Variants in tropomyosins TPM2 and TPM3 causing muscle hypertonia.

Patients with myopathies caused by pathogenic variants in tropomyosin genes TPM2 and TPM3 usually have muscle hypotonia and weakness, their muscle biopsies often showing fibre size disproportion and nemaline bodies. Here, we describe a series of patients with hypercontractile molecular phenotypes, high muscle tone, and mostly non-specific myopathic biopsy findings without nemaline bodies. Three of the patients had trismus, whilst in one patient, the distal joints of her fingers flexed on extension of the wrists. In one biopsy from a patient with a rare TPM3 pathogenic variant, cores and minicores were observed, an unusual finding in TPM3-caused myopathy. The variants alter conserved contact sites between tropomyosin and actin.

Marked neuropsychiatric involvement and dysmorphic features in nemaline myopathy.

BACKGROUND: Inherited nemaline myopathy is one of the most common congenital myopathies. This genetically heterogeneous disease is defined by the presence of nemaline bodies in muscle biopsy. The phenotypic spectrum is wide and cognitive involvement has been reported, although not extensively evaluated. METHODS: We report two nemaline myopathy patients presenting pronounced central nervous system involvement leading to functional compromise and novel facial and skeletal dysmorphic findings, possibly expanding the disease phenotype. RESULTS: One patient had two likely pathogenic NEB variants, c.2943G > A and c.8889 + 1G > A, and presented cognitive impairment and dysmorphic features, and the other had one pathogenic variant in ACTA1, c.169G > C (p.Gly57Arg), presenting autism spectrum disorder and corpus callosum atrophy. Both patients had severe cognitive involvement despite milder motor dysfunction. CONCLUSION: We raise the need for further studies regarding the role of thin filament proteins in the central nervous system and for a systematic cognitive assessment of congenital myopathy patients.

A brief history of the congenital myopathies - the myopathological perspective.

Congenital myopathies are defined by early clinical onset, slow progression, hereditary nature and disease-specific myopathological lesions - however, with exceptions - demanding special techniques in regard to morphological diagnostic and research work-up. To identify an index disease in a family requires a muscle biopsy - and no congenital myopathy has ever been first described at autopsy. The nosographic history commenced when - in addition to special histopathological techniques in the earliest classical triad of central core disease, 1956, nemaline myopathy, 1963, and centronuclear myopathy, 1966/67, within a decade - electron microscopy and enzyme histochemistry were applied to unfixed frozen muscle tissue and, thus, revolutionized diagnostic and research myopathology. During the following years, the list of structure-defined congenital myopathies grew to some 40 conditions. Then, the introduction of immunohistochemistry allowed myopathological documentation of proteins and their abnormalities in individual congenital myopathies. Together with the diagnostic evolution of molecular genetics, many more congenital myopathies were described, without new disease-specific lesions or only already known ones. These were nosographically defined by individual mutations in hitherto congenital myopathies-unrelated genes. This latter development may also affect the nomenclature of congenital myopathies in that the mutant gene needs to be attached to the individually identified congenital myopathies with or without the disease-specific lesion, such as CCD-RYR1 or CM-RYR1. This principle is similar to that of the nomenclature of Congenital Disorders of Glycosylation. Retroactive molecular characterization of originally and first described congenital myopathies has only rarely been achieved.

Congenital myopathies.

The congenital myopathies are inherited muscle disorders characterized clinically by hypotonia and weakness, usually from birth, with a static or slowly progressive clinical course. Historically, the congenital myopathies have been classified according to major morphological features seen on muscle biopsy as nemaline myopathy, central core disease, centronuclear or myotubular myopathy, and congenital fiber type disproportion. However, in the past two decades, the genetic basis of these different forms of congenital myopathy has been further elucidated with the result being improved correlation with histological and genetic characteristics. However, these notions have been challenged for three reasons. First, many of the congenital myopathies can be caused by mutations in more than one gene that suggests an impact of genetic heterogeneity. Second, mutations in the same gene can cause different muscle pathologies. Third, the same genetic mutation may lead to different pathological features in members of the same family or in the same individual at different ages. This chapter provides a clinical overview of the congenital myopathies and a clinically useful guide to its genetic basis recognizing the increasing reliance of exome, subexome, and genome sequencing studies as first-line analysis in many patients.

