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3.
Acta Neuropathol ; 139(3): 565-582, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31897643

RESUMEN

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.


Asunto(s)
Distroglicanos/metabolismo , Glucosiltransferasas/genética , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Animales , Animales Modificados Genéticamente , Drosophila melanogaster , Femenino , Estudios de Asociación Genética , Glicosilación , Humanos , Masculino , Músculo Esquelético/metabolismo , Distrofia Muscular de Cinturas/metabolismo , Mutación , Linaje , Células Satélite del Músculo Esquelético/patología
4.
Neuromuscul Disord ; 27(12): 1087-1098, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29054425

RESUMEN

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.


Asunto(s)
Síndromes Miasténicos Congénitos/genética , Síndromes Miasténicos Congénitos/fisiopatología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Miasténicos Congénitos/clasificación , Síndromes Miasténicos Congénitos/epidemiología , España/epidemiología , Adulto Joven
5.
Neuromuscul Disord ; 26(11): 789-795, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27634344

RESUMEN

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders. Mutations in CHRNE are one of the most common cause of them and the ɛ1267delG frameshifting mutation is described to be present on at least one allele of 60% of patients with CHRNE mutations. We present a comprehensive description of the heterogeneous clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit in nine members of two large Gipsy kindreds. Our observations indicate that founder Roma mutation 1267delG leads to a phenotype further characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP; but also by facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness that sometimes entails the loss of ambulation. Interestingly, we found in our series a remarkable proportion of patients with a progressive or fluctuating course of the disease. This finding is in some contrast with previous idea that considered this form of CMS as benign, non progressive, and with a low impact on the capacity of ambulation.


Asunto(s)
Síndromes Miasténicos Congénitos/genética , Síndromes Miasténicos Congénitos/fisiopatología , Receptores Nicotínicos/genética , Adolescente , Adulto , Niño , Familia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Miasténicos Congénitos/patología , Síndromes Miasténicos Congénitos/terapia , Fenotipo , Romaní , España , Adulto Joven
6.
Neuromuscul Disord ; 25(7): 548-53, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25998610

RESUMEN

We aimed to screen for Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) or asymptomatic hyperCKemia using dried blood spot (DBS) assays. Subsequently, we aimed to calculate the diagnostic delay between initial symptom presentation and the diagnosis. A prospective, multicenter, observational study was conducted in 348 patients: 146 with unclassified LGMD and 202 with asymptomatic or paucisymptomatic hyperCKemia. We quantified levels of acid alpha-glucosidase (GAA) from dried blood spots analyzed fluorometrically. The test was positive in 20 patients, and Pompe disease was confirmed by genetic testing in 16. Undiagnosed Pompe disease was detected in 7.5% of patients with LGMD and in 2.5% of patients with persistent, idiopathic elevation of serum creatine kinase. The c.-32-13 T > G mutation was found most commonly. The diagnostic delay was 15 years on average. In conclusion, DBS tests are useful and reliable screening tools for Pompe disease. We recommend the dried blood spot test to be included in the diagnostic work-up of patients with unclassified myopathies with proximal weakness and/or hyperCKemia of unknown cause and, when positive, to define the diagnosis, it will have to be confirmed by biochemical and/or molecular genetic analysis.


Asunto(s)
Creatina Quinasa/sangre , Pruebas con Sangre Seca , Enfermedad del Almacenamiento de Glucógeno Tipo II/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedades Metabólicas/sangre , Distrofia Muscular de Cinturas/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Tardío , Femenino , Pruebas Genéticas , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Humanos , Masculino , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/genética , Persona de Mediana Edad , Distrofia Muscular de Cinturas/complicaciones , Distrofia Muscular de Cinturas/enzimología , Mutación , Estudios Prospectivos , Adulto Joven , alfa-Glucosidasas/sangre
8.
J Neurol ; 259(5): 851-4, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-21984193

