SIL1 mutations and clinical spectrum in patients with Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expressio

Argentine consensus on late-onset Pompe's disease

Pompe's disease (PD) is an infrequent metabolic autosomic recessive disorder produced by the lack or deficiency of the acid alpha-glucosidase lysosomal enzyme in tissues of involved individuals. Delayed-onset PD is considered whenever symptoms onset start after one year of age. We present an update of the recommendations for the management of delayed-onset PD, taking as reference the guidelines from the Argentine Consensus for diagnosis, treatment and follow-up of PD published in 2013. The present consensus gathered several experts in PD in the areas of internal medicine, laboratory diagnosis, neuropathology, pulmonology, nutrition, neurology, metabolic and neuromuscular disorders as well as rehabilitation to perform an update of the literature of delayed-onset PD, with special attention on relevant information published within the last 4 years. The entire working group approved the final version of the consensus. Each participant provided a declaration of conflict of interest. As a result, it is an update of the previous Argentine PD Consensus with focus on the delayed-onset presentation of the disease. Being such infrequent disorder, available data were rather limited and thus, the recommendations represent expert opinion

Inmunoglobulina endovenosa en enfermedades neuromusculares. Guía para su utilización

La Inmunoglobulina Endovenosa (IgEV) ha mostrado eficacia en varias enfermedades inmunomediadas del Sistema Nervioso Periférico. Los mecanismos postulados son: inhibir la producción de autoanticuerpos, neutralizarlos y aumentar su catabolismo, inducir bloqueo sobre monocitos y células T, interferir con el Complemento e interactuar con diversas citoquinas. La IgEV es elaborada a partir de la purificación y concentración del plasma de individuos sanos; aplicando diversas metodologías, como tratamiento a pH ácido con trazas de pepsina, cromatografía de intercambio iónico y precipitación con polietilenglicol, para eliminar los polímeros de alto peso molecular. Las entidades en las cuales se evaluó la IgEV más frecuentemente son: Neuropatías inmunomediadas Agudas (Síndrome Guillain-Barré y sus variedades: Síndrome de Miller-Fisher, Neuropatía Axonal Aguda Motora y Neuropatía Axonal Aguda Motora y Sensitiva) y Crónicas (Polineuropatía Inflamatoria Desmielinizante Crónica, Neuropatía Multifocal Motora, Neuropatía Desmielinizante Multifocal Sensitiva y Motora, Neuropatías Asociadas a Paraproteinemia y Neuropatías Atáxicas Crónicas Predominantemente Sensitivas), Enfermedades de la Unión Neuromuscular (Miastenia Gravis y Síndrome de Eaton-Lambert), Miopatías Inflamatorias (Dermatomiositis, Polimiositis y Miositis por Cuerpos de Inclusión) Ganglionopatías Sensitivas y Síndrome de Persona Rígida. La IgEV es fácilmente administrable y generalmente bien tolerada. Los efectos adversos raramente son serios, frecuentemente escalofríos, náuseas, cefalea, mialgias, fatiga y fiebre entre otros, controlables con tratamiento sintomático, y raramente falla renal, infartos miocárdicos, accidentes cerebrovasculares, reacción anafiláctica y meningitis aséptica. La IgEV se contraindica en hipersensibilidad a Inmunoglobulinas y en pacientes con déficit congénito de IgA. La dosis es de 2 g/kg, Clásicamente se distribuye a lo largo de 2-5 días con velocidad de infusión de 40-80 ml/hora.Fil: Figueredo, Alejandra. Sociedad Neurológica Argentina; ArgentinaFil: Altamirano, Lorena. Sociedad Neurológica Argentina; ArgentinaFil: Amores, Mirtha Graciela. Sociedad Neurológica Argentina; ArgentinaFil: Bertotti, Alicia Cristina. Sociedad Neurológica Argentina; ArgentinaFil: Cueto, Alicia. Sociedad Neurológica Argentina; ArgentinaFil: Díaz Livadiotis, Guillermo. Sociedad Neurológica Argentina; ArgentinaFil: Di Egidio, Mariana. Sociedad Neurológica Argentina; ArgentinaFil: Doumic, Javier. Sociedad Neurológica Argentina; ArgentinaFil: Dubrovsky, Alberto. Sociedad Neurológica Argentina; ArgentinaFil: Fulgenzi, Ernesto. Sociedad Neurológica Argentina; ArgentinaFil: Lautre, Andrea. Sociedad Neurológica Argentina; ArgentinaFil: Losavio, Adriana Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Marchesone, Cintia. Sociedad Neurológica Argentina; ArgentinaFil: Martinez Alvarez, Mariana. Sociedad Neurológica Argentina; ArgentinaFil: Mazia, Claudio Gabriel. Sociedad Neurológica Argentina; ArgentinaFil: Melano, Raúl. Sociedad Neurológica Argentina; ArgentinaFil: Orellano, Anabel. Sociedad Neurológica Argentina; ArgentinaFil: Pagano, Miguel Angel. Sociedad Neurológica Argentina; ArgentinaFil: Pardal, Ana Maria. Sociedad Neurológica Argentina; ArgentinaFil: Pirra, Laura. Sociedad Neurológica Argentina; ArgentinaFil: Politei, Juan. Sociedad Neurológica Argentina; ArgentinaFil: Reisin, Ricardo. Sociedad Neurológica Argentina; ArgentinaFil: Rey, Roberto. Sociedad Neurológica Argentina; ArgentinaFil: Rodriguez, Gabriel. Sociedad Neurológica Argentina; ArgentinaFil: Rugiero, Marcelo. Sociedad Neurológica Argentina; ArgentinaFil: Yorio, Alberto. Sociedad Neurológica Argentina; Argentin

