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1.
Eur J Immunol ; 53(11): e2250326, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37562045

RESUMEN

We aimed to verify whether the immune system may represent a source of potential biomarkers for the stratification of immune-mediated necrotizing myopathies (IMNMs) subtypes. A group of 22 patients diagnosed with IMNM [7 with autoantibodies against signal recognition particle (SRP) and 15 against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR)] and 12 controls were included. A significant preponderance of M1 macrophages was observed in both SRP+ and HMGCR+ muscle samples (p < 0.0001 in SRP+ and p = 0.0316 for HMGCR+ ), with higher values for SRP+ (p = 0.01). Despite the significant increase observed in the expression of TLR4 and all endosomal Toll-like receptors (TLRs) at protein level in IMNM muscle tissue, only TLR7 has been shown considerably upregulated compared to controls at transcript level (p = 0.0026), whereas TLR9 was even decreased (p = 0.0223). Within IMNM subgroups, TLR4 (p = 0.0116) mRNA was significantly increased in SRP+ compared to HMGCR+ patients. Within IMNM group, only IL-7 was differentially expressed between SRP+ and HMGCR+ patients, with higher values in SRP+ patients (p = 0.0468). Overall, innate immunity represents a key player in pathological mechanisms of IMNM. TLR4 and the inflammatory cytokine IL-7 represent potential immune biomarkers able to differentiate between SRP+ and HMGCR+ patients.


Asunto(s)
Enfermedades Autoinmunes , Miositis , Humanos , Interleucina-7 , Músculo Esquelético/patología , Receptor Toll-Like 4/genética , Miositis/diagnóstico , Miositis/patología , Autoanticuerpos , Biomarcadores , Partícula de Reconocimiento de Señal , Necrosis/patología
2.
Int J Mol Sci ; 25(5)2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38473988

RESUMEN

Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting the quadriceps, deep finger flexors, and foot extensors. At present, there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathological phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and the accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis, including environmental factors, autoimmunity, abnormalities of protein transcription and processing, the accumulation of several toxic proteins, the impairment of autophagy and the ubiquitin-proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has also been proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging.


Asunto(s)
Miositis por Cuerpos de Inclusión , Humanos , Anciano , Miositis por Cuerpos de Inclusión/genética , Linfocitos T CD8-positivos/metabolismo , Inflamación/complicaciones , Envejecimiento , Proteínas , Miocardio/metabolismo
3.
Curr Issues Mol Biol ; 45(4): 2847-2860, 2023 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-37185710

RESUMEN

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

4.
Clin Genet ; 104(6): 705-710, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37553249

RESUMEN

Missense mutations in MYOT encoding the sarcomeric Z-disk protein myotilin cause three main myopathic phenotypes including proximal limb-girdle muscular dystrophy, spheroid body myopathy, and late-onset distal myopathy. We describe a family carrying a heterozygous MYOT deletion (Tyr4_His9del) that clinically was characterized by an early-adult onset distal muscle weakness and pathologically by a myofibrillar myopathy (MFM). Molecular modeling of the full-length myotilin protein revealed that the 4-YERPKH-9 amino acids are involved in local interactions within the N-terminal portion of myotilin. Injection of in vitro synthetized mutated human MYOT RNA or of plasmid carrying its cDNA sequence in zebrafish embryos led to muscle defects characterized by sarcomeric disorganization of muscle fibers and widening of the I-band, and severe motor impairments. We identify MYOT novel Tyr4_His9 deletion as the cause of an early-onset MFM with a distal myopathy phenotype and provide data supporting the importance of the amino acid sequence for the structural role of myotilin in the sarcomeric organization of myofibers.


Asunto(s)
Miopatías Distales , Proteínas Musculares , Adulto , Animales , Humanos , Conectina/genética , Proteínas de Microfilamentos/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Mutación , Pez Cebra
5.
Int J Mol Sci ; 24(14)2023 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-37511242

