Review Article C9ORF72 repeat expansion: a genetic mutation associated with Amyotrophic Lateral Sclerosis Abhishek Vats a,b , Meenakshi Verma c , M. Gourie-Devi d,e , Vibha Taneja a,* a Department of Research, Sir Ganga Ram Hospital, Rajinder Nagar, Delhi, 110060, India b Department of Biotechnology, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, Delhi, India c CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi 110007, India d Department of Neurophysiology, Sir Ganga Ram Hospital, Rajinder Nagar, Delhi, 110060, India e Emeritus Professor of Neurology, Institute of Human Behaviour and Allied Sciences, New Delhi 110095, India article info Article history: Received 15 June 2014 Accepted 21 July 2014 Available online 14 August 2014 Keywords: C9ORF72 Neurodegenerative disorders Motor neuron disease abstract The advent of genome-wide sequencing and genotyping technologies has made significant contribution towards the understanding of Amyotrophic Lateral Sclerosis (ALS) genetics. The etiology of about 70% of the familial cases and 11% of the sporadic ALS cases can now be attributed to various genes. Since the identification of an expanded hexanucleotide repeat in the intronic region of C9ORF72 as the most common mutation associated with fALS, sALS and FTD, researchers have focused to understand the function and toxicity of this gene. In this review, we discuss the biology of C9ORF72 and describe its genetic and functional association with ALS. Copyright © 2014, Sir Ganga Ram Hospital. Published by Reed Elsevier India Pvt. Ltd. All rights reserved. 1. Introduction Amyotrophic Lateral Sclerosis (ALS), is a neurodegenerative disorder and is the classical form of motor neuron disease (MND). It is a progressive disorder characterized by involvement of upper and lower motor neurons and also the cortical neurons predominantly in the frontal and temporal cortex. The clinical features are muscle atrophy, weakness, fasciculations, spasticity, difficulty in speaking, swallowing and ventilatory dysfunction. The age at onset is in the fifth to seventh decades and the course is usually rapid with survival of 3e5 years and rarely 10 years. 1 Majority of the cases are (90%) sporadic (sALS) and only <10% are familial (fALS). The histopathology of spinal cord shows atrophy of motor neurons, swelling of perikarya and proximal axons, and accumulation of TDP-43-positive and FUS-positive ubiquitinated inclusions. Small eosinophilic inclusions containing cystatin C referred to as bunina bodies are also observed. Extra motor pathology is observed in fronto- temporal cortex, thalamus, spinocerebellar tracts, dorsal columns and substantia nigra. According to the ALS diagnostic guidelines defined at Consensus Conference held inEl Escorial, Spain, in 1990, cognitive impairment was considered as an exclusion crite- rion for the diagnosis of ALS. 2 However in the recent years, it has been recognized that in ALS, changes beyond the motor * Corresponding author. E-mail address: vibha17@yahoo.com (V. Taneja). Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/cmrp current medicine research and practice 4 (2014) 161 e167 http://dx.doi.org/10.1016/j.cmrp.2014.07.002 2352-0817/Copyright © 2014, Sir Ganga Ram Hospital. Published by Reed Elsevier India Pvt. Ltd. All rights reserved.