Proof of genetic heterogeneity in X-linked Charcot–Marie–Tooth disease

Abstract

This study is the first to confirm the CMTX3 locus and to refine the genetic interval to a 5.7-Mb region flanked by the markers DXS1041 and DXS8106. GJB1 mutation-negative forms of X-linked CMT, such as CMTX3, may account for a significant proportion of X-linked CMT.

X‐linked neuropathy of the Charcot–Marie–Tooth type

“…Among 77 families with probable X-linked CMT, only 51% had mutations in GJB1 suggesting that other forms of X-linked CMT including CMTX2-6 as well as additional unknown loci are affected in a significant number of cases [42]. Kennerson et al [43] described an X-linked form of distal hereditary motor neuropathy with a CMT phenotype linked to Xq13.1-21 and associated with missense mutations in ATP7A, the same gene involved in Menkes disease.…”

Neuropathies périphériques héréditaires

“…Les hommes sont plus sévèrement atteints que les femmes et il n'y a pas de transmission père-fils. Il existe d'exceptionnels cas de CMTX récessif dans lesquels les femmes transmettrices sont asymptomatiques [24]. La connexine 32 est exprimée dans différents tissus (foie, cellules épithéliales, oligodendrocytes) mais ses mutations n'induisent que des phénotypes CMT.…”

Re‐analysis of an original CMTX3 family using exome sequencing identifies a known BSCL2 mutation

“…The CMTX3 locus was first described in 1991 in 2 American families. Combined LOD scores of 2.29 (DXS86; h 5 0.0) and 2.32 (DXS105; h 5 0.0) stablished linkage to a 31.2-Mb region on Xq26–28.6 Over a decade later, significant linkage in a large, multigenerational UK and New Zealand family (CMT623) confirmed and refined the CMTX3 locus to a 5.7-Mb interval (Xq26.3–27.1) 12. Re-analysis of 1 of the original American CMTX3 families (US-PED2) and a second large Australian family (CMT193-ext) confirmed segregation of a CMTX3 haplotype and prioritized the gene search to the distal region of the 5.7-Mb interval based on a founder haplotype in US-PED2 13.…”

“…Both USPED2 and CMT623 show axonal involvement with typical signs of CMT, including distal atrophy, high-arched feet (pes cavus), and loss of deep tendon reflexes. Both families show late onset of the disease, and US-PED2 displayed additional signs of spasticity 6,12. In this study we performed exome sequencing analysis on family members from US-PED2.…”