Sporadic Late-onset Nemaline Myopathy Research Articles

Sporadic Late-onset Nemaline Myopathy Associated with Sjögren's Syndrome: A Case Report.

We report the case of a 46-year-old female patient who developed a subacute progression of axial and proximal muscle weakness. Laboratory findings revealed mildly elevated serum creatine kinase levels. No monoclonal gammopathy was detected. A muscle biopsy revealed that she had nemaline myopathy. Serological tests and a lip biopsy revealed Sjögren's syndrome (SjS). We diagnosed her as having sporadic late-onset nemaline myopathy without monoclonal gammopathy of undetermined significance associated with SjS. Her symptoms improved after methylprednisolone pulse therapy followed by intravenous immunoglobulin therapy. A good response to immunotherapy demonstrates the necessity of making a correct diagnosis, for which a muscle biopsy is required.

Sporadic Late-Onset Nemaline Myopathy: Current Landscape.

Sporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset, acquired, muscle disease that can be associated with monoclonal gammopathy or HIV infection. The pathological hallmark of SLONM is the accumulation of nemaline rods in muscle fibers. We review here current knowledge about its presentation, pathophysiology, and management. SLONM usually manifests with subacutely progressive proximal and axial weakness, but it can also present with chronic progressive weakness mimicking muscular dystrophy. The pathophysiology of the disease remains poorly understood, with evidence pointing to both autoimmune mechanisms and hematological neoplasia. Recent studies have identified histological, proteomic, and transcriptomic alterations that shed light on disease mechanisms and distinguish SLONM from inherited nemaline myopathies. A majority of SLONM patients respond to intravenous immunoglobulins, chemotherapy, or hematopoietic stem cell transplant. SLONM is a treatable myopathy, although its underlying etiology and pathomechanisms remain unclear. A high degree of suspicion should be maintained for this disease to reduce diagnostic delay and treatment in SLONM and facilitate its distinction from inherited nemaline myopathies.

Sporadic late onset nemaline myopathy with concurrent dermatological symptoms responding to immunosuppressive treatment

BackgroundSporadic late onset nemaline myopathy is a rare, progressive muscle disease, presenting in adulthood, mainly affecting proximal limb and bulbar muscles. Muscle biopsies show characteristic nemaline rods. The putative mechanism is considered immune-related. Other manifestations aside from neuromuscular symptoms have not been described previously.Case presentationWe present a case with atypical sporadic late onset nemaline myopathy (SLONM) of a non-HIV, non-MGUS subtype, where skin manifestations preceded neuromuscular symptoms, and a residual thymus with the histology of thymic follicular hyperplasia was detected during the diagnostic workup. Thorough dermatological investigations could not explain the skin presentations. Muscle biopsy revealed variation in fiber diameter, ragged-red and COX-negative fibers associated with discrete fibrosis. Electron microscopy detected atrophic muscle fibres with disorganization of the myofibrils, nemaline rods and abnormal mitochondria. Single-fiber EMG suggested signs of a neuromuscular transmission defect, EMG showed signs of myopathy. Analyses of antibodies associated with myasthenia gravis were negative. The patient showed improvement after intravenous immunoglobulin treatment regarding both the skin and the muscle symptoms.ConclusionsOur case highlights the heterogeneity of SLONM with its varied spectrum of presentation. A unique combination of dermatological symptoms and SLONM could be seen with skin lesions as primary presenting symptoms. An association can be considered between the different manifestations, presumably based on immune etiology, where immunosuppressive therapy has been beneficial.

HTLV-1-associated myelopathy/tropical spastic paraplegia with sporadic late-onset nemaline myopathy: a case report

BackgroundSporadic late onset nemaline myopathy (SLONM) is a muscle disorder characterized by the presence of nemaline rods in muscle fibers. SLONM has no known genetic cause but has been associated with monoclonal gammopathy of undetermined significance and with human immunodeficiency virus (HIV) infection. Human T-cell leukemia virus-1 (HTLV-1) is a known causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraplegia (HAM/TSP), a chronic inflammatory neurological disease. HTLV-1 has been reported to be implicated in inflammatory myopathies, as well as in HIV infection.; however, there have been no reports of an association between HTLV-1 infection and SLONM to date.Case presentationA 70-year-old Japanese woman presented with gait disturbance, lumbar kyphosis, and respiratory dysfunction. The diagnosis of HAM/TSP with SLONM was made based on characteristic clinical symptoms of HAM/TSP, such as spasticity in the lower extremities, and cerebrospinal fluid test results; and of SLONM, such as generalized head drooping, respiratory failure, and muscle biopsy results. Steroid treatment was initiated and improvement in her stooped posture was observed after 3 days of treatment.ConclusionThis is the first case report of SLONM combined with HTLV-1 infection. Further studies are needed to elucidate the relationship between retroviruses and muscle diseases.

