A French family with Charcot–Marie–Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations
Neuromuscular Disorders. 2012-08-01; 22(8): 735-741
DOI: 10.1016/J.NMD.2012.04.001
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1. Neuromuscul Disord. 2012 Aug;22(8):735-41. doi: 10.1016/j.nmd.2012.04.001. Epub
2012 Apr 28.
A French family with Charcot-Marie-Tooth disease related to simultaneous
heterozygous MFN2 and GDAP1 mutations.
Vital A(1), Latour P, Sole G, Ferrer X, Rouanet M, Tison F, Vital C, Goizet C.
Author information:
(1)Institut des Maladies Neurodégénératives, CNRS UMR 5293, Univ. Bordeaux,
Bordeaux, France.
Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1
encoding ganglioside-induced differentiation associated protein 1 may be
associated with mild neuropathy. The proband, a 41-year-old woman, and her
daughter present a severe axonal form of Charcot-Marie-Tooth (CMT) disease. Both
are heterozygous for the well-described mild variant p.R120W in GDAP1, which was
transmitted by the pauci symptomatic proband’s mother. Given that they had an
early onset in the first decade and delayed walking acquisition, the other genes
implicated in axonal forms of CMT disease were analyzed. A second mutation
truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This
mutation was transmitted by the proband’s father who has normal neurological
examination. The proband underwent two nerve biopsies which showed an axonal
degeneration, myelin modifications, and intra-axonal mitochondria with distorted
cristae. Such abnormal mitochondria have been reported in cases with autosomal
dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1
mutation. Our two cases show that heterozygous truncation of MFN2, which is
silent at least until the sixth decade, when combined with the mild p.R120W GDAP1
variant, leads to a severe neuropathy. This supports the emerging hypothesis of
cumulative effects of MFN2 and GDAP1 mutation.
Copyright © 2012 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.nmd.2012.04.001
PMID: 22546700 [Indexed for MEDLINE]