The molecular basis of the frontotemporal lobar degeneration–amyotrophic lateral sclerosis spectrum

Figures & data

Table I. Diagnostic categories of the FTLD-ALS disease spectrum.

		Main clinical characteristics
FTLD	bvFTD	Disinhibition, apathy, lack of emotional concern, hyperorality, stereotypic behavior and executive dysfunction
	PNFA	Labored speech, agrammatism with relatively spared comprehension
	SD	Comprehension deficits, naming errors with fluent speech
FTLD-MND-like		FTLD with minor motor system dysfunction
FTLD-ALS		Meeting the diagnostic criteria of both FTLD and ALS
ALSci		ALS with minor cognitive impairment
ALSbi		ALS with minor behavioral impairment
ALS		Muscle weakness, hyperreflexia, spasticity, atrophy and fasciculations

ALSbi = ALS with a mild behavioral impairment; ALSci = ALS with a mild cognitive impairment; bvFTD = behavioral variant FTLD; LMN = lower motor neuron; PNFA = progressive non-fluent aphasia; SD = semantic dementia; UMN = upper motor neuron; MND = motor neuron disease.

Figure 1. A: FTLD and ALS form a clinical disease continuum. B: Molecular relationships between FTLD and ALS. Pathological proteins are indicated in blue, causal genes in yellow. Full lines indicate strong correlations; dotted lines represent putative correlations. Correlations between genes and pathological proteins are indicated by light gray lines.

Figure 2. TDP-43 proteinopathy in FTLD. Ubiquitin and TDP-43 immunohistochemistry of sections from the superficial frontal cortex (FCx) and temporal cortex (TCx) of a patient with a VCP mutation (176). Frequent intranuclear inclusions (arrow-heads) are seen that stain positive for ubiquitin and TDP-43.

Table II. Genes associated with FTLD and ALS.

Gene	Locus	Inheritance	Mutation type	Mutation frequency FTLD	Mutation frequency ALS	Molecular pathology	Comment
MAPT (94)	17q21	AD	Missense, splice site, deletion	5%–10%	–	Tau
PGRN (92,93)	17q21	AD	Nonsense, splice site, frameshift, deletion, met1, missense	5%–10%	–	TDP-43	FTLD-TDP type A
VCP (105)	9p13	AD	Missense	< 1%	< 1%	TDP-43	In combination with IBM and PDB; FTLD-TDP type D
CHMP2B (100)	3p11	AD	Nonsense	< 1%	–	UPS
TMEM106B (131)	7p21	Risk factor	/	/	/	TDP-43
C9orf72 (132–134)	9p21	AD	GGGGCC expansion	5%–10%?	5%–10%?	TDP-43, UPS	FTLD-TDP type B?
SOD1 (106)	21q22	AD and AR	Missense, frameshift nonsense	–	∼5%	SOD1
TARDBP (110,111)	1p36	AD	Missense, nonsense	< 1%	∼1%	TDP-43
FUS (65,66)	16q12	AD and AR	Missense, nonsense, splice site, frameshift	< 1%	∼1%	FUS	Also associated with juvenile ALS with BIBD
ATXN2 (112)	12q24	AD and risk factor	GAG expansion	–	∼1%	TDP-43	Intermediate expanded alleles cause ALS, longer alleles cause SCA2
ANG (115)	14q11	AD and risk factor	Missense	–	< 1%	TDP-43
OPTN (117)	10p13	AD and AR	Missense, exon-deletion nonsense	–	< 1%	TDP-43
VAPB (116)	20q13	AD	Missense	–	< 1%	?	Classic ALS, slow-progressive ALS, late onset SMA
UBQLN2 (118)	Xp11	AD	Missense	< 1%	< 1%	TDP-43

Sub-classification of FTLD-TDP is according to (135).

AD = autosomal dominant; AR = autosomal recessive; BIBD = basophilic inclusion body disease; IBM = inclusion body myositis; met1 = mutation of Met1 translation initiation codon; PDB = Paget's disease of the bone; SCA2 = spinocerebellar ataxia type 2; SMA = spinal muscular atrophy.

Table III. Characteristics of chromosome 9p-linked FTLD-ALS families.

Reference	No. families (n patients)	FTLD or dementia	FTLD-ALS	ALS	Mean AAO (range)	Mean DD (range)	Molecular pathology (n patients)
Morita et al. 2006	1 (14)	9 (64%)	0 (0%)	5 (36%)	55.3 (45–64)	4.3 (9)	NK (2)
Vance et al. 2006	1 (12)	2 (17%)	3 (25%)	7 (58%)	60.3 (39–72)	3.0 (1–8)	Ub + (5)
Valdmanis et al. 2007	2 (16)	3 (19%)	3 (19%)	10 (63%)	55.1 (45–63)	3.6 (9)	0
Luty et al. 2008	1 (11)	7 (64%)	2 (18%)	2 (18%)	52.9 (43–68)	8.6 (1–18)	Ub +, TDP-43 +, FUS + (3)
Le Ber et al. 2009	6 (31)	10 (32%)	12 (39%)	9 (29%)	57.9 (41–84)	3.6 (1–9)	Ub +, TDP-43 + (3)
Gijselinck et al. 2010	1 (9)	8 (89%)	0 (0%)	1 (11%)	58.1 (51–65)	6.4 (1–17)	Ub +, TDP-43 + (1)
Boxer et al. 2010	1 (10)	5 (50%)	3 (30%)	2 (20%)	45.7 (35–57)	5.8 (3–10)	Ub +, TDP-43 +, FUS- (3)
Pearson et al. 2010	1 (9)	0 (0%)	6 (67%)	3 (33%)	42.2 (31–52)	3.6 (1–13)	Ub +, TDP-43 + (3)
All families	12 (112)	35 (31%)	38 (34%)	39 (35%)	53.4 (31–84)	4.9 (1–18)

No. = number; AAO = age at onset; DD = disease duration; NK = not known.

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