Neurophysiological, behavioral and morphological abnormalities in the Fabry knockout mice.
Fabry disease (OMIM 301500) is a rare X-linked recessive disorder caused by mutations in the alpha-galactosidase gene (GLA). Loss of alpha-galactosidase (alpha-Gal) activity leads to the abnormal accumulation of glycosphingolipids in lysosomes predominantly of vascular endothelial cells. Clinically the disorder presents with angiokeratomas, clouding of the cornea, and renal, cardiac, and cerebrovascular complications. In addition, there is an increased incidence of neuropathic pain in Fabry patients. In this study, we investigated the implications of loss of alpha-galactosidase A activity on sensorimotor function and peripheral nervous system. Similar to the described in Fabry disease patients, the sensorimotor assessment of Fabry mice revealed diminished locomotor activity and warm hypoalgesia as assessed in the hot-plate. Moreover Fabry mice displayed alterations both in balance and co-ordination. By histological analysis, the cyto-architecture of Fabry mice sciatic nerves showed an increase in mean cross-sectional area accompanied by a decrease in the density of non-myelinated fibers as well as a trend for a decreased number of small myelinated fibers, a well established feature of Fabry disease. A relative preservation of large myelinated fibers and nerve conduction velocity measurements was observed. Our findings demonstrate for the first time that Fabry knockout mice have Gb3 accumulation in the peripheral nervous system, alterations in sensorimotor function, hypoalgesia and no impairment of motor nerve conduction.
Lysosome and Peroxisome Biology Unit, Instituto de Biologia Molecular e Celular, Porto, Portugal. lorena@ibmc.up.pt
L G
LG
Rodrigues
M J
MJ
Ferraz
D
D
Rodrigues
M
M
Pais-Vieira
D
D
Lima
R O
RO
Brady
M M
MM
Sousa
M C
MC
Sá-Miranda
D000818:Animals; D001259:Ataxia / Q000503:physiopathology; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D005260:Female; D006028:Glycosphingolipids / Q000378:metabolism; D006358:Hot Temperature; D006987:Hypesthesia / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009412:Nerve Fibers / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D009431:Neural Conduction / Q000502:physiology; D010146:Pain / Q000503:physiopathology; D017933:Peripheral Nervous System / Q000473:pathology* / Q000503:physiopathology* / Q000648:ultrastructure; D010641:Phenotype; D004856:Postural Balance; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D013697:Thermosensing; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
D006028:Glycosphingolipids; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase