RARE DISEASE
Adult-onset nemaline myopathy
Adult-onset nemaline myopathy
Adult-onset nemaline myopathy
Drug discovery
102
papers
On emerging therapies
Overview
Adult-onset nemaline myopathy is a rare, acquired or sporadic neuromuscular disorder characterized by progressive proximal and axial muscle weakness, myalgia, and rapid functional decline. Diagnosis is confirmed by muscle biopsy showing nemaline rods, often with inflammatory infiltrates or monoclonal gammopathy (20–50% of cases). Associated with variants in ACTA1, NEB, or TPM3 genes, it lacks familial inheritance and may involve dysimmune mechanisms or hematological malignancy. Respiratory/cardiac complications contribute to morbidity, necessitating early immunomodulatory or chemotherapeutic intervention [1][2][11][12].
Burden
Rapid progression leads to wheelchair dependency (≤2 years) and respiratory failure in 40% of cases [2][4][12].
Mortality exceeds 50% in untreated SLONM with monoclonal gammopathy due to cardiorespiratory complications [3][11].
Requires multidisciplinary management, increasing healthcare utilization and long-term care costs [12][16].
Therapies
Immunotherapy: High-dose corticosteroids, IV immunoglobulin, or plasmapheresis for non-MGUS cases [8][12].
Chemotherapy/ASCT: Preferred for SLONM with monoclonal gammopathy (e.g., melphalan + ASCT achieves complete remission in 46% of cases) [3][8].
Supportive care: Respiratory support, physical therapy, and cardiac monitoring to mitigate progression [14][16].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
102 drug discovery papers about Adult-onset nemaline myopathy. Recent publications:
102 drug discovery papers about Adult-onset nemaline myopathy. Recent publications:
categories:
Small molecules
proteins
2025-06-12 | KLHL41 orchestrates sarcomere assembly and size to drive skeletal muscle hypertrophy in vivo.
Sarcomere assembly and growth are fundamental processes essential for the development, function, and repair of skeletal muscle. However, the mechanisms underlying sarcomere formation and assembly in vivo , which are critical for the formation of functional myofibers in vertebrates, remain poorly understood. Defects in sarcomeres contribute to muscle dysfunction in numerous genetic and acquired myopathies, yet the lack of a clear understanding of specific sarcomeric defects has hindered the development of effective therapies. Nemaline myopathy (NM) is caused by mutations in genes that primarily affect sarcomere structure and function. The disease is clinically heterogeneous, with the congenital form being the most severe. Using zebrafish models of congenital forms of NM, we investigated sarcomere assembly in vivo during skeletal muscle development to identify key steps contributing to myofibril formation and muscle growth under both normal and disease conditions. Our findings demonstrate that the gene encoding the sarcomeric protein KLHL41 plays a critical role in the formation and directional organization of new sarcomeres within developing myofibrils, facilitating both radial and longitudinal muscle growth. Dysregulation of sarcomeric proteins and impaired protein turnover in the KLHL41-NM zebrafish model resulted in the development of sarcomeric defects. Moreover, we show that the interaction between the KLHL41-troponin complex is essential for muscle growth and cross-bridge regulation in developing muscle. These studies address a significant gap in the understanding of sarcomeric defects in myopathies and will help guide the development of targeted therapies aimed at rescuing these processes.
2020-08-17 | The loss of slow skeletal muscle isoform of troponin T in spindle intrafusal fibres explains the pathophysiology of Amish nemaline myopathy.
The pathogenic mechanism and the neuromuscular reflex-related phenotype (e.g. tremors accompanied by clonus) of Amish nemaline myopathy, as well as of other recessively inherited TNNT1 myopathies, remain to be clarified. The truncated slow skeletal muscle isoform of troponin T (ssTnT) encoded by the mutant TNNT1 gene is unable to incorporate into myofilaments and is degraded in muscle cells. By contrast to extrafusal muscle fibres, spindle intrafusal fibres of normal mice contain a significant level of cardiac TnT and a low molecular weight splice form of ssTnT. Intrafusal fibres of ssTnT-knockout mice have significantly increased cardiac TnT. Rotarod and balance beam tests have revealed abnormal neuromuscular co-ordination in ssTnT-knockout mice and a blunted response to a spindle sensitizer, succinylcholine. The loss of ssTnT and a compensatory increase of cardiac TnT in intrafusal nuclear bag fibres may increase myofilament Ca2+ -sensitivity and tension, impairing spindle function, thus identifying a novel mechanism for the development of targeted treatment. A nonsense mutation at codon Glu180 of TNNT1 gene causes Amish nemaline myopathy (ANM), a recessively inherited disease with infantile lethality. TNNT1 encodes the slow skeletal muscle isoform of troponin T (ssTnT). The truncated ssTnT is unable to incorporate into myofilament and is degraded in muscle cells. The symptoms of ANM include muscle weakness, atrophy, contracture and tremors accompanied by clonus. An ssTnT-knockout (KO) mouse model recapitulates key features of ANM such as atrophy of extrafusal slow muscle fibres and increased fatigability. However, the neuromuscular reflex-related symptoms of ANM have not been explained. By isolating muscle spindles from ssTnT-KO and control mice aiming to examine the composition of myofilament proteins, we found that, in contrast to extrafusal fibres, intrafusal fibres contain a significant level of cardiac TnT and the low molecular weight splice form of ssTnT. Intrafusal fibres from ssTnT-KO mice have significantly increased cardiac TnT. Rotarod and balance beam tests revealed impaired neuromuscular co-ordination in ssTnT-KO mice, indicating abnormality in spindle functions. Unlike the wild-type control, the beam running ability of ssTnT-KO mice had a blunted response to a spindle sensitizer, succinylcholine. Immunohistochemistry detected ssTnT and cardiac TnT in nuclear bag fibres, whereas fast skeletal muscle TnT was detected in nuclear chain fibres, and cardiac α-myosin was present in one of the two nuclear bag fibres. The loss of ssTnT and a compensatory increase of cardiac TnT in nuclear bag fibres would increase myofilament Ca2+ -sensitivity and tension, thus affecting spindle activities. This mechanism provides an explanation for the pathophysiology of ANM, as well as a novel target for treatment.
