RESUMEN
Lipoid proteinosis (LP) is a rare form of dermatosis with autosomal recessive inheritance. The present study hypothesized that an extracellular matrix protein 1 (ECM1) gene mutation forms the pathological basis of LP. The association between ECM1 mutation and LP; however, requires further investigation and was thus investigated in the present study. Injury skin tissue samples from patients with LP were collected, along with venous blood samples for genomic DNA extraction. Immunohistochemical staining was performed. Polymerase chain reaction (PCR) was then used to obtain an ECM1 gene fragment, which was sequenced and compared with healthy individuals. Histopathological examination revealed that all included patients fitted the features of LP and PCR amplification of the ECM1 gene in all patients obtained positive results. Patients with LP in the present study exhibited point mutations in the ECM1 gene, including one homozygous mutation (C220G) as previously reported, and one novel homozygous mutation c.508insCTG and two heterozygous mutations (C220G/P.R481X and c507delT/c.l473delT). LP is correlated with ECM1 gene mutation.
Asunto(s)
Proteínas de la Matriz Extracelular/genética , Proteinosis Lipoidea de Urbach y Wiethe/genética , Mutación , Adulto , Anciano , Alelos , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Genotipo , Humanos , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
Lipoid proteinosis (LP) is a rare autosomal recessive disease characterized by deposition of hyaline material in skin and mucosae. Epilepsy, as an extracutaneous manifestation associated with typical mesial temporal calcifications, has already been identified, but its characteristics and long-term prognosis have not been thoroughly investigated. We included 7 consecutive patients with LP with typical intracranial calcifications out of 16 patients with ECM1 mutations and investigated the semiologic features, ictal and interictal EEG findings, and long-term prognosis of epilepsy in this genodermatosis. Four of them had seizures (57.1%), and focal seizures with motionless staring were the most common seizure phenotype, originating from bilateral mesial temporal areas, but interictal spikes were scant. Auras were observed in three patients, mostly as epigastric sensation and déjà vu, which indicated mesial temporal lobe origin. Three patients with homozygous mutations in sixth and seventh exons of the ECM1 gene had a drug-resistant course at the end of long-term follow-up. Molecular genetic testing showed a rare compound heterozygous mutation in one patient, which was also associated with seizures but without drug-resistance. Our findings indicated a spectrum for epilepsy with a desperate drug-resistant course for decades in most patients with LP, which is still an underrecognized disease by neurologists.
Asunto(s)
Epilepsia del Lóbulo Temporal/diagnóstico , Proteínas de la Matriz Extracelular/genética , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Mutación/genética , Convulsiones/diagnóstico , Adulto , Niño , Electroencefalografía/métodos , Epilepsia/genética , Epilepsia/fisiopatología , Epilepsia del Lóbulo Temporal/fisiopatología , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Convulsiones/genética , Convulsiones/fisiopatologíaRESUMEN
Lipoid proteinosis is a rare inherited genodermatosis characterized by hyaline deposits in various tissues. Clinically, it manifests with cutaneous as well as extracutaneous features. Periodic acid-Schiff (PAS)-reactive hyaline deposits in the upper dermis, with localization around blood vessels and eccrine sweat glands, in particular, is the histopathological hallmark finding. On brain imaging, bilateral symmetrical temporal lobe calcifications are considered to be pathognomonic of this disorder. We report a case of lipoid proteinosis in which hyaline deposits were present in the papillary and reticular dermis, without being seen at the periphery of eccrine sweat glands, along with dystrophic calcification. Magnetic resonance imaging (MRI) of brain revealed hydrocephalus, subependymal heterotropia and absent splenium of corpus callosum with no evidence of temporal lobe calcification. Thus, our case highlights the inherent diverse nature of lipoid proteinosis.
Asunto(s)
Calcinosis , Cuerpo Calloso , Dermis/patología , Glándulas Ecrinas/patología , Hidrocefalia , Proteinosis Lipoidea de Urbach y Wiethe , Imagen por Resonancia Magnética , Lóbulo Temporal , Adulto , Calcinosis/diagnóstico por imagen , Calcinosis/metabolismo , Calcinosis/patología , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Dermis/metabolismo , Glándulas Ecrinas/metabolismo , Humanos , Hialina/metabolismo , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/metabolismo , Hidrocefalia/patología , Proteinosis Lipoidea de Urbach y Wiethe/diagnóstico por imagen , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/patología , Masculino , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/metabolismo , Lóbulo Temporal/fisiologíaRESUMEN
MOTIVATION: RNA sequencing enables allele-specific expression (ASE) studies that complement standard genotype expression studies for common variants and, importantly, also allow measuring the regulatory impact of rare variants. The Genotype-Tissue Expression (GTEx) project is collecting RNA-seq data on multiple tissues of a same set of individuals and novel methods are required for the analysis of these data. RESULTS: We present a statistical method to compare different patterns of ASE across tissues and to classify genetic variants according to their impact on the tissue-wide expression profile. We focus on strong ASE effects that we are expecting to see for protein-truncating variants, but our method can also be adjusted for other types of ASE effects. We illustrate the method with a real data example on a tissue-wide expression profile of a variant causal for lipoid proteinosis, and with a simulation study to assess our method more generally.
Asunto(s)
Proteínas de la Matriz Extracelular/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Polimorfismo de Nucleótido Simple/genética , ARN/análisis , Alelos , Proteínas de la Matriz Extracelular/genética , Humanos , Proteinosis Lipoidea de Urbach y Wiethe/genética , Especificidad de Órganos , Isoformas de Proteínas , ARN/genéticaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is associated with multiple factors such as obesity, insulin resistance, and oxidative stress. Nopal, a cactus plant widely consumed in the Mexican diet, is considered a functional food because of its antioxidant activity and ability to improve biomarkers of metabolic syndrome. The aim of this study was to assess the effect of nopal consumption on the development of hepatic steatosis and hepatic oxidative stress and on the regulation of genes involved in hepatic lipid metabolism. Obese Zucker (fa/fa) rats were fed a control diet or a diet containing 4% nopal for 7 wk. Rats fed the nopal-containing diet had â¼50% lower hepatic TG than the control group as well as a reduction in hepatomegaly and biomarkers of hepatocyte injury such as alanine and aspartate aminotransferases. Attenuation of hepatic steatosis by nopal consumption was accompanied by a higher serum concentration of adiponectin and a greater abundance of mRNA for genes involved in lipid oxidation and lipid export and production of carnitine palmitoyltransferase-1 and microsomal TG transfer proteins in liver. Hepatic reactive oxygen species and lipid peroxidation biomarkers were significantly lower in rats fed nopal compared with the control rats. Furthermore, rats fed the nopal diet had a lower postprandial serum insulin concentration and a greater liver phosphorylated protein kinase B (pAKT):AKT ratio in the postprandial state. This study suggests that nopal consumption attenuates hepatic steatosis by increasing fatty acid oxidation and VLDL synthesis, decreasing oxidative stress, and improving liver insulin signaling in obese Zucker (fa/fa) rats.
Asunto(s)
Alimentación Animal , Hígado Graso/dietoterapia , Obesidad/dietoterapia , Opuntia , Estrés Oxidativo , Adiponectina/sangre , Adiponectina/metabolismo , Animales , Dieta , Ingestión de Alimentos , Regulación de la Expresión Génica , Insulina/metabolismo , Metabolismo de los Lípidos , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Hígado/metabolismo , Masculino , Ratas , Ratas Zucker , Transducción de Señal , Aumento de PesoRESUMEN
BACKGROUND: Extracellular matrix protein 1 (ECM1) is a secreted protein expressed in skin. Its dermatological relevance has been highlighted by the discovery of loss-of-function mutations in ECM1 in patients with lipoid proteinosis (LiP). OBJECTIVES: To determine the role of ECM1 in epidermal differentiation by examining gene and protein expression of epidermal differentiation markers in individuals with LiP and histological assessment of transgenic mouse skin that overexpresses Ecm1a in basal or suprabasal epidermis. METHODS: Subconfluent, confluent and postconfluent LiP and control keratinocyte cultures were analysed by Northern and Western blotting for differences in expression of differentiation markers. Expression of these markers was analysed in skin of patients with LiP by immunohistochemistry. To study effects of Ecm1 overexpression on epidermal differentiation, transgenic mice were generated under control of either a keratin 14 or an involucrin promoter. RESULTS: No differential expression of the different markers analysed was observed in LiP keratinocytes compared with controls. No histological differences were found in Ecm1-overexpressing mouse skin compared with wild-type. CONCLUSIONS: Absence of ECM1 does not lead to differences in epidermal differentiation. Moreover, overexpression of Ecm1a in vivo does not exert dramatic effects on epidermal structure. Collectively, these findings suggest no role of ECM1 in epidermal differentiation.