RESUMEN

Cerebellar adult onset ataxia is a heterogeneous condition. The aim of this study was to ascertain if there is a heightened autoimmune background in patients with sporadic cerebellar ataxia of unknown origin, and if autoimmunity correlates with a more rapid evolution of the ataxia. We selected patients with sporadic progressive adult onset cerebellar ataxia with a follow-up of >5 years. As controls we included 43 patients with genetically demonstrated hereditary ataxia. All patients were tested for a panel of neuronal (onconeuronal, glutamate-decarboxylase [GAD], IgG/IgA transglutaminase 6 antibodies) and systemic non-neuronal antibodies (including IgG/IgA gliadin and transglutaminase 2, thyroperoxidase, thyroglobulin, antinuclear, striational, smooth muscle, mitochondrial, liver kidney microsomal, and parietal gastric cells antibodies). Correlation between the antibodies and disease progression was studied with Cox regression models and Kaplan-Meier plots. Forty-four patients were included. All patients were negative for onconeuronal or GAD antibodies. There were no significant differences between patients and controls in the prevalence of transglutaminase 6, 2, gliadin, or thyroid antibodies. However, when we studied the panel of systemic non-neuronal autoantibodies as a group, antibodies were more frequent in patients with sporadic ataxia (p = 0.018). The presence of one or more systemic non-neuronal antibodies correlated with a faster evolution to stage 2 (loss of independent gait) (p = 0.03) and shorter survival (p = 0.03) in patients with sporadic ataxia. We conclude that there is probably a heightened autoimmune background in some patients with sporadic cerebellar ataxia of unknown origin. The presence of systemic non-neuronal autoantibodies is a prognostic marker.


Asunto(s)
Autoinmunidad/fisiología , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/inmunología , Anciano , Autoanticuerpos/inmunología , Progresión de la Enfermedad , Femenino , Proteínas de Unión al GTP/inmunología , Gliadina/inmunología , Glutamato Descarboxilasa/inmunología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/inmunología , Proteína Glutamina Gamma Glutamiltransferasa 2 , Estudios Retrospectivos , Estadísticas no Paramétricas , Transglutaminasas/inmunología
9.
Clin Genet ; 81(5): 491-4, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-21395566

RESUMEN

Laing myopathy is a distal myopathy caused by mutations in the tail of the slow beta-myosin heavy chain gene MYH7. A large cluster of patients belonging to different families, with Laing myopathy due to p.K1729del mutation, was found in the Safor region, Spain. The same mutation was previously reported in an American family with Italian ancestry. The possibility that p.K1729del in MYH7 might be a founder mutation in the Safor patients and the chance of a common origin with the Italian-American family mutation was investigated by haplotype analyses, mutation data origin estimation and historical inquiry. Our results show that the p.K1729del in MYH7 harboured by patients from the Safor indeed is a founder mutation. A common ancestral origin of this mutation in the Spanish and Italian families is also suggested because they all share a core SNP haplotype at locus MYH7. Data estimation yields the origin of the mutation in the Safor at the beginning of the XVII century, when the Moorish were spelt and the region was resettled with Italian families.


Asunto(s)
Miosinas Cardíacas/genética , Efecto Fundador , Enfermedades Musculares/genética , Mutación , Cadenas Pesadas de Miosina/genética , Población Blanca/genética , Haplotipos , Humanos , Italia , Polimorfismo de Nucleótido Simple , España
10.
Neurology ; 76(2): 172-8, 2011 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-21220721

RESUMEN

OBJECTIVE: We studied a case series of peripheral nerve hyperexcitability (PNH) aiming to describe clinical characteristics, immunologic and cancer associations, antibodies against neuronal antigens (voltage-gated potassium channel antibodies [VGKC-Abs] and other), and muscle biopsy findings. METHODS: Patients presenting with clinical and electrophysiologic signs of PNH were selected. We studied clinical and electrophysiologic features; a panel of non-neuronal organ-specific antibodies, immunofluorescence on rat nervous tissues, and radioimmunoprecipitation for VGKC-Abs; and muscle biopsies. RESULTS: Thirty-eight patients were included. After the exclusion of 6 cases with axonopathy of known origin, patients were subdivided according to the presence of electrophysiologic findings of motor axonopathy and association with cancer: axonopathic-PNH (group A: 12 patients), isolated nonparaneoplastic PNH (group B: 16 patients), and isolated paraneoplastic PNH (3 with thymoma and myasthenia gravis, 1 with thyroid carcinoma). PNH clinical features were similar in groups A and B. We found an overall high prevalence of clinical autoimmunity (33% of group A and 63% of group B) and systemic non-neuronal autoantibodies (42% of group A and 75% of group B). However, VGKC-Abs were only positive in 2 patients of group B. Ten patients underwent muscle biopsy, which showed inflammatory changes in 2 cases and nonspecific myopathic features in 8. CONCLUSIONS: PNH is a heterogeneous disorder involving the peripheral nerves in patients with a high propensity for developing autoimmunity. Associated muscle diseases are frequent in the form of myositis, myasthenia gravis, or nonspecific myopathic pathologic findings. VGKC-Abs were uncommon in this series.


