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PURPOSE OF REVIEW: RYR1-related myopathy (RYR1-RM) is a group of myopathies caused by mutations in the RYR1 gene, which encodes the ryanodine receptor 1 (RYR1). This review discusses recent advances in the clinical features, pathology, pathogenesis, and therapeutics of RYR1-RM. RECENT FINDINGS: Although treatments such as salbutamol, pyridostigmine, and N-acetylcysteine have been explored as potential therapies for RYR1-RM, none have been conclusively proven to be effective. However, recent clinical trials of Rycal ARM210 in patients with RYR1-RM have shown promising results, including reduced fatigue and improved proximal muscle strength.Recent advances in three-dimensional structural analysis of RYR1 channels, facilitated by cryo-electron microscopy (cryo-EM), have elucidated the distinct molecular mechanisms underlying RYR1 functionality. Additionally, high-throughput screening methods, including FRET-based and endoplasmic reticulum Ca2+-based assays, have been successful in identifying potential candidates for the treatment of RYR1-RM. SUMMARY: Recent advances in clinical and pathological understanding have provided new insights into RYR1-RM. Novel pathomechanisms elucidated by cryo-EM and rapid screening methods have led to the identification of several promising drug candidates. We are hopeful about the potential of Rycal, other new drugs, and gene therapy, offering a promising outlook for the future.
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Glomerulonefrite , Infecções Estreptocócicas , Humanos , Infecções Estreptocócicas/complicações , Glomerulonefrite/complicações , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/etiologia , Criança , Masculino , Feminino , Vasoespasmo Intracraniano/diagnóstico por imagem , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/complicações , Imageamento por Ressonância MagnéticaAssuntos
Blefaroptose , Cefaleia , Síndrome de Tolosa-Hunt , Humanos , Síndrome de Tolosa-Hunt/diagnóstico , Síndrome de Tolosa-Hunt/complicações , Blefaroptose/etiologia , Blefaroptose/diagnóstico , Cefaleia/etiologia , Cefaleia/diagnóstico , Criança , Imageamento por Ressonância Magnética , Masculino , FemininoAssuntos
Dor Abdominal , Vômito , Humanos , Masculino , Vômito/etiologia , Dor Abdominal/etiologia , Dor Abdominal/diagnóstico , Pré-Escolar , Duodeno/diagnóstico por imagem , Duodeno/patologia , Estômago/diagnóstico por imagem , Estômago/patologia , Tomografia Computadorizada por Raios X , Dilatação PatológicaRESUMO
BACKGROUND AND OBJECTIVES: Oculopharyngodistal myopathy (OPDM) is an autosomal dominant myopathy clinically characterized by distal muscle weakness. Even though the identification of four causative genes, LRP12, GIPC1, NOTCH2NLC and RILPL1, it is unclear whether the myopathy progressed similarly among OPDM subtypes. We aimed to establish diagnostic clues in muscle imaging of OPDM in comparison with clinicopathologically similar oculopharyngeal muscular dystrophy (OPMD). METHODS: Axial muscle CT and/or T1-weighted MRI data from 54 genetically confirmed patients with OPDM (OPDM_LRP12; n = 43, OPDM_GIPC1; n = 6, OPDM_NOTCH2NLC; n = 5) and 57 with OPMD were evaluated. We scored the degree of fat infiltration in each muscle by modified Mercuri score and performed hierarchical clustering analyses to classify the patients and infer the pattern of involvement on progression. RESULTS: All OPDM subtypes showed a similar pattern of distribution in the affected muscles; soleus and medial gastrocnemius involved in the early stage, followed by tibialis anterior and extensor digitorum longus. For differentiating OPDM and OPMD, severely affected gluteus medius/minimus and adductor magnus was indicative of OPMD. DISCUSSION: We identified a diagnostic muscle involvement pattern in OPDM reflecting its natural history. The results of this study will help in the appropriate intervention based on the diagnosis of OPDM, including its stage.