2020-01-25 | Nebulin: big protein with big responsibilities
Abstract Nebulin, encoded by NEB , is a giant skeletal muscle protein of about 6669 amino acids which forms an integral part of the sarcomeric thin filament. In recent years, the nebula around this protein has been largely lifted resulting in the discovery that nebulin is critical for a number of tasks in skeletal muscle. In this review, we firstly discussed nebulin’s role as a structural component of the thin filament and the Z-disk, regulating the length and the mechanical properties of the thin filament as well as providing stability to myofibrils by interacting with structural proteins within the Z-disk. Secondly, we reviewed nebulin’s involvement in the regulation of muscle contraction, cross-bridge cycling kinetics, Ca 2+ -homeostasis and excitation contraction (EC) coupling. While its role in Ca 2+ -homeostasis and EC coupling is still poorly understood, a large number of studies have helped to improve our knowledge on how nebulin affects skeletal muscle contractile mechanics. These studies suggest that nebulin affects the number of force generating actin-myosin cross-bridges and may also affect the force that each cross-bridge produces. It may exert this effect by interacting directly with actin and myosin and/or indirectly by potentially changing the localisation and function of the regulatory complex (troponin and tropomyosin). Besides unravelling the biology of nebulin, these studies are particularly helpful in understanding the patho-mechanism of myopathies caused by NEB mutations, providing knowledge which constitutes the critical first step towards the development of therapeutic interventions. Currently, effective treatments are not available, although a number of therapeutic strategies are being investigated.
2019-04-11 | Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy
Abstract Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific adaptors for Cullin 3 (CUL3) E3 ubiquitin ligase to regulate protein turnover through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM; however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin-related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric proteins contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease-causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.
2018-06-19 | KLHL41 stabilizes skeletal muscle sarcomeres by nonproteolytic ubiquitination.
Maintenance of muscle function requires assembly of contractile proteins into highly organized sarcomeres. Mutations in Kelch-like protein 41 (KLHL41) cause nemaline myopathy, a fatal muscle disorder associated with sarcomere disarray. We generated KLHL41 mutant mice, which display lethal disruption of sarcomeres and aberrant expression of muscle structural and contractile proteins, mimicking the hallmarks of the human disease. We show that KLHL41 is poly-ubiquitinated and acts, at least in part, by preventing aggregation and degradation of Nebulin, an essential component of the sarcomere. Furthermore, inhibition of KLHL41 poly-ubiquitination prevents its stabilization of nebulin, suggesting a unique role for ubiquitination in protein stabilization. These findings provide new insights into the molecular etiology of nemaline myopathy and reveal a mechanism whereby KLHL41 stabilizes sarcomeres and maintains muscle function by acting as a molecular chaperone. Similar mechanisms for protein stabilization likely contribute to the actions of other Kelch proteins.
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.
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.
2025-05-05 | Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.
In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca2+ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. KEY POINTS: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.
2024-09-01 | Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.
Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.
2024-06-12 | L-tyrosine for treatment of an infant with nemaline rod myopathy.
Nemaline rod myopathy is an extremely rare muscle disease responsible for hypotonia and poor muscle strength in infants. The disease has variable phenotypic presentations across different ages, ranging from neonatal to the adult onset and from severe to asymptomatic varieties. Clinical features, muscle biopsy and genetic testing help in diagnosis. The histopathological examination shows the presence of rod-like structures or nemaline bodies in muscles. Management remains mainly supportive, and currently, there is no available curative treatment. This case report describes an infant presenting with gross hypotonia, poor handling of secretions and multiple extubation failures who was diagnosed by clinical exome sequencing. The patient harboured compound heterozygous variants in the NEB gene suggestive of nemaline rod myopathy. The newborn showed significant improvement in muscle strength after he was started on dietary L-tyrosine supplementation. This case highlights the emerging role of L-tyrosine in the supportive care of infants with nemaline rod myopathy.
antibodies
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.
2026-03-06 | Concurrent Sporadic Late-Onset Nemaline Myopathy and an Excessive Glycogen Accumulation Associated With Monoclonal Gammopathy.
