107 results on '"C. Domínguez-González"'
Search Results
2. [Myotonic dystrophy type 1: a series of 107 patients]
- Author
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D, Sánchez-Tejerina, J, Palomino-Doza, M, Valverde-Gómez, A, Ruiz-Curiel, R, Salguero-Bodes, A, Hernández-Voth, J, Sayas-Catalán, and C, Domínguez-González
- Subjects
Adult ,Male ,Adolescent ,Child, Preschool ,Infant, Newborn ,Humans ,Infant ,Myotonic Dystrophy ,Female ,Child ,Retrospective Studies - Abstract
Myotonic dystrophy type 1 is the most common muscular dystrophy in adults. It is a genetic disorder of autosomal dominant inheritance and one of its most striking features is its multi-systemic involvement with a wide clinical phenotype.Data from 107 patients with a genetically confirmed diagnosis of the disease were retrospectively analysed from the database of a national reference division for neuromuscular diseases. Demographic and clinical data were collected over a 7-year period.The most frequent age of symptom onset was adulthood (66.4%). 35% showed exclusive distal weakness and a majority (63.6%) had clinical myotonia. Only 10 patients lacked neuromuscular symptoms at diagnosis and up to 9.5% were restricted to a wheelchair. The implantation of a pacemaker or cardioverter-defibrillator was conducted in 16 patients but no sudden cardiac death was detected. A venous thromboembolic disease incidence rate of 5.6 cases per 1000 patient-year was identified. More than half of the patients (54%) in the series developed respiratory failure. 13 patients died during the follow-up period, with respiratory failure being the main cause of death.The follow-up and clinical management of patients with DM1 should be multidisciplinary. In our series, the main cause of morbidity and mortality was respiratory disorders, whereas the incidence of cardiac disorders was lower. In addition, there is a notable frequency of complications derived from falls, which can have serious consequences. Finally, a higher than expected incidence of thromboembolic events was identified, which deserves further study in other cohorts of patients.Distrofia miotónica de tipo 1: una serie de 107 pacientes.Introducción. La distrofia miotónica de tipo 1 (DM1) es la distrofia muscular más frecuente en adultos, aunque puede comenzar a cualquier edad. Genéticamente determinada y de transmisión dominante, se caracteriza por la afectación constante, aunque variable, de múltiples sistemas. Pacientes y métodos. Se analizaron retrospectivamente datos de 107 pacientes con diagnóstico genético de DM1 en seguimiento en una unidad de referencia nacional en enfermedades neuromusculares raras. Se recopilaron datos demográficos y clínicos de un período de seguimiento de siete años. Resultados. El 66,4% de los pacientes comenzó en la edad adulta. El 35,5% tenía debilidad distal exclusiva y la mayoría (63,6%) presentaba miotonía clínica. Sólo 10 pacientes no tenían síntomas neuromusculares en el diagnóstico. En un 8,6%, las caídas ocasionaron complicaciones graves y hasta un 9,5% perdió la deambulación autónoma. Se implantó un dispositivo cardíaco en 16 pacientes y no se registró ninguna muerte súbita de origen cardíaco. Se identificó una tasa de incidencia de enfermedad tromboembólica venosa de 5,6 casos/1.000 pacientes-año. Un 54% de los pacientes desarrolló insuficiencia respiratoria. Durante el seguimiento fallecieron 13 pacientes y la insuficiencia respiratoria fue la principal causa de muerte (38,5%). Conclusiones. El manejo clínico y el seguimiento de los pacientes con DM1 debe ser multidisciplinar. En nuestra serie, la principal causa de morbimortalidad fueron los trastornos respiratorios, mientras que la incidencia de complicaciones cardiológicas graves fue baja. Destacan, además, las complicaciones derivadas de las caídas, que pueden tener consecuencias graves. Finalmente, se identificó una incidencia mayor de la esperada de eventos tromboembólicos, que merece ser estudiada en mayor profundidad.
- Published
- 2021
3. [Steinert's disease and refusal to treatment]
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A, Rosado-Bartolomé and C, Domínguez-González
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Treatment Refusal ,SARS-CoV-2 ,Quality of Life ,Vertebrobasilar Insufficiency ,COVID-19 ,Humans ,Myotonic Dystrophy ,Female ,Middle Aged ,Cognition Disorders ,Lung ,COVID-19 Serological Testing - Abstract
Enfermedad de Steinert y rechazo de la actuación médica.
- Published
- 2021
4. Miopatías metabólicas, mitocondriales y tóxicas
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C. Domínguez-González and M.A. Martín-Casanueva
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Gynecology ,03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,business.industry ,030220 oncology & carcinogenesis ,medicine ,030212 general & internal medicine ,General Medicine ,business - Abstract
Resumen Las miopatias metabolicas y mitocondriales son trastornos hereditarios que tienen en comun ser secundarias a un defecto en la obtencion de energia en forma de ATP desde los nutrientes. Pueden estar alteradas las vias del metabolismo de los hidratos de carbono o los lipidos o la fosforilacion oxidativa mitocondrial, que es la via final comun del metabolismo aerobico. Se pueden manifestar de forma episodica o con debilidad muscular de curso progresivo. La historia clinica es el pilar fundamental a partir del cual dirigir el diagnostico diferencial y, en ella, debera incluirse siempre un interrogatorio detallado sobre los antecedentes de exposicion a farmacos. Muchos de ellos pueden tener efectos adversos sobre el musculo, con sintomas similares a los caracteristicos de los trastornos metabolicos musculares. El diagnostico definitivo debe ser molecular, puesto que ademas de asegurar un correcto asesoramiento genetico a las familias, permitira desde ya o en el futuro ofrecer un tratamiento personalizado. Metabolic and mitochondrial myopathies are inherited disorders characterized by incompetence to provide energy substrate (ATP) from nutrients. Both carbohydrate or lipid metabolism or mitochondrial oxidative phosphorylation, (final common pathway for aerobic metabolism), may be altered. Clinically can appear like episodes besides to progressive muscle weakness. Differential diagnosis is based on clinical history, including detailed search for history of exposure to drugs, that might have adverse effects similar to muscle metabolic disorders. Molecular diagnosis allows establishing definitive diagnosis, as well as to perform genetic counseling and to provide a personalized treatment, now or in the future.
- Published
- 2019
5. [From in-person didactic sessions to videoconferencing during the COVID-19 pandemic: satisfaction survey among participants]
- Author
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A, Villarejo-Galende, F J, Azcárate-Díaz, M I, Laespada-García, P, Rábano-Suárez, M, Ruiz-Ortiz, C, Domínguez-González, P, Calleja-Castaño, A, Martínez-Salio, S, Moreno-García, and D A, Pérez-Martínez
- Subjects
Adult ,Male ,Students, Medical ,Hospital Departments ,Patient Handoff ,COVID-19 ,Internship and Residency ,Consumer Behavior ,Middle Aged ,Hospitals, University ,Cross-Sectional Studies ,Neurology ,Education, Medical, Graduate ,Surveys and Questionnaires ,Videoconferencing ,Humans ,Education, Medical, Continuing ,Female ,Neurologists ,Pandemics ,Aged - Abstract
COVID-19 pandemic has disturbed many hospital activities, including medical education. We describe the switch from in-person didactic sessions to videoconferencing in a Neurology department. We analyse the opinions and satisfaction of participants.Narrative description of the adopted measures; Online survey among participants.One of the three weekly sessions was cancelled, and two switched to videoconferencing. There were more participants online than in the conference hall. 49 users answered the survey, 51% women, mean age 40.5 years (range 25-65). Satisfaction was higher for previous face-to-face meetings (8.68) than for videoconferencing (8.12) (p=0.006). There was a significant inverse correlation between age and satisfaction with virtual sessions (r=-0.37; p=0.01), that was not found for in-person attendance. Most users (75.5%) would prefer to continue with online sessions when the pandemic is over, and 87.8% support inter-hospital remote meetings, but the safety of web platforms is a concern (53.1%).The change from in-person to virtual sessions is an easy measure to implement in a neurology department, with a good degree of satisfaction among users. There are some unsolved problems with the use of commercial web platforms and inter-hospital connection. Most users recommend leadership and support from educational and health authorities.Cambio de sesiones docentes presenciales a virtuales durante la pandemia de COVID-19 en un servicio de neurología: descripción del proceso y satisfacción de los usuarios.Introducción y objetivo. La pandemia de COVID-19 ha trastornado la actividad hospitalaria, incluyendo la docente. Se describe el cambio de un sistema presencial a otro de sesiones en línea en un servicio de neurología, y se analizan la satisfacción y las opiniones de los usuarios. Material y métodos. Exposición de las medidas adoptadas para pasar a modalidad en línea y análisis de una encuesta entre los participantes. Resultados. Se pasó de tres a dos sesiones semanales, con restricción del público presencial. El público virtual superó al presencial. Contestaron la encuesta 49 participantes, un 51% mujeres, con una media de 40,5 años (rango: 25-65). La satisfacción de los asistentes fue mayor para las sesiones presenciales (8,68) que para las en línea (8,12) (p = 0,006). Existía una correlación inversa significativa entre la edad y la satisfacción con las sesiones en línea (r = –0,37; p = 0,01) que no se daba para las sesiones presenciales. El 75,5% fue partidario de mantener las sesiones virtuales cuando se eliminaran las restricciones de aforo. Una mayoría (87,8%) apoyó sesiones interhospitalarias y recomienda que las autoridades sanitarias faciliten aplicaciones informáticas seguras (53,1%). Conclusiones. La introducción de sesiones virtuales es una medida fácil de implementar en un servicio de neurología, con un alto grado de satisfacción de los usuarios, aunque menor que con las sesiones presenciales. Existen problemas no resueltos respecto al uso de plataformas comerciales y conexión interhospitalaria. Sería recomendable que las autoridades sanitarias y educativas desarrollaran aplicaciones seguras y fomentaran la educación médica en línea.
