RESUMO
Anti-HMGCR myopathy is decribed as an immune-mediated necrotizing myopathy which is characterised by subacute, progressive proximal muscle weakness and elevated creatine kinase (CK) level. In pediatric population, anti-HMGCR myopathy has been reported solely as small case reports, albeit rare. Although treatment consensus has not yet been established, proper treatment with several immunomodulators to include IVIg can show remarkable improvement. We report an 11-year-old-girl diagnosed with anti-HMGCR myopathy with 6 years of follow-up.
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Doenças Musculares , Humanos , Criança , Feminino , Doenças Musculares/induzido quimicamente , Doenças Musculares/imunologia , Doenças Musculares/tratamento farmacológico , Seguimentos , Hidroximetilglutaril-CoA Redutases/imunologia , Autoanticorpos , Imunoglobulinas Intravenosas/uso terapêuticoRESUMO
Anti-Ku autoantibodies are associated with several autoimmune inflammatory diseases. We aimed to review our anti-Ku positive pediatric patients in this study. Four pediatric patients (all female) who had anti-Ku positivity were included (Patients 1-2-3 with idiopathic inflammatory myopathy (IIM); Patient 4 with chronic urticaria). Patient 1 (onset:10.5 years) had proximal muscle weakness, Raynaud phenomenon, sclerodactyly, hyperpigmentation, joint contracture, and tenosynovitis. The disease course was progressive despite treatment with corticosteroids, intravenous immunoglobulin (IVIG), plasma exchange, and 11 different immunosuppressive drugs. Patient 2 (onset:15 years) presented with proximal muscle weakness, fatigue, weight loss. She recovered normal muscle strength after treatment with corticosteroids, IVIG, methotrexate, cyclosporine A, mycophenolate mofetil. Patient 3 (onset:10 years) had juvenile dermatomyositis with proximal muscle weakness, Gottron's papules, and calcinosis. She also had anti-NXP2 positivity. Remission was achieved with corticosteroids, methotrexate, azathioprine, and infliximab. Muscle biopsy findings revealed a variable spectrum of necrosis, regeneration, perifascicular pattern, and inflammation. Patient 4 had only chronic urticaria (onset: 6.5 years). The striking features of this series were heterogeneity in clinical presentations including solely chronic urticaria and IIM; variable response to immunosuppressive treatments; and histopathology revealing a spectrum of necrosis, regeneration and inflammatory infiltration. Expanding the spectrum of anti-Ku positivity will allow better understanding of anti-Ku-associated phenotype clusters.
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Autoanticorpos , Autoantígeno Ku , Fenótipo , Humanos , Feminino , Adolescente , Criança , Autoantígeno Ku/imunologia , Autoanticorpos/sangue , Miosite/imunologia , Miosite/tratamento farmacológico , Urticária Crônica/tratamento farmacológico , Urticária Crônica/imunologiaAssuntos
Doenças Musculares , Humanos , Masculino , Feminino , Criança , Doenças Musculares/genética , Mutação , Idade de Início , LinhagemRESUMO
PURPOSE: Mutations in transforming growth factor beta-induced (TGFBI) protein are associated with a group of corneal dystrophies (CDs), classified as TGFBI-associated CDs, characterized by deposits in the cornea. Mouse models were not proper in several aspects for modelling human disease. The goal of this study was to generate zebrafish mutants to investigate the corneal phenotype and to decide whether zebrafish could be a potential model for TGFBI-associated CDs. METHODS: The conserved arginine residue, codon 117, in zebrafish tgfbi gene was targeted with Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 method. Cas9 VQR variant was used with two target-specific sgRNAs to generate mutations. The presence of mutations was evaluated by T7 Endonuclease Enzyme (T7EI) assay and the type of the mutations were evaluated by Sanger sequencing. The mutant zebrafish at 3 months and 1 year of age were investigated under the microscope for corneal opacity and eye sections were evaluated histopathologically with hematoxylin-eosin, masson-trichrome and congo red stains for corneal deposits. RESULTS: We achieved indel variation at the target sequence that resulted in p.Ser115_Arg117delinsLeu (c. 347_353delinsT) by nonhomology mediated repair in F1. This zebrafish mutation had the potential to mimic two disease-causing mutations reported in human cases previously: R124L and R124L + del125-126. Mutant zebrafish did not show any corneal opacity or corneal deposits at 3 months and 1 year of age. CONCLUSION: This study generated the first zebrafish model mimicking the R124 hot spot mutation in TGFBI-associated CDs. However, evaluations even at 1 year of age did not reveal any deposits in the cornea histopathologically. This study increased the cautions for modelling TGFBI-associated CDs in zebrafish in addition to differences in the corneal structure between zebrafish and humans.
