Académique Documents
Professionnel Documents
Culture Documents
Miguel Pocov
Consideraciones iniciales
Descrita en 1914 por el pediatra alemn Albert Niemann y 1927 patlogo alemn Ludwig Pick. En 1961 el pediatra Allen Crocker distingue cuatro tipos (A, B, C y D) Los tipos C y D tienen como causa un defecto en el transporte intracelular del colesterol que se acumula en su forma libre sin esterificar Un sntoma distintivo es el problema de la mirada fija vertical o parlisis supranuclear de la mirada vertical, consistente en la prdida de la habilidad para mirar arriba o abajo y entonces la persona recurre a mover la cabeza para poder mirar en esas direcciones.
Caractersticas NPC
Autosmica recesiva Totalmente distinta a Niemann-Pick tipos A/B Clnica es muy heterognea Edad de inicio: perodo perinatal - 50 aos Neuro-visceral.
Implicacin subaguda del sistema nervioso Evolucin lenta Deposito visceral leve
Normal cells
NPC cells
Producida por un error en el trafico intracelular del colesterol exgeno que Produce un acumulacin de colesterol no esterificado
rLDL
Colesterol
ApoB LDL
ApoB
Aa
ACAT
ster de Colesterol
Diagnstico
Transition of nonspecific clear foam cells (A) to characteristic sea blue histiocytes; (B) with the gradual accumulation of coarse blue cytoplasmic granules; (C) Bone marrow aspirate, Leishman stain
Algoritmo diagnstico
pdf format
a)
b)
c)
d)
a) Typical NPC patient; b) Subject control ; c) NPC patient with variant phenotype. d) NPC patient with variant phenotype( cells cultured in presence of LDL during 24h)
Tincin citoqumica del colesterol libre con el antibitico fluorescente filipin en fibroblastos cultivados tratados con el inhibidor de esterificacin de colesterol
Tincin citoqumica del colesterol libre con el antibitico fluorescente filipin en fibroblastos cultivados de pacientes afectos con Niemann-Pick tipo C y controles
Tincin citoqumica del colesterol libre con el antibitico fluorescente filipin en fibroblastos cultivados de pacientes afectos con Niemann-Pick tipo C y controles
Otros hallazgos
Descenso en el colesterol HDL Aumento actividad plasmtica Quitotriosidasa Aumento de la concentracin plasmtica de CCL18/PARC Esfingomielinasa normal o ligeramente disminuida
3500
nmol / ml.h
3000 2500
INFANTIL PRECOZ
1 2 4 6
INFANTIL TARDIA
7 9 8
3 5
Meses
1000
500
Meses
10 12 14 11 13 15
19 No Tratamiento
300 400
JUVENIL
ASINTOMATICO
nmol / ml.h
500
200
100
0
16 m 20 m 28 m 32 m 40 m 44 m a os a os 4a
baseline
6m
1 ao
16m
20m
2 aos
28m
32m
3 aos
40m
44m
4 aos
ba se lin
Meses
Meses
a os
a o
6m
4m
3500
INFANTIL PRECOZ
1 2 4
3000 2500
INFANTIL TARDIA
7 8
ngr / ml
2000
3 5
1500
1000 500 0
baseline 6m 1 ao 16m 20m 2 aos 28m 32m 3 aos 40m 44m 4 aos
Meses
1000
500
Meses
19 No Tratamiento
400
JUVENIL
10 12 14
11 13 15
ASINTOMATICO
300
ngr / ml
500
200
100
0
16 m 20 m 28 m 32 m 40 m 44 m a os a os 4a
Meses
Meses
baseline
6m
1 ao
16m
20m
2 aos
28m
32m
3 aos
40m
44m
4 aos
ba se lin
a os
a o
6m
4m
Key facts
The NPC1 gene is located in chromosome 18 and its 55 kb in length, and comprises 25 exons that encode a protein with 1,278 residues. The average size of a NPC1 exon is about 160bp, with very large introns. There are about 240 described mutations of different types, mainly missense/nonsense, distributed along the gene. There isnt a specially frequent mutation in general population. NPC is panethnic and has an estimated prevalence of approximately 1:150,000.
Key facts
The NPC2 gene is located in the chromosome 14 and its 13.4 kb in length, and comprises five exons that encode a protein with 151 residues. The average size of a NPC2 exon (UTRs excluded) is less than 100 bp, with large introns. There are 18 described mutations, mainly missense/nonsense. There isnt a specially frequent mutation in general population. NPC is panethnic and has an estimated prevalence of approximately 1:150,000.
Escala de discapacidad
Tratamiento sintomtico
Tratamientos especficos
En enero 2009se autoriz en la Unin Europea el uso de Miglustat. Experimental Ciclodextrinas ? Aumentar actividad esfingomielinasa acida ?-> clulas pacientes baja actividad? Chaperonas farmacologicas -> mutacin I1061T
(NB-DNJ) Miglustat
Zavesca
Gangliosides
Glucosylceramide synthase
Globosides
Lactosides Glucocerebrosidase
Glucose + Ceramide
CICLODEXTRINAS