- Published
- 2021
6. [Cognitive impairment in myotonic dystrophy type 1 (Steinert's disease)]
- Author
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A, Rosado Bartolomé, V, Puertas Martín, C, Domínguez González, and M, Ramos Miranda
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Humans ,Myotonic Dystrophy ,Cognitive Dysfunction - Abstract
Traditionally, it has been recognized that patients with myotonic dystrophy type 1 (MD-1) - also known as Steinert disease -, they show a specific behaviour, not including those who suffer from mental or neurodevelopmental diseases. The neurological substrate of this behaviour is described. The aim of this text has two purposes. The first intention is that clinical staff, when faced with a patient with MD-1, always consider the cognitive aspects of the disease. On the other hand, it is intended to combat preconceived ideas about the particular behaviour of these patients.
- Published
- 2021
7. [Myotonic dystrophy and primary care]
- Author
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C, Domínguez-González
- Subjects
Primary Health Care ,Plant Extracts ,Humans ,Myotonic Dystrophy ,Follow-Up Studies - Published
- 2020
8. CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES
- Author
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C. Fuenmayor-Fernández de la Hoz, A. Hernández-Laín, A. Arteche López, A. Hernández Voth, M. Olivé, and C. Domínguez-González
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Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2021
9. POMPE DISEASE
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D. Reyes-Leiva, A. Nascimento, N. Muelas, C. Domínguez-González, C. Paradas, M. Olivé, J. Grau, M. Barba-Romero, M. Gómez-Caravaca, J. Diaz-Manera, and null S. Spanish Pompe Study Group
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Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2021
10. IMAGING
- Author
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N. Løkken, K. Revsbech, L. Jacobsen, A. Martinuzzi, A. Toscano, M. Martin, J. Díaz Manera, C. Stefan, C. Domínguez-González, G. Brondani, O. Musumeci, C. Merino-Sanchez, C. Nuñez, P. Montesinos, F. Granata, T. Khawajazada, and J. Vissing
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Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2021
11. MITOCHONDRIAL DISEASES
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C. Domínguez-González, S. Laine-Menéndez, A. Delmiro, I. García-Consuegra, M. Fernández-de la Torre, A. Hernández-Laín, J. Sayas, C. de Fuenmayor, M. Martin, and M. Morán
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Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2021
12. Distrofia miotónica y atención primaria
- Author
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C Domínguez-González
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Public Health, Environmental and Occupational Health ,medicine ,Primary health care ,MEDLINE ,Follow up studies ,Family Practice ,business - Published
- 2020
13. Enfermedad de Steinert y rechazo de la actuación médica
- Author
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A Rosado-Bartolomé and C Domínguez-González
- Subjects
Gynecology ,medicine.medical_specialty ,business.industry ,medicine ,MEDLINE ,Neurology (clinical) ,General Medicine ,business - Published
- 2021
14. Distrofia miotónica de tipo 1: una serie de 107 pacientes
- Author
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C Domínguez-González, A Hernández-Voth, M Valverde-Gómez, A Ruiz-Curiel, D Sánchez-Tejerina, Julián Palomino-Doza, J Sayas-Catalán, and Rafael Salguero-Bodes
- Subjects
Pediatrics ,medicine.medical_specialty ,Weakness ,business.industry ,Incidence (epidemiology) ,General Medicine ,Myotonia ,medicine.disease ,Myotonic dystrophy ,Sudden cardiac death ,Respiratory failure ,medicine ,Neurology (clinical) ,medicine.symptom ,Muscular dystrophy ,business ,Cause of death - Abstract
Introduction Myotonic dystrophy type 1 is the most common muscular dystrophy in adults. It is a genetic disorder of autosomal dominant inheritance and one of its most striking features is its multi-systemic involvement with a wide clinical phenotype. Patients and methods Data from 107 patients with a genetically confirmed diagnosis of the disease were retrospectively analysed from the database of a national reference division for neuromuscular diseases. Demographic and clinical data were collected over a 7-year period. Results The most frequent age of symptom onset was adulthood (66.4%). 35% showed exclusive distal weakness and a majority (63.6%) had clinical myotonia. Only 10 patients lacked neuromuscular symptoms at diagnosis and up to 9.5% were restricted to a wheelchair. The implantation of a pacemaker or cardioverter-defibrillator was conducted in 16 patients but no sudden cardiac death was detected. A venous thromboembolic disease incidence rate of 5.6 cases per 1000 patient-year was identified. More than half of the patients (54%) in the series developed respiratory failure. 13 patients died during the follow-up period, with respiratory failure being the main cause of death. Conclusions The follow-up and clinical management of patients with DM1 should be multidisciplinary. In our series, the main cause of morbidity and mortality was respiratory disorders, whereas the incidence of cardiac disorders was lower. In addition, there is a notable frequency of complications derived from falls, which can have serious consequences. Finally, a higher than expected incidence of thromboembolic events was identified, which deserves further study in other cohorts of patients.