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Distrofias Hereditárias da Córnea , Opacidade da Córnea , Animais , Humanos , Camundongos , Córnea/metabolismo , Distrofias Hereditárias da Córnea/genética , Opacidade da Córnea/metabolismo , Análise Mutacional de DNA , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Mutação , Linhagem , RNA Guia de Sistemas CRISPR-Cas , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Peixe-Zebra/genéticaRESUMO
BACKGROUND/OBJECTIVE: Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy is rare in children. Here, we present a boy with relapsing refractory anti-HMGCR myopathy along with a systematic literature review. CASE REPORT: 17-year-old boy with five years of muscle weakness, rash, high creatinine kinase (CK) levels, and muscle biopsy compatible with inflammatory myopathy was diagnosed with juvenile dermatomyositis. He was treated with corticosteroids, intravenous immunoglobulin (IVIG), and methotrexate. His muscle weakness improved with this treatment although never completely resolved. CK levels decreased from â¼15000 U/L to â¼3000 U/L. At the age of 15, muscle weakness relapsed after an upper respiratory tract infection; pulse corticosteroid treatment was administered. The re-evaluated muscle biopsy showed a necrotizing pattern and the HMGCR antibody was positive confirming anti-HMGCR myopathy when he was 16. The diagnostic delay was 50 months. Disease activity was monitored by Medical Research Council score, MRI and functional tests. Despite corticosteroids, methotrexate, IVIG, cyclosporine A, and rituximab therapies, muscle weakness improved only slightly during the first three months and remained stable afterwards.Results of the Literature Search:We identified 16 articles describing 50 children (76% female) with anti-HMGCR myopathy by reviewing the English literature up to March 1st, 2022. Proximal muscle weakness was the most common clinical symptom (70.8%). Corticosteroids (84.8%), IVIG (58.7%), and methotrexate (56.5%) were preferred in most cases. Complete remission was achieved in nine patients (28.1%). CONCLUSION: Diagnosis and management of children with anti-HMGCR myopathy are challenging. Complete remission is achieved in only one third of these patients. Imaging biomarkers may aid treatment.
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Doenças Musculares , Oxirredutases , Masculino , Humanos , Criança , Feminino , Adolescente , Oxirredutases/uso terapêutico , Coenzima A/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Metotrexato/uso terapêutico , Diagnóstico Tardio , Autoanticorpos , Doenças Musculares/patologia , Debilidade MuscularRESUMO
BACKGROUND/OBJECTIVES: The aim of our study is twofold: To evaluate the presentation, diagnosis, clinical course, and management of juvenile dermatomyositis (JDM) in children under three years of age, and to compare with older-onset patients. METHODS: Nine patients with early-onset, and 63 patients with older-onset JDM followed between December 2010 and April 2022 are included. We also reviewed the literature on early-onset JDM from the inceptions of the PubMed/MEDLINE and Scopus databases up to April 1st, 2022. RESULTS: Early-onset JDM patients were characterized by longer median diagnostic delay (p = 0.005), calcinosis (p = 0.006), anti-NXP2 antibody (p = 0.049). Diagnostic pathway included muscle biopsy (77.7% versus 50.8%). Muscle biopsy findings were more severe in the early-onset group (p<0.001). Although there was no difference in the partial and complete remission rates, the relapse rate was significantly higher in the early-onset group (p = 0.001), reflected to requirement of intravenous immunoglobulin (p = 0.001), cyclophosphamide (p = 0.011), and biological agents (p = 0.016). Literature search revealed 32 articles reporting 75 patients. The median diagnostic delay was 5 (1-30) months. Calcinosis was present in 29.5%. Twenty-three of the 44 patients (52.3%) had a muscle biopsy. Forty-one patients (64.1%) received second and third-line treatments. Complete remission was achieved in almost half of these patients (48.9%), but relapse was observed in 75%. The mortality rate was 10.2%. CONCLUSION: Diagnosis can be challenging and delayed in early-onset JDM patients. Compared to older-onset JDM patients, this group had higher relapse rate, more severe muscle biopsy findings, and received intensive immunosuppressive treatment.
