Compound Charcot-Marie-Tooth disease may determine unusual and milder phenotypes

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.

Co‐segregation of a homozygous SMN1 deletion and a heterozygous PMP22 duplication in a patient

“…Sometimes, the combination of two different entities results in a more severe phenotype [9,[13][14][15][16][17]. In other occasions, in contrast, multiple mutations may be associated with milder phenotypes [8,18]. The case here reported represents a different scenario in which an unexpected finding has concluded with the diagnosis of two different entities, although the clinical manifestations correspond only to one of the conditions (SMA).…”

Combination of myotonic dystrophy and hereditary motor and sensory neuropathy

“…Recent studies suggested that atypical or severe phenotypes of CMT may result from combined effects of multiple mutated genes expressing in the peripheral nerves or in the neuromuscular system [14]. Combinations of CMT1A and the other inherited muscle disorders (Duchenne/Becker muscular dystrophy, facioscapulohumeral muscular dystrophy) with severe phenotype were previously reported in the literature [15][16][17].…”

“…They pointed out that the presence of two mutations in the PMP22 gene resulted in attenuation of the individual effects of each mutation. Therefore multiple mutations may be associated not only with more severe forms of disease, but also with milder and/or atypical phenotypes [14].…”

Novel Mutations Involved in Charcot-Marie-Tooth 4C and Intrafamilial Variability: Let's Not Miss the Forest for the Trees

“…12 Indeed, compound heterozygosity in CMT can give genesis to atypical phenotypes and should be considered in cases with the standard clinical course. 13 At the same time, MRI findings inevitably raise the question of whether and to what extent mild ventricular dilation and the sacral cyst have contributed to the severity of symptoms. The fact that these conditions have remained unchanged despite the evolution of the patient's symptoms renders this possibility rather unlikely.…”