Molecular screening of TTR, GLA and SCN9A genes in patients with painful small fiber neuropathy

• Grant number: 12/14802-9
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): November 01, 2012
• Effective date (End): October 31, 2015
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Wilson Marques Junior
• Grantee: Adriana Borges Genari
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Small nerve fiber neuropathy (SFN) is a relatively common disorder of thinly myelinated and unmyelinated nerve fibers recently recognized as a distinct clinical syndrome. The clinical picture is typically a progressive painful neuropathy beginning in adulthood, and frequently accompanied by autonomic symptoms. This is an incapacitating disease whose etiology is unknown in most patients even after a detailed investigation. Recently it has been raised the possibility that genetic causes may be responsible for at least some of these cases. Sodium channel NaV1.7, encoded by SCN9A, is preferentially expressed within dorsal root ganglion and sympathetic ganglion neurons and their small-diameter peripheral axons. Gain-of-function variants of NaV1.7 have recently been described in patients with SFN and no other found abnormality. Fabry disease (FD) is a rare pathology caused by mutations in the gene GLA encoding the enzyme ±-galactosidase A, a lysosomal hydrolase which detaches the galactose bound in ± from globotriaosylceramide (Gb3) during glycosphingolipid metabolism. The alteration of this process leads to the accumulation of Gb3 inside lysosomes of different cell types, with consequent cellular damage, giving rise to the phenotype of FD. Recent studies suggest that FD is under-diagnosed in the general population. More than 100 mutations in the TTR gene have been found to cause transthyretin amyloidosis. Nearly all of these mutations change one protein building block in the transthyretin protein. The most common mutation found in people with transthyretin amyloidosis replaces the amino acid valine with the amino acid methionine at position 30 in the transthyretin protein (Val30Met). This mutation is seen most commonly in the Portuguese and Swedish populations, although it is found in affected people worldwide. Most of the TTR gene mutations that cause transthyretin amyloidosis are thought to alter the structure of transthyretin, impairing its ability to bind to other transthyretin proteins and altering its normal function. The aim of this study will be screened patients with a suspected clinical diagnosis of SFN. (AU)