Huntington disease in subjects from an Israeli Karaite community carrying alleles of intermediate and expanded CAG repeats in the HTT gene: Huntington disease or phenocopy? Yuval O. Herishanu a, ⁎, Ruti Parvari b , Yaakov Pollack b , Ilan Shelef c , Batia Marom a , Tiziana Martino d , Milena Cannella d , Ferdinando Squitieri d, ⁎ a Department of Neurology, Soroka University Medical Center, Beer-Sheva, Israel b Department of Immunology and Microbiology Ben-Gurion University of the Negev Faculty of Health Sciences, Beer-Sheva, Israel c Neuroradiology Unit, Soroka University Medical Center, Beer-Sheva, Israel d Neurogenetics Unit, IRCCS Neuromed, Pozzili (IS), Italy abstract article info Article history: Received 2 January 2008 Received in revised form 1 October 2008 Accepted 10 November 2008 Available online xxxx Keywords: Karaite community Movement disorder Huntington disease pre-mutations Huntington disease mutation penetrance Huntington disease phenocopies We report a cluster of patients from a Karaite Jew community with a movement disorder suggestive of Huntington disease (HD), in some cases associated with repeat lengths below the edge of 36 CAG repeats. The study describes the clinical and genetic features of four patients who were followed over several years. Patients belonged to an inbred family in whom progressive chorea, manifesting predominantly with dystonia and cerebellar features, developed during middle age. Although severe psychiatric symptoms ultimately developed in two of the four patients, cognitive function remained reasonably well preserved in all of them even after several disease years. Moderate cognitive deficits were limited to the visuomotor organization and abstract thinking subtests in three of the four patients. Qualitative brain imaging showed atrophy of brain predominantly involving cortex and cerebellum. Genetic testing revealed a variable mutation penetrance among family members, some affected members showing an upper allele size ranging from 34 to 49, whereas others remained unaffected despite the presence of the full mutation beyond 40 CAG repeats. Co-morbidity with recessive hereditary inclusion body myopathy was found in two subjects from one family. Although the main diagnosis of HD remains to be confirmed by further neuropathological studies, these cases may suggest that HD could manifest with as few as 34 CAG repeats, in some geographic areas, the disease phenotype most probably being influenced by additional, as yet unidentified, genes. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Huntington disease (HD) is dominantly transmitted and caused by a CAG repeat expansion beyond 35 triplets [1]. The first manifestation of HD is often chorea, although in about 8% of the cases the disease may begin with atypical motor symptoms, other than choreic movements [2,3]. The small Jewish sect of Karaites (about 10,000 people in Israel today) represents a movement which broke away from mainstream Judaism in the 8th century in Persia and spread throughout the Middle East to Egypt, and to Southern Russia, Lithuania and Latvia. Because fundamental differences in religious practice prevent Karaites from inter-marrying with rabbinical (non-Karaite) Jews, the high consangui- nity rate in the community favours genetic disease clustering. In one of the Karaite communities, members of several families had HD that manifested with unusual clinical features in some cases associated with 34–35 repeat alleles and co-morbidity with a recessive myopathy. The so called “intermediate” triplet number included in the range between 27 and 35 CAG, susceptible to expand further to a full mutation in offspring during paternal intergenera- tional transmission, is considered pre-mutated and has never so far been described in association with signs and symptoms of HD [4,5,6]. In this study we describe the clinical and genetic findings of the neurological syndrome manifested by six affected individuals from this community, some carrying alleles of intermediate length. 2. Patients and methods 2.1. Family history and genetic testing All subjects were recruited within the Israeli Karaite community, and came from different family branches in two of which the family history disclosed a clear relationship among subjects (Fig. 1). After Journal of the Neurological Sciences xxx (2008) xxx–xxx Abbreviations: HD, Huntington's disease; SCA, spinocerebellar ataxias; LOTCA, Loewenstein occupational therapy cognitive assessment; MMSE, mini-mental state examination; TFC, total functional capacity; CT, computerized tomography; MRI, magnetic resonance imaging; HIBM, hereditary inclusion body myopathy; UHDRS, unified Huntington's disease rating scale. ⁎ Corresponding authors. Herishanu is to be contacted at Omer, PO Box 1161 Israel 84965. Squitieri, Neurogenetics Unit IRCCS Neuromed Localita' Camerelle 86077 – Pozzilli (IS) Italy. E-mail addresses: yuvalh@bgu.ac.il (Y.O. Herishanu), squitieri@neuromed.it (F. Squitieri). JNS-10765; No of Pages 4 0022-510X/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.11.005 Contents lists available at ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns ARTICLE IN PRESS Please cite this article as: Herishanu YO, et al, Huntington disease in subjects from an Israeli Karaite community carrying alleles of intermediate and expanded CAG repeats in the HTT gene..., J Neurol Sci (2008), doi:10.1016/j.jns.2008.11.005