Asunto(s)
Epidermis/patología , Proteínas de la Matriz Extracelular/fisiología , Proteinosis Lipoidea de Urbach y Wiethe/patología , Adulto , Animales , Diferenciación Celular , Células Cultivadas , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Queratinocitos/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Ratones , Ratones Transgénicos , Mutación , Piel/metabolismo , Piel/patologíaRESUMEN
BACKGROUND: Lipoid proteinosis is a rare autosomal recessive disorder characterized by deposition of hyaline-like material in several organs, including skin. Pathogenic mutations have been found in the extracellular matrix protein 1 gene (ECM1). Recent studies have disclosed that ECM1 is also a target antigen for autoantibodies in patients with the acquired disease, lichen sclerosus. Both conditions have been reported to show abnormalities in dermal blood vessels but these changes have not been fully assessed. OBJECTIVE: The purpose of this study was to investigate the architecture of the cutaneous microvasculature in lipoid proteinosis and lichen sclerosus to better determine the role of ECM1 in the skin pathology observed in these disorders. METHODS: Labeling of skin biopsies (lipoid proteinosis, lichen sclerosus and control skin) with antibodies to type IV collagen and laminin-1 and reconstruction of the dermal blood vessels using laser confocal microscopy and computer imaging. RESULTS: In both lipoid proteinosis and lichen sclerosus there was reduplication of the basement membranes surrounding blood vessel walls. There were enlarged vessels in the mid and deep dermis that were orientated parallel to the dermal-epidermal junction. In addition, the normal capillary loop network in the dermal papillae, as well as the subcutaneous plexus and transverse connecting vessels were lacking in both disorders. CONCLUSION: This study demonstrates that skin microvasculature is grossly altered when ECM1 is targeted by inherited mutations (lipoid proteinosis) or acquired autoantibodies (lichen sclerosus) and that this glycoprotein appears to have an important role in regulating blood vessel physiology and anatomy in the skin.
Asunto(s)
Liquen Escleroso y Atrófico/patología , Proteinosis Lipoidea de Urbach y Wiethe/patología , Piel/irrigación sanguínea , Secuencia de Bases , Membrana Basal/patología , Colágeno Tipo VII/metabolismo , ADN/genética , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/fisiología , Proteínas Ligadas a GPI , Glicoproteínas/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Liquen Escleroso y Atrófico/genética , Liquen Escleroso y Atrófico/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/genética , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Masculino , Microcirculación/patología , Microscopía Confocal , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/metabolismo , NetrinasRESUMEN
Hyalinosis cutis et mucosae (lipoid proteinosis, Urbach-Wiethe disease) is a rare syndrome with autosomal recessive inheritance. The disease is characterized by diffuse deposition of a hyalinelike substance in the dermis, submucosal connective tissue, and various internal organs. In this study, the patient demonstrated classic signs and symptoms of lipoid proteinosis except for gingival infiltration. Gingival infiltration is still an unexplainable feature of this disease. In the context of this case, the diagnostic significance of the microscopic findings of the gingival tissues and the possible factors playing a role in gingival hypertrophy, are discussed.
Asunto(s)
Hipertrofia Gingival/etiología , Proteinosis Lipoidea de Urbach y Wiethe/patología , Adulto , Hipertrofia Gingival/metabolismo , Humanos , Hialina/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/complicaciones , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Masculino , SíndromeRESUMEN
The aim of this study has been to assess the clinical presentation and biochemical profile of lipoid proteinosis within a defined pedigree. Glycoprotein analysis was compared to normal values in an attempt to define a biochemical phenotype. Six affected family members were identified with variable degrees of disease expression. The most likely mode of inheritance is autosomal recessive due to consanguinity. Routine laboratory investigations were normal in all family members tested. The total content of mucopolysaccharides, sialic acid and hexosamine in biopsed tissue was significantly lower than normal. Our findings demonstrate that a defect in glycoprotein synthesis, possibly enzymatic, may be the cause of lipid proteinosis and its protean clinical manifestations.
