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Gaucher
Jauregui Hernandez Leonardo
Sandoval Gutirrez Jos Mara
Philippe Charles Ernest
Gaucher
Realiz por primera vez la descripcin del trastorno en
el ao 1882
Tras observar a un paciente que presentaba aumento
del tamao del hgado y bazo
Qu es la enfermedad de
Gaucher?
Enfermedad hereditaria poco frecuente, pero la
enfermedad de almacenamiento lisosomal ms
comn.
Es causado por mutaciones en el gen GBA.
Dficit en la cantidad de una enzima lisosomal
llamada glucocerebrosidasa/ acido-beta-
glucosidasa
Esto causa una acumulacin de glusocesfingolpidos
como la glucosilceramida/glucodilesfingosina en
macrfagos de todo el cuerpo, principalmente en
bazo, hgado, pulmones, huesos y en el cerebro.
Vigan, Marie et al. Modeling Changes in Biomarkers in Gaucher Disease Patients Receiving
Enzyme Replacement Therapy Using a Pathophysiological Model. Orphanet Journal of Rare
Diseases 9 (2014): 95. PMC. Web. 10 May 2015.
Childrens Gaucher Reasearch Fund, (2010, 10). Gaucher Basics. Children's Gaucher Research Fund .
Recuperado 05, 2015, de http://www.childrensgaucher.org/about-gaucher/gaucher-basics/
Incidencia
La enfermedad de Gaucher se transmite en forma autosmica
recesiva.
Gene cards (2014, 05) GBA Gene. gene cards. Recuperado 05, 2015, de
http://www.genecards.org/cgi-bin/carddisp.pl?gene=GBA
MUTACIONES GBA
Poblacin juda Ashkenazi Poblacin general:
N370S N370S
84GG L444P
L444P
D409H
IVS2+1.8
R463C
IVS2+1.9
LN, C. (2007, 01). Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease.. PubMed.
Recuperado 01, 2015, de http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835853/
Mutation Phenotype Features Enzyme activity Structural features
N370S Mild 70% of mutant Reduced activity; stable Located on longest helix in protein (helix 7),
alleles in Ashkenazi protein at interface of domains II and III. Several
Jews; invariably other mutations are found on this helix
predisposes to mild
(type 1) disease
V394L Severe Reduced activity; stable Near aromatic residues that line one side of
protein the active-site pocket; may disrupt this lining
and, therefore, catalytic activity
L444P Severe Most common Reduced activity; Hydrophobic core of Ig-like domain (domain
mutation that unstable protein II), which may lead to protein instability due
predisposes to to disruption of the hydrophobic core and
severe (types 2 and altered folding of this domain
3) disease
R463C Mild Reduced activity; stable Located on Ig-like domain, distant from the
protein active site
Dvir, H., Harel, et al(2003). X-ray structure of human acid--glucosidase, the defective enzyme in
Gaucher disease. EMBO Reports, 4(7), 704709.
GLUCOCEREBOSIDASA
Dvir, H., Harel, et al(2003). X-ray structure of human acid--glucosidase, the defective
enzyme in Gaucher disease. EMBO Reports, 4(7), 704709.
GLUCOCEREBOSIDASA
536 aminocidos
5 isoformas
3 dominos
DI
DII: Inmunoglobulin-LIKE
DIII: Catalitico, Barril TIM
Sitios activos en E235 y
E340
Dvir, H., Harel, et al(2003). X-ray structure of human acid--glucosidase, the defective enzyme in
Gaucher disease. EMBO Reports, 4(7), 704709.
Mecanismo de Accin
Dvir, H., Harel, et al(2003). X-ray structure of human acid--glucosidase, the defective enzyme in
Gaucher disease. EMBO Reports, 4(7), 704709.
GLUCOCEREBOSIDASA
Mutada
Dvir, H., Harel, et al(2003). X-ray structure of human acid--glucosidase, the defective
enzyme in Gaucher disease. EMBO Reports, 4(7), 704709.
Acumulacin de
Glucocerebrsidos
Los macrfagos con acumulacin de
Glucocerebrsidos son llamados clulas de Gaucher.
Los macrfagos se acumulan en un inicio en hgado,
bazo y mdula sea.
Provocan incremetnto en la produccin de ferritina y
Quitotriosidasa y reducen la hemoglobina y la
concentracin plaquetaria.
van Dussen, L. et al (2014). Modelling Gaucher disease progression: long-term enzyme replacement thera
reduces the incidence of splenectomy and bone complications. PMC. Recuperado 05, 2015, de
Caracteristicas Clinicas
SIGNOS CLINICOS MAS FERCUENTES:
Anemia
Hepatoesplenomegalia
Esplenomegalia
Trombocitopenia
Osteopenia Gaucher
Dolor seo tipo 1
Osteonecrosis Sistema Oseo
discapacidad a largo plazo.
Enfermedad intersticial
Pulmonar
Hipertensin pulmonar.
LABORATORIO:
Actividad enzimtica*
Quitotriosidasa
Glucosilesfingolisina
Rolfs, A., Giese, et al (2013). Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-
Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients. PLoS ONE, 8(11)
TRATAMIENTO
Chaperones moleculares
Celastrol, Ambroxol
Esplenectoma