RESUMEN

Myofibrillar myopathies (MFMs) are a group of hereditary neuromuscular disorders sharing common histological features, such as myofibrillar derangement, Z-disk disintegration, and the accumulation of degradation products into protein aggregates. They are caused by mutations in several genes that encode either structural proteins or molecular chaperones. Nevertheless, the mechanisms by which mutated genes result in protein aggregation are still unknown. To unveil the role of myotilin and αB-crystallin in the pathogenesis of MFM, we injected zebrafish fertilized eggs at the one-cell stage with expression plasmids harboring cDNA sequences of human wildtype or mutated MYOT (p.Ser95Ile) and human wildtype or mutated CRYAB (p.Gly154Ser). We evaluated the effects on fish survival, motor behavior, muscle structure and development. We found that transgenic zebrafish showed morphological defects that were more severe in those overexpressing mutant genes. which developed a myopathic phenotype consistent with that of human myofibrillar myopathy, including the formation of protein aggregates. Results indicate that pathogenic mutations in myotilin and αB-crystallin genes associated with MFM cause a structural and functional impairment of the skeletal muscle in zebrafish, thereby making this non-mammalian organism a powerful model to dissect disease pathogenesis and find possible druggable targets.


Asunto(s)
Cristalinas , Miopatías Estructurales Congénitas , Animales , Humanos , Cadena B de alfa-Cristalina/genética , Cadena B de alfa-Cristalina/metabolismo , Cristalinas/genética , Músculo Esquelético/patología , Mutación , Miofibrillas/metabolismo , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/metabolismo , Agregado de Proteínas , Pez Cebra/genética
6.
Neurogenetics ; 23(1): 19-25, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34608571

RESUMEN

Familial periodic paralyses (PPs) are inherited disorders of skeletal muscle characterized by recurrent episodes of flaccid muscle weakness. PPs are classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. HypoPP is an autosomal dominant disease caused by mutations in the CACNA1S gene, encoding for Cav1.1 channel (HypoPP-1), or SCN4A gene, encoding for Nav1.4 channel (HypoPP-2). In the present study, we included 60 patients with a clinical diagnosis of HypoPP. Fifty-one (85%) patients were tested using the direct sequencing (Sanger method) of all reported HypoPP mutations in CACNA1S and SCN4A genes; the remaining 9 (15%) patients were analyzed through a next-generation sequencing (NGS) panel, including the whole CACNA1S and SCN4A genes, plus other genes rarely associated to PPs. Fifty patients resulted mutated: 38 (76%) cases showed p.R528H and p.R1239G/H CACNA1S mutations and 12 (24%) displayed p.R669H, p.R672C/H, p.R1132G/Q, and p.R1135H SCN4A mutations. Forty-one mutated cases were identified among the 51 patients managed with Sanger sequencing, while all the 9 cases directly analyzed with the NGS panel showed mutations in the hotspot regions of SCN4A and CACNA1S. Ten out of the 51 patients unresolved through the Sanger sequencing were further analyzed with the NGS panel, without the detection of any mutation. Hence, our data suggest that in HypoPP patients, the extension of genetic analysis from the hotspot regions using the Sanger method to the NGS sequencing of the entire CACNA1S and SCN4A genes does not lead to the identification of new pathological mutations.


Asunto(s)
Parálisis Periódica Hipopotasémica , Canales de Calcio Tipo L/genética , Pruebas Genéticas , Humanos , Parálisis Periódica Hipopotasémica/genética , Parálisis Periódica Hipopotasémica/patología , Músculo Esquelético/patología , Mutación , Canal de Sodio Activado por Voltaje NAV1.4/genética
7.
Eur J Neurosci ; 56(3): 4214-4223, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35666680

RESUMEN

Two likely causative mutations in the RYR1 gene were identified in two patients with myopathy with tubular aggregates, but no evidence of cores or core-like pathology on muscle biopsy. These patients were clinically evaluated and underwent routine laboratory investigations, electrophysiologic tests, muscle biopsy and muscle magnetic resonance imaging (MRI). They reported stiffness of the muscles following sustained activity or cold exposure and had serum creatine kinase elevation. The identified RYR1 mutations (p.Thr2206Met or p.Gly2434Arg, in patient 1 and patient 2, respectively) were previously identified in individuals with malignant hyperthermia susceptibility and are reported as causative according to the European Malignant Hyperthermia Group rules. To our knowledge, these data represent the first identification of causative mutations in the RYR1 gene in patients with tubular aggregate myopathy and extend the spectrum of histological alterations caused by mutation in the RYR1 gene.


