Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease
Niemann-Pick disease (NPD) is a group of rare autosomal recessive lysosomal storage diseases; it comprises two different entities: 1) acid sphingomyelinase deficiency (ASMD) (including NPD types A and B), activity coded by SMPD1 gene, and 2) transport proteins deficiency coded by N...
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Universidad Nacional Cba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2019
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| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/26165 |
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I10-R10-article-26165 |
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Universidad Nacional de Córdoba |
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Revistas de la UNC |
| language |
Español |
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Artículo revista |
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Niemann- Pick disease hepatosplenomegaly acid sphingomyelinase cholesterol lysosome Enfermedad Niemann-Pick hepatoesplenomegalia esfingomielinasa ácida colesterol lisosoma |
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Niemann- Pick disease hepatosplenomegaly acid sphingomyelinase cholesterol lysosome Enfermedad Niemann-Pick hepatoesplenomegalia esfingomielinasa ácida colesterol lisosoma Giner-Ayala, A Angaroni, C Oropeza, G Dodelson de Kremer, R Martinez, LD Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease |
| topic_facet |
Niemann- Pick disease hepatosplenomegaly acid sphingomyelinase cholesterol lysosome Enfermedad Niemann-Pick hepatoesplenomegalia esfingomielinasa ácida colesterol lisosoma |
| author |
Giner-Ayala, A Angaroni, C Oropeza, G Dodelson de Kremer, R Martinez, LD |
| author_facet |
Giner-Ayala, A Angaroni, C Oropeza, G Dodelson de Kremer, R Martinez, LD |
| author_sort |
Giner-Ayala, A |
| title |
Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease |
| title_short |
Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease |
| title_full |
Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease |
| title_fullStr |
Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease |
| title_full_unstemmed |
Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease |
| title_sort |
clinical, biochemical and molecular identification and characterization of argentinean patients with niemann- pick disease |
| description |
Niemann-Pick disease (NPD) is a group of rare autosomal recessive lysosomal storage diseases; it comprises two different entities: 1) acid sphingomyelinase deficiency (ASMD) (including NPD types A and B), activity coded by SMPD1 gene, and 2) transport proteins deficiency coded by NPC1 and NPC2 genes (Types C and D). Type A NPD is a fatal neurodegenerative disorder of infancy. Type B NPD is characterized by being phenotypically variable withhepatosplenomegaly and pulmonary infiltrates. Type C NPD presents a heterogeneous clinical spectrum leading to progressive neurological deterioration.
The aim of this study was to report the clinical, biochemical and molecular studies for the characterization of patients, in the context of a systematic research protocol of this pathology in Argentina.
Research protocol: 1- compatible patient selection, 2- histological and biochemical studies, 3- enzymatic determinations, 4- filipin test in fibroblast culture, 5- molecular analysis.
Out of twenty three studied patients with phenotype compatibility, we diagnosed three patients with NPD: two type B NPD and one type C NPD. Hepatosplenomegaly was observed in Type B NPD patients; they did not present any neurological symptoms. Foam cells were seen in bone marrow biopsy. The liver biopsy transmission electron microscopy (TEM) indicated the presence of electron-lucent vacuoles and electron-dense membranes in hepatocytes. The plasma chitotriosidase enzyme was slightly increased. Sphingomyelinase enzyme level was lower. The SMPD1 gene sequencing revealed that patient 1 is homozygote for the mutation p.R608del. Patient 2 is compound heterozygous, allele 1 p-Ser147leufsTer19 and allele 2 a novel mutation (p.Lys578Thr). The NPD-C patient presented ataxia, mental and motor retardation and language impairment with seizures and hepatosplenomegaly. The skin TEM indicated the presence of electron-lucent vacuoles and multivesicular bodies in fibroblasts. The plasma chitotriosidase was slightly increased. Functional studies in fibroblasts with Filipin were positive. The NPC1 gene sequencing indicated that the patient is homozygote for the missense mutation p.R1186H.