Monoclonal gammopathy-associated myopathies (MGAMs) include light chain (AL) amyloid myopathy, sporadic late-onset nemaline myopathy (SLONM), and vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS). These subtypes usually occur separately, although rare overlap has been described. We report a patient with monoclonal gammopathy and concurrent SLONM and excessive glycogen accumulation, resembling VAMMGAS but with distinct features. Case report with clinical, electrophysiological, pathological, and therapeutic characterization of a patient with IgG-kappa monoclonal gammopathy and coexisting SLONM and glycogen accumulation within muscle fibers. A 69-year-old man developed subacute progressive axial and limb weakness, head drop, dysphagia, and weight loss. Examination showed proximal/distal weakness, neck extensor weakness, and lumbar hyperlordosis. EMG revealed myopathic motor unit potentials without electrical myotonia or complex repetitive discharges. Serum studies identified IgG-kappa monoclonal protein with elevated kappa light chain and ratio. Muscle biopsy demonstrated nemaline rods (1% of fibers) and scattered fibers with non-rimmed vacuoles (0.3% of fibers) containing PAS-positive, diastase-labile material consistent with concurrent SLONM and glycogen storage myopathy-like pathology. Genetic testing for congenital nemaline and glycogen storage myopathies was negative. Plasma-cell directed therapy with daratumumab, lenalidomide, and dexamethasone led to rapid functional improvement and M-protein reduction. Further gains followed autologous stem cell transplantation. This case expands the MGAM spectrum, highlighting co-occurrence of SLONM and an excessive glycogen accumulation responsive to immunotherapy and transplantation. These findings suggest a spectrum of related disease processes. Recognition of this combined pathology is clinically important, as affected patients may benefit from targeted immunotherapy or stem cell transplantation.
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.
2023-10-30 | Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force.
Nemaline myopathy is one of the most common non-dystrophic congenital myopathies. Individuals affected by this condition experience muscle weakness and muscle smallness, often requiring supportive measures like wheelchairs or respiratory support. A significant proportion of patients, approximately one-third, exhibit compound heterozygous nebulin mutations, which usually give rise to the typical form of the disease. Currently, there are no approved treatments available for nemaline myopathy. Our research explored the modulation of myostatin, a negative regulator of muscle mass, in combating the muscle smallness associated with the disease. To investigate the effect of myostatin inhibition, we employed a mouse model with compound heterozygous nebulin mutations that mimic the typical form of the disease. The mice were treated with mRK35, a myostatin antibody, through weekly intraperitoneal injections of 10 mg/kg mRK35, commencing at two weeks of age and continuing until the mice reached four months of age. The treatment resulted in an increase in body weight and an approximate 20% muscle weight gain across most skeletal muscles, without affecting the heart. The minimum Feret diameter of type IIA and IIB fibers exhibited an increase in compound heterozygous mice, while only type IIB fibers demonstrated an increase in wild-type mice. In vitro mechanical experiments conducted on intact extensor digitorum longus muscle revealed that mRK35 augmented the physiological cross-sectional area of muscle fibers and enhanced absolute tetanic force in both wild-type and compound heterozygous mice. Furthermore, mRK35 administration improved grip strength in treated mice. Collectively, these findings indicate that inhibiting myostatin can mitigate the muscle deficits in nebulin-based typical nemaline myopathy, potentially serving as a much-needed therapeutic option.
2022-08-01 | 2227 Sporadic late-onset nemaline rod myopathy associated with monoclonal gammopathy
A 72-year-old man developed progressive camptocormia associated with head drop, dysphagia, proximal muscle weakness, numbness to the ankles, and 20kg weight loss over a 2 year period. Background history was significant for thyroid cancer treated with total thyroidectomy resulting in left accessory nerve injury, type 2 diabetes mellitus, hypertension, and gout. Examination revealed a man with reduced muscle bulk who walked with a flexed spine. He had weakness of neck flexion and proximal muscles with normal reflexes and reduced pin-prick sensation to both feet. Nerve conduction studies showed length-dependent axonal sensorimotor neuropathy. Concentric needle electromyography showed widespread reduced recruitment of small polyphasic units consistent with a myopathic process. Creatine kinase level was normal. Myositis panel demonstrated low positive Mi2 of uncertain significance. An initial deltoid muscle biopsy did not show evidence of myopathy. Due to worsening of symptoms, a repeat muscle biopsy of vastus lateralis was performed, revealing atrophic myofibres with a patchy granular appearance. Electron microscopy identified nemaline rods. An IgG kappa paraprotein was identified. HIV serology was negative. A diagnosis of sporadic late-onset nemaline myopathy (SLONM) associated with monoclonal gammopathy was made. He was commenced on IVIG and referred for haematological evaluation. SLONM is a rare acquired adult-onset progressive myopathy associated with monoclonal gammopathy and HIV infection. It may present with head drop or dysphagia and is characterised electrophysiologically by a combination of axonal neuropathy and proximal myopathy. First-line treatment with intravenous immunoglobulin and second-line treatment with haematological/immunological therapies may result in significant improvement.
gene therapies
2025-03-20 | Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.
Biallelic pathogenic variants in the nebulin (NEB) gene lead to the congenital muscle disease nemaline myopathy. In-frame deletion of exon 55 (ΔExon55) is the most common disease-causing variant in NEB. Previously, a mouse model of NebΔExon55 was developed; however, it presented an uncharacteristically severe phenotype with a near complete reduction in Neb transcript expression that is not observed in NEB exon 55 patients. We identified by RNA sequencing that the cause of this unexpectedly severe presentation in mice is the generation of a pseudoexon containing two premature termination codons (and promoting nonsense mediated decay) at the Neb exon 55 deletion site. To prove that this is the cause of the loss of Neb transcript, and to generate a more faithful model of the human disease, we used CRISPR gene editing to remove the pseudoexon sequence and replace it with human intron 54 sequence containing a validated cas9 gRNA protospacer. The resulting "hmz" mice have a significant reduction in pseudoexon formation (93.6% reduction), and a re-introduction of stable Neb transcript expression. This new model has the characteristic features of nemaline myopathy at the physiological, histological, and molecular levels. Importantly, unlike the existing exon 55 deletion mice (which die by age 7 days), it survives beyond the first months and exhibits obvious signs of neuromuscular dysfunction. It thus provides a new, robust model for studying pathomechanisms and developing therapies for NEB related nemaline myopathy.
