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1.
J Clin Med ; 12(17)2023 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-37685755

RESUMEN

Fabry disease (FD) is a rare lysosomal disorder caused by α-galactosidase A deficiency, and it leads to the systemic deposition of globotriasylceramide. Demonstrations of the storage material in biopsies support this diagnosis. We report a histological and ultrastructural study of biopsies that were performed on 11 individuals from a family with the variant p.Gln279Arg in GLA, which is associated with the classical phenotype of Fabry disease. Intralysosomal deposits were found in all biopsies, corresponding to the skin, kidney, and endomyocardium in both sexes and at different ages. In nine of the skin biopsies, deposits were analysed by immunofluorescence and quantified at the ultrastructural level. Then, the findings were compared according to sex, genotype, and treatment. The quantification of the deposits in the skin biopsies revealed a broader involvement in men than in women. A significant clearance of the deposits was observed in one case after treatment. Tissue involvement was remarkable at diagnosis in all individuals. The findings from the skin biopsies were demonstrative of classic FD, thus supporting the diagnosis; repeated biopsy analyses suggested the benefit of early treatment.

2.
J Neurol ; 269(8): 4253-4263, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35294616

RESUMEN

Gerstmann-Sträussler-Scheinker disease (GSS) is a rare neurodegenerative illness that belongs to the group of hereditary or familial Transmissible Spongiform Encephalopathies (TSE). Due to the presence of different pathogenic alterations in the prion protein (PrP) coding gene, it shows an enhanced proneness to misfolding into its pathogenic isoform, leading to prion formation and propagation. This aberrantly folded protein is able to induce its conformation to the native counterparts forming amyloid fibrils and plaques partially resistant to protease degradation and showing neurotoxic properties. PrP with A117V pathogenic variant is the second most common genetic alteration leading to GSS and despite common phenotypic and neuropathological traits can be defined for each specific variant, strikingly heterogeneous manifestations have been reported for inter-familial cases bearing the same pathogenic variant or even within the same family. Given the scarcity of cases and their clinical, neuropathological, and biochemical variability, it is important to characterize thoroughly each reported case to establish potential correlations between clinical, neuropathological and biochemical hallmarks that could help to define disease subtypes. With that purpose in mind, this manuscript aims to provide a detailed report of the first Spanish GSS case associated with A117V variant including clinical, genetic, neuropathological and biochemical data, which could help define in the future potential disease subtypes and thus, explain the high heterogeneity observed in patients suffering from these maladies.


Asunto(s)
Enfermedad de Gerstmann-Straussler-Scheinker , Priones , Amiloide/genética , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Enfermedad de Gerstmann-Straussler-Scheinker/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/patología , Humanos , Mutación , Placa Amiloide , Priones/genética , Priones/metabolismo
3.
Virchows Arch ; 479(1): 57-67, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33447899

RESUMEN

Clear cytoplasm is a major characteristic feature of most malignant renal neoplasms. Benign clear cells in the renal parenchyma, usually histiocytes, can occasionally be found, but they are infrequently of an epithelial nature. We report histological, immunohistochemical, ultrastructural, and cytogenomic features of clear epithelial cell clusters incidentally found in four kidney specimens. Multiple microscopic clear cell clusters were present in the cortex, often in subcapsular location. They were composed of large epithelial cells with strikingly clear cytoplasm, without nuclear atypia, arranged in solid nests, and some tubules with narrow lumina. Immunohistochemically, they were positive for AE1AE3, PAX 8, EMA, kidney-specific cadherin, cytokeratin 7, E cadherin, and CD117, with focal immunoreactivity for CD10. Carbonic anhydrase IX, vimentin, and markers related to apoptosis and proliferation were negative. Ultrastructurally, the cytoplasms were enlarged and poor in organelles, showing ballooning degeneration. Array comparative genomic hybridization showed no chromosomal gains or losses. Clear cell clusters constitute a rare finding in the kidney and must be differentiated from benign lesions (ectopic adrenal tissue, osmotic tubulopathy, histiocytic clusters, renal adenomas) and renal cell carcinomas. Clear cell clusters appear to be generated from "endocrine-type" atrophic tubules whose cells are enlarged due to intracellular oedema. Immunohistochemistry shows a distal nephron phenotype with a limited expression of a proximal marker, CD10. Coexisting chronic renal disease or ischemic conditions seem to be related to the development of clear cell clusters. Pathological, ultrastructural, and cytogenomic features do not support a preneoplastic nature of this lesion, at least in the cases studied here.