Usefulness of the identification of antibodies in peripheral neuropathies, neuronopathies and ganglionopathies: review

Introducción: En los últimos anos ˜ la identificación de anticuerpos y gammapatías monoclonales ha permitido comprender la fisiopatología y favorecer el diagnóstico y tratamiento de una multiplicidad de neuropatías inmunomediadas. Objetivo: Describir los anticuerpos de mayor relevancia clínica en las neuropatías, ganglionopatías y neuronopatías inmunomediadas caracterizando en cada caso su valor fisiopatológico o diagnóstico, así como la sensibilidad y especificidad de los métodos utilizados para su determinación. Desarrollo: Se analizarán los anticuerpos identificados en 1) síndrome de Guillain-Barré; 2) polineuropatía inflamatoria desmielinizante crónica (PDIC), 3) neuropatía motora con bloqueo multifocal (NMM); 4) CANOMAD (neuropatía atáxica crónica, oftalmoplejía, proteína IgM monoclonal, aglutininas frías y anticuerpos disialosil); 5) ganglionopatías y neuronopatías y la utilidad de identificar las gammapatías monoclonales. Conclusiones: Los anticuerpos y las gammapatías monoclonales son herramientas que han permitido mejorar el diagnóstico y la comprensión fisiopatológica de las neuropatías inmunomediadas y algunas criptogénicas, así como orientar el tratamiento más adecuado.Introduction: Over the last several years the identification of both antineural antibodies and monoclonal gammopathies allowed a better understanding of pathophysiology and improvement in the diagnosis and treatment of many different immune mediated neuropathies. Objective: To describe the antineural antibodies of greater clinical utility in the diagnosis of immune mediated neuropathies and neuronopathies. In each case we underline their value in either the pathophysiology or diagnosis of these disorders as well as the sensitivity and specificity of the diagnostic techniques currently in use. Development: We will review the antibodies identified in 1) Guillain-Barré syndrome; 2) Chronic inflammatory demyelinating polyneuropathy (CIDP); 3) Multifocal motor neuropathy (MMN); 4) Chronic Ataxic Neuropathy Ophthalmoplegia M-protein Agglutination Disialosyl antibodies syndrome (CANOMAD); 5) Ganglionopathies and Neuropathies and the value of identifying monoclonal gammopathies. Conclusions: The antibodies and monoclonal gammopathies are useful tools in both the diagnosis and understanding of the mechanisms involved in immune mediated and cryptogenic neuropathies and orienting treatment.Fil: Reisin, Ricardo C.. Hospital Británico de Buenos Aires; ArgentinaFil: Salutto, Valeria Luján. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Aguirre, Florencia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos; ArgentinaFil: Alvarez, Valeria. Hospital Italiano. Departamento de Medicina. Servicio de Neurologia.; ArgentinaFil: Barroso, Fabio. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Bendersky, Mariana. Hospital Italiano. Departamento de Medicina. Servicio de Neurologia.; ArgentinaFil: Berardo, Andrés. Columbia University; Estados UnidosFil: Bettini, Mariela. Hospital Italiano; ArgentinaFil: Borrelli, Mariano M.. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; ArgentinaFil: Chaves, Marcelo. Hospital San Martín de Paraná; ArgentinaFil: Cisneros, Elisa M.. Complejo Medico Policial Bartolome Churruca Andres Visca; ArgentinaFil: Conti, Eugenia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Crespo, José M.. Hospital Británico de Buenos Aires; ArgentinaFil: di Egidio, Mariana. Hospital Enrique Tornú; ArgentinaFil: Figueredo, María Alejandra. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Jáuregui, Agustín. Universidad Favaloro; ArgentinaFil: Landriscina, Paula. Instituto de Neurociencias Buenos Aires S. A.; ArgentinaFil: León Cejas, Luciana. Hospital Británico de Buenos Aires; ArgentinaFil: Martínez Perea, María del Carmen. Hospital Rivadavia; ArgentinaFil: Pirra, Laura. Universidad Favaloro; ArgentinaFil: Pivetta, Paola. Complejo Medico Policial Bartolome Churruca Andres Visca; ArgentinaFil: Quarracino, Cecilia. Complejo Medico Policial Bartolome Churruca Andres Visca; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rattagan, María Lucía. Hospital Italiano; ArgentinaFil: Rey, Roberto. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal General de Agudos Presidente Peron; ArgentinaFil: Rodriguez, Alejandro. Instituto de Neurociencias Buenos Aires S. A.; ArgentinaFil: Rodriguez, Gabriel E.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Rugiero, Marcelo. Hospital Italiano; ArgentinaFil: Tillard, Belen. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Zuberhbuler, Paz. Hospital Alvarez; Argentin

Sil1 Mutations and Clinical Spectrum in Patients with Marinesco-Sjogren Syndrome

Marinesco-Sjogren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjogren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjogren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjogren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjogren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjogren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.Wo