2023-01-26 | Early clinical and pre-clinical therapy development in Nemaline myopathy.
Nemaline myopathies (NM) represent a group of clinically and genetically heterogeneous congenital muscle disorders with the common denominator of nemaline rods on muscle biopsy. NEB and ACTA1 are the most common causative genes. Currently, available treatments are supportive. We explored experimental treatments for NM, identifying at least eleven mainly pre-clinical approaches utilizing murine and/or human muscle cells. These approaches target either i) the causative gene or associated genes implicated in the same pathway; ii) pathophysiologically relevant biochemical mechanisms such as calcium/myosin regulation of muscle contraction; iii) myogenesis; iv) other therapies that improve or optimize muscle function more generally; v) and/or combinations of the above. The scope and efficiency of these attempts is diverse, ranging from gene-specific effects to those widely applicable to all NM-associated genes. The wide range of experimental therapies currently under consideration for NM is promising. Potential translation into clinical use requires consideration of additional factors such as the potential muscle type specificity as well as the possibility of gene expression remodeling. Challenges in clinical translation include the rarity and heterogeneity of genotypes, phenotypes, and disease trajectories, as well as the lack of longitudinal natural history data and validated outcomes and biomarkers.
2022-07-29 | Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits.
Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common cause. Skeletal muscle atrophy is tightly linked to upregulation of MuRF1, an E3 ligase, that targets proteins for proteasome degradation. Here, we report a large increase in MuRF1 protein levels in both patients with nebulin-based NM, also named NEM2, and in mouse models of the disease. We hypothesized that knocking out MuRF1 in animal models of NM with muscle atrophy would ameliorate the muscle deficits. To test this, we crossed MuRF1 KO mice with two NEM2 mouse models, one with the typical form and the other with the severe form. The crosses were viable, and muscles were studied in mice at 3 months of life. Ultrastructural examination of gastrocnemius muscle lacking MuRF1 and with severe NM revealed a small increase in vacuoles, but no significant change in the myofibrillar fractional area. MuRF1 deficiency led to increased weights of various muscle types in the NM models. However, this increase in muscle size was not associated with increased in vivo or in vitro force production. We conclude that knocking out MuRF1 in NEM2 mice increases muscle size, but does not improve muscle function.
2021-07-28 | Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function.
Nebulin is a critical thin filament-binding protein that spans from the Z-disk of the skeletal muscle sarcomere to near the pointed end of the thin filament. Its massive size and actin-binding property allows it to provide the thin filaments with structural and regulatory support. When this protein is lost, nemaline myopathy occurs. Nemaline myopathy causes severe muscle weakness as well as structural defects on a sarcomeric level. There is no known cure for this disease. We studied whether sarcomeric structure and function can be improved by introducing nebulin's Z-disk region into a nebulin-deficient mouse model (Neb cKO) through adeno-associated viral (AAV) vector therapy. Following this treatment, the structural and functional characteristics of both vehicle-treated and AAV-treated Neb cKO and control muscles were studied. Intramuscular injection of this AAV construct resulted in a successful expression of the Z-disk fragment within the target muscles. This expression was significantly higher in Neb cKO mice than control mice. Analysis of protein expression revealed that the nebulin fragment was localized exclusively to the Z-disks and that Neb cKO expressed the nebulin fragment at levels comparable to the level of full-length nebulin in control mice. Additionally, the Z-disk fragment displaced full-length nebulin in control mice, resulting in nemaline rod body formation and a worsening of muscle function. Neb cKO mice experienced a slight functional benefit from the AAV treatment, with a small increase in force and fatigue resistance. Disease progression was also slowed as indicated by improved muscle structure and myosin isoform expression. This study reveals that nebulin fragments are well-received by nebulin-deficient mouse muscles and that limited functional benefits are achievable.
2021-07-01 | Generating an iPSC line (with isogenic control) from the PBMCs of an ACTA1 (p.Gly148Asp) nemaline myopathy patient
To produce an in vitro model of nemaline myopathy, we reprogrammed the peripheral blood mononuclear cells (PBMCs) of a patient with a heterozygous p.Gly148Asp mutation in exon 3 of the ACTA1 gene to iPSCs. Using CRISPR/Cas9 gene editing we corrected the mutation to generate an isogenic control line. Both the mutant and control show a normal karyotype, express pluripotency markers and could differentiae into the three cell states that represent embryonic germ layers (endoderm, mesoderm and neuroectoderm) and the dermomyotome (precursor of skeletal muscle). When differentiated these cell lines will be used to explore disease mechanisms and evaluate novel therapeutics.
other
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.
2022-05-23 | Clinicopathologic Profiles of Sporadic Late-Onset Nemaline Myopathy
Background and Objectives
Sporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort.
Methods
We performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc–associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5).
Results
Most of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti–α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti–α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti–α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant.
Discussion
SLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti–α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.
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.
2018-04-19 | Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance.