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Doenças Musculares , Distrofia Muscular Oculofaríngea , Humanos , Distrofia Muscular Oculofaríngea/genética , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/genética , Progressão da DoençaRESUMO
Fukutin (FKTN) c.647+2084G>T creates a pseudo-exon with a premature stop codon, which causes Fukuyama congenital muscular dystrophy (FCMD). We aimed to ameliorate aberrant splicing of FKTN caused by this variant. We screened compounds focusing on splicing regulation using the c.647+2084G>T splicing reporter and discovered that the branchpoint, which is essential for splicing reactions, could be a potential therapeutic target. To confirm the effectiveness of branchpoints as targets for exon skipping, we designed branchpoint-targeted antisense oligonucleotides (BP-AONs). This restored normal FKTN mRNA and protein production in FCMD patient myotubes. We identified a functional BP by detecting splicing intermediates and creating BP mutations in the FKTN reporter gene; this BP was non-redundant and sufficiently blocked by BP-AONs. Next, a BP-AON was designed for a different FCMD-causing variant, which induces pathogenic exon trapping by a common SINE-VNTR-Alu-type retrotransposon. Notably, this BP-AON also restored normal FKTN mRNA and protein production in FCMD patient myotubes. Our findings suggest that BPs could be potential targets in exon-skipping therapeutic strategies for genetic disorders.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.
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Esclerose Lateral Amiotrófica , Distrofias Musculares , Doenças Neurodegenerativas , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Neurônios Motores/patologia , Distrofias Musculares/genética , Doenças Neurodegenerativas/genética , Proteína C9orf72/genética , Expansão das Repetições de DNA , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genéticaRESUMO
In this review, we focus on congenital myopathies, which are a genetically heterogeneous group of hereditary muscle diseases with slow or minimal progression. They are mainly defined and classified according to pathological features, with the major subtypes being core myopathy (central core disease), nemaline myopathy, myotubular/centronuclear myopathy, and congenital fiber-type disproportion myopathy. Recent advances in molecular genetics, especially next-generation sequencing technology, have rapidly increased the number of known causative genes for congenital myopathies; however, most of the diseases related to the novel causative genes are extremely rare. There remains no cure for congenital myopathies. However, there have been recent promising findings that could inform the development of therapy for several types of congenital myopathies, including myotubular myopathy, which indicates the importance of prompt and correct diagnosis. This review discusses the major causative genes (NEB, ACTA1, ADSSL1, RYR1, SELENON, MTM1, DNM2, and TPM3) for each subtype of congenital myopathies and the relevant latest findings.
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Miopatias Congênitas Estruturais , Humanos , Sequenciamento de Nucleotídeos em Larga Escala , Músculo Esquelético/patologia , Mutação , Miopatias Congênitas Estruturais/genética , TecnologiaRESUMO
Oculopharyngodistal myopathy (OPDM) and oculopharyngeal muscular dystrophy (OPMD) are similar and even believed to be indistinguishable in terms of their myopathological features. To address the diagnostic gap, we evaluated the muscle biopsy samples for p62 expression by immunohistochemistry and compared the occurrence and the frequency of intranuclear inclusions among the individuals with OPDM (harboring CGG repeat expansion in LRP12 (n = 19), GIPC1 (n = 6), or NOTCH2NLC (n = 7)), OPMD (n = 15), and other rimmed vacuolar myopathies. We found that myonuclei with p62-positive intra-nuclear inclusions (myo-INIs) were significantly more frequent in OPMD (11.9 ± 1.1%, range 5.9-18.6%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (0.9-1.5% on average, range 0.0-2.8%, p < 0.0001). In contrast, INIs in non-muscle cells such as blood vessels, peripheral nerve bundles, and muscle spindles (non-muscle-INIs) were present in OPDM, but absent in OPMD. These results indicate that OPMD can be differentiated from OPDM and other RVMs by the frequent presence of myo-INIs; and in OPDM, the presence of non-muscle-INIs in muscle pathology should be a diagnostic hallmark.
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Distrofia Muscular Oculofaríngea , Humanos , Distrofia Muscular Oculofaríngea/diagnóstico , Corpos de Inclusão IntranuclearRESUMO
BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and mild encephalopathy associated with excitotoxicity (MEEX) are the most frequent acute encephalopathies in pediatric patients in Japan. AESD typically presents with biphasic seizures and delayed reduced diffusion in the subcortical area, called bright tree appearance (BTA), on radiological examination. In patients with AESD, arterial spin labeling (ASL) shows decreased cerebral blood flow (CBF) in the hyperacute stage and increased CBF in the acute stage, suggesting the usefulness of ASL for the early diagnosis of AESD. Additionally, proton magnetic resonance spectroscopy (MRS) shows elevated glutamate (Glu) and glutamine (Gln) in AESD. MEEX is a group of mild encephalopathies with transient elevation of Gln on MRS similar to that in AESD; however, MEEX does not include any clinical biphasic course or abnormalities, including BTA on diffusion-weighted imaging. Although the usefulness of ASL for AESD has been reported, there are no reports for patients with MEEX. In this study, we report our experience with a 4-year-old girl diagnosed with MEEX who showed unique findings on ASL. CASE PRESENTATION: The patient was a 4-year-old girl admitted to the emergency room with febrile status epilepticus. Considering the possibility of AESD, vitamin therapy was initiated. ASL-MR imaging (MRI) of the brain performed on the second day showed increased blood flow in the frontal, temporal, and occipital regions with spared central sulcus, which indicated AESD with central sparing. The patient was diagnosed with AESD, and the treatment included pulse steroid therapy and immunoglobulin therapy from day 3. The patient remained mildly unconscious but gradually became conscious by day 7 with no seizures. Brain MRI performed on day 8 did not show any characteristic AESD findings, such as BTA. Furthermore, MRS showed elevated Gln, which, along with the clinical course, led to the diagnosis of MEEX. The patient was discharged on day 16 without obvious sequelae. CONCLUSIONS: ASL may be useful in the early diagnosis of MEEX as well as AESD, facilitating early intervention.
