Essential Tremor in a Charcot-Marie-Tooth Type 2C Kindred Does Not Segregate with the TRPV4 R269H Mutation

Abstract

Background: We investigated 4 members of a family with type 2C Charcot-Marie-Tooth (CMT) and self-reported essential tremor (ET). A heterozygous missense mutation, R269H, in the TRPV4 gene was previously reported in this family. Our genotypic data provided a rare opportunity to determine the etiology of the tremor.

Methods: Family study; the 4 tremor cases underwent a detailed neurological assessment.

Results: The clinical diagnosis of ET was confirmed in all 4 tremor cases based on stringent published research criteria. Two of these also had CMT. We genotyped all 4 family members for the TRPV4 R269H mutation. We confirmed the presence of the TRPV4 R269H mutation in the 2 family members with ET and CMT; however, the TRPV4 R269H mutation did not segregate with ET in the same family.

Conclusions: In this particular CMT family, the tremor was clinically attributed to ET. Furthermore, genotype data indicated that the tremor was unlikely to be caused by incomplete penetrance or variable expressivity of the TRPV4 R269H mutation. Hence, the tremor likely represents ET. This establishes that in some CMT families the tremor diathesis likely represents a second disorder, namely ET.

Keywords: Charcot-Marie-Tooth; Essential tremor; Genetics; Neuropathy.

Fig. 1

Pedigree of family and electropherograms showing clinical diagnosis of CMT or ET and family members who carry the TRPV4 mutation. The proband is denoted by an arrow. Squares and circles denote males and females, respectively, and diagonal lines represent deceased individuals. Black squares inside of grey shading represent family members diagnosed with CMT and ET, black squares without gray shading represent family members diagnosed with ET only, and gray shading without black squares represents family members diagnosed with CMT only, and open symbols indicate unaffected individuals. M = TRPV4 c.806G>A (p.R269H); W = wild-type allele.