Untangling the Signatures of Acquired Sporadic Late Onset Nemaline Myopathy (SLONM) and Inherited Nemaline Myopathy (S7.001)

<h3>Objective:</h3> To identify biomarkers distinguishing acquired sporadic late onset nemaline myopathy (SLONM) from inherited nemaline myopathy (iNM) and investigate the pathophysiology leading to nemaline rod formation in these different disorders. <h3>Background:</h3> SLONM and iNM both feature accumulation of nemaline rods in muscle fibers. Unlike iNM, SLONM is amenable to therapy. The distinction between these disorders is therefore crucial, especially when the diagnosis remains ambiguous after initial clinical assessment and investigations. <h3>Design/Methods:</h3> Twenty-two muscle samples from patients affected by SLONM or genetically characterized iNM underwent quantitative histological analysis, laser capture microdissection for proteomic analysis of nemaline rod areas and rod-free areas, and transcriptomic analysis. <h3>Results:</h3> In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in 70% of SLONM samples. In SLONM, muscle fibers harboring nemaline rods were smaller than those without rods, while the opposite was seen in iNM. Necrotic fibers, increased endomysial connective tissue, and atrophic fibers filled with nemaline rods were significantly more common in SLONM. Proteomic analysis detected 142 differentially expressed proteins between nemaline rod areas and rod-free areas across all samples. Comparing SLONM and iNM, fifty-one proteins were differentially expressed in nemaline rod areas and 10 proteins were differentially expressed in rod-free areas. These differentially expressed proteins implicated immune, structural, metabolic, and cellular processes in disease pathophysiology. Notably, immunoglobulin overexpression with accumulation in nemaline rod areas was detected in SLONM, supporting use of plasma cell-targeting chemotherapy for SLONM treatment. Transcriptomic analysis corroborated the proteomic findings and further revealed substantial gene expression differences between SLONM and iNM. <h3>Conclusions:</h3> We identified unique pathological and molecular signatures associated with SLONM and iNM, suggesting distinct underlying pathophysiological mechanisms. These findings are a critical step towards optimizing diagnostic tools that can better distinguish these disorders and accelerating SLONM treatment. <b>Disclosure:</b> The institution of Dr. Nicolau has received research support from Muscular Dystrophy association. The institution of Dr. Nicolau has received research support from American Brain Foundation. The institution of Dr. Nicolau has received research support from American Neuromuscular Foundation. Dr. Dasgupta has nothing to disclose. Prof. Dasari has nothing to disclose. Dr. Charlesworth has nothing to disclose. Mr. Johnson has received intellectual property interests from a discovery or technology relating to health care. Dr. Pandey has nothing to disclose. Dr. Doles has nothing to disclose. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, AAN. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.

Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies

Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers. Unlike iNM, SLONM is amenable to therapy. The distinction between these disorders is therefore crucial when the diagnosis remains ambiguous after initial investigations. We sought to identify biomarkers facilitating this distinction and to investigate the pathophysiology of nemaline rod formation in these different disorders. Twenty-two muscle samples from patients affected by SLONM or iNM underwent quantitative histological analysis, laser capture microdissection for proteomic analysis of nemaline rod areas and rod-free areas, and transcriptomic analysis. In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples. In SLONM, muscle fibers harboring nemaline rods were smaller than those without rods. Necrotic fibers, increased endomysial connective tissue, and atrophic fibers filled with nemaline rods were more common in SLONM. Proteomic analysis detected differentially expressed proteins between nemaline rod areas and rod-free areas, as well as between SLONM and iNM. These differentially expressed proteins implicated immune, structural, metabolic, and cellular processes in disease pathophysiology. Notably, immunoglobulin overexpression with accumulation in nemaline rod areas was detected in SLONM. Transcriptomic analysis corroborated proteomic findings and further revealed substantial gene expression differences between SLONM and iNM. Overall, we identified unique pathological and molecular signatures associated with SLONM and iNM, suggesting distinct underlying pathophysiological mechanisms. These findings represent a step towards enhanced diagnostic tools and towards development of treatments for SLONM.