- Published
- 2021
15. MITOCHONDRIAL DISEASES & METABOLIC MYOPATHIES
- Author
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C. Domínguez-González, C. Garone, G. D'Souza, B. Thompson, M. Morton, J. Quan, and M. Hirano
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Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2020
16. CONGENITAL MUSCULAR DYSTROPHIES
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D. Natera-de Benito, A. Reghan-Foley, C. Domínguez-González, C. Ortez, M. Jain, A. Mebrahtu, S. Donkervoort, Y. Hu, M. Fink, P. Yun, T. Ogata, J. Medina, J. Díaz-Manera, L. Carrera-García, J. Expósito-Escudero, M. Olivé, J. Colomer, C. Jiménez-Mallebrera, C. Bönnemann, and A. Nascimento
- Subjects
Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Genetics (clinical) - Published
- 2020
17. PRO119 A NOVEL MAPPING APPROACH FOR ESTIMATING UTILITIES IN NON-DYSTROPHIC MYOTONIA
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C. Schneider-Gold, C. Domínguez-González, M. Farrugia, A. Lloyd, J. Granerod, and J.D. Marshall
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business.industry ,Health Policy ,Non dystrophic myotonia ,Public Health, Environmental and Occupational Health ,Medicine ,business ,Neuroscience - Published
- 2019
18. [Hemiparkinsonism secondary to sphenoid wing meningioma]
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C, Domínguez-González, M, Amosa Delgado, and A, Ramos-González
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Male ,Parkinsonian Disorders ,Meningeal Neoplasms ,Humans ,Meningioma ,Aged - Published
- 2011
19. Abstract OT3-3-05: Neurotoxicity characterization phase II randomized study of nab-paclitaxel versus conventional paclitaxel as first-line therapy of metastatic HER2-negative breast cancer. An ONSOCUR Study Group
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S Enrech, Jorge Luciano Alió Sanz, Saenz Ja García, Maria Jose Echarri, Hernán Cortés-Funes, Blanca Cantos, MA Lara, J Baquero, C Domínguez-González, C Bueno, Noelia Martínez, Juan Manuel Sepúlveda, Cristina Rodríguez-Antona, Eva Ciruelos, Juan Antonio Guerra, and R Carrión
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Cancer ,Pharmacology ,Evaluable Disease ,medicine.disease ,Metastatic breast cancer ,Clinical trial ,chemistry.chemical_compound ,Breast cancer ,Paclitaxel ,chemistry ,Internal medicine ,Toxicity ,medicine ,business - Abstract
Background: Nab-paclitaxel (Nab-P) is a nanoparticle albumin-bound form of paclitaxel that is thought to exploit natural albumin pathways to enhance the selective uptake and accumulation of paclitaxel at the site of the tumour, thus reducing its diffusion to normal tissues. Nab-P has been approved for the treatment of metastatic breast cancer patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. Toxicity profile of Nab-P is well characterized with significantly less haematological toxicities compared with conventional paclitaxel (P). Nab-P derived grade III neuropathy is short-lasting and more reversible than conventional P-derived neuropathy, probably due to absence of Cremophor solvent, or due to P itself. However there is still a lack of clinical and physiological characterisation of Nab-P induced neuropathy. The Current used tools for early detection and continuous evaluation of neurotoxicity are not optimal. Most used toxicity scales are limited, as they do not provide a detailed information of the severity of the neuropathy, its impact on quality of life, or physiopathology mechanisms. In addition, an inter-individual variability exists in terms of neurotoxicity predisposition when taxanes are used; it seems to be related to polymorphic differences in genes implicated in transport and metabolism of these drugs. Specific aims: Primary objective is to characterize neurotoxicity according to Total Neuropathy Score (TNS) and electromyographic changes. Secondary endpoints are determine the rate of neuropathy chemo-induced, the predictive value of some genetic variants (SNPs) for the development of neuropathy, clinical activity, toxicity profile and safety of treatments and quality of life (EORTC QLQ-C30 and CIPN20). Trial design: Phase II open-label randomised clinical trial with four parallel arms: a) conventional paclitaxel 80 mg/m2 on days 1, 8 and 15; b) Nab-P 100 mg/m2 on days 1, 8 and 15; c) Nab-P 150 mg/m2 on days 1, 8 and 15; d) Nab-P 150 mg/m2 on days 1 and 15. Study treatments will be administered in a 28-day cycle until progression disease, intolerable toxicity or investigator's decision. Eligibility criteria: Women >18 years, with cytological or histological confirmation of HER2-negative breast cancer, metastatic disease, not prior chemotherapy for advanced disease, no prior grade > 1 neuropathy from any cause, measurable or evaluable disease, ECOG >2 and adequate bone marrow, renal and hepatic functions. No Relevant comorbidities. Statistical methods: This is an exploratory safety study to better characterize neurotoxicity in patients treated with Nab-P compared toP. Therefore no formal sample size or power calculations will be performed. We expect to recruit 60 patients, 15 in each treatment arm, in 18 months. Recruitment will start on October 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-05.
- Published
- 2012
20. Ganglionopatía sensitiva como manifestación de enfermedad celiaca
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L Ballesteros-Plaza, C Domínguez-González, R Gordo-Manas, A Martinez-Salio, Aurelio Hernández-Laín, and J Hernandez-Gallego
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business.industry ,Medicine ,Neurology (clinical) ,General Medicine ,business ,Humanities - Abstract
Introduccion. Las manifestaciones neurologicas de la enfermedad celiaca (EC) pueden deberse a la propia enfermedad, a las enfermedades autoinmunes asociadas o a complicaciones de los tumores que pueden desarrollar a largo plazo. Presentamos un caso de ganglionopatia sensitiva asociada a una EC. Caso clinico. Mujer de 59 anos con diarrea cronica y perdida de peso, que acude por un cuadro de trastorno de la marcha, que progresa hasta llegar a impedirla. Diagnosticada como EC, el hallazgo de una ganglionopatia sensitiva con disautonomia, manifestacion atipica para esta enfermedad, llevo al diagnostico de un sindrome de Sjogren (SS) asociado. Conclusiones. Las manifestaciones neurologicas de la EC son muy variadas, pero ante la presencia de una ganglionopatia sensitiva, cuadro neurologico atipico en esta enfermedad, es obligado sospechar un SS, asociacion infrecuente, pero bien establecida. De igual manera, en todo paciente con SS debe realizarse un cribado de EC, que, aunque subclinica, puede complicarse a largo plazo con el desarrollo de tumores. Discutimos el diagnostico diferencial de las manifestaciones neurologicas de la EC y de la ganglionopatia sensitiva, asi como la asociacion entre la celiaquia y el SS.
- Published
- 2007
21. Nistagmo vertical secundario a la administración de morfina epidural
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L Ballesteros-Plaza, A Villarejo-Galende, C Domínguez-González, R Gordo-Manas, and G Ruiz-López Del Prado
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medicine.medical_specialty ,business.industry ,General Medicine ,Nystagmus ,Surgery ,Anesthesia ,Morphine ,Medicine ,Vertical nystagmus ,Neurology (clinical) ,medicine.symptom ,Epidural administration ,business ,Opioid analgesics ,medicine.drug - Published
- 2007
22. Absence of Pathogenic Mutations and Strong Association With HLA-DRB1*11:01 in Statin-Naïve Early-Onset Anti-HMGCR Necrotizing Myopathy.
- Author
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Llansó L, Segarra-Casas A, Domínguez-González C, Malfatti E, Kapetanovic S, Rodríguez-Santiago B, de la Calle O, Blanco R, Dobrescu A, Nascimento-Osorio A, Paipa A, Hernandez-Lain A, Jou C, Mariscal A, González-Mera L, Arteche A, Lleixà C, Caballero-Ávila M, Carbayo Á, Vesperinas A, Querol L, Gallardo E, and Olivé M
- Subjects
- Humans, Female, Male, Adult, Young Adult, Child, Adolescent, Child, Preschool, Mutation, Autoantibodies blood, Autoantibodies immunology, Necrosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Myositis immunology, Myositis genetics, Hydroxymethylglutaryl CoA Reductases genetics, Hydroxymethylglutaryl CoA Reductases immunology, HLA-DRB1 Chains genetics
- Abstract
Background and Objectives: Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype., Methods: Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed., Results: Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls., Discussion: WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.
- Published
- 2024
- Full Text
- View/download PDF
23. Adult Pompe disease: Analysis of 13 patients.
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Martín-Jiménez P, Bermejo-Guerrero L, Hernandez-Voth A, Arteche-López A, Hernández-Lain A, Rabasa M, and Domínguez-González C
- Abstract
Introduction: Pompe Disease (PD) is a lysosomal disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), primarily manifesting as a progressive myopathy with early respiratory involvement. Enzyme replacement therapy (ERT) is available since 2006., Materials and Methods: We describe 13 patients with partial GAA deficiency, followed at Hospital 12 de Octubre, 8 of whom were receiving treatment., Results: 8 patients exhibit symptoms, all with late onset. They display axial and proximal weakness predominantly in the lower limbs but maintain autonomous gait. Five patients require non-invasive mechanical ventilation due to respiratory insufficiency. All symptomatic patients receive ERT, and in 7/8 (87.5%), there is a decline in motor and pulmonary function after an average of 8.25 years of treatment (baseline and post-treatment FVC and 6MWT mean 86.6% vs 70.8% and 498 vs 430 meters, respectively)., Conclusion: Not all patients with partial GAA deficiency experience symptoms of PD, and symptomatic patients, despite ERT with recombinant alpha-glucosidase, mostly experience a gradual decline in motor and respiratory function., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
24. Decoding the muscle transcriptome of patients with late onset Pompe disease reveals markers of disease progression.
- Author
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Monceau A, Gokul Nath R, Suárez-Calvet X, Musumeci O, Toscano A, Kierdaszuk B, Kostera-Pruszczyk A, Domínguez-González C, Hernández-Lain A, Paradas C, Rivas E, Papadimas G, Papadopoulos C, Chrysanthou-Piterou M, Gallardo E, Olivé M, Lilleker J, Roberts ME, Marchese D, Lunazzi G, Heyn H, Fernández-Simón E, Villalobos E, Clark J, Katsikis P, Collins C, Mehra P, Laidler Z, Vincent A, Tasca G, Marini-Bettolo C, Guglieri M, Straub V, Raben N, and Díaz-Manera J
- Abstract
Late-onset Pompe Disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction due to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage - a classic manifestation of the disease - has been extensively studied by analysing the whole muscle tissue; however, little, if any, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single nuclei RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age and gender matched healthy controls. We matched these changes with histology findings using GeoMx Spatial Transcriptomics to compare the transcriptome of control myofibers from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibers of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibers and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibers, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes, and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. The upregulation of the genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibers. Notably, enzyme replacement therapy - the only available therapy for the disease - showed a tendency to restore metabolism dysregulation, particularly within slow fibers. A combination of single nuclei RNA sequencing and spatial transcriptomics revealed the landscape of normal and the diseased muscle, and highlighted the early abnormalities associated with the disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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25. Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.