Sporadic late-onset nemaline myopathy (SLONM) with monoclonal gammopathy of undetermined significance (MGUS) is a rare subacute progressive muscle disease. The prognosis is poor due to severe respiratory insufficiency. Recently, however, autologous stem-cell transplantation following high-dose melphalan has been shown to be effective unless there is delay before the treatment. Therefore, early recognition of the disease is important. This review gives an overview of recent advances in SLONM-MGUS, which could help to understand clinical and pathological features and treatment. Efficacy of autologous stem-cell transplantation following high-dose melphalan has been demonstrated in a long-term observation study. Subsequently, reports from other groups also have supported it. Furthermore, efficacy of chemotherapy toward plasma cell dyscrasia without stem-cell transplantation have been reported as well. A few case reports have suggested the presence of cardiac involvement related to SLONM-MGUS. SLONM-MGUS is now considered as a treatable disease. Antiplasma cell dyscrasia therapy is a promising therapeutic option. Meanwhile, the pathomechanic link between muscle degeneration and monoclonal gammopathy remains unclear and further investigations are warranted.
proteins
2025-06-12 | KLHL41 orchestrates sarcomere assembly and size to drive skeletal muscle hypertrophy in vivo.
Sarcomere assembly and growth are fundamental processes essential for the development, function, and repair of skeletal muscle. However, the mechanisms underlying sarcomere formation and assembly in vivo , which are critical for the formation of functional myofibers in vertebrates, remain poorly understood. Defects in sarcomeres contribute to muscle dysfunction in numerous genetic and acquired myopathies, yet the lack of a clear understanding of specific sarcomeric defects has hindered the development of effective therapies. Nemaline myopathy (NM) is caused by mutations in genes that primarily affect sarcomere structure and function. The disease is clinically heterogeneous, with the congenital form being the most severe. Using zebrafish models of congenital forms of NM, we investigated sarcomere assembly in vivo during skeletal muscle development to identify key steps contributing to myofibril formation and muscle growth under both normal and disease conditions. Our findings demonstrate that the gene encoding the sarcomeric protein KLHL41 plays a critical role in the formation and directional organization of new sarcomeres within developing myofibrils, facilitating both radial and longitudinal muscle growth. Dysregulation of sarcomeric proteins and impaired protein turnover in the KLHL41-NM zebrafish model resulted in the development of sarcomeric defects. Moreover, we show that the interaction between the KLHL41-troponin complex is essential for muscle growth and cross-bridge regulation in developing muscle. These studies address a significant gap in the understanding of sarcomeric defects in myopathies and will help guide the development of targeted therapies aimed at rescuing these processes.
2020-08-17 | The loss of slow skeletal muscle isoform of troponin T in spindle intrafusal fibres explains the pathophysiology of Amish nemaline myopathy.
The pathogenic mechanism and the neuromuscular reflex-related phenotype (e.g. tremors accompanied by clonus) of Amish nemaline myopathy, as well as of other recessively inherited TNNT1 myopathies, remain to be clarified. The truncated slow skeletal muscle isoform of troponin T (ssTnT) encoded by the mutant TNNT1 gene is unable to incorporate into myofilaments and is degraded in muscle cells. By contrast to extrafusal muscle fibres, spindle intrafusal fibres of normal mice contain a significant level of cardiac TnT and a low molecular weight splice form of ssTnT. Intrafusal fibres of ssTnT-knockout mice have significantly increased cardiac TnT. Rotarod and balance beam tests have revealed abnormal neuromuscular co-ordination in ssTnT-knockout mice and a blunted response to a spindle sensitizer, succinylcholine. The loss of ssTnT and a compensatory increase of cardiac TnT in intrafusal nuclear bag fibres may increase myofilament Ca2+ -sensitivity and tension, impairing spindle function, thus identifying a novel mechanism for the development of targeted treatment. A nonsense mutation at codon Glu180 of TNNT1 gene causes Amish nemaline myopathy (ANM), a recessively inherited disease with infantile lethality. TNNT1 encodes the slow skeletal muscle isoform of troponin T (ssTnT). The truncated ssTnT is unable to incorporate into myofilament and is degraded in muscle cells. The symptoms of ANM include muscle weakness, atrophy, contracture and tremors accompanied by clonus. An ssTnT-knockout (KO) mouse model recapitulates key features of ANM such as atrophy of extrafusal slow muscle fibres and increased fatigability. However, the neuromuscular reflex-related symptoms of ANM have not been explained. By isolating muscle spindles from ssTnT-KO and control mice aiming to examine the composition of myofilament proteins, we found that, in contrast to extrafusal fibres, intrafusal fibres contain a significant level of cardiac TnT and the low molecular weight splice form of ssTnT. Intrafusal fibres from ssTnT-KO mice have significantly increased cardiac TnT. Rotarod and balance beam tests revealed impaired neuromuscular co-ordination in ssTnT-KO mice, indicating abnormality in spindle functions. Unlike the wild-type control, the beam running ability of ssTnT-KO mice had a blunted response to a spindle sensitizer, succinylcholine. Immunohistochemistry detected ssTnT and cardiac TnT in nuclear bag fibres, whereas fast skeletal muscle TnT was detected in nuclear chain fibres, and cardiac α-myosin was present in one of the two nuclear bag fibres. The loss of ssTnT and a compensatory increase of cardiac TnT in nuclear bag fibres would increase myofilament Ca2+ -sensitivity and tension, thus affecting spindle activities. This mechanism provides an explanation for the pathophysiology of ANM, as well as a novel target for treatment.