Asunto(s)
Hipertermia Maligna , Miopatías Estructurales Congénitas , Humanos , Hipertermia Maligna/genética , Hipertermia Maligna/patología , Músculo Esquelético/patología , Mutación/genética , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Canal Liberador de Calcio Receptor de Rianodina/genética
8.
Int J Mol Sci ; 23(23)2022 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-36498898

RESUMEN

OBJECTIVE: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants. METHODS: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression. RESULTS: In Step I, we identified variants in COLVI-related genes in 48 patients, of which three were homozygous variants (Group 1). Then, we sorted variants according to their CADD score, clinical data and complementary studies (such as muscle and skin biopsy, study of expression of COLVI on fibroblast or muscle and muscle magnetic resonance). We finally assessed how potentially pathogenic variants (two biallelic and 12 monoallelic) destabilize COL6A1-A2-A3 subunits. Overall, 15 out of 512 patients were prioritized according to this pipeline. In seven of them, we confirmed reduced or absent immunocytochemical expression of collagen VI in cultured skin fibroblasts or in muscle tissue. CONCLUSIONS: In a real-world diagnostic scenario applied to heterogeneous neuromuscular conditions, a multistep integration of clinical and molecular data allowed the identification of about 3% of those patients harboring pathogenetic collagen VI variants.


Asunto(s)
Colágeno Tipo VI , Enfermedades Neuromusculares , Humanos , Colágeno Tipo VI/genética , Colágeno Tipo VI/metabolismo , Enfermedades Neuromusculares/epidemiología , Enfermedades Neuromusculares/genética , Homocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Músculos/metabolismo , Mutación
9.
Muscle Nerve ; 64(5): 567-575, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34368974

RESUMEN

INTRODUCTION/AIMS: Stromal interaction molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. In this study we aimed to expand the features related to new variants in STIM1. METHODS: We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited at five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel. RESULTS: We identified seven individuals (age range, 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain, and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism, and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients. DISCUSSION: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas , Miopatías Estructurales Congénitas , Trastornos de las Plaquetas Sanguíneas/genética , Trastornos de las Plaquetas Sanguíneas/metabolismo , Trastornos de las Plaquetas Sanguíneas/patología , Calcio/metabolismo , Estudios Transversales , Humanos , Miosis/genética , Miosis/metabolismo , Miosis/patología , Miopatías Estructurales Congénitas/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/metabolismo
10.
Neurol Sci ; 42(7): 2819-2827, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33170376

RESUMEN

BACKGROUND: Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype. METHODS: We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM. RESULTS: In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement. CONCLUSIONS: Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations.


Asunto(s)
Miopatías Estructurales Congénitas , Agregado de Proteínas , Femenino , Humanos , Mutación/genética , Miopatías Estructurales Congénitas/genética , Fenotipo , Secuenciación del Exoma
11.
Clin Neuropathol ; 40(6): 310-318, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34281632

RESUMEN

AIM: Since the immune system plays a role in the pathogenesis of several muscular dystrophies, we aim to characterize several muscular inflammatory features in α- (LGMD R3) and γ-sarcoglycanopathies (LGMD R5). MATERIALS AND METHODS: We explored the expression of major histocompatibility complex class I molecules (MHCI), and we analyzed the composition of the immune infiltrates in muscle biopsies from 10 patients with LGMD R3 and 8 patients with LGMD R5, comparing the results to Duchenne muscular dystrophy patients (DMD). RESULTS: A consistent involvement of the immune response was observed in sarcoglycanopathies, although it was less evident than in DMD. LGMD R3-R5 and DMD shared an abnormal expression of MHCI, and the composition of the muscular immune cell infiltrate was comparable. CONCLUSION: These findings might serve as a rationale to fine-tune a disease-specific immunomodulatory regimen, particularly relevant in view of the rapid development of gene therapy for sarcoglycanopathies.


Asunto(s)
Distrofias Musculares , Miositis , Sarcoglicanopatías , Biopsia , Humanos , Músculo Esquelético , Sarcoglicanopatías/genética
12.
Neurogenetics ; 21(2): 87-96, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31900734

RESUMEN

Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the "Nationwide Italian Collaborative Network of Mitochondrial Diseases" (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5-92 years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19 years (range, 0.2-68; < 3 years in 14/97 (14%), 3-19 years in 36/97 (37%), > 19 years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50-100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification.