Asunto(s)
Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Riñón/patología , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Carcinoma de Células Renales/química , Carcinoma de Células Renales/ultraestructura , Hibridación Genómica Comparativa , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , Humanos , Inmunohistoquímica , Riñón/química , Riñón/ultraestructura , Neoplasias Renales/química , Neoplasias Renales/ultraestructura , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas
4.
Neuron ; 107(2): 292-305.e6, 2020 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-32375063

RESUMEN

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Dipéptidos/genética , Demencia Frontotemporal/genética , Proteínas Mutantes Quiméricas/genética , Ataxias Espinocerebelosas/genética , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Elementos sin Sentido (Genética)/genética , Expansión de las Repeticiones de ADN , Femenino , Humanos , Intrones/genética , Ratones , Ratones Endogámicos C57BL , Embarazo , Secuencias Repetitivas de Ácidos Nucleicos
5.
Clin Nutr ; 39(5): 1331-1344, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31255348

RESUMEN

Myo-neuropathy of the critically ill patient is a difficult nosological entity to understand and manage. It appears soon after injury, and it is estimated that 20-30% of patients admitted to Intensive Care Units will develop it in some degree. Although muscular and nervous involvement are related, the former has a better prognosis. Myo-neuropathy associates to more morbidity, longer stay in Intensive Care Unit and in hospital, and also to higher costs and mortality. It is considered part of the main determinants of the new entities: the Chronic Critical Patient and the Post Intensive Care Syndrome. This update focuses on aetiology, pathophysiology, diagnosis and strategies that can prevent, alleviate and/or improve muscle (or muscle-nerve) weakness.


Asunto(s)
Enfermedad Crítica , Debilidad Muscular/patología , Enfermedades Musculares/patología , Enfermedades del Sistema Nervioso Periférico/patología , Humanos , Debilidad Muscular/terapia , Enfermedades Musculares/terapia , Enfermedades del Sistema Nervioso Periférico/terapia
6.
Orphanet J Rare Dis ; 13(1): 52, 2018 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-29631605

RESUMEN

BACKGROUND: Fabry disease is a multisystemic lysosomal storage disorder caused by the impairment of α-galactosidase A. The incidence of this rare disease is underestimated due to delayed diagnosis. Moreover, the management of the identified subjects is often complicated by the detection of variants of unclear diagnostic interpretation, usually identified in screening studies. We performed an observational study based on biochemical and genetic analysis of 805 dried blood spot samples from patients with clinical symptoms or family history of this pathology, which were collected from 109 Spanish hospitals, all over the country. RESULTS: We identified 77 new diagnosed patients with mutations related to classical Fabry disease, as well as 2 subjects with c.374A > T; p.His125Leu, a possible new mutation that need to be confirmed. Additionally, we detected 8 subjects carrying genetic variants possibly linked to late onset Fabry disease (p.Arg118Cys and p.Ala143Thr), 4 cases with polymorphism p.Asp313Tyr and 36 individuals with single nucleotide polymorphisms in intronic regions of GLA. Five of the identified mutations (c.431delG; c.1182delA; c.374A > T; c.932 T > C; c.125 T > A; c.778G > A), which were associated with a classical phenotype have not been previously described. Moreover 3 subjects presenting complex haplotypes made up by the association of intronic variants presented impaired levels of GLA transcripts and Gb3 deposits in skin biopsy. CONCLUSIONS: Enzymatic screening for Fabry Disease in risk population (2 or more clinical manifestations or family history of the disease) helped to identify undiagnosed patients and unravel the impairment of GLA expression in some subjects with complex haplotypes.


Asunto(s)
Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/epidemiología , alfa-Galactosidasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Enfermedad de Fabry/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Persona de Mediana Edad , España/epidemiología , Adulto Joven
7.
Clin Neuropathol ; 35(2): 58-65, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26709713

RESUMEN

BACKGROUND: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a clinically and genetically distinct and uncommon variant of SMA that results from irreversible degeneration of α-motor neurons in the anterior horns of the spinal cord and in ganglion cells on the spinal root ganglia. AIMS: To describe the clinical, electrophysiological, neuropathological, and genetic findings, at different stages from birth to death, of a Spanish child diagnosed with SMARD1. PATIENT AND METHODS: We report the case of a 3-monthold girl with severe respiratory insufficiency and, later, intense hypotonia. Paraclinical tests included biochemistry, chest X-ray, and electrophysiological studies, among others. Muscle and nerve biopsies were performed at 5 and 10 months and studied under light and electron microscopy. Post-mortem examination and genetic investigations were performed. RESULTS: Pre- and post-mortem histopathological findings demonstrated the disease progression over time. Muscle biopsy at 5 months of age was normal, however a marked neurogenic atrophy was present in post-mortem samples. Peripheral motor and sensory nerves were severely involved likely due to a primary axonal disorder. Automatic sequencing of IGHMBP2 revealed a compound heterozygous mutation. CONCLUSIONS: The diagnosis of SMARD1 should be considered in children with early respiratory insufficiency or in cases of atypical SMA. Direct sequencing of the IGHMBP2 gene should be performed.