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Calcinose , Dermatomiosite , Criança , Humanos , Pré-Escolar , Dermatomiosite/diagnóstico , Dermatomiosite/tratamento farmacológico , Centros de Atenção Terciária , Diagnóstico Tardio , Estudos Retrospectivos , Calcinose/diagnósticoRESUMO
BACKGROUND: Intestinal alkaline phosphatase (iAP) is an intestinal brush border enzyme that is one of the factors involved in the pathogenesis of inflammatory bowel disease (IBD). The aim of the study was to investigate the relationship between iAP enzyme and histological inflammatory activity in patients with IBD. METHODS: A total of 44 children were enrolled in this study including IBD patients (n=24; 12 Crohn`s disease [CD] and 12 ulcerative colitis [UC]) and controls (n=20). Anti-human iAP antibody stained ileocolonoscopic biopsy specimens were graded for the terminal ileum and each section of the colon. Hematoxylin-eosin stained sections were used to determine inflammatory activity. Histopathological findings were compared in pre- and post-treatment biopsies of each group and with the control group (CG). RESULTS: A low grade of iAP staining was detected in IBD patients compared to the CG (p=0.02). iAP was remarkably concentrated in the terminal ileum (TI) and especially in region 1, which involved the apical surface, brush border, and epithelial cells. A significant negative correlation was found between the grade of iAP staining and inflammatory activity both in pre- and post-treatment biopsies (p=0.02, p=0.008, respectively) in the terminal ileum of CD patients. Likewise, pre-treatment biopsies of UC and CD patients and biopsies of the CG were compared with each other according to the grade of iAP staining. There were significant negative correlations for CD patients compared to UC and the CG in region1 of TI, and regions 1 and 2 (lamina propria and goblet cells) of the colon (p= 0.015, p= 0.006, p < 0.001, respectively). CONCLUSIONS: As a histological marker, iAP can be of value in monitoring the histological activity of IBD, particularly in remarkable inflammation in the small intestine.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Criança , Fosfatase Alcalina , Mucosa Intestinal/patologiaRESUMO
INTRODUCTION/AIMS: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. METHODS: Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls. RESULTS: A significant decrease in IGF-I levels (mean ± SD: -1.39 ± 1.46 vs. 0.017 ± 0.83, p = .02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4 ng/mL vs. 1003.4 ± 274.3 ng/mL, p = .03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway. DISCUSSION: Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.
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Fator de Crescimento Insulin-Like I , Atrofia Muscular Espinal , Criança , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Receptor IGF Tipo 1 , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina , Atrofia Muscular Espinal/patologia , Fatores de Crescimento Neural/metabolismoRESUMO
AIM: We aimed to report a severe and rare pediatric rhabdomyolysis case associated with a dual viral infection. CASE: A 13 year-old, healthy girl presented with the complaints of fever, abdominal pain, weakness and dark-colored urine. She was diagnosed with rhabdomyolysis based on clinical signs and laboratory findings. The diagnosis was confirmed by serological tests and real-time polymerase chain reaction for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), respectively. Other potential genetic, metabolic and infectious causes were evaluated meticulously but no evidence was found. This case is also important as it is the first reported case to our knowledge on rhabdomyolysis associated with EBV and CMV co-infection in children. CONCLUSION: The presented case experienced tetraplegia due to the severe muscular damage and muscle power returned to normal range after 3 months. This suggests that EBV and CMV may have exert synergistic effects leading to more severe inflammation and degeneration.
Assuntos
Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Rabdomiólise , Adolescente , Citomegalovirus , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/diagnóstico , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Feminino , Herpesvirus Humano 4 , Humanos , Rabdomiólise/complicações , Rabdomiólise/diagnóstico , Rabdomiólise/terapiaRESUMO
Isolated deficiency of complex II is a rare inborn error of metabolism, accounting for approximately 2% of mitochondrial diseases. Mitochondrial complex II deficiency is predominantly seen in cases with bi-allelic SDHA mutations. To our knowledge, only 11 patients and five pathogenic variants have been reported for the SDHB gene. Our patient had a severe clinical presentation with seizures and sepsis, and died at the age of 2 months. Muscle biopsy analysis was compatible with mitochondrial myopathy with complex II deficiency. The family was given a molecular diagnosis for their child 2 years after his death via a clinical exome test of a frozen muscle biopsy specimen and a novel homozygous missense variant c.592 A>G (p.Ser198Gly) in SDHB gene was detected by next-generation sequencing. Here, we present another patient with a novel homozygous SDHB variant causing severe complex II deficiency and early death.