Aberrations in Energetic Metabolism and Stress-Related Pathways Contribute to Pathophysiology in the Neb Conditional Knockout Mouse Model of Nemaline Myopathy.

Nemaline myopathy (NM) is a genetically and clinically heterogeneous disease that is diagnosed on the basis of the presence of nemaline rods on skeletal muscle biopsy. Although NM has typically been classified by causative genes, disease severity or prognosis cannot be predicted. The common pathologic end point of nemaline rods (despite diverse genetic causes) and an unexplained range of muscle weakness suggest that shared secondary processes contribute to the pathogenesis of NM. We speculated that these processes could be identified through a proteome-wide interrogation using a mouse model of severe NM in combination with pathway validation and structural/functional analyses. A proteomic analysis was performed using skeletal muscle tissue from the Neb conditional knockout mouse model compared with its wild-type counterpart to identify pathophysiologically relevant biological processes that might impact disease severity or provide new treatment targets. A differential expression analysis and Ingenuity Pathway Core Analysis predicted perturbations in several cellular processes, including mitochondrial dysfunction and changes in energetic metabolism and stress-related pathways. Subsequent structural and functional studies demonstrated abnormal mitochondrial distribution, decreased mitochondrial respiratory function, an increase in mitochondrial transmembrane potential, and extremely low ATP content in Neb conditional knockout muscles relative to wild type. Overall, the findings of these studies support a role for severe mitochondrial dysfunction as a novel contributor to muscle weakness in NM.

Novel p.Asp27Glu ACTA1 variant features congenital myopathy with finger flexor weakness, cardiomyopathy, and cardiac conduction defects.

Pathogenic variants in the skeletal muscle α-actin 1 gene (ACTA1) cause a spectrum of myopathies with clinical and myopathological diversity. Clinical presentations occur from the prenatal period to adulthood, commonly with proximal-predominant weakness and rarely preferential distal weakness. Myopathological findings are wide-ranging, with nemaline rods being most frequent. Associated cardiomyopathy is rare and conduction defects are not reported. We describe a family with congenital myopathy with prominent finger flexor weakness and cardiomyopathy with cardiac conduction defects. The proband, a 48-year-old Caucasian male, his 73-year-old mother, 41-year-old sister, and 19-year-old nephew presented with prominent finger flexor weakness on a background of neonatal hypotonia and delayed motor milestones. All had progressive cardiomyopathy with systolic dysfunction and/or left ventricular dilation. The proband and sister had intraventricular conduction delay and left anterior fascicular block, respectively. The mother had atrial fibrillation. Muscle biopsy in the proband and sister demonstrated congenital fiber-type disproportion and rare nemaline rods in the proband. A novel dominant variant in ACTA1 (c.81C>A, p.Asp27Glu) segregated within the family. This family expands the genotypic and phenotypic spectrum of ACTA1-related myopathy, highlighting preferential finger flexor involvement with cardiomyopathy and conduction disease. We emphasize early and ongoing cardiac surveillance in ACTA1-related myopathy.

A new homozygous missense variant in LMOD3 gene causing mild nemaline myopathy with prominent facial weakness.

Nemaline myopathy (NEM) type 10, caused by biallelic mutations in LMOD3, is a severe congenital myopathy clinically characterized by generalized hypotonia and muscle weakness, respiratory insufficiency, joint contractures, and bulbar weakness. Here, we describe a family with two adult patients presenting mild nemaline myopathy due to a novel homozygous missense variant in LMOD3. Both patients presented mild delayed motor milestones, frequent falls during infancy, prominent facial weakness and mild muscle weakness in the four limbs. Muscle biopsy showed mild myopathic changes and small nemaline bodies in a few fibers. A neuromuscular gene panel revealed a homozygous missense variant in LMOD3 that co-segregated with the disease in the family (NM_198271.4: c.1030C>T; p.Arg344Trp). The patients described here provide evidence of the phenotype-genotype correlation, suggesting that non-truncating variants in LMOD3 lead to milder phenotypes of NEM type 10.

ACTA1 H40Y mutant iPSC-derived skeletal myocytes display mitochondrial defects in an in vitro model of nemaline myopathy.