Asunto(s)
Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/fisiopatología , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Proteínas de Unión al ADN/genética , Femenino , Humanos , Lactante , Músculo Esquelético/patología , Atrofia Muscular Espinal/genética , Mutación , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Médula Espinal/patología , Factores de Transcripción/genética
8.
J Neurol Neurosurg Psychiatry ; 83(3): 322-8, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22250184

RESUMEN

BACKGROUND: Published genotype/phenotype data on McArdle disease are limited in sample size. A single national (Spanish) registry of patients with McArdle disease was created with the purpose of analysing their genotypic and phenotypic characteristics. METHODS: A cross sectional study was conducted, collecting demographic, family history, clinical, genotype and functional capacity data from all patients diagnosed with McArdle disease in the Spanish National Health System up to December 2010. RESULTS: 239 cases were recorded (all of Caucasian descent, 102 women; mean±SD age 44±18 years (range 9, 93)); prevalence of ∼1/167 000 people. Two mutant PYGM alleles were identified in 99.6% of cases. Although there was heterogeneity in the severity of symptoms, there were four common diagnostic features: (1) 99.5% of patients reported a history of acute crises of exercise intolerance (accompanied by recurrent myoglobinuria in 50% of cases); (2) in 58% of patients, symptoms started in the first decade of life; (3) 86% of patients repeatedly experienced the 'second wind' phenomenon over life; and (4) 99% of patients had a high basal serum level of total creatine kinase (>200 U/l). Clinical presentation of the disease was similar in men and women and worsened with age. Patients who were physically active had higher levels of cardiorespiratory fitness (by 23%, p=0.003) and were more likely to improve their clinical course over a 4 year period compared with inactive patients (OR 225; 95% CI 20.3 to 2496.7). CONCLUSIONS: The main clinical features of McArdle disease are generally homogeneous and frequently appear during childhood; clinical condition deteriorates with ageing. Active patients have a better clinical outcome and functional capacity.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Actividades Cotidianas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Niño , Estudios Transversales , Progresión de la Enfermedad , Femenino , Genotipo , Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/patología , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/patología , Mioglobinuria/patología , Fenotipo , Sistema de Registros , España , Adulto Joven
9.
Neuromuscul Disord ; 21(12): 817-23, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21802952

RESUMEN

McArdle's disease is the most common muscle glycogenosis. It is caused by the deficiency of myophosphorylase, encoded by the PYGM gene. We studied 123 patients previously diagnosed with McArdle's disease and we identified 20 novel mutations (10 missense and 3 nonsense mutations, 3 small deletions, 2 gross deletions and 2 small insertions). Most patients of this cohort belong to Spanish and French populations. This allowed us to determine the differences between the allelic frequencies of the common mutations R50X and G205S of these populations. The R50X has an allelic frequency in this cohort of about 61.7%, being 68.5% in French and 53.7% in Spanish patients. The G205S had a higher allelic frequency in the Spanish (10.2%) than in the French population (3.2%). Moreover, a clinical study of 91 patients was performed to establish both genotype-phenotype correlation and gender influence in the severity of the disease. We conclude that no genotype-phenotype correlation is evident and that no gender effect is related to the phenotype.


Asunto(s)
Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Mutación , Estudios de Cohortes , Análisis Mutacional de ADN , Francia/epidemiología , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Glucógeno Fosforilasa de Forma Muscular/deficiencia , Enfermedad del Almacenamiento de Glucógeno Tipo V/diagnóstico , Humanos , Fenotipo , España/epidemiología
10.
Neuromuscul Disord ; 21(4): 254-62, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21288719

RESUMEN

This study aimed to identify the genetic defect in a multigenerational family presenting an autosomal dominant myopathy with histological features of congenital fiber type disproportion. Linkage analysis and genetic sequencing identified, in all affected members of the family, the c.5807A>G heterozygous mutation in MYH7, which encodes the slow/ß-cardiac myosin heavy chain. This mutation causes skeletal but not cardiac involvement. Myosin heavy chain expression pattern was also characterized by immunohistochemistry, western blot and q-PCR in muscle biopsies from two patients aged 25 and 62, respectively. While only congenital fiber type disproportion was observed in the younger patient, older patient's biopsy presented aggregates of slow myosin heavy chains, in fiber sub-sarcolemmal region. These clinico-pathologic findings suggest a novel phenotype within the emerging group of hereditary myosin myopathies, which in this family presents typical characteristics of congenital fiber type disproportion in early stages and later evolves to myosin storage myopathy.


