Cognitive and behavioral features of c9FTD/ALS

Boeve, Bradley F; Graff-Radford, Neill R

doi:10.1186/alzrt132

Table 1 Key features of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72 across published series with ample numbers of cases with the FTD ± ALS phenotype

From: Cognitive and behavioral features of c9FTD/ALS

Feature	Mayo Clinic	Mayo Clinic Brain Bank	Manchester	Vancouver	Dutch	London	Flanders Belgian	NIH/NINDS	Irish	Total
Reference in text	[21]	[20]	[28]	[25]	[27]	[26]	[24]	[29]	[21]
Cohort characteristics
Number of cases examined (with mutation)	53 (63)	13 (13)	32 (32)	30 (30)	42 (42)	19 (19)	41 (41)	4 (4)	10 (10)	254
Number of kindreds identified	43	20	32	16	37	18	25	4	39	234
Percentage of all FTD ± ALS caes with mutation due to C9ORF72/PGRN/MAPT	12/4/6	NA	8/0/0	55/24/NA	9/7/10	7/7/6	8/7/1	8% for C9ORF72	9% for C9ORF72	Most in 7%-12% range
Percentage of familial FTD ± cases with mutation due to C9ORF72/PGRN/MAPT	20/6/11	NA	?	70/30/NA	18/14/22	13/14/14	26/22/4	NA	NA	Most in 13%-26% range
Percentage of FTD cases not due to known genes	66	NA	?	?	46	45	56	NA	NA	45%-66% range
Demographics
Males/Females	33/30	8/5	18/14	21/8	20/22	11/8	8/7	?	10/11	129/105
Age of onset in years, mean or median	52	65	58	54	57	55	55	58	56	52-65 range
Age of onset in years, range	33-72	50-78	46-72	34-74	39-76	43-68	38-71	?	?	33-78 range
Survival in years, mean or median	5	5	?	5	7	9	5	?	?	5-9 range
Survival in years, range	1-17	3-11	1-11	1-16	1-22	1-22	2-17	?	?	1-22 range
Inheritance
Inheritance pattern	AD	AD	AD	AD	AD	AD	AD	AD	AD	AD
Frequency of sporadic cases	++	++	++	++	++	++	++	++	+	++
Penetrance	High	High	High	High	High	High	High	High	High	High
Anticipation suggested	++	?	?	++	?	?	?	+	?	Many reports
Clinical phenotype
bvFTD phenotype	+++	++	+++	+++	+++	+++	+++	++	0	Frequent
ALS phenotype	++	NA	NA	++	++	NA	++	0	+++	Often
FTD/ALS phenotype	++	0	++	++	++	++	++	++	++	Often
Primary parkinsonian phenotype	0	0	0	0	0	0	0	0	0	None reported
Non-fluent/agrammatic subtype of PPA	0	0	+	++	++	+	0	0	0	Rare
Semantic subtype of PPA	0	0	+	0	+	0	0	0	0	Rare
Corticobasal syndrome phenotype	0	0	NA	0	0	0	0	0	0	None reported
Alzheimer's disease-like phenotype	+	++	NA	+	0	+	0	0	0	Rare
Cognitive features
Memory impairment	++	+++	++	+++	+++	+++	?	?	0	Often to frequent
Executive functioning impairment	+++	+++	+++	+++	+++	+++	Presumably	Presumably	++	Frequent
Language impairment (aphasia)	++	++	+++	+++	++	+++	?	?	0	Frequent and usually late feature
Visuospatial impairment	+	?	+	+	+	+	?	?	?	Rare
Neuropsychological profile of executive/generation deficits with relative sparing of memory and visuospatial functions	++	Presumably in some	++	++	?	++	Presumably in many	Presumably in many	++	Often but certainly not frequent
Behavioral features
Early behavioral disinhibition	+++	Presumably	+++	+++	++	+++	Presumably	Presumably	Presumably	Frequent
Early apathy or inertia	+++	Presumably	+++	+++	++	+++	Presumably	Presumably	Presumably	Frequent
Early loss of sympathy or empathy	+++	Presumably	+++	+++	?	++	Presumably	Presumably	Presumably	Frequent
Hyperorality and dietary changes	+++	Presumably	+++	?	?	+++	Presumably	Presumably	Presumably	Frequent
Pseudobulbar affect	+	?	?	?	?	?	?	?	?	Insufficient data
Psychosis (delusions or hallucinations)	++	?	++	+	+	++	?	?	?	Often
Other clinical features
Frontal release signs	++	?	++	?	?	?	?	?	?	Insufficient data
Parkinsonism	++	++	++	++	?	++	?	?	?	Often
Upper or lower (or both) motor neuron dysfunction not fulfilling ALS criteria	++	?	+	++	?	+++	?	?	?	Often
ALS	++	0	++	++	++	++	++	0	+++	Often in FTD
Limb apraxia	0	?	0	+	+	0	?	?	?	Rare

The Manchester series only included cases with a frontotemporal dementia (FTD) spectrum dementia syndrome and not amyotrophic lateral sclerosis (ALS) or parkinsonism. In the Vancouver series, cases of FTD or ALS or both had progressive non-fluent aphasia plus frontal features and ALS. The percent breakdowns of chromosome 9 open reading frame 72 (C9ORF72) and progranulin (PGRN) are based on autopsied cases with TDP-43⁺ pathology, not all FTD cases. The Irish series involved mostly ALS cases, of which 10 had FTD or ALS or both. 0, feature reported as not present; +, feature reported as present infrequently (<10% of cases); ++, feature reported as often present (10% to 50% of cases); +++, feature reported as frequently present (>50% of cases); ?, feature not discussed sufficiently in the report to make any determinations. AD, Alzheimer's disease; bvFTD, behavioral variant frontotemporal dementia; c9FTD/ALS, frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; GGGGCC, (the hexanucleotide expansion of) guanine-guanine-guanine-guanine-cytosine-cytosine; MAPT, microtubule-associated protein tau; NA, not applicable; NIH/NINDS, National Institutes of Health/National Institute of Neurological Disorders and Stroke; PPA, primary progressive aphasia.

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