Asunto(s)
Epilepsia/epidemiología , Enfermedades Mitocondriales/epidemiología , Convulsiones/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios Transversales , Epilepsia/complicaciones , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Estudios Retrospectivos , Convulsiones/complicaciones , Encuestas y Cuestionarios , Adulto Joven
13.
Muscle Nerve ; 60(5): 586-590, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31443116

RESUMEN

BACKGROUND: Several viruses have been described as causes of acquired inflammatory myopathies; however, the mechanisms by which they cause muscle disease are still unclear. The aim of this study was to describe the laboratory features of benign acute myositis in a small case series. METHODS: A detailed pathological and serological analysis was performed in five African migrants who developed an acute viral myositis complicated by rhabdomyolysis. RESULTS: Muscle biopsies clearly documented an inflammatory myopathy with histological features similar to polymyositis including CD8+ T cells surrounding and invading nonnecrotic muscle fibers, CD68+ macrophages and major histocompatibility complex class I antigen upregulation. In addition, positivity for myositis-specific antibodies (MSA), in particular anti-aminoacyl tRNA synthetases, was found in the serum of two patients. CONCLUSIONS: Our study demonstrated that T-cell mediated injury occurs in muscle of patients with acute viral myositis, and that MSA may be present in the serum of these patients.


Asunto(s)
Autoanticuerpos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Macrófagos/inmunología , Miositis/inmunología , Virosis/inmunología , Adolescente , Aminoacil-ARNt Sintetasas/inmunología , Anticuerpos Antivirales/inmunología , Camerún/etnología , Côte d'Ivoire/etnología , Creatina Quinasa/sangre , Emigrantes e Inmigrantes , Ghana/etnología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Italia , Masculino , Miositis/complicaciones , Miositis/patología , Miositis/fisiopatología , Nigeria/etnología , Rabdomiólisis/sangre , Rabdomiólisis/etiología , Partícula de Reconocimiento de Señal/inmunología , Virosis/complicaciones , Virosis/patología
14.
Mov Disord ; 29(6): 722-8, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24510442

RESUMEN

Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases," we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as "the MERRF mutation"). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term "myoclonic epilepsy" seems inadequate and potentially misleading.


Asunto(s)
Enfermedades Mitocondriales/complicaciones , Mioclonía/epidemiología , Mioclonía/etiología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto Joven
15.
Neurology ; 103(4): e209697, 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39102614

RESUMEN

BACKGROUND AND OBJECTIVES: The diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases. METHODS: Patients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network. RESULTS: Data regarding 132 patients with MFM (mean age 57.0 ± 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 ± 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6-related and PLIN4-related myopathies, with the risk of losing ambulation during the disease course. DISCUSSION: The Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.


Asunto(s)
Miopatías Distales , Miopatías Estructurales Congénitas , Humanos , Femenino , Masculino , Persona de Mediana Edad , Italia , Adulto , Miopatías Distales/genética , Miopatías Distales/patología , Miopatías Distales/epidemiología , Estudios Retrospectivos , Anciano , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología
16.
Mol Cell Proteomics ; 10(4): M110.002964, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21156839

RESUMEN

Mitochondrial diseases (MD) are heterogeneous disorders because of impairment of respiratory chain function leading to oxidative stress. We hypothesized that in MD the vascular endothelium may be affected by increased oxidative/nitrative stress causing a reduction of nitric oxide availability. We therefore, investigated the pathobiology of vasculature in MD patients by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins which undergo tyrosine nitration. We then measured the flow-mediated vasodilatation as a proof of altered nitric oxide generation/bioactivity. Here, we show that 3-nitrotyrosine staining is specifically located in the small vessels of muscle tissue and that the reaction is stronger and more evident in a significant percentage of vessels from MD patients as compared with controls. Eleven specific proteins which are nitrated under pathological conditions were identified; most of them are involved in energy metabolism and are located mainly in mitochondria. In MD patients the flow-mediated vasodilatation was reduced whereas baseline arterial diameters, blood flow velocity and endothelium-independent vasodilatation were similar to controls. The present results provide evidence that in MD the vessel wall is a target of increased oxidative/nitrative stress.


