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.

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

“…These data reveal vulnerable neuroanatomical structures during the presymptomatic and symptomatic stages, which include ventral and dorsomedial prefrontal cortex, ventral and dorsal insula, anterior cingulate, caudate, and the medial thalamus. These regions are highly anatomically congruent with atrophy patterns found in C9orf72 ‐associated frontotemporal dementia 45, 47, 48, 49, 50. Notably, several studies confirmed that the medial thalamus is a region affected across C9orf72 expansion carriers,50 even during the presymptomatic phase 23, 36, 46.…”

“…In parallel with the ROI analysis, the voxel‐wise analysis showed that certain sparse regions of lower grey matter volumes tended to associate with higher poly(GP), which included regions in the bilateral dorsolateral prefrontal, medial frontal, and lateral temporal cortices. Although higher poly(GP) levels showed a relatively weak association with lower grey matter volumes in our analyses, the regions identified include those atrophied in C9orf72‐ associated FTD patients,45, 47, 48, 49 and show reduced volume in presymptomatic C9orf72 expansion carriers 23, 36…”

“…Similarly, previous studies show no correlation between poly(GP) and NfL,14 nor neurofilament heavy chain (a different neurofilament subunit) in C9orf72 ‐associated ALS 20. Because previous studies have shown lower grey matter volumes in both presymptomatic and symptomatic carriers compared to controls,23, 36, 45, 46 we had hypothesized that higher levels of poly(GP) might be associated with lower grey matter volumes in C9orf72 ‐targeted regions. We found a trend toward higher poly(GP) with lower frontal and cingulate volume in our ROI analysis.…”

Psychotic Symptoms in Frontotemporal Dementia

“…In cohorts of patients with clinical diagnosis of FTD and C9ORF72 repeat expansions, the prevalence of psychosis ranges from 3 to 56 % compared to ∼4 to 14 % in non-carriers [5•, 11, 16-19]. Hallucinations occur in up to 50 % [20] and can include visual, auditory, and somatic. Delusions are present in up to 53 % [5•] and most commonly include paranoid, persecutory, or somatoform delusions.…”

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

“…C9orf72 repeat expansions are involved with a wide spectrum of neurological manifestations 37,38 , involving motor and nonmotor (cognitive and behavioral) phenotypes (syndromes) 38 ( Figure 4). Most clinical data come from populational studies in European countries and in US.…”