Clinicopathologic Profiles of Sporadic Late-Onset Nemaline Myopathy: Practical Importance of Anti-α-Actinin Immunostaining.

Background and ObjectivesSporadic 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.MethodsWe 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).ResultsMost 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.DiscussionSLONM 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.

68-year old man with progressive weakness and ventilator dependent respiratory failure: a case report of sporadic late onset nemaline myopathy

BackgroundNeuromuscular pathologies must be considered when caring for patients with persistent or progressive respiratory failure. Pertinent disease states may involve skeletal muscles of respiration or associated neurologic structures including motor neurons, peripheral neurons and the neuromuscular junction. Diagnosis may require pulmonary function testing, neurophysiologic studies, imaging, and/or muscle biopsy.Case presentationA 68-year-old male was transferred to our intensive care unit (ICU) for management of ventilator dependent respiratory failure. Upon further historical review, he described gradually worsening gait instability and muscle weakness, which was previously attributed to vascular Parkinsonism in the setting of known cerebrovascular disease. Upon arrival to our hospital, he was found to have elevated muscle specific enzymes, prompting evaluation for neuromuscular causes of respiratory failure. He was also found to have elevated HMG-CoA Reductase (HMGCR) antibodies. Ultimately, a right quadriceps muscle biopsy was performed and electron microscopy identified nemaline bodies within skeletal myofibers. Given the clinical course and other histopathologic findings, he was diagnosed with Sporadic late-onset nemaline myopathy (SLONM).ConclusionThe diagnosis of neuromuscular disease in patients with ventilator dependent respiratory failure is challenging. A detailed history of a patient’s clinical course prior to hospitalization is key and may raise suspicion for underlying neuromuscular pathology. Further evaluation in non-critically ill patients may include pulmonary function, electromyography and confirmatory muscle biopsy. Sporadic late onset nemaline myopathy remains a rare disease entity which rarely presents with respiratory failure and lacks effective treatment.

Nemaline myopathy in newly diagnosed systemic lupus erythematosus and Sj\xf6gren\u2019s overlap syndrome complicated by macrophage activation syndrome

BackgroundNemaline myopathies are congenital or acquired muscle disorders that typically present in childhood but can occasionally occur in adults with underlying malignant, infectious or autoimmune disorders. There is a great genetic heterogeneity as well as clinical variability among the disease.Case presentationHere, we present a case of nemaline myopathy in a young woman who was newly diagnosed with systemic lupus erythematosus (SLE) and Sjögren’s overlap syndrome complicated by macrophage activation syndrome (MAS). She had no personal or family history of myopathy and was reporting progressive thigh weakness. A muscle biopsy revealed type 1 myofiber predominance with granular material in atrophic myocytes consistent with nemaline myopathy. Her symptoms markedly improved with immunotherapy for her SLE and MAS supporting the diagnosis of sporadic late-onset nemaline myopathy (SLONM) associated with her autoimmune disease.ConclusionsSLONM is a type of nemaline myopathy that presents in adults and can occasionally be associated with autoimmune disease. In these cases, treatment of the underlying disorder with immunosuppression appears to improve symptoms of myopathy.

Proteomic profiling of sporadic late-onset nemaline myopathy.

ObjectiveTo define the proteomic profile of sporadic late‐onset nemaline myopathy (SLONM) and explore its pathogenesis.MethodsWe performed mass spectrometry on laser‐dissected frozen muscle samples from five patients with SLONM, three of whom with an associated monoclonal protein (MP), and four controls, to determine the proteomic profile of SLONM. Furthermore, we assessed the role of the MP by evaluating the expression of the immunoglobulin light chain variable regions (IGVL).ResultsThere were 294 differentially expressed proteins: 272 upregulated and 22 downregulated. Among the top 100 upregulated proteins, the most common categories were: nuclear or nucleic acid metabolism (24%), extracellular matrix and basal lamina (17%), immune response (13%), and actin dynamics (8%). Downregulated proteins consisted mostly of contractile proteins. Among upregulated proteins, there were 65 with a role related to the immune system, including eight proteins involved in major histocompatibility complex 1 (MHC1) and antigen processing, 15 in MHCII complex and phagocytosis, and 23 in B and/or T‐cell function. Among nine upregulated immunoglobulin proteins, there were two IGVL genes. However, these were also detected in SLONM cases without an MP, with no evidence of clonally dominant immunoglobulin deposition. In muscle sections from SLONM patients, nemaline rods tended to accumulate in atrophic fibers with marked rarefaction of the myofibrils. Increased MHC1 reactivity was present in fibers containing nemaline rods as well as adjacent nonatrophic fibers.ConclusionOur findings suggest that aberrant immune activation is present in SLONM, but do not support a direct causal relationship between the MP and SLONM.