2020-01-25 | Nebulin: big protein with big responsibilities
Abstract Nebulin, encoded by NEB , is a giant skeletal muscle protein of about 6669 amino acids which forms an integral part of the sarcomeric thin filament. In recent years, the nebula around this protein has been largely lifted resulting in the discovery that nebulin is critical for a number of tasks in skeletal muscle. In this review, we firstly discussed nebulin’s role as a structural component of the thin filament and the Z-disk, regulating the length and the mechanical properties of the thin filament as well as providing stability to myofibrils by interacting with structural proteins within the Z-disk. Secondly, we reviewed nebulin’s involvement in the regulation of muscle contraction, cross-bridge cycling kinetics, Ca 2+ -homeostasis and excitation contraction (EC) coupling. While its role in Ca 2+ -homeostasis and EC coupling is still poorly understood, a large number of studies have helped to improve our knowledge on how nebulin affects skeletal muscle contractile mechanics. These studies suggest that nebulin affects the number of force generating actin-myosin cross-bridges and may also affect the force that each cross-bridge produces. It may exert this effect by interacting directly with actin and myosin and/or indirectly by potentially changing the localisation and function of the regulatory complex (troponin and tropomyosin). Besides unravelling the biology of nebulin, these studies are particularly helpful in understanding the patho-mechanism of myopathies caused by NEB mutations, providing knowledge which constitutes the critical first step towards the development of therapeutic interventions. Currently, effective treatments are not available, although a number of therapeutic strategies are being investigated.
2019-04-11 | Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy
Abstract Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific adaptors for Cullin 3 (CUL3) E3 ubiquitin ligase to regulate protein turnover through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM; however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin-related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric proteins contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease-causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.
2018-06-19 | KLHL41 stabilizes skeletal muscle sarcomeres by nonproteolytic ubiquitination.
Maintenance of muscle function requires assembly of contractile proteins into highly organized sarcomeres. Mutations in Kelch-like protein 41 (KLHL41) cause nemaline myopathy, a fatal muscle disorder associated with sarcomere disarray. We generated KLHL41 mutant mice, which display lethal disruption of sarcomeres and aberrant expression of muscle structural and contractile proteins, mimicking the hallmarks of the human disease. We show that KLHL41 is poly-ubiquitinated and acts, at least in part, by preventing aggregation and degradation of Nebulin, an essential component of the sarcomere. Furthermore, inhibition of KLHL41 poly-ubiquitination prevents its stabilization of nebulin, suggesting a unique role for ubiquitination in protein stabilization. These findings provide new insights into the molecular etiology of nemaline myopathy and reveal a mechanism whereby KLHL41 stabilizes sarcomeres and maintains muscle function by acting as a molecular chaperone. Similar mechanisms for protein stabilization likely contribute to the actions of other Kelch proteins.
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.
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.
2025-05-05 | Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.
In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca2+ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. KEY POINTS: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.
2024-09-01 | Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.
Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.
2024-06-12 | L-tyrosine for treatment of an infant with nemaline rod myopathy.
Nemaline rod myopathy is an extremely rare muscle disease responsible for hypotonia and poor muscle strength in infants. The disease has variable phenotypic presentations across different ages, ranging from neonatal to the adult onset and from severe to asymptomatic varieties. Clinical features, muscle biopsy and genetic testing help in diagnosis. The histopathological examination shows the presence of rod-like structures or nemaline bodies in muscles. Management remains mainly supportive, and currently, there is no available curative treatment. This case report describes an infant presenting with gross hypotonia, poor handling of secretions and multiple extubation failures who was diagnosed by clinical exome sequencing. The patient harboured compound heterozygous variants in the NEB gene suggestive of nemaline rod myopathy. The newborn showed significant improvement in muscle strength after he was started on dietary L-tyrosine supplementation. This case highlights the emerging role of L-tyrosine in the supportive care of infants with nemaline rod myopathy.
antibodies
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.
2026-03-06 | Concurrent Sporadic Late-Onset Nemaline Myopathy and an Excessive Glycogen Accumulation Associated With Monoclonal Gammopathy.
Monoclonal gammopathy-associated myopathies (MGAMs) include light chain (AL) amyloid myopathy, sporadic late-onset nemaline myopathy (SLONM), and vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS). These subtypes usually occur separately, although rare overlap has been described. We report a patient with monoclonal gammopathy and concurrent SLONM and excessive glycogen accumulation, resembling VAMMGAS but with distinct features. Case report with clinical, electrophysiological, pathological, and therapeutic characterization of a patient with IgG-kappa monoclonal gammopathy and coexisting SLONM and glycogen accumulation within muscle fibers. A 69-year-old man developed subacute progressive axial and limb weakness, head drop, dysphagia, and weight loss. Examination showed proximal/distal weakness, neck extensor weakness, and lumbar hyperlordosis. EMG revealed myopathic motor unit potentials without electrical myotonia or complex repetitive discharges. Serum studies identified IgG-kappa monoclonal protein with elevated kappa light chain and ratio. Muscle biopsy demonstrated nemaline rods (1% of fibers) and scattered fibers with non-rimmed vacuoles (0.3% of fibers) containing PAS-positive, diastase-labile material consistent with concurrent SLONM and glycogen storage myopathy-like pathology. Genetic testing for congenital nemaline and glycogen storage myopathies was negative. Plasma-cell directed therapy with daratumumab, lenalidomide, and dexamethasone led to rapid functional improvement and M-protein reduction. Further gains followed autologous stem cell transplantation. This case expands the MGAM spectrum, highlighting co-occurrence of SLONM and an excessive glycogen accumulation responsive to immunotherapy and transplantation. These findings suggest a spectrum of related disease processes. Recognition of this combined pathology is clinically important, as affected patients may benefit from targeted immunotherapy or stem cell transplantation.