Nemaline myopathies (NM) are a group of congenital myopathies that lead to muscle weakness and dysfunction. While 13 genes have been identified to cause NM, over 50% of these genetic defects are due to mutations in nebulin (NEB) and skeletal muscle actin (ACTA1), which are genes required for normal assembly and function of the thin filament. NM can be distinguished on muscle biopsies due to the presence of nemaline rods, which are thought to be aggregates of the dysfunctional protein. Mutations in ACTA1 have been associated with more severe clinical disease and muscle weakness. However, the cellular pathogenesis linking ACTA1 gene mutations to muscle weakness are unclear To evaluate cellular disease phenotypes, iPSC-derived skeletal myocytes (iSkM) harboring an ACTA1 H40Y point mutation were used to model NM in skeletal muscle. These were generated by Crispr-Cas9, and include one non-affected healthy control (C) and 2 NM iPSC clone lines, therefore representing isogenic controls. Fully differentiated iSkM were characterized to confirm myogenic status and subject to assays to evaluate nemaline rod formation, mitochondrial membrane potential, mitochondrial permeability transition pore (mPTP) formation, superoxide production, ATP/ADP/phosphate levels and lactate dehydrogenase release. C- and NM-iSkM demonstrated myogenic commitment as evidenced by mRNA expression of Pax3, Pax7, MyoD, Myf5 and Myogenin; and protein expression of Pax4, Pax7, MyoD and MF20. No nemaline rods were observed with immunofluorescent staining of NM-iSkM for ACTA1 or ACTN2, and these mRNA transcript and protein levels were comparable to C-iSkM. Mitochondrial function was altered in NM, as evidenced by decreased cellular ATP levels and altered mitochondrial membrane potential. Oxidative stress induction revealed the mitochondrial phenotype, as evidenced by collapsed mitochondrial membrane potential, early formation of the mPTP and increased superoxide production. Early mPTP formation was rescued with the addition of ATP to media. Together, these findings suggest that mitochondrial dysfunction and oxidative stress are disease phenotypes in the in vitro model of ACTA1 nemaline myopathy, and that modulation of ATP levels was sufficient to protect NM-iSkM mitochondria from stress-induced injury. Importantly, the nemaline rod phenotype was absent in our in vitro model of NM. We conclude that this in vitro model has the potential to recapitulate human NM disease phenotypes, and warrants further study.

NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy.

Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients' muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin-deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin-deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.

Early clinical and pre-clinical therapy development in Nemaline myopathy.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.

Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.

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

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.

Coexisting sporadic late onset nemaline myopathy and AL amyloid myopathy - incidental or related?

Sporadic late onset nemaline myopathy (SLONM) and amyloid myopathy are frequently unrecognized acquired and treatable myopathies, which classically present with rapidly progressive and severe proximal muscle weakness. We report a case of SLONM and amyloid myopathy associated with IgM lambda monoclonal gammopathy in a 77-year-old Caucasian man. Creatine kinase (CK) was mildly elevated. Myositis panel was negative. Electromyogram showed prominent fibrillation potentials and positive sharp waves with myopathic motor unit action potentials. Muscle biopsy revealed nemaline rods and amyloid deposits with characteristic apple-green birefringence under polarized light, and liquid chromatography tandem mass spectroscopy detected a peptide profile consistent with AL (lambda) type amyloid deposition. Genetic testing for congenital nemaline rod myopathy was negative. The patient was treated with dexamethasone and chemotherapy x3 cycles with very good partial remission. CK and lambda light chain normalized. Our case emphasizes the importance of completing a thorough histochemical and pathological evaluation by muscle biopsy analysis, to provide timely and optimal treatment of these conditions.

Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).

Nemaline myopathies (NEMs) are genetically and clinically heterogenous. Biallelic or monoallelic variants in TNNT1, encoding slow skeletal troponin T1 (TnT1), cause NEM. We report a 2-year-old patient and his mother carrying the heterozygous TNNT1 variant c.194A>C/p.(Asp65Ala) that occurred de novo in the mother. Both had muscle hypotrophy and muscle weakness. Muscle pathology in the proband's mother revealed slow twitch type 1 fiber hypotrophy and fast twitch type 2 fiber hypertrophy that was confirmed by a reduced ratio of slow skeletal myosin to fast skeletal myosin type 2a. Reverse transcription polymerase chain reaction and immunoblotting data demonstrated increased levels of high-molecular-weight TnT1 isoforms in skeletal muscle of the proband's mother that were also observed in some controls. In an overexpression system, complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced. The previously reported TnT1-E104V and TnT1-L96P mutants showed reduced or no co-immunoprecipitation with TPM3. Our studies support pathogenicity of the TNNT1 p.(Asp65Ala) variant.