What Is in the Myopathy Literature?

This edition concentrates on inflammatory myopathies with reports of reclassification of polymyositis, cancer associations, evaluation of subclinical cardiac involvement, myositis-specific and -associated antibodies, and immune checkpoint inhibitor myositis. A number of reports address sporadic late-onset nemaline myopathy and point out its diagnostic difficulty and the importance of identifying an associated monoclonal gammopathy that is likely of clinical significance and may warrant aggressive immunotherapy. Finally, treatment of nondystrophic channelopathies is addressed.

AUTOIMMUNE & INFLAMMATORY NMD: EP.14 Inflammatory features in sporadic late-onset nemaline myopathy

AUTOIMMUNE & INFLAMMATORY NMD: EP.14 Inflammatory features in sporadic late-onset nemaline myopathy

High prevalence of sporadic late-onset nemaline myopathy in a cohort of whole-exome sequencing negative myopathy patients

Sporadic late-onset nemaline myopathy (SLONM) is an enigmatic, supposedly very rare, putatively immune-mediated late-onset myopathy, typically presenting with subacutely progressive limb-girdle muscular weakness, yet slowly progressing cases have been described too. We systematically studied (para)clinical and histopathological findings in a cohort of 18 isolated yet suspected inherited myopathy patients, showing late-onset, slowly progressive limb-girdle muscle weakness, remaining unsolved after whole-exome sequencing. The presence of a monoclonal gammopathy of unknown significance (MGUS) and anti-HMGCR antibodies was determined. Biopsies were systematically re-evaluated and systematic immunohistochemical and electron microscopy studies were performed to particularly evaluate the presence of rods and/or inflammatory features. Ten patients showed rods as core feature on muscle biopsy on re-evaluation, four of these had an IgG κ MGUS in blood. As such, these ten patients represented suspected slowly progressing SLONM patients, with auxiliary data supporting this diagnosis: 1) additional muscle biopsy features pointing towards Z-disk and myofibrillar pathology; 2) a common selective pattern of muscle involvement on MRI; 3) inflammatory features on muscle biopsy. Findings in this proof-of-concept study highlight difficulties in reliably diagnosing slowly progressing SLONM and the probably underestimated prevalence of this entity in cohorts of whole exome sequencing negative myopathy patients, initially considered having an inherited myopathy.

Inflammatory features in sporadic late-onset nemaline myopathy are independent from monoclonal gammopathy.

ABSTRACTSporadic late‐onset nemaline myopathy (SLONM) is a rare adult‐onset non‐hereditary disease with subacute proximal muscle and often axial muscle weakness, characterized by the presence of nemaline bodies in skeletal muscle biopsies. Considering its association with concurrent monoclonal gammopathy of undetermined significance (MGUS), the disease is classified into two major subtypes (1) SLONM without MGUS (SLONM‐noMGUS) and (2) with MGUS (SLONM‐MGUS) association. SLONM associated with HIV infection (SLONM‐HIV) is also reported. SLONM‐MGUS has been shown to be associated with poorer prognosis and required aggressive treatment including high‐dose melphalan and autologous stem cell transplantation. The approach is currently debatable as recent reports suggested effectiveness of intravenous immunoglobulin as initial treatment with indifference of overall survival despite the presence of MGUS. Our study aimed to find an underlying basis by review of pathological features in 49 muscle biopsy proven‐SLONM from two large tertiary centers in Japan and Germany (n = 49: SLONM‐noMGUS = 34, SLONM‐MGUS = 13, SLONM‐HIV = 2). We compared pathological findings in SLONM‐noMGUS and SLONM‐MGUS and focused on the presence of any detectable inflammatory features by immunohistochemistry. The clinical and histological features in SLONM‐noMGUS and SLONM‐MGUS were not distinctively different except for more common regenerating fibers (>5% of myofibers) present in SLONM‐MGUS (p < 0.01). HLA‐ABC expression and fine granular p62 were observed in 66.7% and 78.3% of SLONM, respectively. The predominant inflammatory cells were CD68+ cells. The inflammatory cells showed positive correlations with the percentage of nemaline‐containing fibers (p < 0.001). In conclusion, inflammatory features are present although rather mild in SLONM. This finding contributes to the hypothesis of an acquired inflammatory disease pathogenesis and opens the possibility to offer immunotherapy in SLONM with inflammatory features regardless of the monoclonal gammopathy status.