Asunto(s)
Anticuerpos Antinucleares/metabolismo , Músculo Esquelético/patología , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Canales de Potasio con Entrada de Voltaje/metabolismo , Adolescente , Adulto , Anciano , Biopsia , Electrofisiología , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Miastenia Gravis/inmunología , Polineuropatía Paraneoplásica/inmunología , Polineuropatía Paraneoplásica/fisiopatología , Enfermedades del Sistema Nervioso Periférico/patología , Ensayo de Radioinmunoprecipitación , Factores de Riesgo , Timoma/inmunología , Neoplasias de la Tiroides/inmunología , Adulto Joven
11.
Neurology ; 75(8): 732-41, 2010 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-20733148

RESUMEN

OBJECTIVE: To describe a wide range of clinical and pathologic myopathic profiles associated with the p.K1729del mutation in the MYH7 gene, known to cause Laing distal myopathy. METHODS: A study conducted in the Safor region (Spain), setting of a large cluster of patients. Clinical, neurophysiologic, muscle imaging, and muscle biopsy studies and MYH7 gene sequencing were investigated in 32 patients from 4 kindreds. Data from 36 deceased or nonexamined patients were collected from hospital records or relatives. RESULTS: Onset ranged from congenital to the 6th decade. All patients presented weakness of great toe/ankle dorsiflexors and many had associated neck flexor, finger extensor, and mild facial weakness. In most cases, involvement of proximal and axial muscles was observed either clinically or by muscle imaging, sometimes giving rise to scapuloperoneal and limb-girdle syndromes. Disabling myalgias, skeletal deformities, and dilated cardiomyopathy in one patient were associated features. Life expectancy was not reduced but the spectrum of disability ranged from asymptomatic to wheelchair confined. Electromyographic neurogenic features were frequently recorded. Muscle fiber type disproportion, core/minicore lesions, and mitochondrial abnormalities were the most relevant pathologic alterations. All patients carried the p.K1729del mutation in MYH7. CONCLUSIONS: The p.K1729del mutation in the MYH7 gene expresses notable clinical variability and electromyographic and pathologic features that can lead to the misdiagnosis of neurogenic atrophies, congenital myopathies, or mitochondrial myopathies. Mutations in genes encoding other sarcomeric and reticulo-sarcoplasmic proteins involved in calcium regulation share pathologic characteristics with our patients, suggesting a possible pathogenetic connection.


Asunto(s)
Miosinas Cardíacas/genética , Miopatías Distales/genética , Eliminación de Gen , Cadenas Pesadas de Miosina/genética , Adolescente , Adulto , Miosinas Cardíacas/deficiencia , Niño , Preescolar , Miopatías Distales/patología , Miopatías Distales/fisiopatología , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Cadenas Pesadas de Miosina/deficiencia , Linaje , Fenotipo , Índice de Severidad de la Enfermedad , Adulto Joven
12.
Rev Clin Esp ; 205(3): 116-8, 2005 Mar.
Artículo en Español | MEDLINE | ID: mdl-15811279

RESUMEN

Migrations are currently one of the most important sociocultural and political phenomena. As a rule, immigrants are in good health, although the immigration is by itself a mental health risk factor. This population shows common specific problems as adaptation processes, depressive syndromes, or other psychiatric problems. "Ulises' syndrome", depression, and dysthymia are the most common mental health conditions among unlawful non-european community immigrants cared in specific facilities. Similarly to the spanish indigenous population, anxiety disorders and readjustment disorders are the most common diagnoses among legal immigrants cared by Mental Health Services (MHS). Given the impact of sociocultural aspects in the development and clinical manifestations of mental health problems, it is necessary to know the demands of the immigrant population and to adjust current facilities for their care.


Asunto(s)
Depresión/epidemiología , Emigración e Inmigración/estadística & datos numéricos , Humanos , España
13.
Rev. clín. esp. (Ed. impr.) ; 205(3): 116-118, mar. 2005.
Artículo en Es | IBECS | ID: ibc-037001

RESUMEN

Las migraciones constituyen actualmente uno de los más importantes fenómenos socioculturales y políticos. En general, los inmigrantes gozan de buena salud, aunque la inmigración es un factor de riesgo para la salud mental. Esta población presenta problemas específicos comunes como procesos de adaptación, síndromes depresivos u otros problemas psiquiátricos. El «síndrome de Ulises», la depresión y la distimia son las patologías más frecuentes entre los inmigrantes extracomunitarios no regularizados atendidos en dispositivos específicos. Entre los atendidos en Servicios de Salud Mental en situación regular, los diagnósticos más frecuentes son trastornos de ansiedad y trastornos adaptativos de forma semejante a la población autóctona española. Dada la repercusión de los aspectos socioculturales en el desarrollo y manifestación de los problemas de salud mental es necesario el conocimiento de las demandas de los pacientes inmigrantes y la adecuación de los dispositivos actuales para su atención