Assuntos
Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Succinato Desidrogenase/genética , Consanguinidade , Complexo II de Transporte de Elétrons/genética , Evolução Fatal , Humanos , Recém-Nascido , MasculinoRESUMO
Megaconial Congenital Muscular Dystrophy (CMD) is a rare autosomal recessive disorder characterized by enlarged mitochondria located mainly at the periphery of muscle fibers and caused by mutations in the Choline Kinase Beta (CHKB) gene. Although the pathogenesis of this disease is not well understood, there is accumulating evidence for the presence of mitochondrial dysfunction. In this study, we aimed to investigate whether imbalanced mitochondrial dynamics affects mitochondrial function and bioenergetic efficiency in skeletal muscle cells of Megaconial CMD. Immunofluorescence, confocal and transmission electron microscopy studies revealed impaired mitochondrial network, morphology, and localization in primary skeletal muscle cells of Megaconial CMD. The organelle disruption was specific only to skeletal muscle cells grown in culture. The expression levels of mitochondrial fission proteins (DRP1, MFF, FIS1) were found to be decreased significantly in both primary skeletal muscle cells and tissue sections of Megaconial CMD by Western blotting and/or immunofluorescence analysis. The metabolomic and fluxomic analysis, which were performed in Megaconial CMD for the first time, revealed decreased levels of phosphonucleotides, Krebs cycle intermediates, ATP, and altered energy metabolism pathways. Our results indicate that reduced mitochondrial fission and altered mitochondrial energy metabolism contribute to mitochondrial dysmorphology and dysfunction in the pathogenesis of Megaconial CMD.
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Metabolismo Energético , Dinâmica Mitocondrial , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofias Musculares/metabolismo , Células Cultivadas , Fluorescência , Humanos , Análise do Fluxo Metabólico , Metabolômica , Proteínas Mitocondriais/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/ultraestrutura , Músculo Esquelético/ultraestruturaRESUMO
Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
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Encefalite/genética , Doenças Mitocondriais/genética , Animais , Evolução Biológica , Sistemas CRISPR-Cas , Linhagem Celular , Encefalite/mortalidade , Feminino , Genes Recessivos , Glicogênio/metabolismo , Humanos , Inflamação/genética , Masculino , Proteínas de Membrana/genética , Doenças Mitocondriais/mortalidade , Linhagem , Convulsões/genética , Convulsões/mortalidade , Peixe-Zebra/genéticaRESUMO
The aim was to define the clinical and histopathologic findings of infants who underwent muscle biopsy and identify the diagnostic yield of muscle biopsy in this cohort. Infants who underwent muscle biopsy from January 2010 to March 2017 at a tertiary hospital were included in the study (N = 87; 64 boys (73.6%), 23 girls (26.4%); age range 0 - 2 years; mean age 9.73 ± 7.04 months). Clinical and histopathologic data were obtained from medical records. Developmental delay (64.4%) and hypotonia (59.8%) were the most frequent clinical findings, and mitochondrial disease (61%) was the most frequent clinical diagnosis, followed by muscular dystrophy (15.9%) and congenital myopathy (11.5%). Creatine kinase level was normal in 65.9% and > 1,000 U/L in 17.1%. Specific pathologic findings were identified from 38 biopsies (43.7%). The most frequent pathologic findings were features compatible with mitochondrial/metabolic myopathy (14 patients, 16.1%) and muscular dystrophy (12 patients, 13.8%). Myopathic changes were present in 7 biopsy samples (8.0%) and neurogenic changes in 5 (5.7%). The clinical and pathologic diagnoses were compatible in 24 patients (63.2%). The diagnostic yield of muscle biopsy remains significant, especially in this age group. Mitochondrial disease is a major diagnostic challenge, and muscle biopsy helps to support the clinical diagnosis and guide further studies.