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Encefalopatias , Convulsões Febris , Feminino , Humanos , Criança , Lactente , Pré-Escolar , Marcadores de Spin , Encefalopatias/diagnóstico por imagem , Circulação Cerebrovascular , Imagem de Difusão por Ressonância Magnética , Convulsões Febris/diagnóstico , GlutaminaRESUMO
Purpose: To investigate the association of risk alleles in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) with complement activation products in the aqueous humor in eyes with neovascular age-related macular degeneration (nAMD) including polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and pachychoroid neovasculopathy (PNV). Design: Prospective, comparative, observational study. Participants: Treatment-naïve patients with nAMD and cataract patients as controls. Methods: The study included 236 eyes of 236 patients with nAMD and 49 control eyes of 49 patients. Aqueous humor samples were collected from 67 eyes with drusen-associated nAMD, 72 eyes with PCV, 26 eyes with RAP, and 71 eyes with PNV before intravitreal anti-VEGF injection and cataract surgery in the 49 control eyes. Clinical samples were measured for complement component 3a (C3a), C4a, and C5a using a bead-based immunoassay. Genotyping of the ARMS2 A69S (rs10490924), CFH I62V (rs800292), and CFH Y402H (rs1061170) was performed using TaqMan genotyping. Main Outcome Measures: The levels of complement activation products (C3a, C4a, and C5a) in the aqueous humor in each genotype of ARMS2 and CFH. Results: The C3a level in the aqueous humor was significantly elevated (P = 0.006) in patients with nAMD and the ARMS2 A69S risk allele, whereas the levels of the complement activation products were not associated with CFH I62V and Y402H genotypes. Among the control eyes, no significant differences were seen in any complement activation products for all genetic polymorphisms. The levels of the complement activation products in the aqueous humor of eyes with the nAMD subtypes for each genetic polymorphism did not show significant differences. Conclusions: The C3a concentration in the aqueous humor was significantly higher in Japanese nAMD patients with the ARMS2 A69S risk allele, whereas it was not elevated in the patients with CFH I62V. Age-related maculopathy susceptibility 2 A69S polymorphism is strongly associated with local complement activation in nAMD patients.
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PURPOSE: To investigate short-term treatment outcomes of intravitreal brolucizumab (IVBr) for treatment-naïve neovascular age-related macular degeneration (AMD) in a Japanese multicenter study. STUDY DESIGN: Retrospective case control study METHODS: The subjects were 58 eyes of 57 patients with neovascular AMD (43 men and 14 women, mean age 74.6 years) of whom 43 eyes of 42 patients completed initial loading of 3 monthly IVBr injections and were followed for more than 3 months. Best-corrected visual acuity (BCVA) changes, anatomical outcomes, and complications were investigated. RESULTS: Of the 43 eyes that completed loading doses, the AMD subtype was type 1 and type 2 macular neovascularization (MNV) in 51%, polypoidal choroidal vasculopathy (PCV) in 42%, and type 3 MNV in 7%. At 3 months after initiating treatment, BCVA significantly improved (P = 0.002) and central retinal thickness significantly decreased (P < 0.0001). At 3 months, complete retinal and subretinal fluid resolution was achieved in 91% of all eyes and complete regression of polypoidal lesions was achieved in 82% of PCV eyes. Iritis occurred in 8 eyes of 8 patients (14%), but resolved using topical or subtenon corticosteroid injection without visual loss in all cases. CONCLUSIONS: IVBr for treatment-naïve neovascular AMD was effective in the short-term, achieving significantly improved BCVA, good retinal fluid resolution, and a high rate of polypoidal lesion regression. However, iritis was noted in 14% of patients which may limit use of this drug.