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Bermejo-Guerrero L, Hernández-Voth A, Serrano-Lorenzo P, Blázquez A, Martin-Jimenez P, Martin MA, and Domínguez-González C
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- Humans, Male, Administration, Oral, Adult, Treatment Outcome, Mitochondrial Diseases drug therapy, Mitochondrial Diseases genetics, Nucleosides therapeutic use, Nucleosides administration & dosage, Thymidine Kinase genetics, Thymidine Kinase deficiency
- Abstract
Objectives: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d., Methods: An adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented., Results: After 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea., Discussion: Treatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MAM and CDG have received consulting fees from UCB, a pharmaceutical company that holds a license for the development of nucleosides as a treatment for TK2 deficiency., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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26. Prevalence of Steinert's Myotonic Dystrophy and Utilization of Healthcare Services: A Population-Based Cross-Sectional Study.
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Hernáez L, Zoni AC, Domínguez-Berjón MF, Esteban-Vasallo MD, Domínguez-González C, Serrano P, and On Behalf Of The Dm-Cm Working Group
- Abstract
Myotonic dystrophy type I (MDI) is the most common muscular dystrophy in adults. The main objectives of this study were to determine the prevalence of MDI in the Community of Madrid (CM) (Spain) and to analyze the use of public healthcare services; a population-based cross-sectional descriptive study was carried out on patients with MDI in CM and data were obtained from a population-based registry (2010-2017). A total of 1101 patients were studied (49.1% women) with average age of 47.8 years; the prevalence of MDI was 14.4/100,000 inhabitants. In the women lineal regression model for hospital admissions, being in the fourth quartile of the deprivation index, was a risk factor (regression coef (rc): 0.80; 95%CI 0.25-1.37). In the overall multiple lineal regression model for primary health care (PHC) attendance, being a woman increased the probability of having a higher number of consultations (rc: 3.99; 95%CI: 3.95-5.04), as did being in the fourth quartile of the deprivation index (rc: 2.10; 95%CI: 0.58-3.63); having received influenza vaccines was a protective factor (rc: -0.46; 95%CI: -0.66-(-0.25)). The prevalence of MDI in the CM is high compared to other settings. Moreover, having any level of risk stratification of becoming ill (high, medium or low) has a positive association with increased PHC consultations and hospital admissions.
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- 2024
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27. Expanding the Clinical Spectrum of DRP2 -Associated Charcot-Marie-Tooth Disease.
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Sivera R, Pelayo-Negro AL, Jericó I, Domínguez-González C, Horga A, Rodriguez De Rivera FJ, Gallardo E, Tembl JI, Bermejo-Guerrero L, Pagola Lorz MI, Azorín I, Cordoba M, Fenollar-Cortés MDM, Millet E, Vilchez JJ, Espinós C, Apellániz-Ruiz M, and Sevilla T
- Subjects
- Female, Humans, Male, Myelin Sheath pathology, Peripheral Nerves diagnostic imaging, Phenotype, Cross-Sectional Studies, Retrospective Studies, Pedigree, Young Adult, Middle Aged, Aged, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease pathology, Germ-Line Mutation
- Abstract
Background and Objectives: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined., Methods: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain., Results: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections., Discussion: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.
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- 2024
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28. Correction to: Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP‑mediated disease reveals characteristic features useful for diagnosis.
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Esteller D, Schiava M, Verdú-Díaz J, Villar-Quiles RN, Dibowski B, Venturelli N, Laforet P, Alonso-Pérez J, Olive M, Domínguez-González C, Paradas C, Vélez B, Kostera-Pruszczyk A, Kierdaszuk B, Rodolico C, Claeys K, Pál E, Malfatti E, Souvannanorath S, Alonso-Jiménez A, de Ridder W, De Smet E, Papadimas G, Papadopoulos C, Xirou S, Luo S, Muelas N, Vilchez JJ, Ramos-Fransi A, Monforte M, Tasca G, Udd B, Palmio J, Sri S, Krause S, Schoser B, Fernández-Torrón R, López de Munain A, Pegoraro E, Farrugia ME, Vorgerd M, Manousakis G, Chanson JB, Nadaj-Pakleza A, Cetin H, Badrising U, Warman-Chardon J, Bevilacqua J, Earle N, Campero M, Díaz J, Ikenaga C, Lloyd TE, Nishino I, Nishimori Y, Saito Y, Oya Y, Takahashi Y, Nishikawa A, Sasaki R, Marini-Bettolo C, Guglieri M, Straub V, Stojkovic T, Carlier RY, and Díaz-Manera J
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- 2024
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29. Clinical and Genetic Analysis of Patients With TK2 Deficiency.
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Ceballos F, Serrano-Lorenzo P, Bermejo-Guerrero L, Blázquez A, Quesada-Espinosa JF, Amigo J, Minguez P, Ayuso C, García-Arumí E, Muelas N, Jaijo T, Nascimento A, Galán-Rodriguez B, Paradas C, Arenas J, Carracedo A, Martí R, Martín MA, and Domínguez-González C
- Abstract
Objectives: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive disorder that stems from a perturbation of the mitochondrial DNA maintenance. Nucleoside treatment has recently shown promise as a disease-modifying therapy. TK2d was initially associated with rapidly progressive fatal myopathy in children featuring mitochondrial DNA depletion. Subsequently, less severe variants of the disease were described, with onset of symptoms during adolescence or adulthood and associated with the presence of multiple mtDNA deletions. These less severe phenotypes have been reported in only 15% of the approximately 120 patients described worldwide. However, some reports suggest that these juvenile and adult-onset presentations may be more common. The objective of this study was to describe the clinical phenotype in a sample of patients from Spain., Methods: This study includes 53 patients harboring biallelic TK2 pathogenic variants, compiling data retrospectively from 7 Spanish centers. We analyzed allele frequency, investigated the most recent common ancestor of core haplotypes, and used the Runs of Homozygosity approach to investigate variant coalescence., Results: Symptom onset distribution revealed that 32 patients (60%) experienced symptoms beyond 12 years of age. Approximately 30% of patients died of respiratory insufficiency, while 56% of surviving patients needed mechanical ventilation. Genetic analysis identified 16 distinct variants in TK2 . Two variants, p.Lys202del and p.Thr108Met, exhibited significantly higher prevalence in the Spanish population than that reported in gnomAD database (86-fold and 13-fold, respectively). These variants are estimated to have originated approximately 16.8 generations ago for p.Thr108Met and 95.2 generations ago for p.Lys202del within the Spanish population, with the increase in frequency attributed to various forms of inbreeding. In late-onset cases, 46.9% carried the p.Lys202del variant., Discussion: The higher frequency of TK2d in Spain can be partially attributed to the increased prevalence of 2 variants and consanguinity. Notably, in 60% of the cohort, the disease was late-onset, emphasizing the potential underdiagnosis of this subgroup of patients in other regions. Raising awareness of this potentially treatable disorder is of utmost importance because early interventions can significantly affect the quality of life and survival of affected individuals., Competing Interests: F. Ceballos reports no disclosures relevant to the manuscript, P. Serrano-Lorenzo reports no disclosures relevant to the manuscript, L. Bermejo-Guerrero reports no disclosures relevant to the manuscript, A. Blázquez reports no disclosures relevant to the manuscript, J.F. Quesada-Espinosa reports no disclosures relevant to the manuscript, J. Amigo reports no disclosures relevant to the manuscript, P. Minguez reports no disclosures relevant to the manuscript, C. Ayuso reports no disclosures relevant to the manuscript, E. García-Arumí reports no disclosures relevant to the manuscript, N. Muelas reports no disclosures relevant to the manuscript, T. Jaijo reports no disclosures relevant to the manuscript; A. Nascimento serves on the advisory board of UCB Pharma; B. Galán-Rodriguez reports no disclosures relevant to the manuscript; C. Paradas serves on the advisory board of UCB Pharma; TK2d Spanish-Group report no disclosures relevant to the manuscript; J. Arenas reports no disclosures relevant to the manuscript; A. Carracedo reports no disclosures relevant to the manuscript; R. Martí serves on the advisory board of UCB Pharma; MAM serves on the advisory board of UCB Pharma; and C. Domínguez-González serves on the advisory board of UCB Pharma. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2024
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30. Magnetic resonance spectroscopy in MELAS syndrome: correlation with CSF and plasma metabolite levels and change after glutamine supplementation.