This study indicates that the relevant clinical evaluations combined with histopathological, biochemical and genetic analyses have contributed to an effective diagnostic process for NPD. |
| publisher |
Universidad Nacional Cba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología |
| publishDate |
2019 |
| url |
https://revistas.unc.edu.ar/index.php/med/article/view/26165 |
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2022-08-20T01:27:04Z |
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I10-R10-article-261652019-11-11T21:18:27Z Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease Investigación clínica, bioquímica y molecular para la identificación y caracterización de pacientes con la enfermedad de Niemann-Pick Giner-Ayala, A Angaroni, C Oropeza, G Dodelson de Kremer, R Martinez, LD Niemann- Pick disease hepatosplenomegaly acid sphingomyelinase cholesterol lysosome Enfermedad Niemann-Pick hepatoesplenomegalia esfingomielinasa ácida colesterol lisosoma Niemann-Pick disease (NPD) is a group of rare autosomal recessive lysosomal storage diseases; it comprises two different entities: 1) acid sphingomyelinase deficiency (ASMD) (including NPD types A and B), activity coded by SMPD1 gene, and 2) transport proteins deficiency coded by NPC1 and NPC2 genes (Types C and D). Type A NPD is a fatal neurodegenerative disorder of infancy. Type B NPD is characterized by being phenotypically variable withhepatosplenomegaly and pulmonary infiltrates. Type C NPD presents a heterogeneous clinical spectrum leading to progressive neurological deterioration. The aim of this study was to report the clinical, biochemical and molecular studies for the characterization of patients, in the context of a systematic research protocol of this pathology in Argentina. Research protocol: 1- compatible patient selection, 2- histological and biochemical studies, 3- enzymatic determinations, 4- filipin test in fibroblast culture, 5- molecular analysis. Out of twenty three studied patients with phenotype compatibility, we diagnosed three patients with NPD: two type B NPD and one type C NPD. Hepatosplenomegaly was observed in Type B NPD patients; they did not present any neurological symptoms. Foam cells were seen in bone marrow biopsy. The liver biopsy transmission electron microscopy (TEM) indicated the presence of electron-lucent vacuoles and electron-dense membranes in hepatocytes. The plasma chitotriosidase enzyme was slightly increased. Sphingomyelinase enzyme level was lower. The SMPD1 gene sequencing revealed that patient 1 is homozygote for the mutation p.R608del. Patient 2 is compound heterozygous, allele 1 p-Ser147leufsTer19 and allele 2 a novel mutation (p.Lys578Thr). The NPD-C patient presented ataxia, mental and motor retardation and language impairment with seizures and hepatosplenomegaly. The skin TEM indicated the presence of electron-lucent vacuoles and multivesicular bodies in fibroblasts. The plasma chitotriosidase was slightly increased. Functional studies in fibroblasts with Filipin were positive. The NPC1 gene sequencing indicated that the patient is homozygote for the missense mutation p.R1186H. This study indicates that the relevant clinical evaluations combined with histopathological, biochemical and genetic analyses have contributed to an effective diagnostic process for NPD. La enfermedad de Niemann-Pick (ENP) constituye un grupo de patologías poco frecuentes de atesoramiento lisosomal de herencia autosómica recesiva; comprende dos entidades diferentes: 1) deficiencia en esfingomielinasa ácida (EMA) (incluye ENP Tipos A y B), codificada por el gen SMPD1 y 2) deficiencia en proteínas transportadoras codificadas por los genes NPC1 y NPC2, correspondiente a la ENP (Tipo C y D). La ENP-A es la forma neurovisceral infantil severa. La ENP-B se caracteriza por ser fenotípicamente variable con hepatoesplenomegalia e infiltrados pulmonares. La ENP-C presenta un espectro clínico muy heterogéneo conduciendo a un deterioro neurológico progresivo. El objetivo fue realizar una investigación clínica, bioquímica y molecular que permita la identificación y caracterización de pacientes en el contexto de un protocolo de investigación sistemática de esta patología en la Argentina. Protocolo de investigación: 1- selección de pacientes compatibles, 2- estudios histológicos y bioquímicos, 3- determinaciones enzimáticas, 4- test de filipin en cultivo de fibroblastos, 5- análisis molecular. De 23 individuos estudiados con compatibilidad fenotípica, se diagnosticaron tres pacientes con ENP: dos con ENP-B y un paciente con ENP-C. En los pacientes con ENP-B se observó hepatoesplenomegalia y no presentaron síntomas neurológicos. Estudios realizados en biopsia medular permitió observar células espumosas. La microscopía electrónica de transmisión (MET) en biopsia hepática indicó la presencia de vacuolas electrolúcidas y membranas electrodensas en hepatocitos. La enzima quitotriosidasa plasmática estuvo ligeramente incrementada. La secuenciación del gen SMPD1 reveló que la paciente 1 es homocigota para la mutación p.R608del. La paciente 2 es heterocigota compuesta, en el alelo 1 p.Ser147LeufsTer19 y en el alelo 2 una mutación nueva (p.Lys578Thr). La paciente con ENP-C presento ataxia, retraso psicomotor, convulsiones y hepatoesplenomegalia. La MET de fibroblastos indicó presencia de vacuolas electron lúcidas y cuerpos multivesiculares. La quitotriosidasa plasmática se observó ligeramente incrementada. Los estudios funcionales con Filipin fueron positivos. La paciente es homocigota para la mutación missense p.R1186H del gen NPC1. Este estudio indica que las evaluaciones clínicas relevantes combinadas con estudios histopatológicos, bioquímicos y genéticos han contribuido a un proceso diagnóstico efectivo para la ENP. Universidad Nacional Cba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2019-10-31 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion application/pdf https://revistas.unc.edu.ar/index.php/med/article/view/26165 Revista de la Facultad de Ciencias Médicas de Córdoba.; 2019: Suplemento JIC XX Revista de la Facultad de Ciencias Médicas de Córdoba; 2019: Suplemento JIC XX Revista da Faculdade de Ciências Médicas de Córdoba; 2019: Suplemento JIC XX 1853-0605 0014-6722 spa https://revistas.unc.edu.ar/index.php/med/article/view/26165/27984 Derechos de autor 2019 Universidad Nacional de Córdoba |