy. Despite differing clinical courses, shared pathology suggests common mechanisms, with mitochondrial abnormalities as a possibly under-recognized feature. Muscle and nerve biopsy including electronmicroscopic analysis is crucial for accurate diagnosis, and clone-directed therapy may provide benefit.
gene therapies
2026-09-25 | KLHL40 gene replacement therapy in severe nemaline myopathy improves survival and skeletal muscle function in a preclinical mouse model
Nemaline myopathy is a severe inherited skeletal muscle disorder characterized by profound muscle weakness, impaired mobility, and early mortality in severe cases. Despite the devastating clinical burden, no disease-modifying therapies are currently available. Nemaline myopathy-causing genes either encode sarcomeric structural proteins or regulators of sarcomeric protein stability, resulting in primary defects in sarcomere structure and function. Recessive mutations in KLHL40 cause one of the most severe forms of nemaline myopathy, frequently resulting in perinatal lethality. Given its loss-of-function mechanism, KLHL40-associated nemaline myopathy is an attractive candidate for gene replacement therapy. We therefore evaluated the therapeutic potential of systemic AAV9-mediated KLHL40 gene replacement in a mouse model of severe nemaline myopathy. A single systemic administration of an AAV9 vector encoding human KLHL40 during early disease produced durable rescue of survival, skeletal muscle pathology, motor performance, and contractile function in KLHL40-deficient mice. Therapeutic benefit was accompanied by restoration of sarcomere organization and normalization of myofiber size without detectable long-term histopathological abnormalities in major organs. Collectively, our findings provide a strong preclinical foundation for developing AAV9-mediated KLHL40 gene replacement as a treatment for severe KLHL40-associated nemaline myopathy.
2026-09-05 | Diagnostic Reappraisal after 12-Year Follow-up of Pediatric Myopathy with Heterozygous NEB Variants and Dystrophy-Like Progression
Background: Mutations in the NEB gene are the most frequent genetic cause of autosomal recessive nemaline myopathy, a clinically heterogeneous congenital myopathy.In pediatric myopathy, longitudinal observation is essential because the evolving phenotype may challenge an initially plausible molecular interpretation and reveal features requiring diagnostic reappraisal.Case presentation: This report describes a 12-year clinical-genetic trajectory in a child with congenital-onset myopathy, persistent hyperCKemia, two heterozygous NEB variants, and later dystrophy-like progression.Clinical exome sequencing performed at 5 years of age identified two heterozygous NEB variants: the canonical splice-site variant c.10872+1G>C and the missense variant c.11333T>C (p.Ile3778Thr).The patient achieved independent ambulation at 20 months but later developed progressive weakness, Gowers' sign, scapular winging, distal muscle wasting, and progressive functional decline, ultimately losing independent ambulation at 12 years.Cardiac and respiratory assessments remained normal during follow-up.Conclusions: This report describes a 12-year clinical-genetic trajectory in a child with congenital-onset myopathy, persistent hyperCKemia, two heterozygous NEB variants of unresolved phase, and later dystrophy-like progression.The longitudinal course highlights the importance of cautious interpretation of exome findings and supports ongoing diagnostic reappraisal when evolving features broaden the neuromuscular differential diagnosis.(
2026-06-24 | Kbtbd13 knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6.
Nemaline myopathy type 6 (NEM6) is a rare neuromuscular disorder caused by pathogenic variants in the Kelch repeat and BTB domain-containing 13 (KBTBD13) gene. Patients experience muscle weakness, excessive fatigue, and impaired muscle relaxation that affect their daily activities related to abnormal protein aggregation in muscle cells and a predominance of slow-twitch myofibers, and no specific therapies are available. Here, we studied a clinically relevant Kbtbd13:p.Arg408Cys knockin mouse model to elucidate the molecular changes driving disease pathogenesis through measurements of muscle contractility, single myofiber assays, super-resolution microscopy, and x-ray diffraction. Kbtbd13:p.Arg408Cys knockin mice closely phenocopied human NEM6 pathology at the morphological, functional, and transcriptional levels, with the p.Arg408Cys variant causing mislocalization of KBTBD13 in the muscle sarcomere, associated with disease onset between 1 and 3 months of age, plateauing by 9 months, and with little progression at 18 months. As a potential therapeutic approach, we knocked down Kbtbd13 using short hairpin RNA against Kbtbd13 delivered intramuscularly via an adeno-associated virus 9 vector at either the prephenotype (1-month-old) or peak-phenotype (3- or 7-month-old) stages. A single treatment at the prephenotype stage prevented the development of impaired relaxation kinetics, nemaline rod aggregation, and slow-twitch myofiber predominance at 3 months of age. A single treatment at 3 months of age, after onset of disease, restored muscle morphology, contractility, and muscle-relaxation kinetics over 6 months. These data provide insights into NEM6 pathogenesis and suggest that Kbtbd13 knockdown might be a promising therapeutic strategy for patients with NEM6.