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Guerrero-Molina MP, Bernabeu-Sanz Á, Ramos-González A, Morales-Conejo M, Delmiro A, Domínguez-González C, Arenas J, Martín MA, and González de la Aleja J
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- Humans, Creatine metabolism, Case-Control Studies, Cohort Studies, Magnetic Resonance Spectroscopy methods, Glutamic Acid metabolism, Proton Magnetic Resonance Spectroscopy methods, Lactates, Dietary Supplements, Glutamine metabolism, MELAS Syndrome diagnostic imaging, MELAS Syndrome drug therapy, MELAS Syndrome metabolism
- Abstract
Purpose: MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF glutamine levels and that oral glutamine supplementation restores these values. Proton magnetic resonance spectroscopy (
1 H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare1 H-MRS of MELAS patients with controls, the1 H-MRS after glutamine supplementation in the MELAS group, and investigate the association between1 H-MRS and CSF lactate, glutamate, and glutamine levels., Methods: We conducted an observational case-control study and an open-label, single-cohort study with single-voxel MRS (TE 144/35 ms). We assessed the brain metabolism changes in the prefrontal (PFC) and parieto-occipital) cortex (POC) after oral glutamine supplementation in MELAS patients. MR spectra were analyzed with jMRUI software., Results: Nine patients with MELAS syndrome (35.8 ± 3.2 years) and nine sex- and age-matched controls were recruited. Lactate/creatine levels were increased in MELAS patients in both PFC and POC (0.40 ± 0.05 vs. 0, p < 0.001; 0.32 ± 0.03 vs. 0, p < 0.001, respectively). No differences were observed between groups in glutamate and glutamine (Glx/creatine), either in PFC (p = 0.930) or POC (p = 0.310). No differences were observed after glutamine supplementation. A positive correlation was found between CSF lactate and lactate/creatine only in POC (0.85, p = 0.003)., Conclusion: No significant metabolite changes were observed in the brains of MELAS patients after glutamine supplementation. While we found a positive correlation between lactate levels in CSF and1 H-MRS in MELAS patients, we could not monitor treatment response over short periods with this tool., Trial Registration: ClinicalTrials.gov Identifier: NCT04948138; initial release 24/06/2021; first patient enrolled on 1/07/2021. https://clinicaltrials.gov/ct2/show/NCT04948138., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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31. Imaging mass cytometry analysis of Becker muscular dystrophy muscle samples reveals different stages of muscle degeneration.
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Piñol-Jurado P, Verdú-Díaz J, Fernández-Simón E, Domínguez-González C, Hernández-Lain A, Lawless C, Vincent A, González-Chamorro A, Villalobos E, Monceau A, Laidler Z, Mehra P, Clark J, Filby A, McDonald D, Rushton P, Bowey A, Alonso Pérez J, Tasca G, Marini-Bettolo C, Guglieri M, Straub V, Suárez-Calvet X, and Díaz-Manera J
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- Humans, Muscular Atrophy metabolism, Muscles metabolism, Collagen metabolism, Disease Progression, Image Cytometry, Muscle, Skeletal metabolism, Muscular Dystrophy, Duchenne pathology
- Abstract
Becker muscular dystrophy (BMD) is characterised by fiber loss and expansion of fibrotic and adipose tissue. Several cells interact locally in what is known as the degenerative niche. We analysed muscle biopsies of controls and BMD patients at early, moderate and advanced stages of progression using Hyperion imaging mass cytometry (IMC) by labelling single sections with 17 markers identifying different components of the muscle. We developed a software for analysing IMC images and studied changes in the muscle composition and spatial correlations between markers across disease progression. We found a strong correlation between collagen-I and the area of stroma, collagen-VI, adipose tissue, and M2-macrophages number. There was a negative correlation between the area of collagen-I and the number of satellite cells (SCs), fibres and blood vessels. The comparison between fibrotic and non-fibrotic areas allowed to study the disease process in detail. We found structural differences among non-fibrotic areas from control and patients, being these latter characterized by increase in CTGF and in M2-macrophages and decrease in fibers and blood vessels. IMC enables to study of changes in tissue structure along disease progression, spatio-temporal correlations and opening the door to better understand new potential pathogenic pathways in human samples., (© 2024. The Author(s).)
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- 2024
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32. Distal hereditary motor neuronopathy as a new phenotype associated with variants in BAG3.
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de Fuenmayor-Fernández de la Hoz CP, Lupo V, Bermejo-Guerrero L, Martín-Jiménez P, Hernández-Laín A, Olivé M, Gallardo E, Esteban-Pérez J, Espinós C, and Domínguez-González C
- Subjects
- Adult, Humans, Female, Middle Aged, Aged, Pedigree, Phenotype, Muscle, Skeletal diagnostic imaging, Muscle, Skeletal pathology, Mutation genetics, Adaptor Proteins, Signal Transducing genetics, Apoptosis Regulatory Proteins genetics, Charcot-Marie-Tooth Disease genetics, Muscular Atrophy, Spinal pathology
- Abstract
Objective: To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy., Methods: This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3., Results: Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members., Conclusions: We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
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- 2024
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33. Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis.
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Esteller D, Schiava M, Verdú-Díaz J, Villar-Quiles RN, Dibowski B, Venturelli N, Laforet P, Alonso-Pérez J, Olive M, Domínguez-González C, Paradas C, Vélez B, Kostera-Pruszczyk A, Kierdaszuk B, Rodolico C, Claeys K, Pál E, Malfatti E, Souvannanorath S, Alonso-Jiménez A, de Ridder W, De Smet E, Papadimas G, Papadopoulos C, Xirou S, Luo S, Muelas N, Vilchez JJ, Ramos-Fransi A, Monforte M, Tasca G, Udd B, Palmio J, Sri S, Krause S, Schoser B, Fernández-Torrón R, López de Munain A, Pegoraro E, Farrugia ME, Vorgerd M, Manousakis G, Chanson JB, Nadaj-Pakleza A, Cetin H, Badrising U, Warman-Chardon J, Bevilacqua J, Earle N, Campero M, Díaz J, Ikenaga C, Lloyd TE, Nishino I, Nishimori Y, Saito Y, Oya Y, Takahashi Y, Nishikawa A, Sasaki R, Marini-Bettolo C, Guglieri M, Straub V, Stojkovic T, Carlier RY, and Díaz-Manera J
- Subjects
- Humans, Mutation genetics, Magnetic Resonance Imaging methods, Valosin Containing Protein genetics, Muscle, Skeletal diagnostic imaging, Muscle, Skeletal pathology, Muscular Diseases diagnostic imaging, Muscular Diseases genetics, Muscular Diseases pathology
- Abstract
Background: The diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far., Methods: We collected muscle MRIs of 80 of the 255 patients who participated in the "VCP International Study" and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs., Results: Fat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy., Conclusions: Patients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles., (© 2023. The Author(s).)
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- 2023
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34. Distal myopathy due to digenic inheritance of TIA1 and SQSTM1 variants in two unrelated Spanish patients.
