COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

Ruth De Diego‐Balaguer ,Katia Youssov,Alexis Brice,Perrine Charles,Amandine Rialland,Cyril Goizet,Emmanuel Dupoux,Bertrand Fontaine,Vincent Damotte,Catherine Schramm,Patrick Maison,Christophe Verny,Charlotte Jacquemot,Alexandra Dürr ,C Tranchant ,Laurent Cléret De Langavant ,Jean‐Philippe Azulay ,I Rebeix ,C Simonin ,David G Schmitz ,Anne‐Catherine Bachoud‐Lévi

doi:10.1371/journal.pone.0161106

Abstract

Little is known about the genetic factors modulating the progression of Huntington’s disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression.

Highlights

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by increased number of CAG repeats in the Huntingtin (Htt) gene on chromosome 4 [1]
Demographics and characteristics of COMT polymorphism groups at the first visit The χ2 goodness-of-fit test confirms that the distribution of COMT genotypes is similar in HD gene carriers and the control group (P = 0.15)
Baseline demographic and clinical characteristics are similar for all COMT polymorphisms except that HD gene carriers with the Met/Val genotype have a lower educational level than those with the Val/Val or Met/Met genotypes

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by increased number of CAG (cytosine adenine guanine) repeats in the Huntingtin (Htt) gene on chromosome 4 [1]. It primarily affects the striatum and manifests as progressive motor, behavioral and cognitive disturbances, leading to death about 15 to 20 years after onset. The factors influencing disease progression remain to be identified [7]. The influence of the number of CAG repeats in the normal Htt allele remains uncertain, either on age at onset or disease progression [3, 9]

Methods

Results

Conclusion