Migrations are currently one of the most important sociocultural and political phenomena. As a rule, immigrants are in good health, although the immigration is by itself a mental health risk factor. This population shows common specific problems as adaptation processes, depressive syndromes, or other psychiatric problems. «Ulises’ syndrome», depression, and disthymia are the most common mental health conditions among unlawful non-european community immigrants cared in specific facilities. Similarly to the spanish indigenous population, anxiety disorders and readjustment disorders are the most common diagnoses among legal immigrants cared by Mental Health Services (MHS). Given the impact of sociocultural aspects in the development and clinical manifestations of mental health problems, it is necessary to know the demands of the immigrant populatin and to adjust current facilities for their care


Asunto(s)
Humanos , Depresión/epidemiología , Emigración e Inmigración/estadística & datos numéricos , España
14.
Artículo en Español | MEDLINE | ID: mdl-1529747

RESUMEN

A study has been made of 107 HIV infected patients by the C/C. Psychiatry unit in the department of infections diseases, during 1987-1988. In this group the psychiatrist studied the following factors: the AIDS risk group, HIV infection stages, the somatic disorders and the neuropsychiatric complications. Also are described the different aspects of the therapy. The results from the study show that 95% were drug abusers and the most common psychopathological diagnosis were delirium and adjustment disorders.


Asunto(s)
Complejo SIDA Demencia/psicología , Complejo SIDA Demencia/tratamiento farmacológico , Adolescente , Adulto , Femenino , Infecciones por VIH/etiología , Humanos , Masculino , Factores de Riesgo , Factores Socioeconómicos , España
15.
Arch Neurobiol (Madr) ; 53(5): 192-5, 1990.
Artículo en Español | MEDLINE | ID: mdl-2091563

RESUMEN

A clinical study of alcohol hallucinosis was made in 25 patients admitted in the hospital Psiquiátrico de Madrid since 1984 until 1990, taking into account the ICD-9. The 88% of the patients under control improved partially o completely in an average period of 18 days.


Asunto(s)
Alcoholismo/complicaciones , Alucinaciones/etiología , Adulto , Anciano , Femenino , Alucinaciones/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad
16.
Arch Neurobiol (Madr) ; 53(2): 70-2, 1990.
Artículo en Español | MEDLINE | ID: mdl-2222125

RESUMEN

The psychiatric disorders related with HIV infection can take various and complex forms. One case of Hypomania in a drug abuser patient with HIV + is reported, and it is suggested that this virus may produce symptomatology indistinguishable from the functional disorders.


Asunto(s)
Complejo SIDA Demencia/diagnóstico , Trastorno Bipolar/diagnóstico , Infecciones por VIH/complicaciones , Trastornos Relacionados con Sustancias/diagnóstico , Adulto , Cocaína/efectos adversos , Diagnóstico Diferencial , Heroína/efectos adversos , Humanos , Masculino , Abuso de Sustancias por Vía Intravenosa/complicaciones
17.
Arch Neurobiol (Madr) ; 53(1): 13-7, 1990.
Artículo en Español | MEDLINE | ID: mdl-2393336

RESUMEN

The factors determining psychiatric assistance demand: diagnosis, therapeutic indication and continuity, were investigated over the pattern of 101 patients who were attended in a Mental Health Centre in Madrid. There were no differences between the sexes of the patients (53% female, 47% male), 47% younger than 35 years. Referral source was the general practitioner in the 26%. 52% were diagnosed with the neurotic disorder. The 87% accepted the therapeutic indication and the 34% of patients stopped the treatment in different moments.


Asunto(s)
Servicios Comunitarios de Salud Mental/estadística & datos numéricos , Necesidades y Demandas de Servicios de Salud , Investigación sobre Servicios de Salud , Trastornos Mentales/epidemiología , Adolescente , Adulto , Anciano , Continuidad de la Atención al Paciente , Femenino , Humanos , Masculino , Trastornos Mentales/terapia , Persona de Mediana Edad , Aceptación de la Atención de Salud , Estudios Prospectivos , Factores Socioeconómicos , España/epidemiología
18.
Arch Neurobiol (Madr) ; 52(5): 225-7, 1989.
Artículo en Español | MEDLINE | ID: mdl-2619438

RESUMEN

The present article tries to assess home care as tool of community mental health programs. To this end, we undertook a study with a sample of 56 patients who were visited in their own homes by workers of the Hortaleza Mental Health Center. The study reveals different conclusions about the characteristics and efficacy of this treatment modality.


Asunto(s)
Servicios Comunitarios de Salud Mental , Servicios de Atención de Salud a Domicilio , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Evaluación como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad
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