2026-06-19 | Congenital ACTA1-associated homozygous nemaline myopathy: case report
Nemaline myopathies are a heterogeneous group of congenital structural myopathies characterized by rod-shaped inclusions in the sarcoplasm and/or nuclei of muscle fibers. Pathogenic variants in the ACTA1 gene represent the second most frequent cause of nemaline myopathies, with 90 % exhibiting autosomal dominant inheritance. Homozygous pathogenic variants typically are manifested by severe infantile phenotype 2B, whereas the phenotypic spectrum of mild and moderate forms has yet to be systematically categorized. This article presents an 8-year-old patient with homozygous actinopathy (NM_001100.4(ACTA1):c.661GC (p.Val221Leu)) corresponding to the typical phenotype of congenital myopathy-2A. Distinctive features of this case were the presence of distal hand joint hypermobility, rimmed vacuolar changes on histological analysis, and abnormal white matter signal intensity on neuroimaging. Magnetic resonance pattern of fatty infiltration and edematous changes in the pelvic girdle and lower extremity muscles were also presented. Combined inheritance of pathogenic homozygous variants in the COQ8A gene (formerly ADCK3) (NM_020247.5(COQ8A):c.1189GA (p.Val397Met)) required differential diagnosis with primary coenzyme Q10 deficiency, which may involve skeletal muscle pathology.
2025-07-01 | Left-Atrial Angiogram With Transthoracic Echocardiogram-Guided Mitral Transcatheter Edge-to-Edge Repair: A Patient With Tracheostomy and Severe Venous Tortuosity
A 35-year-old woman with low body mass index (14 kg/m2) with a background of nemaline myopathy, chronic hypoxic respiratory failure with left pneumonectomy, tracheostomy, and severe scoliosis with Harrington rod placement presented with severe mitral regurgitation with New York Heart Association (NYHA) Class III symptoms. Her transthoracic echocardiogram (TTE) showed left ventricular ejection fraction of 66%, myxomatous mitral valve (MV) with severe regurgitation, moderate tricuspid regurgitation, and right ventricular systolic pressure of 34 mm Hg.
other
2025-11-22 | Sporadic late-onset nemaline myopathy (SLONM): Data from a case series and literature review of 144 patients.
Sporadic Late-Onset Nemaline Myopathy (SLONM) is an acquired myopathy presenting in adulthood with progressive proximal and axial muscle weakness. A substantial proportion of cases are associated with monoclonal gammopathy of undetermined significance (MGUS), referred to as SLONM-MGUS, suggesting a potential immune-mediated pathogenesis. Although the presence of MGUS has clinical and therapeutic implications, its exact role in disease severity and progression remains unclear. We aimed to characterize clinical, pathological, and prognostic differences between SLONM-MGUS and SLONM without MGUS (SLONM-noMGUS). We conducted a systematic review of SLONM case series published over the past 25 years, supplemented by a single-center case series of five additional patients from our institution (Sant'Andrea Hospital, Rome). Eligible subjects included adult patients diagnosed with SLONM based on clinical features and muscle biopsy demonstrating nemaline rods. Data on demographics, laboratory parameters, histopathological findings, treatments and outcomes were extracted and compared between SLONM-MGUS and SLONM-noMGUS cohorts. Of the 144 patients analyzed, 47 % were classified as SLONM-MGUS. These patients exhibited more severe clinical manifestations, including increased respiratory involvement (p = 0.006). Histopathologically, SLONM-MGUS revealed more prominent nemaline rods (p = 0.032), often accompanied by cytoplasmic bodies and lobulated fibers, and frequently required repeat muscle biopsies for diagnosis (p = 0.0285). Inflammatory infiltrates were less frequent in SLONM-MGUS (p = 0.0176). Functional outcomes were significantly worse in this group, with reduced likelihood of full recovery (p = 0.013) and higher rates of non-ambulatory status (p = 0.01). Patients receiving dual or more treatment regimens, particularly those including IVIg and/or autologous stem cell transplantation (ASCT), had more favorable outcomes. These findings indicate that SLONM-MGUS represents a more severe phenotype of SLONM with distinct clinico-pathological features and poorer prognosis. Notably, combined treatment regimens, including IVIg and/or ASCT, were associated with improved outcomes, highlighting the importance of early recognition and aggressive therapeutic strategies in selected patients.
