Prevalence of <b><i>C9ORF72</i></b> Expansion in a Large Series of Patients with Idiopathic Normal-Pressure Hydrocephalus

Abstract

<b><i>Background/Aims:</i></b> The <i>C9ORF72</i> expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the <i>C9ORF72</i> expansion in idiopathic normal pressure hydrocephalus (iNPH). <b><i>Methods:</i></b> We analysed the <i>C9ORF72</i> expansion in a large cohort of patients with possible iNPH (<i>n</i> = 487) and cognitively intact elderly controls (<i>n</i> = 432; age > 65 years). <b><i>Results:</i></b> While the <i>C9ORF72</i> expansion was detected in 1.6% (<i>n</i> = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of <i>C9ORF72</i> expansion carriers was 59 years (range: 52–67 years), 11 years less than non-carriers (<i>p</i> = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted <i>C9ORF72</i> expansion carriers. <b><i>Conclusion:</i></b> This is the first study cohort identifying the underlying <i>C9ORF72</i> expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the <i>C9ORF72</i> expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms.