The GGGGCC repeat expansion in C9ORF72 in a case with discordant clinical and FDG-PET findings: PET trumps syndrome

Abstract

A hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the cause underlying frontotemporal degeneration (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). In this atypical case of c9FTD/ALS, the proband presented with amnestic mild cognitive impairment which evolved into Alzheimer's disease (AD)-type dementia and later developed ALS. Fluorodeoxyglucose-positron emission tomography of the brain demonstrated mild hypometabolism involving the medial frontal and lateral temporal lobes, left more so than right, which progressed over time. He was subsequently confirmed to have the C9ORF72 expansion. This report highlights the need to consider mutations in the FTD-associated genes when a familial disorder is suggested and neuroimaging studies reveal findings atypical of an AD pathophysiological process despite the typical anterograde amnestic syndrome.

Figure 1. Neuropsychological Profile of Impairment

The subject’s performance on serial neuropsychological tests are grouped according to cognitive domain and displayed graphically. Mayo Older American Normative Studies (MOANS) age-adjusted scaled scores are shown in which 10 represents the mean and the standard deviation is 3. Shaded areas represent scores in the abnormal range. Note the isolated weakness in word list memory task early in the course. Performance on all memory tests declined over time, followed by decline in language and executive functioning. Although percent retention of paragraph length information (WMS-R LM % R) at age 73 years appears to be preserved this is somewhat misleading as his immediate retention was significantly impaired. See text for details. Abbreviations: DRS-2 = Dementia Rating Scale-2; WMS-R LM % R = Wechsler Memory Scale-Revised Logical Memory Percent Retention; WMS-R VR % R = Wechsler Memory Scale-Revised Visual Reproductions Percent Retention; AVLT LT % R = Auditory Verbal Learning Test Long Term Percent Retention; BNT = Boston Naming Test; Letter Flu = Letter Fluency; Categ Flu = Category Fluency; TMT A = Trail Making Test Part A; TMT B = Trail Making Test Part B; Stroop CW = Stroop Color-Word; ReyO = Rey-Osterrieth Complex Figure Test; WAIS-BD = Wechsler Adult Intelligence Scale Block Design; WAIS-PC = Wechsler Adult Intelligence Scale Picture Completion.

Figure 2. Brain MRI

MRI scans at ages 70, 73 and 75 demonstrating the topography of atrophy. Left column of images involves T1-weighted coronal slices (with mesial temporal lobe structures enlarged and placed below each coronal image), middle column of images involves FLAIR axial slices, and right column of images involves T1-weighted midsagittal slices. Note the left more so than right hippocampal atrophy and medial frontal atrophy that progressed over time. Atrophy in the posterior cerebrum and cerebellum is minimal to absent.

Figure 3. FDG-PET Scan

FDG-PET scans at ages 70, 73 and 75. The images from left to right represent Z-score projection maps. Top rows: right lateral, left lateral, right medial, and left medial. Bottom rows: Anterior, posterior, superior, and inferior where the right side of the brain corresponds to the left side of each image. Note that the initial FDG-PET scan shows mild hypometabolism primarily involving the medial and dorsolateral frontal and lateral temporal lobes, left more so than right. Over time, the scans show progression of fronto-temporal hypometabolism, worse on the left, with involvement of the posterior cingulate cortex. The cerebellum is slightly affected at ages 73 and 75 as well.

Figure 4. PiB-PET Scan

PiB-PET scan at age 73. Note the absence of significant PiB uptake in the cortex (ratio 1.1) in the proband compared to the AD case example.