Asunto(s)
Glicosaminoglicanos/metabolismo , Hexosaminas/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/genética , Ácidos Siálicos/metabolismo , Adulto , Anciano , Biomarcadores , Femenino , Humanos , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/patología , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
Lipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and visceral lesions, in which large amounts of amorphous material are constantly found in stroma. Morphological and biochemical studies indicate abnormal collagen production, but little attention has been paid to the lipid component of lesions. Microscopic and ultrastructural studies of skin, with special emphasis on fibroblasts, vessels, nerve endings and eccrine sweat glands, were conducted in two patients with lipoid proteinosis. Biochemical studies were undertaken in cultured fibroblasts. Evidence of lysosomal storage in epithelial cells of eccrine sweat glands and in dermal histiocytes, very similar to that found in some metabolic disorders, particularly Farber disease, was found in both cases. Our findings suggest that two alterations might coexist in lipoid proteinosis, one characterized by impaired normal collagen production and the other related to a metabolic defect which may lead to accumulation of ceramide or more complex lipids.
Asunto(s)
Proteinosis Lipoidea de Urbach y Wiethe/patología , Adulto , Colágeno/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal/patología , Masculino , Microscopía Electrónica , Persona de Mediana EdadRESUMEN
The cutaneous deposition disorders are a group of unrelated conditions characterized by the presence of either endogenous or exogenous substances within the dermis or the subcutis. Part I of this two-part series will focus on metabolic processes involved in the endogenous deposition in the various forms of amyloidosis, porphyria, colloid milium, and lipoid proteinosis. We will also review the clinical, histologic, biochemical, and ultrastructural findings relevant to each disorder. Basic mechanisms of pathogenesis, diagnostic modalities, and treatment options are also discussed.
Asunto(s)
Enfermedades Cutáneas Metabólicas/diagnóstico , Amiloidosis/diagnóstico , Amiloidosis/etiología , Amiloidosis/metabolismo , Amiloidosis/patología , Amiloidosis/terapia , Humanos , Proteinosis Lipoidea de Urbach y Wiethe/diagnóstico , Proteinosis Lipoidea de Urbach y Wiethe/etiología , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/patología , Proteinosis Lipoidea de Urbach y Wiethe/terapia , Porfirias/diagnóstico , Porfirias/etiología , Porfirias/metabolismo , Porfirias/patología , Porfirias/terapia , Piel/metabolismo , Piel/patología , Enfermedades Cutáneas Metabólicas/etiología , Enfermedades Cutáneas Metabólicas/metabolismo , Enfermedades Cutáneas Metabólicas/patología , Enfermedades Cutáneas Metabólicas/terapiaRESUMEN
Lipoprotein(a) was discovered over 30 years age and it is an independent risk factor for atherosclerosis, coronary artery disease and peripheral vascular diseases. Among patients with end stage renal failure lipoprotein(a) levels are higher than in general population and being independent of the type of treatment. Cardiovascular diseases are the most important cause of mortality in ESRD patients. Moreover we have interesting information about possibility of influence of Lp(a) serum levels.
Asunto(s)
Enfermedades Renales/complicaciones , Proteinosis Lipoidea de Urbach y Wiethe/etiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Humanos , Enfermedades Renales/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
We describe a 37-year-old woman who presented with progressive mouth dryness. Physical examination revealed long-standing plaques on the face and upper limbs, papular lesions of the oral cavity and tongue firmness. A lower lip biopsy was performed. Light microscopy demonstrated accumulation of PAS-positive material around blood vessels, capillaries and salivary gland canaliculi as well as focally massive hyaline deposits in the submucosa. Immunohistochemistry revealed widespread presence of type IV collagen in the hyaline material and around thickened blood vessels. Laminin immunoreactivity was particularly strong at thickened basement membranes. The above findings were compatible with lipoid proteinosis, which is likely to involve primary perturbation of collagen metabolism and production of glycoproteins.