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.
2023-10-30 | Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force.
Nemaline myopathy is one of the most common non-dystrophic congenital myopathies. Individuals affected by this condition experience muscle weakness and muscle smallness, often requiring supportive measures like wheelchairs or respiratory support. A significant proportion of patients, approximately one-third, exhibit compound heterozygous nebulin mutations, which usually give rise to the typical form of the disease. Currently, there are no approved treatments available for nemaline myopathy. Our research explored the modulation of myostatin, a negative regulator of muscle mass, in combating the muscle smallness associated with the disease. To investigate the effect of myostatin inhibition, we employed a mouse model with compound heterozygous nebulin mutations that mimic the typical form of the disease. The mice were treated with mRK35, a myostatin antibody, through weekly intraperitoneal injections of 10 mg/kg mRK35, commencing at two weeks of age and continuing until the mice reached four months of age. The treatment resulted in an increase in body weight and an approximate 20% muscle weight gain across most skeletal muscles, without affecting the heart. The minimum Feret diameter of type IIA and IIB fibers exhibited an increase in compound heterozygous mice, while only type IIB fibers demonstrated an increase in wild-type mice. In vitro mechanical experiments conducted on intact extensor digitorum longus muscle revealed that mRK35 augmented the physiological cross-sectional area of muscle fibers and enhanced absolute tetanic force in both wild-type and compound heterozygous mice. Furthermore, mRK35 administration improved grip strength in treated mice. Collectively, these findings indicate that inhibiting myostatin can mitigate the muscle deficits in nebulin-based typical nemaline myopathy, potentially serving as a much-needed therapeutic option.
2022-08-01 | 2227 Sporadic late-onset nemaline rod myopathy associated with monoclonal gammopathy
A 72-year-old man developed progressive camptocormia associated with head drop, dysphagia, proximal muscle weakness, numbness to the ankles, and 20kg weight loss over a 2 year period. Background history was significant for thyroid cancer treated with total thyroidectomy resulting in left accessory nerve injury, type 2 diabetes mellitus, hypertension, and gout. Examination revealed a man with reduced muscle bulk who walked with a flexed spine. He had weakness of neck flexion and proximal muscles with normal reflexes and reduced pin-prick sensation to both feet. Nerve conduction studies showed length-dependent axonal sensorimotor neuropathy. Concentric needle electromyography showed widespread reduced recruitment of small polyphasic units consistent with a myopathic process. Creatine kinase level was normal. Myositis panel demonstrated low positive Mi2 of uncertain significance. An initial deltoid muscle biopsy did not show evidence of myopathy. Due to worsening of symptoms, a repeat muscle biopsy of vastus lateralis was performed, revealing atrophic myofibres with a patchy granular appearance. Electron microscopy identified nemaline rods. An IgG kappa paraprotein was identified. HIV serology was negative. A diagnosis of sporadic late-onset nemaline myopathy (SLONM) associated with monoclonal gammopathy was made. He was commenced on IVIG and referred for haematological evaluation. SLONM is a rare acquired adult-onset progressive myopathy associated with monoclonal gammopathy and HIV infection. It may present with head drop or dysphagia and is characterised electrophysiologically by a combination of axonal neuropathy and proximal myopathy. First-line treatment with intravenous immunoglobulin and second-line treatment with haematological/immunological therapies may result in significant improvement.
gene therapies
2025-03-20 | Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.
Biallelic pathogenic variants in the nebulin (NEB) gene lead to the congenital muscle disease nemaline myopathy. In-frame deletion of exon 55 (ΔExon55) is the most common disease-causing variant in NEB. Previously, a mouse model of NebΔExon55 was developed; however, it presented an uncharacteristically severe phenotype with a near complete reduction in Neb transcript expression that is not observed in NEB exon 55 patients. We identified by RNA sequencing that the cause of this unexpectedly severe presentation in mice is the generation of a pseudoexon containing two premature termination codons (and promoting nonsense mediated decay) at the Neb exon 55 deletion site. To prove that this is the cause of the loss of Neb transcript, and to generate a more faithful model of the human disease, we used CRISPR gene editing to remove the pseudoexon sequence and replace it with human intron 54 sequence containing a validated cas9 gRNA protospacer. The resulting "hmz" mice have a significant reduction in pseudoexon formation (93.6% reduction), and a re-introduction of stable Neb transcript expression. This new model has the characteristic features of nemaline myopathy at the physiological, histological, and molecular levels. Importantly, unlike the existing exon 55 deletion mice (which die by age 7 days), it survives beyond the first months and exhibits obvious signs of neuromuscular dysfunction. It thus provides a new, robust model for studying pathomechanisms and developing therapies for NEB related nemaline myopathy.
2023-01-26 | Early clinical and pre-clinical therapy development in Nemaline myopathy.