Asunto(s)
Miosinas Cardíacas/genética , Fibras Musculares Esqueléticas/patología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación/genética , Mutación/fisiología , Cadenas Pesadas de Miosina/genética , Miosinas/genética , Secuencia de Bases , ADN/química , ADN/genética , Familia , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica/fisiología , Ligamiento Genético , Humanos , Inmunohistoquímica , Isomerismo , Microscopía Electrónica , Datos de Secuencia Molecular , Músculo Esquelético/patología , Miosinas/química , Linaje , Fenotipo , ARN/biosíntesis , ARN/genética
11.
J Inherit Metab Dis ; 33 Suppl 3: S105-11, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20157781

RESUMEN

OBJECTIVE: To perform the ultrastructural examination of a chorionic villi biopsy as a predictor of foetal involvement in the infantile form of glycogenosis type II (Pompe disease). METHODS: Ultrastructural, biochemical and genetic analyses were performed on chorionic villi biopsies of three consecutive pregnancies in a woman with a previous child affected by Pompe disease. RESULTS: In the only affected foetus, glycogen storage was observed in fibrocytes and endothelial cells of a chorionic villi sample at 11 week's gestation. Severe multi-organ involvement was demonstrated in the tissues of the aborted foetus. No abnormal material was found in the chorionic samples of two subsequent pregnancies, and a healthy boy and girl were born at term and remain unaffected. Both exhibited a partial reduction in acid maltase and were carriers of the maternal mutation. CONCLUSIONS: Ultrastructural findings correlated with biochemical and genetic results, providing a clear and early indicator of the definite diagnosis for future pregnancy management or an early therapeutic approach.


Asunto(s)
Muestra de la Vellosidad Coriónica , Vellosidades Coriónicas/ultraestructura , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Microscopía Electrónica de Transmisión , Diagnóstico Prenatal/métodos , Células Cultivadas , Vellosidades Coriónicas/enzimología , Análisis Mutacional de ADN , Células Endoteliales/enzimología , Resultado Fatal , Femenino , Fibroblastos/enzimología , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Edad Gestacional , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Heterocigoto , Humanos , Recién Nacido , Masculino , Mutación , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Embarazo , alfa-Glucosidasas/deficiencia , alfa-Glucosidasas/genética
13.
Vet J ; 183(2): 222-5, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19010069

RESUMEN

Canine Lafora disease is a genetic disorder of carbohydrate metabolism characterised by neurological signs and accumulation of a type of polyglucosan body (PGB), the Lafora body (LB), in the brain and other organs. Normal canine ageing is associated with accumulation of PGBs in the brain, especially those corresponding to corpora amylacea (CA). In this study, two aged dogs that presented with progressive tremors, ataxia and paraplegia had abundant PGBs throughout the brain, mainly in the hypothalamus and molecular layer of the cerebellum. Hypothalamic and cerebellar PGBs from both cases had lower alcohol-resistant metachromasia than CA when stained with toluidine blue. Immunohistochemical studies of these PGBs against neurone-specific enolase (NSE), glial fibrillary acid protein (GFAP), 200 KDa neurofilaments, S-100, Tau, ubiquitin and heat shock proteins 25 and 70, showed some differences to CA.


Asunto(s)
Enfermedades de los Perros/patología , Cuerpos de Inclusión/patología , Enfermedad de Lafora/veterinaria , Envejecimiento/patología , Animales , Encéfalo/patología , Perros , Femenino , Enfermedad de Lafora/patología , Masculino , Sistema Nervioso/patología
14.
Muscle Nerve ; 40(3): 350-7, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19670320

RESUMEN

McArdle disease is an autosomal recessive muscle glycogenosis. In the typical clinical presentation, only exercise-related symptoms are noted. Nevertheless, permanent weakness may occur, usually late in life. In this study we report on the clinical and genetic features of fixed muscle weakness in McArdle disease. Among the 80 McArdle patients being followed at the Institute of Myology of the Salpêtrière Hospital, 9 patients have permanent weakness. The diagnosis of McArdle disease was confirmed by muscle biopsy and genetic investigations. Two patterns of muscle weakness and wasting were noted: (1) proximal and symmetric in 5 patients; and (2) asymmetric, mimicking facioscapulohumeral dystrophy (FSHD) in 4 patients. Computerized tomography scan showed fatty infiltration in the shoulder and pelvic girdle muscles. There was no clear correlation between genotype and the severity of muscle weakness. Proximal muscle weakness appeared after the age of 40 years and affected 11% of subjects in our series of 80 McArdle patients. Among patients over 40 years of age, 37.5% had muscle weakness.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo V/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo V/patología , Debilidad Muscular/etiología , Anciano , Estudios de Cohortes , Análisis Mutacional de ADN , Electromiografía/métodos , Femenino , Predisposición Genética a la Enfermedad , Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Debilidad Muscular/patología , Músculo Esquelético/patología , Distrofia Muscular Facioescapulohumeral/diagnóstico , Mutación/genética , Mioglobinuria/etiología , Mioglobinuria/genética , Tomógrafos Computarizados por Rayos X
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