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

BACKGROUND: Neuromuscular 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 PRESENTATION: A 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). CONCLUSION: The 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.

Clinical and genetic features of infancy-onset congenital myopathies from a Chinese paediatric centre.

BACKGROUND: Congenital myopathies are a group of rare neuromuscular diseases characterized by specific histopathological features. The relationship between the pathologies and the genetic causes is complex, and the prevalence of myopathy-causing genes varies among patients from different ethnic groups. The aim of the present study was to characterize congenital myopathies with infancy onset among patients registered at our institution. METHOD: This retrospective study enrolled 56 patients based on the pathological and/or genetic diagnosis. Clinical, histopathological and genetic features of the patients were analysed with long-term follow-up. RESULTS: Twenty-six out of 43 patients who received next-generation sequencing had genetic confirmation, and RYR1 variations (12/26) were the most prevalent. Eighteen novel variations were identified in 6 disease-causing genes, including RYR1, NEB, TTN, TNNT1, DNM2 and ACTA1. Nemaline myopathy (17/55) was the most common histopathology. The onset ages ranged from birth to 1 year. Thirty-one patients were followed for 3.83 ± 3.05 years (ranging from 3 months to 11 years). No patient died before 1 year. Two patients died at 5 years and 8 years respectively. The motor abilities were stable or improved in 23 patients and deteriorated in 6 patients. Ten (10/31) patients developed respiratory involvement, and 9 patients (9/31) had mildly abnormal electrocardiograms and/or echocardiograms. CONCLUSION: The severity of congenital myopathies in the neonatal/infantile period may vary in patients from different ethnic groups. More concern should be given to cardiac monitoring in patients with congenital myopathies even in those with static courses.

A homozygous CAP2 pathogenic variant in a neonate presenting with rapidly progressive cardiomyopathy and nemaline rods.

Nemaline Myopathy (NM) is a disorder of skeletal muscles caused by mutations in sarcomere proteins and characterized by accumulation of microscopic rod or thread-like structures (nemaline bodies) in skeletal muscles. Patients diagnosed with both NM and infantile cardiomyopathy are very rare. A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction. A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods. Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs. Both parents were heterozygous for the same variant but have no history of heart or muscle disease. Analysis of patient derived fibroblasts and cardiomyocytes derived from induced pluripotent stem cells confirmed the p.C430fs mutation (pathogenic variant), which appears to cause loss of both CAP2 protein and mRNA. The CAP2 gene encodes cyclase associated protein 2, an actin monomer binding and filament depolymerizing protein and CAP2 knockout mice develop severe dilated cardiomyopathy and muscle weakness. The patient underwent a heart transplant at 1 year of age. Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure. Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring. This is the first description of a patient presenting with nemaline myopathy associated with a pathogenic variant of CAP2.

An autopsied case of ADSSL1 myopathy.

ADSSL1 myopathy is an inherited myopathy with limb weakness, respiratory muscle paralysis, dysphagia, and myocardial symptoms. We present an autopsy case of a 66-year-old male carrying compound heterozygous variants c.781G>A (p.D261N) and c.919delA (p.I307fs) in ADSSL1. He had not run fast since school with no family history. He showed a gradual progression of limb weakness and developed dyspnoea, dysphagia, and Brugada syndrome at the age of 56. The magnetic resonance imaging (MRI) revealed bright tongue sign. Muscle biopsy showed only chronic myopathic changes. He died of respiratory muscle weakness at the age of 66. Autopsy revealed that there were many fibres with vacuoles and nemaline rods in the biceps brachii, tongue, diaphragm, and iliopsoas. Many lipopigments and nuclear clumps were also detected. The myocardium and central nervous system had only nonspecific age-related changes. This is the first autopsied case to clarify the terminal state of ADSSL1 myopathy.

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

Sporadic 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.

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.