REPORT Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism Torunn Fiskerstrand, 1,12, * Dorra H’mida-Ben Brahim, 2,11,12 Stefan Johansson, 1 Abderrahim M’zahem, 3 Bjørn Ivar Haukanes, 1 Nathalie Drouot, 2 Julian Zimmermann, 4 Andrew J. Cole, 5 Christian Vedeler, 6,7 Cecilie Bredrup, 8 Mirna Assoum, 2 Meriem Tazir, 9 Thomas Klockgether, 4,10 Abdelmadjid Hamri, 3 Vidar M. Steen, 1,7 Helge Boman, 1 Laurence A. Bindoff, 6,7 Michel Koenig, 2, * and Per M. Knappskog 1,7 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demy- elinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects. Inherited neurodegenerative diseases affecting both the peripheral and central nervous systems and the eye can be caused by a variety of metabolic disturbances. Mito- chondrial dysfunction is a potent cause, 1,2 arising either from mutation in the mitochondrial genome—e.g., neuropathy, ataxia, retinitis pigmentosa (NARP, MIM 551500) and Kearns-Sayre syndrome (ophthalmoplegia, retinal pigmentation, ataxia, and frequently peripheral neuropathy, MIM 530000)—or from a mutated nuclear gene. Friedreich ataxia (MIM 229300) and POLG-related diseases (MIM 174763) are examples of the latter. Defects involving peroxisomal metabolism, such as Refsum disease (MIM 266500) and alpha-methylacyl-CoA racemase (AMACR; MIM 604489) deficiency, also give rise to similar phenotypes. 3 Recently, in a Norwegian family we described a progres- sive, autosomal-recessive, neurodegenerative disease that we ascertained initially as a phenocopy for Refsum disease (Figures 1A–1E). We named the disorder polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, or PHARC 4 (MIM 612674). The disease is slowly progressive, with recognition of the first symptoms typically in the late teens. Although the condition has similarities to Re- fsum disease, patients do not have anosmia and both phy- tanic acid levels and peroxisomal function are normal. We mapped the disease to a 16 Mb region on chromosome 20. 4 Subsequently, additional affected individuals in four coun- tries were identified, and we used homozygosity mapping to identify candidate regions for the mutated gene, fol- lowed by sequencing of candidate genes. For the present study, DNA was obtained from 19 persons affected with PHARC disease and from healthy siblings and parents. The patients (10 females and 9 males) had a mean age of 32.5 years (range 6–62 years) and origi- nated from Norway (n ¼ 8), Algeria (n ¼ 7), the United Arab Emirates (n ¼ 3), and the USA (n ¼ 1) (Table 1). In the previously published Norwegian family, individuals 1.1 and 1.2 are siblings and 1.3 is their third cousin. There are two affected siblings in families 2, 8, 9, and 10, and three affected in family 6. The adults gave informed consent to the investigation and publication of the results. The healthy individuals were not subject to clinical inves- tigation, whereas the affected individuals have all been examined by neurologists, ophthalmologists, and otolo- gists (Table 1). The study was approved of by the Regional Ethics Committee of Western Norway and by the local ethics committees of the University Hospitals of Bonn, Constantine, and Algiers. 1 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; 2 Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), CNRS-INSERM-Universite de Strasbourg, F-67000 Illkirch, France; 3 Centre Hospitalo-Universitaire Benbadis, 25000 Constantine, Algeria; 4 Klinik und Poliklinik fu ¨r Neurologie, Universita ¨tsklinikum, D-53105 Bonn, Germany; 5 The MGH Epilepsy Service, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA; 6 Department of Neurology, Haukeland University Hospital, N-5021 Bergen, Norway; 7 Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway; 8 Department of Ophthalmology, Haukeland University Hospital, N-5021 Bergen, Norway; 9 Service de Neurologie, Centre Hospitalo-Universitaire Mustapha, 16000 Algiers, Algeria; 10 Deutsches Zentrum fu ¨r Neurodegenerative Erkrangungen (DZNE), D-53105 Bonn, Germany; 11 Service de Cytoge ´ne ´tique de Ge ´ne ´tique Mole ´culaire et de Biologie de la Reproduc- tion, CHU Farhat Hached, 4000 Sousse, Tunisia 12 These authors contributed equally to this work *Correspondence: torunn.fiskerstrand@helse-bergen.no (T.F.), mkoenig@igbmc.fr (M.K.) DOI 10.1016/j.ajhg.2010.08.002. Ó2010 by The American Society of Human Genetics. All rights reserved. 410 The American Journal of Human Genetics 87, 410–417, September 10, 2010