What is the best treatment approach for sporadic late‐onset nemaline myopathy associated with “monoclonal gammopathy of neurological significance”?

What is the best treatment approach for sporadic late‐onset nemaline myopathy associated with “monoclonal gammopathy of neurological significance”?

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance: Report of four patients

Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired muscle disease presenting with subacute progression in adulthood. It can be accompanied by a monoclonal gammopathy of undetermined significance (MGUS). We describe clinical and histopathological findings of four SLONM patients with MGUS. In all patients, nemaline rod, inter-myofibrillary network disruption, atrophic changes, peripheral basophilic discoloration, vacuole without rim, and cytoplasmic body without inflammation were seen. Three out of four patients were treated with prednisolone in combination with IVIG monthly and had an appropriate response to the treatment. The optimal first-line treatment remains unclear in SLONM-MGUS, although corticosteroids plus IVIg is associated with favorable clinical response. These treatment modalities might be used as an optional treatment before autologous stem cell transplantation; however, further studies with a higher number of patients are required.

CONGENITAL MYOPATHIES 1 – NEMALINE: P.28 Distinctive pathological features of inherited and sporadic late-onset nemaline myopathies

Inherited nemaline myopathies (iNM) are a genetically heterogeneous group of disorders characterized by accumulation of Z-disc derived nemaline rods in muscle fibres and presenting from infancy to adulthood. Nemaline rods are also a pathological feature of sporadic late onset nemaline myopathy (SLONM), an acquired myopathy sometimes associated with monoclonal gammopathies or HIV infection. We sought to identify pathological parameters distinguishing these two myopathies. This distinction has significant implications, as SLONM may respond to pharmacological therapy. We randomly selected 9 patients with iNM and 10 with non-HIV SLONM. Their median ages were 11 and 64 years, respectively. The causative genes in iNM were ACTA1 (3 patients), NEB (1 patient) or unknown (5 patients, aged 2-11). Six SLONM patients had monoclonal gammopathies. Muscle fibre sizes and the proportion of fibres harbouring nemaline rods were determined using unbiased sampling methods. The proportion of fibres harbouring nemaline rods was higher in iNM (median 53%, range: 39-99%) than in SLONM (median 11%, range: 1.2-47%). In SLONM, fibres containing nemaline rods had a smaller diameter than fibres devoid of rods (median ratio 0.60), while the opposite was observed in iNM (median ratio 1.12). Atrophic fibres filled with rods occurred in 8/10 SLONM patients and, less conspicuously, in 1/9 iNM patients. In 6/10 SLONM patients, nemaline rods were spread diffusely within the individual fibres, while rods occurred in clusters in 8/9 iNM patients. Necrotic fibres were present in 7/10 SLONM patients, but only in 1/9 iNM patients. In summary, SLONM can be distinguished from iNM on the basis of clinical and pathological features. The pathological differences are particularly relevant when the underlying genetic defect cannot be found in adult patients with iNM, and can guide identification of patients amenable to treatment.

Sporadic late onset nemaline myopathy with monoclonal gammopathy of undetermined significance: two cases with long term stability.

Monoclonal gammopathy of undetermined significance (MGUS) associated to sporadic late onset nemaline myopathy (SLONM) is a rare and severely disabling condition of quickly progressive limb girdle acquired myopathy. It is believed by some authors to be due to myotoxicity of light chain deposits. Two female patients were diagnosed with MGUS associated SLONM. In the first case, diagnosis was delayed by 6 years thus giving time for a severe generalized myopathy and cardiomyopathy to develop. A single anti-myeloma chemotherapy with lenalidomide markedly improved and stabilized the patient’s condition despite respiratory and cardiac insufficiency. In our second patient the condition was identified one year after onset of the first symptom and markedly improved after autologous bone marrow transplantation and lenalidomide. Clinicians should be aware of monoclonal gammopathy associated sporadic late onset nemaline myopathy as this acquired muscle disorder, although extremely rare, may be reversed by adequate management.

Sporadic late onset nemaline myopathy with monoclonal gammopathy of undetermined significance: two cases with long term stability

Monoclonal gammopathy of undetermined significance (MGUS) associated to sporadic late onset nemaline myopathy (SLONM) is a rare and severely disabling condition of quickly progressive limb girdle acquired myopathy. It is believed by some authors to be due to myotoxicity of light chain deposits. Two female patients were diagnosed with MGUS associated SLONM. In the first case, diagnosis was delayed by 6 years thus giving time for a severe generalized myopathy and cardiomyopathy to develop. A single anti-myeloma chemotherapy with lenalidomide markedly improved and stabilized the patient’s condition despite respiratory and cardiac insufficiency. In our second patient the condition was identified one year after onset of the first symptom and markedly improved after autologous bone marrow transplantation and lenalidomide. Clinicians should be aware of monoclonal gammopathy associated sporadic late onset nemaline myopathy as this acquired muscle disorder, although extremely rare, may be reversed by adequate management.

Editors' note: Sporadic late-onset nemaline myopathy: Clinical spectrum, survival, and treatment outcomes

In the article “Sporadic late-onset nemaline myopathy: Clinical spectrum, survival, and treatment outcomes,” Drs. Naddaf et al. reported that the overall survival among 28 patients with sporadic late-onset nemaline myopathy (SLONM)—identified by retrospective chart review—did not seem to be affected by the presence of a monoclonal protein (MP). They concluded that initial treatment with intravenous immunoglobulin (IVIg) was reasonable in all patients, followed by autologous stem cell transplant (ASCT) or chemotherapy as second-line therapy in patients with an associated MP. In response, Drs. Chahin and Karam suggest clarifying the degree of weakness and disability of those patients who received IVIg vs those who received ASCT because this could result in selection bias. They report that in their experience, patients with SLONM and MP with a severe phenotype who were treated with IVIg initially appeared stable over 6 months but then rapidly deteriorated—becoming too weak for ASCT—and died. They also cite a previous study that showed worse survival in patients with MP and posit that the absence of such a difference in this study may relate to the recent approach of aggressive treatment of such patients. In the absence of a study comparing IVIg and ASCT in such patients, they conclude that some patients with aggressive SLONM may be best treated with ASCT directly. Responding to these comments, Drs. Naddaf et al. reported no difference in the Neuropathy Impairment Score-Weakness at presentation between patients who received IVIg vs ASCT. They acknowledge the inherent limitations of referral bias and retrospective design but note that severely affected patients were still among those referred to their institution who showed good response to IVIg, with none rendered ineligible for ASCT by previous treatment failure. They counter that given the risks of morbidity, mortality, and other post-ASCT side effects, IVIg should still be the first-line treatment in the absence of evidence of superiority of ASCT, with ASCT considered for patients not responding after 2–3 months. This exchange demonstrates the clinical equipoise regarding the choice of IVIg vs ASCT as first-line therapy for patients with SLONM, particularly in the presence of MP. In the article “Sporadic late-onset nemaline myopathy: Clinical spectrum, survival, and treatment outcomes,” Drs. Naddaf et al. reported that the overall survival among 28 patients with sporadic late-onset nemaline myopathy (SLONM)—identified by retrospective chart review—did not seem to be affected by the presence of a monoclonal protein (MP). They concluded that initial treatment with intravenous immunoglobulin (IVIg) was reasonable in all patients, followed by autologous stem cell transplant (ASCT) or chemotherapy as second-line therapy in patients with an associated MP. In response, Drs. Chahin and Karam suggest clarifying the degree of weakness and disability of those patients who received IVIg vs those who received ASCT because this could result in selection bias. They report that in their experience, patients with SLONM and MP with a severe phenotype who were treated with IVIg initially appeared stable over 6 months but then rapidly deteriorated—becoming too weak for ASCT—and died. They also cite a previous study that showed worse survival in patients with MP and posit that the absence of such a difference in this study may relate to the recent approach of aggressive treatment of such patients. In the absence of a study comparing IVIg and ASCT in such patients, they conclude that some patients with aggressive SLONM may be best treated with ASCT directly. Responding to these comments, Drs. Naddaf et al. reported no difference in the Neuropathy Impairment Score-Weakness at presentation between patients who received IVIg vs ASCT. They acknowledge the inherent limitations of referral bias and retrospective design but note that severely affected patients were still among those referred to their institution who showed good response to IVIg, with none rendered ineligible for ASCT by previous treatment failure. They counter that given the risks of morbidity, mortality, and other post-ASCT side effects, IVIg should still be the first-line treatment in the absence of evidence of superiority of ASCT, with ASCT considered for patients not responding after 2–3 months. This exchange demonstrates the clinical equipoise regarding the choice of IVIg vs ASCT as first-line therapy for patients with SLONM, particularly in the presence of MP.