Recent Advances in the Genetics of the ALS-FTLD Complex
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There is a clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of autosomal-dominant genes have been described that primarily cause ALS or FTLD such as progranulin (GRN), valosin-containing protein (VCP), and TAR DNA-Binding Protein (TARDBP), and for each of these conditions there are a small number of cases with both ALS and FTLD. Two major genes were described in 2011, which cause FTLD and/or ALS within extended kindreds. Ubiquilin2 (UBQLN2) is responsible for X-linked FTLD/ALS. A hexanucleotide repeat expansion in C9ORF72 causes chromosome 9p linked FTLD/ALS and is the most common cause of familial ALS accounting for about 40 % of familial cases. Both UBQLN2 and C9ORF72 mutations lead to TDP-43 positive neuropathology, and C9ORF72-positive cases have p62/ubiquitin-positive pathology, which is not stained by TDP-43 antibodies. Ubiquilin2 is one of a family of proteins thought to be important in targeting abnormal proteins for degradation via lysosomal and proteasomal routes. The pathogenic mechanism of the C9ORF72 expansion is unknown but may involve partial haploinsufficiency of C9ORF72 and/or the formations of toxic RNA inclusions. The identification of mutations in these genes represents an important step forward in our understanding of the clinical, pathological, and genetic spectrum of ALS/FTLD diseases.
KeywordsFrontotemporal dementia Frontotemporal lobar degeneration FTLD C9ORF72 Chromosome 9 Motor neuron disease Amyotrophic lateral sclerosis ALS Autosomal dominant X-linked Genetics UBQLN2
Conflicts of interest: H.R. Morris: has board membership with GlaxoSmithKline, Orion, Boehringer, Abbott, Solvay, and TEVA; has received grant support from Medical Research Council, Ipsen Fund, Welsh Assembly Government, Parkinson’s UK; has received payment for lectures including service on speakers bureaus from UCB Pharma, Orion, Boehringer, GlaxoSmithKline, TEVA; has received travel/accommodations/meeting expenses unrelated to activities listed from UCB, Orion, GlaxoSmithKline, Boehringer, TEVA; A.J. Waite: has received grant support from Motor Neuron Disease Association (MNDA), and has received support for travel to meetings for the study or other purposes from MNDA and Guarantors of brain; N.M. Williams: has received grant support from MNDA; J.W. Neal: none; D.J. Blake: has received grant support from MNDA.
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- 6.Jackson M, Lennox G, Lowe J. Motor neurone disease-inclusion dementia. Neurodegeneration: J Neurodegener Disord, Neuroprotection, Neuroregeneration. 1996;5(4):339–50.Google Scholar
- 28.••Deng H-X, Chen W, Hong S-T, Boycott KM, Gorrie GH, Siddique N, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477(7363):211–5. The first description of UBQLN2 as causing X-linked ALS, illustrating the effect of pathogenic mutations on proteasomal function, and the occurrence of ubiquilin2 pathology in sporadic ALS.PubMedCrossRefGoogle Scholar
- 29.Millecamps S, Corcia P, Cazeneuve C, Boillée S, Seilhean D, Danel-Brunaud V, et al. Mutations in UBQLN2 are rare in French amyotrophic lateral sclerosis. Neurobiol Aging. 2011.Google Scholar
- 40.•• Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257–68. The first description of pathogenic mutations in C9orf72 in families with FTLD/ALS, in back-to-back publications with DeJesus-Hernandez et al. [41••]. Together with Mok et al. (39), illustrates that the hexanucleotide expansion occurs on a common haplotype, and shows that there is an exceptionally high rate of mutations in Finnish ALS patients.PubMedCrossRefGoogle Scholar
- 41.•• DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):1–12. The first description of pathogenic mutations in C9orf72 in families with FTLD/ALS, in back-to-back publications with Renton et al. [40••]. Describes haploinsufficiency of some isoforms of C9ORF72 and the occurrence of nuclear RNA inclusions.CrossRefGoogle Scholar
- 45.Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012;11(1):54–65.PubMedCrossRefGoogle Scholar