Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72

Abstract

Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

Figure 1

Per cent of subjects with impaired neuropsychological test scores. Cognitive impairment defined as test scores less than −1.5 SDs from respective normative sample. AVLT = Auditory Verbal Learning Test; B.Design = Block Design; BNT = Boston Naming Test; Cat. Fluency = Category Fluency; COWAT = Controlled Oral Word Association Test; CVLT-II = California Verbal Learning Test-II; D.Span = Digit Span; JLO = Judgement of Line Orientation; L. Mem = Logical Memory; Stroop C/W = Stroop colour-word interference trial; TMT-B = Trail Making Test part B; V. Rep = Visual Reproduction; WRAT-3 = Reading subtest from the Wide Range Achievement Test-3. Asterisk represents no subject impaired in WRAT-3 Reading test.

Figure 2

Atrophy patterns in individual subjects. MRI scans of individual subjects overlaid with regions of severe atrophy in yellow using MRI STAND-maps (Z-score less than −2.5 relative to normals was used as a threshold). The brightness of the overlaid colour indicates the degree of atrophy. Numbers represent age of each subject in years. Kind = kindred; P = proband; R = relative.

Figure 3

Individual subject relative SPECT intensity maps. SPECT maps shown for a 54-year-old healthy control subject (A), 51-year-old with behavioural variant FTD (B), 51-year-old with behavioural variant FTD (C), 56-year-old with FTDP/ALS (D), and 63-year-old with behavioural variant FTD (E). The relative SPECT intensity for each subject's normalized SPECT scans is overlaid on a template brain for anatomical reference. The healthy control subject is displayed at the top (blue box), and images for subjects B to E are arranged in increasing order of severity of anterior cingulate reduction in SPECT intensity. Colour bar encodes SPECT intensity relative to pontine region of interest.

Figure 4

Fluorodeoxyglucose-PET Z-score 3D-SSP images. PET images shown for a 68-year-old with behavioural variant FTD (A), 69-year-old with behavioural variant FTD (B), 64-year-old with behavioural variant FTD (C), 53-year-old with behavioural variant FTD (D), and 57-year-old with behavioural variant FTD (E). The images from left to right are right lateral, left lateral, right medial, and left medial Z-score projection maps. The upper two rows show mild frontal cortical and cingulate hypometabolism while the lower two show moderate to severe dorsolateral frontal, anterior temporal cortical and cingulate hypometabolism. The middle subject images show a parietal/precuneus pattern of hypometabolism. Subject D in this figure is the same person as Subject B in Fig. 3.

Figure 5

Microscopic findings of c9FTD/ALS. Ubiquitin immunohistochemistry (A) compared with phospho-TDP-43 immunohistochemistry (B) in adjacent sections of dentate fascia of hippocampus (Kindred 14, Case 1.III.1). Note considerably more neuronal inclusions and neurites with ubiquitin. Ubiquitin-positive cerebellar inclusions in same case at lower magnification (C) and higher magnification (D). Frontal cortex phospho-TDP-43 immunohistochemistry: type A in Patient III.1 from Kindred 5 shows short neurites, neuronal inclusions and intranuclear inclusions (inset); and type B in Patient IV.1 from Kindred 12 shows mostly neuronal inclusions, including so-called ‘pre-inclusions’. Scale bar = 30 μm for A–C, E and F and 6 μm for D and E inset.