Nemaline myopathies (NM) represent a group of clinically and genetically heterogeneous congenital muscle disorders with the common denominator of nemaline rods on muscle biopsy. NEB and ACTA1 are the most common causative genes. Currently, available treatments are supportive. We explored experimental treatments for NM, identifying at least eleven mainly pre-clinical approaches utilizing murine and/or human muscle cells. These approaches target either i) the causative gene or associated genes implicated in the same pathway; ii) pathophysiologically relevant biochemical mechanisms such as calcium/myosin regulation of muscle contraction; iii) myogenesis; iv) other therapies that improve or optimize muscle function more generally; v) and/or combinations of the above. The scope and efficiency of these attempts is diverse, ranging from gene-specific effects to those widely applicable to all NM-associated genes. The wide range of experimental therapies currently under consideration for NM is promising. Potential translation into clinical use requires consideration of additional factors such as the potential muscle type specificity as well as the possibility of gene expression remodeling. Challenges in clinical translation include the rarity and heterogeneity of genotypes, phenotypes, and disease trajectories, as well as the lack of longitudinal natural history data and validated outcomes and biomarkers.
2022-07-29 | Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits.
Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common cause. Skeletal muscle atrophy is tightly linked to upregulation of MuRF1, an E3 ligase, that targets proteins for proteasome degradation. Here, we report a large increase in MuRF1 protein levels in both patients with nebulin-based NM, also named NEM2, and in mouse models of the disease. We hypothesized that knocking out MuRF1 in animal models of NM with muscle atrophy would ameliorate the muscle deficits. To test this, we crossed MuRF1 KO mice with two NEM2 mouse models, one with the typical form and the other with the severe form. The crosses were viable, and muscles were studied in mice at 3 months of life. Ultrastructural examination of gastrocnemius muscle lacking MuRF1 and with severe NM revealed a small increase in vacuoles, but no significant change in the myofibrillar fractional area. MuRF1 deficiency led to increased weights of various muscle types in the NM models. However, this increase in muscle size was not associated with increased in vivo or in vitro force production. We conclude that knocking out MuRF1 in NEM2 mice increases muscle size, but does not improve muscle function.
2021-07-28 | Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function.
Nebulin is a critical thin filament-binding protein that spans from the Z-disk of the skeletal muscle sarcomere to near the pointed end of the thin filament. Its massive size and actin-binding property allows it to provide the thin filaments with structural and regulatory support. When this protein is lost, nemaline myopathy occurs. Nemaline myopathy causes severe muscle weakness as well as structural defects on a sarcomeric level. There is no known cure for this disease. We studied whether sarcomeric structure and function can be improved by introducing nebulin's Z-disk region into a nebulin-deficient mouse model (Neb cKO) through adeno-associated viral (AAV) vector therapy. Following this treatment, the structural and functional characteristics of both vehicle-treated and AAV-treated Neb cKO and control muscles were studied. Intramuscular injection of this AAV construct resulted in a successful expression of the Z-disk fragment within the target muscles. This expression was significantly higher in Neb cKO mice than control mice. Analysis of protein expression revealed that the nebulin fragment was localized exclusively to the Z-disks and that Neb cKO expressed the nebulin fragment at levels comparable to the level of full-length nebulin in control mice. Additionally, the Z-disk fragment displaced full-length nebulin in control mice, resulting in nemaline rod body formation and a worsening of muscle function. Neb cKO mice experienced a slight functional benefit from the AAV treatment, with a small increase in force and fatigue resistance. Disease progression was also slowed as indicated by improved muscle structure and myosin isoform expression. This study reveals that nebulin fragments are well-received by nebulin-deficient mouse muscles and that limited functional benefits are achievable.
2021-07-01 | Generating an iPSC line (with isogenic control) from the PBMCs of an ACTA1 (p.Gly148Asp) nemaline myopathy patient
To produce an in vitro model of nemaline myopathy, we reprogrammed the peripheral blood mononuclear cells (PBMCs) of a patient with a heterozygous p.Gly148Asp mutation in exon 3 of the ACTA1 gene to iPSCs. Using CRISPR/Cas9 gene editing we corrected the mutation to generate an isogenic control line. Both the mutant and control show a normal karyotype, express pluripotency markers and could differentiae into the three cell states that represent embryonic germ layers (endoderm, mesoderm and neuroectoderm) and the dermomyotome (precursor of skeletal muscle). When differentiated these cell lines will be used to explore disease mechanisms and evaluate novel therapeutics.
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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.
2022-05-23 | Clinicopathologic Profiles of Sporadic Late-Onset Nemaline Myopathy
Background and Objectives
Sporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort.
Methods
We performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc–associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5).
Results
Most of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti–α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti–α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti–α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant.
Discussion
SLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti–α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.
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.
2018-04-19 | Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance.
Sporadic late-onset nemaline myopathy (SLONM) with monoclonal gammopathy of undetermined significance (MGUS) is a rare subacute progressive muscle disease. The prognosis is poor due to severe respiratory insufficiency. Recently, however, autologous stem-cell transplantation following high-dose melphalan has been shown to be effective unless there is delay before the treatment. Therefore, early recognition of the disease is important. This review gives an overview of recent advances in SLONM-MGUS, which could help to understand clinical and pathological features and treatment. Efficacy of autologous stem-cell transplantation following high-dose melphalan has been demonstrated in a long-term observation study. Subsequently, reports from other groups also have supported it. Furthermore, efficacy of chemotherapy toward plasma cell dyscrasia without stem-cell transplantation have been reported as well. A few case reports have suggested the presence of cardiac involvement related to SLONM-MGUS. SLONM-MGUS is now considered as a treatable disease. Antiplasma cell dyscrasia therapy is a promising therapeutic option. Meanwhile, the pathomechanic link between muscle degeneration and monoclonal gammopathy remains unclear and further investigations are warranted.
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