Abstract
Compound forms of Charcot-Marie-Tooth (CMT) disease have been recently associated with unusually severe neuropathies, an observation that prompted the proposition that the additive effects of two mutations should be searched in patients whose clinical severity falls outside the common CMT phenotypes. In this report, we present a father and a daughter with a very mild and unusual disease that segregates with two mutations in PMP22 gene, the 17p11.2-p12 duplication and a Ser72Leu point mutation. We propose that the deleterious effects of each mutation are partially compensated by the functional effect of the other.
References
Martyn CN, Hughes RA (1997) Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 62:310–318
Thomas PK, Marques W Jr, Davis MB, Sweeney MG, King RH, Bradley JL, Muddle JR, Tyson J, Malcolm S, Harding AE (1997) The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 120(Pt 3):465–478
Garcia CA, Malamut RE, England JD, Parry GS, Liu P, Lupski JR (1995) Clinical variability in two pairs of identical twins with the Charcot-Marie-Tooth disease type 1A duplication. Neurology 45:2090–2093
Marques W Jr, Hanna MG, Marques SR, Sweeney MG, Thomas PK, Wood NW (1999) Phenotypic variation of a new P0 mutation in genetically identical twins. J Neurol 246:596–599
Baas F, Lammens M, de Wissel M, Gabreëls-Festen A, Willemsen M, Fock JM (2007) Severe neuropathy phenotypes are controlled by the action of multiple genes. J Peripher Nerv Syst 12(suppl 1):6
Chung KW, Sunwoo IN, Kim SM, Park KD, Kim WK, Kim TS, Ko H, Cho M, Lee J, Choi BO (2005) Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family. Neurogenetics 6:159–163
Hodapp JA, Carter GT, Lipe HP, Michelson SJ, Kraft GH, Bird TD (2006) Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes. Arch Neurol 63:112–117
Meggouh F, de Visser M, Arts WF, De Coo RI, van Schaik IN, Baas F (2005) Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease. Ann Neurol 57:589–591
Marques W Jr, Sweeney MG, Wood NW (2003) Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type1a due to the 17p duplication. Braz J of Med Biol Res 36:1403–1407
Shy ME, Scavina MT, Clark A, Krajewski KM, Li J, Kamholz J, Kolodny E, Szigeti K, Fischer RA, Saifi GM, Scherer SS, Lupski JR (2006) T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. Ann Neurol 59:358–364
Takashima H, Boerkoel CF, Lupski JR (2001) Screening for mutations in a genetically heterogeneous disorder: DHPLC versus DNA sequence for mutation detection in multiple genes causing Charcot-Marie-Tooth neuropathy. Genet Med 3:335–342
Marques W Jr, Thomas PK, Sweeney MG, Carr L, Wood NW (1998) Dejerine–Sottas neuropathy and PMP22 point mutations: a new base pair substitution and a possible "hot spot" on Ser72. Ann Neurol 43:680–683
Al-Thihli K, Rudkin T, Carson N, Poulin C, Melançon S, Der Kaloustian VM (2008) Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine–Sottas disease phenotype. Am J Med Genet A 146A(18):2412–2416
Marques W Jr, Freitas MR, Nascimento OJM, Oliveira AB, Calia L, Melo A, Lucena R, Rocha V, Barreira AA (2005) 17p duplicared Charcot-Marie-Tooth 1A. Characteristics of a new population. J Neurol 252:972–979
Shy ME, Chance PF, Klein CJ, Dyck PJ (2005) Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic, and pathologic features. In: Dyck PJ, Thomas PK (eds) Peripheral Neuropathy Vol 2. Elsevier, Philadelphia, pp 1623–1658
Marques W Jr, Neto JMP, Barreira AA (2004) Dejerine-Sottas’ neuropathy caused by the missense mutation PMP22 Ser72Leu. Acta Neurol Scand 110:196–199
Houlden HR, Reilly MM (2006) Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease. NeuroMolecular Med 8:43–62
Acknowledgment
The authors thank Mrs. Sandra E. M. Nemoto and Mr. Antônio R. Meireles for their skillful laboratory works. This study was supported by CNPq and FAPESP, Brazil.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gouvea, S.P., S. Borghetti, V.H., Bueno, K.C. et al. Compound Charcot-Marie-Tooth disease may determine unusual and milder phenotypes. Neurogenetics 11, 135–138 (2010). https://doi.org/10.1007/s10048-009-0211-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-009-0211-3