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Bermejo-Guerrero L, de Fuenmayor Fernández-de la Hoz CP, González-Quereda L, Segarra-Casas A, Nedkova V, Gallano P, Martín-Jiménez P, Hernández-Laín A, Olivé M, Arteche-López A, and Domínguez-González C
- Subjects
- Adult, Humans, Electromyography, Muscle, Skeletal pathology, Sequestosome-1 Protein genetics, T-Cell Intracellular Antigen-1 genetics, Distal Myopathies pathology, Muscular Diseases genetics
- Abstract
Welander distal myopathy typically manifests in late adulthood and is caused by the founder TIA1 c.1150G>A (p.Glu384Lys) variant in families of Swedish and Finnish descent. Recently, a similar phenotype has been attributed to the digenic inheritance of TIA1 c.1070A>G (p.Asn357Ser) and SQSTM1 c.1175C>T (p.Pro392Leu) variants. We describe two unrelated Spanish patients presenting with slowly progressive gait disturbance, distal-predominant weakness, and mildly elevated creatine kinase (CK) levels since their 6th decade. Electromyography revealed abnormal spontaneous activity and a myopathic pattern. Muscle magnetic resonance imaging (MRI) showed marked fatty replacement in distal leg muscles. A muscle biopsy, performed on one patient, revealed myopathic changes with rimmed vacuoles. Both patients carried the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variants. Digenic inheritance is supported by evidence from unrelated pedigrees and a plausible biological interaction between both proteins in protein quality control processes. Recent functional studies and additional case descriptions further support this. Clinical suspicion is necessary to seek both variants., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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35. Expanding the phenotypic spectrum of TRAPPC11- related muscular dystrophy: 25 Roma individuals carrying a founder variant.
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Justel M, Jou C, Sariego-Jamardo A, Juliá-Palacios NA, Ortez C, Poch ML, Hedrera-Fernandez A, Gomez-Martin H, Codina A, Dominguez-Carral J, Muxart J, Hernández-Laín A, Vila-Bedmar S, Zulaica M, Cancho-Candela R, Castro MDC, de la Osa-Langreo A, Peña-Valenceja A, Marcos-Vadillo E, Prieto-Matos P, Pascual-Pascual SI, López de Munain A, Camacho A, Estevez-Arias B, Musokhranova U, Olivella M, Oyarzábal A, Jimenez-Mallebrera C, Domínguez-González C, Nascimento A, García-Cazorla À, and Natera-de Benito D
- Subjects
- Humans, Phenotype, Muscle Weakness, Vesicular Transport Proteins, Microcephaly, Intellectual Disability, Roma genetics, Muscular Dystrophies, Muscular Dystrophies, Limb-Girdle genetics
- Abstract
Background: Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders. TRAPPC11-related LGMD is an autosomal-recessive condition characterised by muscle weakness and intellectual disability., Methods: A clinical and histopathological characterisation of 25 Roma individuals with LGMD R18 caused by the homozygous TRAPPC11 c.1287+5G>A variant is reported. Functional effects of the variant on mitochondrial function were investigated., Results: The c.1287+5G>A variant leads to a phenotype characterised by early onset muscle weakness, movement disorder, intellectual disability and elevated serum creatine kinase, which is similar to other series. As novel clinical findings, we found that microcephaly is almost universal and that infections in the first years of life seem to act as triggers for a psychomotor regression and onset of seizures in several individuals with TRAPPC11 variants, who showed pseudometabolic crises triggered by infections. Our functional studies expanded the role of TRAPPC11 deficiency in mitochondrial function, as a decreased mitochondrial ATP production capacity and alterations in the mitochondrial network architecture were detected., Conclusion: We provide a comprehensive phenotypic characterisation of the pathogenic variant TRAPPC11 c.1287+5G>A, which is founder in the Roma population. Our observations indicate that some typical features of golgipathies, such as microcephaly and clinical decompensation associated with infections, are prevalent in individuals with LGMD R18., Competing Interests: Competing interests: Authors report no disclosures. ÀG-C has received honoraria for lectures from PTC Therapeutics International GT, Immedica, Biomarin and Recordati Rare Diseases Foundation; she has also received a research grant from PTC Therapeutics and is a co-founder of the Sant Joan de Déu start up ‘Neuroprotect Life Sciences’., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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36. Anoctamin-5 related muscle disease: clinical and genetic findings in a large European cohort.
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de Bruyn A, Montagnese F, Holm-Yildiz S, Scharff Poulsen N, Stojkovic T, Behin A, Palmio J, Jokela M, De Bleecker JL, de Visser M, van der Kooi AJ, Ten Dam L, Domínguez González C, Maggi L, Gallone A, Kostera-Pruszczyk A, Macias A, Łusakowska A, Nedkova V, Olive M, Álvarez-Velasco R, Wanschitz J, Paradas C, Mavillard F, Querin G, Fernández-Eulate G, Quinlivan R, Walter MC, Depuydt CE, Udd B, Vissing J, Schoser B, and Claeys KG
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- Female, Male, Humans, Myalgia genetics, Retrospective Studies, Anoctamins genetics, Mutation genetics, Muscle, Skeletal pathology, Atrophy pathology, Muscular Diseases epidemiology, Muscular Diseases genetics, Muscular Diseases pathology, Muscular Dystrophies, Limb-Girdle epidemiology, Muscular Dystrophies, Limb-Girdle genetics, Muscular Dystrophies, Limb-Girdle diagnosis
- Abstract
Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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37. Genetic diagnosis of Duchenne and Becker muscular dystrophy through mRNA analysis: new splicing events.
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Segarra-Casas A, Domínguez-González C, Hernández-Laín A, Sanchez-Calvin MT, Camacho A, Rivas E, Campo-Barasoain A, Madruga M, Ortez C, Natera-de Benito D, Nascimento A, Codina A, Rodriguez MJ, Gallano P, and Gonzalez-Quereda L
- Subjects
- Humans, Dystrophin genetics, RNA, Messenger genetics, Mutation, Multiplex Polymerase Chain Reaction, Muscular Dystrophy, Duchenne diagnosis, Muscular Dystrophy, Duchenne genetics
- Abstract
Background: Up to 7% of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) remain genetically undiagnosed after routine genetic testing. These patients are thought to carry deep intronic variants, structural variants or splicing alterations not detected through multiplex ligation-dependent probe amplification or exome sequencing., Methods: RNA was extracted from seven muscle biopsy samples of patients with genetically undiagnosed DMD/BMD after routine genetic diagnosis. RT-PCR of the DMD gene was performed to detect the presence of alternative transcripts. Droplet digital PCR and whole-genome sequencing were also performed in some patients., Results: We identified an alteration in the mRNA level in all the patients. We detected three pseudoexons in DMD caused by deep intronic variants, two of them not previously reported. We also identified a chromosomal rearrangement between Xp21.2 and 8p22. Furthermore, we detected three exon skipping events with unclear pathogenicity., Conclusion: These findings indicate that mRNA analysis of the DMD gene is a valuable tool to reach a precise genetic diagnosis in patients with a clinical and anatomopathological suspicion of dystrophinopathy that remain genetically undiagnosed after routine genetic testing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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38. Delayed Diagnosis of Congenital Myasthenic Syndromes Erroneously Interpreted as Mitochondrial Myopathies.
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Muñoz-García MI, Guerrero-Molina MP, de Fuenmayor-Fernández de la Hoz CP, Bermejo-Guerrero L, Arteche-López A, Hernández-Laín A, Martín MA, and Domínguez-González C
- Abstract
Background: Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness., Methods: Our method involved the description of three cases of CMS that were initially characterized as probable PMM., Results: All patients were male and presented with ptosis and/or external ophthalmoplegia at birth, with proximal muscle weakness and fatigue on physical exertion. After normal repetitive nerve stimulation (RNS) studies performed on facial muscles, a muscle biopsy (at a median age of 9) was performed to rule out congenital myopathies. In all three cases, the biopsy findings (COX-negative fibers or respiratory chain defects) pointed to PMM. They were referred to our neuromuscular unit in adulthood to establish a genetic diagnosis. However, at this time, fatigability was evident in the physical exams and RNS in the spinal accessory nerve showed a decremental response in all cases. Targeted genetic studies revealed pathogenic variants in the MUSK , DOK7 , and RAPSN genes. The median diagnostic delay was 29 years. Treatment resulted in functional improvement in all cases., Conclusions: Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy.
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- 2023
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39. Reply: High-dose oral glutamine can reduce cerebrospinal fluid glutamate in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes without a beneficial clinical or cerebral tissue effect.
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Guerrero-Molina MP, Domínguez-González C, and González de la Aleja J
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- Humans, Glutamine, Glutamic Acid, DNA, Mitochondrial, Acidosis, Lactic, Mitochondrial Encephalomyopathies, Stroke
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- 2023
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40. Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome.
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Bermejo-Guerrero L, de Fuenmayor-Fernández de la Hoz CP, Guerrero-Molina MP, Martín-Jiménez P, Blázquez A, Serrano-Lorenzo P, Lora D, Morales-Conejo M, González-Martínez I, López-Jiménez EA, Martín MA, and Domínguez-González C
- Abstract
Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS). Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility. This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5). The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.
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- 2023
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41. Myosin post-translational modifications and function in the presence of myopathy-linked truncating MYH2 mutations.
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Sonne A, Peverelli L, Hernandez-Lain A, Domínguez-González C, Andersen JL, Milone M, Beggs AH, and Ochala J
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- Adult, Humans, Mutation genetics, Muscle, Skeletal metabolism, Myosin Heavy Chains genetics, Myosin Heavy Chains metabolism, Protein Processing, Post-Translational genetics, Actomyosin, Muscular Diseases pathology
- Abstract
Congenital myopathies are a vast group of genetic muscle diseases. Among the causes are mutations in the MYH2 gene resulting in truncated type IIa myosin heavy chains (MyHCs). The precise cellular and molecular mechanisms by which these mutations induce skeletal muscle symptoms remain obscure. Hence, in the present study, we aimed to explore whether such genetic defects would alter the presence as well as the post-translational modifications of MyHCs and the functionality of myosin molecules. For this, we dissected muscle fibers from four myopathic patients with MYH2 truncating mutations and from five human healthy controls. We then assessed 1 ) MyHCs presence/post-translational modifications using LC/MS; 2 ) relaxed myosin conformation and concomitant ATP consumption with a loaded Mant-ATP chase setup; 3 ) myosin activation with an unloaded in vitro motility assay; and 4 ) cellular force production with a myofiber mechanical setup. Interestingly, the type IIa MyHC with one additional acetylated lysine (Lys35-Ac) was present in the patients. This was accompanied by 1 ) a higher ATP demand of myosin heads in the disordered-relaxed conformation; 2 ) faster actomyosin kinetics; and 3 ) reduced muscle fiber force. Overall, our findings indicate that MYH2 truncating mutations impact myosin presence/functionality in human adult mature myofibers by disrupting the ATPase activity and actomyosin complex. These are likely important molecular pathological disturbances leading to the myopathic phenotype in patients.
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- 2023
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42. High-dose oral glutamine supplementation reduces elevated glutamate levels in cerebrospinal fluid in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.
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Guerrero-Molina MP, Morales-Conejo M, Delmiro A, Morán M, Domínguez-González C, Arranz-Canales E, Ramos-González A, Arenas J, Martín MA, and de la Aleja JG
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- Adult, Female, Humans, Male, Cohort Studies, Dietary Supplements, Glutamic Acid therapeutic use, Glutamine therapeutic use, Acidosis, Lactic, MELAS Syndrome drug therapy, MELAS Syndrome genetics, MELAS Syndrome metabolism, Stroke
- Abstract
Background and Purpose: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA mutations. There are no disease-modifying therapies, and treatment remains mainly supportive. It has been shown previously that patients with MELAS syndrome have significantly increased cerebrospinal fluid (CSF) glutamate and significantly decreased CSF glutamine levels compared to controls. Glutamine has many metabolic fates in neurons and astrocytes, and the glutamate-glutamine cycle couples with many metabolic pathways depending on cellular requirements. The aim was to compare CSF glutamate and glutamine levels before and after dietary glutamine supplementation. It is postulated that high-dose oral glutamine supplementation could reduce the increase in glutamate levels., Method: This open-label, single-cohort study determined the safety and changes in glutamate and glutamine levels in CSF after 12 weeks of oral glutamine supplementation., Results: Nine adult patients with MELAS syndrome (66.7% females, mean age 35.8 ± 3.2 years) were included. After glutamine supplementation, CSF glutamate levels were significantly reduced (9.77 ± 1.21 vs. 18.48 ± 1.34 μmol/l, p < 0.001) and CSF glutamine levels were significantly increased (433.66 ± 15.31 vs. 336.31 ± 12.92 μmol/l, p = 0.002). A side effect observed in four of nine patients was a mild sensation of satiety. One patient developed mild and transient elevation of transaminases, and another patient was admitted for an epileptic status without stroke-like episode., Discussion: This study demonstrates that high-dose oral glutamine supplementation significantly reduces CSF glutamate and increases CSF glutamine levels in patients with MELAS syndrome. These findings may have potential therapeutic implications in these patients., Trial Registration Information: ClinicalTrials.gov Identifier: NCT04948138. Initial release 24 June 2021, first patient enrolled 1 July 2021. https://clinicaltrials.gov/ct2/show/NCT04948138., (© 2022 European Academy of Neurology.)
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- 2023
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43. Loss of function variants in DNAJB4 cause a myopathy with early respiratory failure.
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Weihl CC, Töpf A, Bengoechea R, Duff J, Charlton R, Garcia SK, Domínguez-González C, Alsaman A, Hernández-Laín A, Franco LV, Sanchez MEP, Beecroft SJ, Goullee H, Daw J, Bhadra A, True H, Inoue M, Findlay AR, Laing N, Olivé M, Ravenscroft G, and Straub V
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- Animals, Mice, Mutation genetics, Molecular Chaperones genetics, Molecular Chaperones metabolism, Mutation, Missense, Muscle, Skeletal pathology, Muscular Diseases diagnostic imaging, Muscular Diseases genetics, Respiratory Insufficiency genetics, Respiratory Insufficiency complications, Respiratory Insufficiency pathology
- Abstract
DNAJ/HSP40 co-chaperones are integral to the chaperone network, bind client proteins and recruit them to HSP70 for folding. We performed exome sequencing on patients with a presumed hereditary muscle disease and no genetic diagnosis. This identified four individuals from three unrelated families carrying an unreported homozygous stop gain (c.856A > T; p.Lys286Ter), or homozygous missense variants (c.74G > A; p.Arg25Gln and c.785 T > C; p.Leu262Ser) in DNAJB4. Affected patients presented with axial rigidity and early respiratory failure requiring ventilator support between the 1st and 4th decade of life. Selective involvement of the semitendinosus and biceps femoris muscles was seen on MRI scans of the thigh. On biopsy, muscle was myopathic with angular fibers, protein inclusions and occasional rimmed vacuoles. DNAJB4 normally localizes to the Z-disc and was absent from muscle and fibroblasts of affected patients supporting a loss of function. Functional studies confirmed that the p.Lys286Ter and p.Leu262Ser mutant proteins are rapidly degraded in cells. In contrast, the p.Arg25Gln mutant protein is stable but failed to complement for DNAJB function in yeast, disaggregate client proteins or protect from heat shock-induced cell death consistent with its loss of function. DNAJB4 knockout mice had muscle weakness and fiber atrophy with prominent diaphragm involvement and kyphosis. DNAJB4 knockout muscle and myotubes had myofibrillar disorganization and accumulated Z-disc proteins and protein chaperones. These data demonstrate a novel chaperonopathy associated with DNAJB4 causing a myopathy with early respiratory failure. DNAJB4 loss of function variants may lead to the accumulation of DNAJB4 client proteins resulting in muscle dysfunction and degeneration., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2023
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44. [Medical emergency card for Steinert's disease: an unmet need].
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Rosado-Bartolomé A and Domínguez-González C
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- Humans, Male, Female, Muscle Weakness, Paresis, Myotonic Dystrophy diagnosis, Myotonic Dystrophy genetics, Myotonic Dystrophy therapy, Emergency Medical Services
- Abstract
Introduction: Myotonic dystrophy type 1 (DM1) or Steinert's disease (ORPHA 273; OMIM #160900) is a rare disorder of genetic origin with muscular manifestations (muscle weakness and myotonia), early-onset cataracts (before 50 years of age) and systemic manifestations (cerebral, endocrine, cardiac, gastrointestinal tract, uterus, skin and immune system). Its clinical expressivity is highly variable and ranges from lethal forms in infancy to mild late-onset disease. Its low frequency prevents emergency medical professionals from becoming familiar with the essential precautions for its treatment. In order to alleviate this lack of information, those affected by DM1 have, in the countries of our environment, a medical emergency card (Tarjeta de Emergencias Medicas, TEM) that the patient should always carry with him/her and give to the physician before receiving emergency care., Objectives: To define the TEM. To describe the TEM for DM1 already implemented. To list the advantages for patients and professionals of their use., Material and Methods: Some of the TEM for DM1 currently in use in France and the United Kingdom are described., Results: The arguments justifying their implantation in our setting are presented in detail., Conclusions: The TEM for DM1 managed by a physician can improve the emergency medical care of patients affected by Steinert's disease.