Asunto(s)
Proteinosis Lipoidea de Urbach y Wiethe/diagnóstico , Enfermedades de la Boca/diagnóstico , Mucosa Bucal/patología , Adulto , Colágeno/metabolismo , Diagnóstico Diferencial , Dimetilsulfóxido/uso terapéutico , Femenino , Depuradores de Radicales Libres/uso terapéutico , Humanos , Técnicas para Inmunoenzimas , Labio/metabolismo , Labio/patología , Proteinosis Lipoidea de Urbach y Wiethe/tratamiento farmacológico , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Enfermedades de la Boca/tratamiento farmacológico , Enfermedades de la Boca/metabolismo , Mucosa Bucal/metabolismo , Reacción del Ácido Peryódico de Schiff , Porfirias/metabolismo , Porfirias/patología , Piel/metabolismo , Piel/patologíaAsunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/tratamiento farmacológico , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Oxígeno/metabolismo , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/uso terapéutico , Antihipertensivos/administración & dosificación , Quimioterapia Combinada , Prueba de Esfuerzo , Femenino , Fosinopril/administración & dosificación , Fosinopril/uso terapéutico , Humanos , Hipertensión/complicaciones , Proteinosis Lipoidea de Urbach y Wiethe/complicaciones , Masculino , Microcirculación/efectos de los fármacos , Persona de Mediana Edad , Pravastatina/administración & dosificación , Pravastatina/uso terapéuticoRESUMEN
We describe a 65-year-old-man who presented with acute gastrointestinal bleeding secondary to massive submucosal deposits of hyaline material in the small bowel. The histochemical and ultrastructural features of the hyaline substance were typical of lipoid proteinosis, a rare cutaneous disorder in which, to our knowledge, symptomatic compromise of internal organs has not been described previously. The patient was later found to have mild but characteristic mucocutaneous lesions of lipoid proteinosis, as well as asymptomatic deposits in other gastrointestinal sites. Our case documents that severe visceral involvement may occur in lipoid proteinosis, even in previously undiagnosed patients with mild cutaneous manifestations of the disease.
Asunto(s)
Intestino Delgado , Proteinosis Lipoidea de Urbach y Wiethe/patología , Hemorragia/etiología , Humanos , Hialina/metabolismo , Enfermedades Intestinales/complicaciones , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/patología , Intestino Delgado/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/complicaciones , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Surfactant protein D (SP-D) (CP4) is a collagenous surfactant-associated carbohydrate binding protein that is synthesized and secreted by alveolar epithelial cells. Previous studies have shown that intratracheal administration of crystalline silica to rats elicits a marked increase in the alveolar accumulation of surfactant lipids and surfactant protein A (SP-A). The authors examined the accumulation of SP-D using this animal model of alveolar proteinosis. Immunoperoxidase localization of SP-D studies at 2 weeks after silica instillation showed intense staining of intra-alveolar exudates, and cytoplasmic staining of hypertrophic type II cells. Immunoelectron microscopy showed that airspace SP-D was specifically associated with granular material, but not tubular myelin or other membranous structures. SP-D was quantified in bronchoalveolar lavage by immunoassay using antibodies specific for SP-D, and by reversephase HPLC after affinity purification of SP-D on maltosyl-agarose. Within 2 weeks after silica instillation, there was a greater than 45-fold increase in lavage SP-D per lung compared with saline controls, including an almost ten-fold increase in the insoluble or surfactant-associated protein. These studies indicate that the extracellular accumulation of SP-D is markedly increased in silica-induced lipoproteinosis, and that SP-D is associated with amorphous components identified by electron microscopy.
Asunto(s)
Glicoproteínas/metabolismo , Proteinosis Lipoidea de Urbach y Wiethe/metabolismo , Enfermedades Pulmonares/metabolismo , Surfactantes Pulmonares/metabolismo , Animales , Anticuerpos/inmunología , Líquido del Lavado Bronquioalveolar/química , Cromatografía Líquida de Alta Presión , Epitelio/metabolismo , Epitelio/ultraestructura , Glicoproteínas/análisis , Glicoproteínas/inmunología , Técnicas para Inmunoenzimas , Proteinosis Lipoidea de Urbach y Wiethe/inducido químicamente , Enfermedades Pulmonares/inducido químicamente , Microscopía Electrónica , Microscopía Inmunoelectrónica , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/ultraestructura , Proteína D Asociada a Surfactante Pulmonar , Surfactantes Pulmonares/análisis , Surfactantes Pulmonares/inmunología , Ratas , Ratas Endogámicas , Dióxido de SilicioRESUMEN
Lipoid proteinosis is described in a family of Scottish descent. Chromosome studies performed on five members were normal. Direct immunofluorescence studies performed on skin with anti-collagen antibodies showed an abnormal distribution of collagen within the skin. No abnormality was detected in DNA extracted from lymphocytes taken from five family members, when probed with gene probes to collagen types alpha 1 (I), alpha 2 (I), alpha 1 (III) and alpha 2 (V).