Refining the Clinical Presentation of the C9ORF72 Hexanucleotide Repeat Expansion

Abstract

In 2011, two papers simultaneously described a large hexanucleotide repeat expansion in the first intron of C9ORF72 that is a frequent cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD (1,2). It is a common autosomal dominant gene mutation that encodes a protein of unknown function. Patients with the mutation have a mean disease onset at 56 to 58 years and typically present with behavioral symptoms suggestive of behavioral variant FTD (bvFTD), although there are some individuals in whom ALS is the presenting feature (3). Often, there is a long psychiatric prodrome with myriad symptoms that can suggest bipolar illness, borderline personality disorder, antisocial personality or obsessive-compulsive disorder. Rarely, these patients are misdiagnosed with parkinsonian disorders or Alzheimer’s disease. In this issue of Biological Psychiatry, Galimberti et al. provide a detailed genotype-phenotype description of the clinical characteristics of carriers and noncarriers of the C9ORF72 hexanucleotide repeat expansion (4). With any new discovery in genetics, an accurate clinical description of the presentation helps to determine if diagnostic genetic testing of the patient or predictive genetic testing in the family is warranted. With the potentially long prodromal period with psychiatric symptoms, a detailed phenotype will help to recognize individuals in the early clinical stages of this illness. Of the 39 carriers in their study, 74% had bvFTD, 21% had bvFTD with motor neuron disease, and 5% had semantic variant primary progressive aphasia. Interestingly, none of the patients with diagnoses of corticobasal syndrome, progressive supranuclear palsy, or nonfluent/agrammatic variant primary progressive aphasia were carriers, nor were any of the control participants. Late-onset psychosis (predominant symptoms included hallucinations and delusions) and cognitive impairment (learning and delayed recall) occurred more often in carriers than noncarriers. Most carriers also had a family history of dementia, ALS, or both. These results of this study verify the psychiatric and cognitive clinical presentation of the C9ORF72 repeat. Refining the clinical presentation of each type of pathological or genetic FTD is an essential task as we approach disease-modifying treatments. Accurate diagnoses are essential to build appropriate cohorts for clinical trials, and reliable biomarkers or clinical endpoints are needed to measure the results of treatment to know if the treatment is working.