The influence of gender on phenotype and disease progression in patients with Huntington’s disease Daniel Zielonka a, * , 1 , Johan Marinus b, 1 , Raymund A.C. Roos b , Giuseppe De Michele c , Stefano Di Donato d , Hein Putter e , Jerzy Marcinkowski a , Ferdinando Squitieri f , Anna Rita Bentivoglio g , G. Bernhard Landwehrmeyer h a Poznan University of Medical Sciences, Department of Social Medicine, Rokietnicka Str., No. 5 “C”, 60-806 Poznan, Poland b Leiden University Medical Center (LUMC), Department of Neurology, K5, Leiden, Netherlands c Dipartimento di Scienze Neurologiche, Università Federico II, Napoli, Italy d Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy e Leiden University Medical Centre (LUMC), Department of Medical Statistics and Bioinformatics, Leiden, Netherlands f Neurogenetics and Rare Disease Centre, IRCCS Neuromed, Pozzilli, Italy g Institute of Neurology U.C.S.C Policlinico “A.Gemeli” Rome, Italy h Universitätsklinik Ulm, Abteilung Neurologie, Ulm, Germany article info Article history: Received 23 July 2012 Received in revised form 25 September 2012 Accepted 26 September 2012 Keywords: Gender CAG repeats Huntington’s disease UHDRS Progression abstract Introduction: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The aim of this study is to determine whether gender plays a role in the phenotypic expression and progression of HD. Methods: 1267 patients with HD (636 women) from the Registry project of the EHDN were included. A cross-sectional analysis (ANCOVA) controlling for differences in age at onset, disease burden, disease duration, smoking status, alcohol abuse, depression and the number of years of education, was per- formed to evaluate if there were differences between men and women in UHDRS motor, function and cognitive scores. Additionally, analyses on follow-up data using linear mixed models with the same covariates were performed to test for gender-related differences in progression. Results: Baseline features did not differ between genders, with the exception of a higher frequency of past and current depression among women, and a higher number of years of education as well as more frequent alcohol abuse and smoking among men. In the cross-sectional ANCOVA analyses of patients with a mid-age HD onset, women showed worse scores than men in the functional domain (TFC, P ¼ 0.001; UHDRS functional, P ¼ 0.033), UHDRS motor (P ¼ 0.033). The longitudinal analyses showed a faster rate of progression in women in the functional assessment (P ¼ 0.025), the motor assessment (P ¼ 0.032) and the independence scale (P ¼ 0.008). Conclusions: These results suggest a complex gender effect on the phenotypical presentation and the rate of disease progression in HD, with slightly more severe phenotype and faster rate of progression in women in especially the motor and functional domains. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Huntington disease (HD) is a neurodegenerative autosomal dominant disorder, caused by a CAG repeat expansion mutation in the HTT gene on the short arm of chromosome 4 [1]. HD is clinically characterized by motor abnormalities, cognitive impairment and behavioural abnormalities [1]. The symptoms usually appear between 30 and 50 years of age (range 2e85 years) in both sexes, which are equally susceptible to HD [1]. Despite the monogenic nature of the disease patients show extensive variation both in presentation and progression. It is recognized that variations in CAG repeat size accounts for up to 73% of the variation in age at onset (AO) [2]. In addition, some features of the phenotypic expression of HD, as well as the rate of disease progression are influenced by the length of the CAG repeat expansion [3,4]. One recent report suggested some influence of gender on disease progression [5], but the relationship between rate of progression and gender has not yet been studied in a large cohort of HD. In the * Corresponding author. Tel.: þ48 504609951; fax: þ48 618547390. E-mail addresses: daniel.zielonka@gmail.com (D. Zielonka), bernhard.landwehrmeyer@uni-ulm.de (G.B. Landwehrmeyer). 1 Both authors contributed equally. Contents lists available at SciVerse ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis 1353-8020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2012.09.012 Parkinsonism and Related Disorders 19 (2013) 192e197