Asunto(s)
Síndrome MELAS/metabolismo , Síndrome MERRF/metabolismo , Músculo Esquelético/irrigación sanguínea , Tirosina/análogos & derivados , Adolescente , Adulto , Anciano , Secuencia de Bases , Arteria Braquial/fisiopatología , Estudios de Casos y Controles , Sordera/genética , Sordera/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Endotelio Vascular/metabolismo , Femenino , Arteria Femoral/fisiopatología , Humanos , Síndrome de Kearns-Sayre/genética , Síndrome de Kearns-Sayre/metabolismo , Síndrome MELAS/genética , Síndrome MERRF/genética , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Mutación Puntual , Eliminación de Secuencia , Tirosina/metabolismo , Vasodilatación
17.
Genes (Basel) ; 14(2)2023 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-36833224

RESUMEN

Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype-phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype-phenotype correlations, we found clustering to overcome the limits of the "single-dimension" paradigm traditionally used to describe genotype-phenotype relationships.


Asunto(s)
Enfermedades Musculares , Canal Liberador de Calcio Receptor de Rianodina , Humanos , Canal Liberador de Calcio Receptor de Rianodina/genética , Enfermedades Musculares/genética , Estudios de Asociación Genética , Genotipo , Fenotipo
18.
Clin Sci (Lond) ; 122(6): 289-97, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21970465

RESUMEN

MDs (mitochondrial diseases) are a clinically heterogeneous group of disorders characterized by impairment of the respiratory chain function with altered oxidative phosphorylation. We tested the hypothesis that the function of vascular endothelium is affected by increased oxidative stress in MDs. A total of 12 patients with MDs and pair-matched controls were studied. Endothelial function was assessed by measuring FMD (flow-mediated vasodilation) of brachial and common femoral arteries. The test was repeated after vitamin C (500 mg, twice a day) and E (400 mg, once a day) supplementation for 30 days and 90 days after vitamin withdrawal. FMD was reduced in patients compared with controls [AUC/τ (time-averaged area under the curve) for the brachial artery, 1.05±0.24 compared with 4.19±0.59% respectively, P<0.001; AUC/τ for the femoral artery, 0.98±0.19 compared with 2.36±0.29% respectively, P=0.001; values are means±S.E.M.] and correlated (brachial artery) with plasma lactate (r=-0.63, P<0.01). Urinary 8-iso-PGF2α (8-iso-prostaglandin F2α) was higher in patients than controls (505.6±85.9 compared with 302.5±38.7 pg/mg of creatinine; P<0.05) and correlated with plasma lactate (r=0.70, P<0.05). Immunohistochemical analysis showed 8-iso-PGF2α staining in MD-affected striated muscle cells and in blood vessels in muscle biopsies of patients. Antioxidant vitamins transiently restored FMD in patients [ΔAUC/τ (change in AUC/τ) for the brachial artery, +1.38±0.49%, P<0.05; ΔAUC/τ for the femoral artery, +0.98±0.24%, P<0.01] but had no effect on FMD in controls (brachial artery, -1.3±0.63%; and common femoral artery, -0.58±0.30%), thus abolishing the differences between patients and controls. The results of the present study indicate that oxidative stress is increased and is, at least partly, responsible for endothelial dysfunction in MDs.


Asunto(s)
Endotelio Vascular/fisiopatología , Enfermedades Mitocondriales/fisiopatología , Estrés Oxidativo , Adulto , Dinoprost/análogos & derivados , Dinoprost/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico/fisiología , Especies Reactivas de Oxígeno , Vasodilatación
19.
Muscle Nerve ; 45(6): 831-4, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22581536

RESUMEN

INTRODUCTION: The clinical course of late-onset Pompe disease is heterogeneous, and new clinical outcome measures are needed to evaluate enzyme replacement therapy (ERT). METHODS: We correlated the 6-Minute Walk Test (6MWT), Walton and Gardner-Medwin (WGM) score, and GSGC (Gait, Stairs, Gower, Chair) scores in 40 patients. RESULTS: At baseline, the GSGC score correlated with both WGM (P < 0.001, n = 33) and 6MWT (P < 0.001, n = 26). After 1 year of ERT, we observed a significant change in gait, stairs and chair performance on the GSGC scale. The 6MWT significantly increased from 319 to 371 meters in 32 patients, and the WGM score was reduced. CONCLUSIONS: GSGC is a group of functional tests that requires only a few minutes to perform, therefore, this score might be a good indicator to be used in future studies.


Asunto(s)
Evaluación de la Discapacidad , Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Actividad Motora/fisiología , Evaluación de Resultado en la Atención de Salud , Adulto , Edad de Inicio , Anciano , Femenino , Estudios de Seguimiento , Marcha/fisiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Caminata/fisiología
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