2024-03-17 | Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy
Abstract Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.
2023-05-08 | NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.
Nemaline myopathy (NM) is a rare neuromuscular disorder associated with congenital or childhood-onset of skeletal muscle weakness and hypotonia, which results in limited motor function. NM is a genetic disorder and mutations in 12 genes are known to contribute to autosomal dominant or recessive forms of the disease. Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients. Because of the large size of the NEB gene and lack of mutational hot spots, developing therapies that can benefit a wide group of patients is challenging. Although there are several promising therapies under investigation, there is no cure for NM. Therefore, targeting disease modifiers that can stabilize or improve skeletal muscle function may represent alternative therapeutic strategies. Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM. We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish. Our findings suggest that Nrap is a disease modifier that affects skeletal muscle structure and function in NM; thus, therapeutic targeting of Nrap in nebulin-related NM and related diseases may be beneficial for patients.
2022-01-28 | A case of sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance: long-term observation of neurological symptoms after autologous stem-cell transplantation.
A 47-year-old woman presented with progressive limb weakness. A neurological examination revealed proximal dominant symmetrical muscle weakness in her limbs, and electromyography revealed complex repetitive discharges and short motor unit potentials with positive sharp waves in the biceps. We observed early recruitment in the quadriceps, and laboratory tests revealed normal creatine kinase. Serum protein electrophoresis showed monoclonal IgG-lambda, but the bone marrow aspiration specimen was normal. A muscle biopsy revealed nemaline rod accumulations in the muscle fibers; based on the results, we diagnosed the patient with sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance (SLONM-MGUS). We administered repeated intravenous immunoglobulin, but her limb weakness continued, and she developed a restrictive ventilatory defect. The patient received melphalan, followed by autologous stem-cell transplantation (ASCT). Her upper extremity strength and respiratory capability improved within one year after ASCT; however, it was not until six years after ASCT that her atrophied lower extremities strengthened. A discrepancy in the timeline of treatment response between the upper or respiratory muscles and the atrophied lower limb was characteristic in the patient, suggesting that the efficacy of ASCT on SLONM-MGUS should be evaluated in the long term, especially in severely atrophied muscles. In addition, this case showed that ASCT for SLOMN-MGUS is an effective treatment option in Asian populations.
2020-12-22 | Sporadic late-onset nemaline myopathy: a case report of a treatable cause of cardiac failure
Abstract Background Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired, adult-onset myopathy, characterized by proximal muscle weakness and the pathognomonic feature of nemaline rods in muscle fibres. Sporadic late-onset nemaline myopathy is associated with cardiac pathology in case reports and small case series, but the severity of cardiac disease is generally mild and rarely requires specific treatment. This case report describes severe heart failure as an early feature of SLONM, which responded to specific treatments, and highlights SLONM as a potentially reversible cause of heart failure. Case summary A 65-year-old woman presented with progressive muscle weakness and a dramatic loss of muscle bulk in her thighs, followed by progressive effort breathlessness over an 18-month period. She required a wheelchair to ambulate. A diagnosis of SLONM was made on histopathological assessment of a muscle biopsy along with electron microscopy. An echocardiogram showed a severely dilated and impaired left ventricle. She was treated with standard heart failure medications and autologous stem cell transplantation, which resulted in improvement of both her cardiac and muscle function, and allowed her to walk again and resume near-normal functional performance status. Discussion Cardiomyopathy can be a relatively early and life-threatening feature of SLONM and even in severe cases can be effectively treated with standard heart failure medications and autologous stem cell transplantation.
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