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Doenças Mitocondriais/diagnóstico , Músculo Esquelético/patologia , Miotonia Congênita/diagnóstico , Biópsia , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/patologia , Miotonia Congênita/patologiaRESUMO
Desmin is a muscle-specific intermediate filament protein that has fundamental role in muscle structure and force transmission. Whereas human desmin protein is encoded by a single gene, two desmin paralogs (desma and desmb) exist in zebrafish. Desma and desmb show differential spatiotemporal expression during zebrafish embryonic and larval development, being similarly expressed in skeletal muscle until hatching, after which expression of desmb shifts to gut smooth muscle. We generated knockout (KO) mutant lines carrying loss-of-function mutations for each gene by using CRISPR/Cas9. Mutants are viable and fertile, and lack obvious skeletal muscle, heart or intestinal defects. In contrast to morphants, knockout of each gene did not cause any overt muscular phenotype, but did alter calcium flux in myofibres. These results point to a possible compensation mechanism in these mutant lines generated by targeting nonsense mutations to the first coding exon.
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Cálcio/metabolismo , Desmina/genética , Técnicas de Inativação de Genes , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Peixe-Zebra/genética , Animais , Sequência de Bases , Desmina/metabolismo , Embrião não Mamífero/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/ultraestrutura , Mutação/genética , Junção Neuromuscular/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/embriologiaRESUMO
Congenital myopathies (CMs) are a heterogeneous group of inherited muscle disorders characterized by muscle weakness at birth, while limb-girdle muscular dystrophies (LGMD) have a later onset and slower disease progression. Thus, detailed clinical phenotyping of genetically defined disease entities are required for the full understanding of genotype-phenotype correlations. A recently defined myopathic genetic disease entity is caused by bi-allelic variants in a gene coding for pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) with unknown substrates. Here, we present three patients from two consanguineous Turkish families with mild LGMD, facial weakness, normal CK levels, and slow progress. Genomic analyses revealed a homozygous known pathogenic missense variant (c.464A>G, p.Asn155Ser) in family 1 with two affected females. In the affected male of family 2, we found this variant in a compound heterozygous state together with a novel frameshift variant (c.329_332delTCTG, p.Leu112Valfs*8), which is the second frameshift variant known so far in PYROXD1. We have been able to define a large homozygous region in family 1 sharing a common haplotype with family 2 in the critical region. Our data suggest that c.464A>G is a Turkish founder mutation. To gain deeper insights, we performed a systematic review of all published PYROXD1-related myopathy cases. Our analysis showed that the c.464A > G variant was found in 87% (20/23) of the patients and that it may cause either a childhood- or adult-onset phenotype, irrespective of its presence in a homozygous or compound heterozygous state. Interestingly, only four patients had elevated CK levels (up to 1000 U/L), and cardiac involvement was found in few compound heterozygous cases.
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Debilidade Muscular/genética , Doenças Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Lactente , Recém-Nascido , Masculino , Debilidade Muscular/patologia , Doenças Musculares/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem , Fenótipo , Adulto JovemRESUMO
OBJECTIVES: In 2017, a new set of criteria was proposed by EULAR/ACR to classify idiopathic inflammatory myopathies. Our aim was to validate the EULAR/ACR 2017 classification criteria in juvenile dermatomyositis (JDM) patients. METHODS: This study was carried out at Hacettepe University Children's Hospital Department of Paediatrics, Divisions of Rheumatology, Neurology and Paediatric Pathology Unit. Control patients included inborn errors of metabolism presenting with myopathy and/or rhabdomyolysis, idiopathic rhabdomyolysis, dystrophinopathies, neuromyotonia and systemic rheumatic disorders. Patients' data were collected retrospectively from patient files. RESULTS: Fifty-eight JDM patients (60.3% female) and 40 controls (32.5% female) were included in this study. When the probability cut-off was set at 55% as recommended, the sensitivity/specificity of the new criteria to diagnose JDM were 96.5%/85% in the total cohort, 95.8%/84.6% without the muscle biopsy data and 97%/85.7% with biopsy data. With the ROC curve analysis, the optimal probability cut-off for the whole cohort was found to be >62%; providing a sensitivity/specificity of 96.6% (95% CI: 88.1% to 99.6)/90% (95% CI: 76.3% to 97.2%), and >68.5% for the patients with muscle biopsy providing sensitivity/specificity of 97% (84.7-99.9%)/100% (76.8-100%), respectively. The new EULAR/ACR criteria were the most sensitive, however, the least specific compared to the Tanimoto criteria (sensitivity/specificity 64%/97.5%) and Bohan-Peter criteria (sensitivity/ specificity 74.1%/92.5%). CONCLUSIONS: The new EULAR/ACR criteria performed favourably in our JDM cohort especially with the probability cut-off of >62%.
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Dermatomiosite , Miosite , Reumatologia , Criança , Dermatomiosite/diagnóstico , Dermatomiosite/epidemiologia , Feminino , Humanos , Masculino , Miosite/diagnóstico , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy of childhood. OBJECTIVE: To analyze clinical features, paraclinical examinations, MSAs, treatment response and long-term outcome in a JDM cohort METHODS: 58 patients (35F, 23 M) from a tertiary referral center in the last two decades are included. RESULTS: Mean age at onset was 8.1 ± 4.3, with a mean follow-up period of 5.66±3.59 years. Dermatological manifestations (91%) and muscle weakness (76%) were the key diagnostic elements. Elevated serum creatine kinase levels (86%), electromyography (23/25), muscle MRI (12/15), and muscle biopsy (n = 35) were compatible with the diagnosis. Out of 46 patients tested, 34 (76%) had autoantibodies, with NXP2 (21.7%), followed by TIF1g (17.4%), MDA5 (8.7%), and Mi-2 (8.7%). Presence of TIF1g and NXP2 indicated a severe course; and Ku a much severe course compared to previous studies. Corticosteroids (100%) combined with methotrexate (93%) was the initial treatment. Biological disease modifying anti-rheumatic drugs (DMARDs) were used in 22% of the cohort. Calcinosis (36%) was the most common long-term complication, associated with disease onset ≤6 years, higher muscle biopsy scores and MDA5 positivity. Complete remission was achieved in 65.5% of the patients in a median 24 (IQR 11.8-42.5) months with a relapse rate of 26.3%. 43.9% of NXP2 and 33.3% of TIF-1 g positive patients had a relapse. Course was monophasic (31%), polyphasic (17.2%), chronic (51.8%) without mortality. CONCLUSION: Integration of clinical features with laboratory and biopsy findings may help to predict prognosis and guide treatment in JDM. In our cohort calcinosis was associated with age, MDA5 autoantibodies, and muscle biopsy scores.
Assuntos
Dermatomiosite , Miosite , Autoanticorpos , Biópsia , Dermatomiosite/tratamento farmacológico , Humanos , MúsculosRESUMO
Juvenile dermatomyositis (JDM) is an inflammatory myopathy which causes severe morbidity and high mortality if untreated. In this study, we aimed to define the T-helper cell profile in the muscle biopsies of JDM patients. Muscle biopsies of twenty-six patients (50% female) were included in the study. Immunohistochemical expression of CD3, CD20, CD138, CD68, IL-17, Foxp3, IFN-É£, IFN-alpha and IL-4 was studied and muscle biopsies were scored using the JDM muscle biopsy scoring tool. Inflammatory cells were in small clusters in perimysium and perivascular area or scattered throughout the endomysium in most biopsies; however in 2 biopsies, lymphoid follicle-like big clusters were observed, and in one, there was a very dense and diffuse inflammatory infiltration nearly destroying all the muscle architecture. Seventy-three per cent of the biopsies had T cells, 88% had B cells, 57% had plasma cells, and all had macrophages. As for T-helper cell subtypes, 80% of the biopsies were Th1 positive, 92% Th17 positive and 30% Treg positive. No IL-4 positive inflammatory cell was detected, and only 2 biopsies showed IFN-alpha positivity. The mean JDM biopsy score was 17.6, meaning moderate to severe muscular involvement. Visual analogue score of the pathologist was strongly correlated with histopathological features. B cells, macrophages, plasma cells and T cells constitute the inflammatory milieu of the JDM muscle biopsies. As for T cells, JDM is a disease mainly related with Th1 and Th17 T-helper cell subtypes and to some extend Treg. Th2 cells are not involved in the pathogenesis.