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

Bradley F. Boeve; Kevin B. Boylan; Neill R. Graff-Radford; Mariely DeJesus-Hernandez; David S. Knopman; Otto Pedraza; Prashanthi Vemuri; David Jones; Val Lowe; Melissa E. Murray; Dennis W. Dickson; Keith A. Josephs; Beth K. Rush; Mary M. Machulda; Julie A. Fields; Tanis J. Ferman; Matthew Baker; Nicola J. Rutherford; Jennifer Adamson; Zbigniew K. Wszolek; Anahita Adeli; Rodolfo Savica; Brendon Boot; Karen M. Kuntz; Ralitza Gavrilova; Andrew Reeves; Jennifer Whitwell; Kejal Kantarci; Clifford R. Jack, Jr; Joseph E. Parisi; John A. Lucas; Ronald C. Petersen; Rosa Rademakers

doi:10.1093/brain/aws004

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Brain. 2012 Mar; 135(3): 765–783.

Published online 2012 Feb 24. doi: 10.1093/brain/aws004

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Table 6

Key features of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72 compared with FTLD due to mutations in the genes encoding MAPT and PGRN

Feature	C9ORF72	MAPT	PGRN
Demographic
Sex	Male = Female	Male = Female	Male = Female
Age at onset, median (range) (years)	52 (33–72)	45 (25–65)	59 (35–85)
Survival, median (range) (years)	5 (1–17)	7 (2–25)	6 (3–15)
Inheritance
Inheritance pattern	Autosomal dominant	Autosomal dominant	Autosomal dominant
Frequency of sporadic cases	++	+	+
Penetrance	Probably high	Almost 100%	90% by age 70
Anticipation suggested	++	0	+
Clinical
Behavioural variant FTD phenotype	++++	++++	+++
ALS phenotype	++++	+	+
FTD/ALS phenotype	+++	+	+
Parkinsonism	++	+++	++
PPA/corticobasal syndrome phenotype^a	0	+	++
Alzheimer-like phenotype^a	+	+	+
Neuropsychological
Impaired psychomotor speed	++++	++++	++++
Impaired complex attention/executive functioning	++++	++++	++++
Impaired word retrieval	++++	+++	+++
Impaired episodic memory	++	++	++
Impaired gross visuospatial functioning	+	+	+
Impaired confrontation naming	+	+++	++
Impaired word reading	0	+	+
MRI
Dorsolateral frontal/insular atrophy	+++	++	++
Parietal cortex atrophy	++	+	++
Temporal cortex atrophy	+	+++	++
Markedly focal or asymmetric atrophy	0	+	+++
White matter signal changes	0	+	++
SPECT/PET
Dorsomedial frontal/cingulate abnormal	+++	++	++
Parietal cortex abnormal	++	+	++
Temporal cortex abnormal	+	+++	++
Markedly focal or asymmetric findings	0	+	+++
Subcortical structures abnormal	0	+	+
Neuropathology
Key proteinopathy	TDP-43	tau	TDP-43
TDP-43 type pathology	A and B	Not applicable	A only

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0 = not present;+ =infrequent;++ occurred with some frequency; +++ moderately frequent; ++++ very frequent.

a Since only probands with the behavioural variant FTD, non-fluent/agrammatic and semantic subtypes of primary progressive aphasia (PPA), and ALS were screened for the GGGGCC expansion, the frequency of primary progressive aphasia, corticobasal syndrome, autosomal dominant, and other phenotypes with this mutation may be higher than suggested here. Yet among those probands screened, and their affected relatives, the frequencies of these syndromes were low.