NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement Andoni Echaniz-Laguna a,b,c, * , Bertrand Degos a , Ce ´line Bonnet d , Philippe Latour e , Tarik Hamadouche f , Nicolas Le ´vy f , Bruno Leheup d a De ´partement de Neurologie, Ho ˆpital Civil de Strasbourg, 1 Place de l’Ho ˆpital, BP426, 67091 Strasbourg, France b INSERM U692, Laboratoire de Signalisations Mole ´culaires et Neurode ´ge ´ne ´rescence, 67085 Strasbourg, France c Universite ´ Louis Pasteur, Faculte ´ de Me ´decine, UMRS692, 67085 Strasbourg, France d Service de Me ´decine Infantile 3 et de Ge ´ne ´tique Clinique, Centre Hospitalier Universitaire, Ho ˆpitaux de Brabois-Ho ˆpital d’Enfants, 54511 Vandoeuvre Cedex, France e Unite ´ de Neuroge ´ne ´tique Mole ´culaire, Laboratoire Central de Biologie, Ho ˆpital de l’Antiquaille, 1 rue de l’Antiquaille, 69321 Lyon Cedex 05, France f INSERM U-491, Faculte ´ de Me ´decine de la Timone, 13385 Marseille Cedex 05, France Received 24 June 2006; received in revised form 24 August 2006; accepted 17 October 2006 Abstract Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive demyelinating polyneuropathy, associated with deaf- ness exclusively found in Gypsies and resulting from a homozygous R148X mutation in the N-myc downstream-regulated gene 1 (NDRG1). We report the detailed phenotypic study of a family without Gypsy ancestry, who presented with severe demyelinating polyneuropathy, deafness, subcortical white matter abnormalities on brain magnetic resonance imaging studies, and the R148X mutation in NDRG1. For the first time, central nervous system white matter lesions are demonstrated in CMT4D. This report extends the clinical knowledge of CMT4D and indicates that the role of the R148X mutation in NDRG1 in the central nervous system should be further studied. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Charcot-Marie-Tooth disease type 4D; NDRG1; Deafness; Gypsies 1. Introduction Hereditary motor and sensory neuropathy (HMSN), also called Charcot-Marie-Tooth (CMT) disease, is a common but heterogeneous group of disorders of the peripheral nervous system causing weakness and sensory impairment [1]. The different forms of CMT, either demyelinating or axonal, can be distinguished by electrophysiological determination of motor nerve conduction velocity of the median nerve, the type of inheritance and the mutated gene [1]. The recessive forms of CMT, classified as CMT4, are frequently associated with severe phenotypes and in the past years several genes and loci for either demyelinating or axonal forms of the disease have been identified [1]. Autosomal recessive mutations in the N-myc downstream-regulated gene 1 (NDRG1) cause HMSN-Lom, a demyelinating neuropathy associated with deafness that is also referred as CMT4D [2]. CMT4D is almost exclusively found in Gypsies and results from the private R148X mutation in NDRG1 [2,3]. We report the phenotypic findings in a family without Gypsy ancestry and with CMT4D that presented with 0960-8966/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2006.10.002 * Corresponding author. Tel.: +33 3 88 11 66 62; fax: +33 3 88 11 57 81. E-mail address: Echaniz-Laguna@medecine.u-strasbg.fr (A. Echaniz- Laguna). www.elsevier.com/locate/nmd Neuromuscular Disorders 17 (2007) 163–168