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- 2023
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45. Survey on the management of Pompe disease in routine clinical practice in Spain.
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Domínguez-González C, Díaz-Marín C, Juntas-Morales R, Nascimiento-Osorio A, Rivera-Gallego A, and Díaz-Manera J
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- Humans, alpha-Glucosidases genetics, alpha-Glucosidases therapeutic use, Spain, Surveys and Questionnaires, Glycogen Storage Disease Type II drug therapy
- Abstract
Background: Despite the availability of several clinical guidelines, not all health professionals use their recommendations to manage patients with Pompe disease, a rare genetic disorder involving high-impact therapy. Through several discussion meetings and a survey, the present study aimed to learn about the management of Pompe disease in routine clinical practice in Spain, to improve clinical care in a real-life situation., Results: The survey was sent to 42 healthcare professionals who manage patients with Pompe disease in their clinical practice. Although most respondents followed the clinical guidelines, clinical practice differed from the expert recommendations in many cases. Approximately 7% did not request a genetic study to confirm the diagnosis before starting treatment, and 21% considered that only two dried blood spot determinations suffice to establish the diagnosis. About 76% requested anti-GAA antibodies when there is a suspicion of lack of treatment efficacy, though a significant percentage of respondents have never requested such antibodies. According to 31% of the respondents, significant impairment of motor function and/or respiratory insufficiency is a requirement for authorizing medication at their hospital. Up to 26% waited for improvements over the clinical follow-up to maintain treatment and withdrew it in the absence of improvement since they did not consider disease stabilization to be a satisfactory outcome., Conclusions: The results highlight the lack of experience and/or knowledge of some professionals caring for patients with Pompe disease. It is necessary to develop and disseminate simple guidelines that help to apply the expert recommendations better or centralize patient follow-up in highly specialized centers., (© 2022. The Author(s).)
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- 2022
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46. A novel MLIP truncating variant in an 80-year-old patient with late-onset progressive weakness.
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Bermejo-Guerrero L, Arteche-López A, de Fuenmayor Fernández de la Hoz C, Hernández-Laín A, Martín MA, and Domínguez-González C
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- Aged, 80 and over, Humans, Muscle Weakness genetics, Genetic Variation
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- 2022
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47. Clinical, Biochemical, and Molecular Characterization of Two Families with Novel Mutations in the LDHA Gene (GSD XI).
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Serrano-Lorenzo P, Rabasa M, Esteban J, Hidalgo Mayoral I, Domínguez-González C, Blanco-Echevarría A, Garrido-Moraga R, Lucia A, Blázquez A, Rubio JC, Palma-Milla C, Arenas J, and Martín MA
- Subjects
- Humans, Female, Lactate Dehydrogenase 5, Isoenzymes genetics, Isoenzymes metabolism, Codon, Nonsense, Lactic Acid metabolism, Pyruvic Acid, Mutation, Glycogen Storage Disease, Dermatitis
- Abstract
Lactate dehydrogenase (LDH) catalyzes the reversible conversion of L-lactate to pyruvate. LDH-A deficiency is an autosomal recessive disorder (glycogenosis type XI, OMIM#612933) caused by mutations in the LDHA gene. We present two young adult female patients presenting with intolerance to anaerobic exercise, episodes of rhabdomyolysis, and, in one of the patients, psoriasis-like dermatitis. We identified in the LDHA gene a homozygous c.410C>A substitution that predicts a p.Ser137Ter nonsense mutation in Patient One and a compound heterozygous c.410C>A (p.Ser137Ter) and c.750G>A (p.Trp250Ter) nonsense mutation in Patient Two. The pathogenicity of the variants was demonstrated by electrophoretic separation of LDH isoenzymes. Moreover, a flat lactate curve on the forearm exercise test, along with the clinical combination of myopathy and psoriatic-like dermatitis, can also lead to the diagnosis.
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- 2022
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48. Adult-onset nemaline myopathy due to a novel homozygous variant in the TNNT1 gene.
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Martín-Jiménez P, Fuenmayor-Fernández de la Hoz CP, Hernández-Laín A, Arteche-López A, Quesada-Espinosa JF, Voth AH, Vesperinas A, Olivé M, and Domínguez-González C
- Subjects
- Adult, Homozygote, Humans, Muscle, Skeletal, Troponin T, Myopathies, Nemaline genetics
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- 2022
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49. Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study.
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Domínguez-González C, Hernández-Voth A, de Fuenmayor-Fernández de la Hoz CP, Guerrero LB, Morís G, García-García J, Muelas N, León Hernández JC, Rabasa M, Lora D, Blázquez A, Arenas J, and Martin MÁ
- Subjects
- Adult, Cohort Studies, Creatinine, Humans, Prognosis, Thymidine Kinase, Vital Capacity physiology, DNA, Mitochondrial
- Abstract
This historical cohort study evaluated clinical characteristics of progression and prognosis in adults with thymidine kinase 2 deficiency (TK2d). Records were available for 17 untreated adults with TK2d (mean age of onset, 32 years), including longitudinal data from 6 patients (mean follow-up duration, 26.5 months). Pearson's correlation assessed associations between standard motor and respiratory assessments, clinical characteristics, and laboratory values. Longitudinal data were assessed by linear regression mixed models. Respiratory involvement progressed at an annual rate of 8.16% decrement in forced vital capacity (FVC). Most patients under noninvasive ventilation (NIV) remained ambulant (12/14, 86%), reduced FVC was not associated with concomitant decline in 6-minute walk test (6MWT), and 6MWT results were not correlated with FVC. Disease severity, assessed by age at NIV onset, correlated most strongly at diagnosis with: creatinine levels (r = 0.8036; P = 0.0009), followed by FVC (r = 0.7265; P = 0.0033), mtDNA levels in muscle (r = 0.7933; P = 0.0188), and age at disease onset (r = 0.7128; P = 0.0042). This population of adults with TK2d demonstrates rapid deterioration of respiratory muscles, which progresses independently of motor impairment. The results support FVC at diagnosis, mtDNA levels in muscle, and age at disease onset as prognostic indicators. Creatinine levels may also be potentially prognostic, as previously reported in other neuromuscular disorders., (Copyright © 2022. Published by Elsevier B.V.)
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- 2022
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50. BNIP3 Is Involved in Muscle Fiber Atrophy in Late-Onset Pompe Disease Patients.
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Carrasco-Rozas A, Fernández-Simón E, Suárez-Calvet X, Piñol-Jurado P, Alonso-Pérez J, de Luna N, Schoser B, Meinke P, Domínguez-González C, Hernández-Laín A, Paradas C, Rivas E, Illa I, Olivé M, Gallardo E, and Díaz-Manera J
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- Atrophy pathology, Humans, Membrane Proteins genetics, Muscle Fibers, Skeletal metabolism, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases metabolism, Glycogen Storage Disease Type II genetics, Glycogen Storage Disease Type II pathology
- Abstract
Late-onset Pompe disease (LOPD) is a rare genetic disorder produced by mutations in the GAA gene and is characterized by progressive muscle weakness. LOPD muscle biopsies show accumulation of glycogen along with the autophagic vacuoles associated with atrophic muscle fibers. The expression of molecules related to muscle fiber atrophy in muscle biopsies of LOPD patients was studied using immunofluorescence and real-time PCR. BCL2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a well-known atrogene, was identified as a potential mediator of muscle fiber atrophy in LOPD muscle biopsies. Vacuolated fibers in LOPD patient muscle biopsies were smaller than nonvacuolated fibers and expressed BNIP3. The current data suggested that BNIP3 expression is regulated by inhibition of the AKT-mammalian target of rapamycin pathway, leading to phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1) at Ser317 by AMP-activated protein kinase. Myoblasts and myotubes obtained from LOPD patients and age-matched controls were studied to confirm these results using different molecular techniques. Myotubes derived from LOPD patients were likewise smaller and expressed BNIP3. Conclusively, transfection of BNIP3 into control myotubes led to myotube atrophy. These findings suggest a cascade that starts with the inhibition of the AKT-mammalian target of rapamycin pathway and activation of BNIP3 expression, leading to progressive muscle fiber atrophy. These results open the door to potential new treatments targeting BNIP3 to reduce its deleterious effects on muscle fiber atrophy in Pompe disease., (Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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