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Anticorpos Monoclonais Humanizados , Corioide , Degeneração Macular Exsudativa , Idoso , Inibidores da Angiogênese , Anticorpos Monoclonais Humanizados/uso terapêutico , Corioide/irrigação sanguínea , Feminino , Angiofluoresceinografia/métodos , Humanos , Injeções Intravítreas , Japão/epidemiologia , Masculino , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin ß2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
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Esclerose Lateral Amiotrófica , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Distrofia Muscular Oculofaríngea , Esclerose Lateral Amiotrófica/genética , Animais , Mutação da Fase de Leitura , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Heterozigoto , Humanos , Distrofia Muscular Oculofaríngea/genéticaRESUMO
BACKGROUND/PURPOSE: Observation of choroidal thickness after anti-vascular endothelial growth factor (VEGF) therapy may be important for the ideal management of neovascular age-related macular degeneration (AMD). This study investigated changes in subfoveal choroidal thickness (SCT) during loading doses of intravitreal injections of brolucizumab in eyes with neovascular AMD. METHODS: This study included 73 eyes of 72 patients with neovascular AMD at five university hospitals in Japan. All 73 eyes underwent three monthly 6.0 mg intravitreal injections of brolucizumab at baseline, 1 month, and 2 months. The SCT at 3 months was evaluated using optical coherence tomography. RESULTS: The 73 eyes were classified into the treatment-naïve group (43 eyes) and the switched group (30 eyes) that were switched from other anti-VEGF treatments. After three intravitreal injections of brolucizumab, SCT significantly decreased from 236.5 ± 98.8 µm at baseline to 200.4 ± 98.3 µm at 3 months (percent of baseline 84.7%, P < 0.001) in the treatment-naïve group. In the switched group, SCT also significantly decreased from 229.0 ± 113.2 µm at baseline to 216.9 ± 110.2 µm at 3 months (percent of baseline 94.7%, P = 0.039), although the decrease was not as marked compared to that of the treatment-naïve group. CONCLUSION: Intravitreal injections of brolucizumab for neovascular AMD significantly reduced the SCT in both the treatment-naïve and switched groups. Brolucizumab may cause significant anatomic changes in the choroid, particularly in treatment-naïve AMD eyes, possibly more than that previously reported for other anti-VEGF agents.
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Inibidores da Angiogênese , Degeneração Macular Exsudativa , Anticorpos Monoclonais Humanizados , Corioide , Angiofluoresceinografia/métodos , Humanos , Injeções Intravítreas , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Fator A de Crescimento do Endotélio Vascular , Acuidade Visual , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
AIMS: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy. METHODS: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2). RESULTS: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy. CONCLUSION: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.
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Corpos de Inclusão Intranuclear , Distrofias Musculares , Biópsia , Humanos , Corpos de Inclusão Intranuclear/patologia , Distrofias Musculares/genética , Doenças NeurodegenerativasRESUMO
OBJECTIVES: The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis. METHODS: We performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing. RESULTS: A 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in TNNI1 in the family. DISCUSSION: The altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with TNNI2 variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a TNNI1 nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of TNNI1 in the disease.
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Histopathologic evaluation of muscle biopsy samples is essential for classifying and diagnosing muscle diseases. However, the numbers of experienced specialists and pathologists are limited. Although new technologies such as artificial intelligence are expected to improve medical reach, their use with rare diseases, such as muscle diseases, is challenging because of the limited availability of training datasets. To address this gap, we developed an algorithm based on deep convolutional neural networks (CNNs) and collected 4041 microscopic images of 1400 hematoxylin-and-eosin-stained pathology slides stored in the National Center of Neurology and Psychiatry for training CNNs. Our trained algorithm differentiated idiopathic inflammatory myopathies (mostly treatable) from hereditary muscle diseases (mostly non-treatable) with an area under the curve (AUC) of 0.996 and achieved better sensitivity and specificity than the diagnoses done by nine physicians under limited diseases and conditions. Furthermore, it successfully and accurately classified four subtypes of the idiopathic inflammatory myopathies with an average AUC of 0.958 and classified seven subtypes of hereditary muscle disease with an average AUC of 0.936. We also established a method to validate the similarity between the predictions made by the algorithm and the seven physicians using visualization technology and clarified the validity of the predictions. These results support the reliability of the algorithm and suggest that our algorithm has the potential to be used straightforwardly in a clinical setting.