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New advances in Amyotrophic Lateral Sclerosis genetics: Towards gene therapy opportunities for familial and young cases |
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| Authors: | M-D-M Amador F Muratet E Teyssou S Boillée S Millecamps |
| Affiliation: | 1. Department of interventional Neuroradiology, Fondation Rotschild, Paris, France;2. Department of Diagnostic and Therapeutic Neuroradiology, Hôpital Foch, Suresnes, France |
| Abstract: | Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease. |
| Keywords: | Motor neuron diseases Frontotemporal dementia Inclusion body myopathy Paget's disease of bone Pathogenic mutation ALS"} {"#name":"keyword" "$":{"id":"kw0035"} "$$":[{"#name":"text" "_":"Amyotrophic Lateral Sclerosis CMT"} {"#name":"keyword" "$":{"id":"kw0045"} "$$":[{"#name":"text" "_":"Charcot-Marie-Tooth disease DDR"} {"#name":"keyword" "$":{"id":"kw0055"} "$$":[{"#name":"text" "_":"DNA damage response ERAD"} {"#name":"keyword" "$":{"id":"kw0065"} "$$":[{"#name":"text" "_":"Endoplasmic-reticulum-associated protein degradation FALS"} {"#name":"keyword" "$":{"id":"kw0075"} "$$":[{"#name":"text" "_":"familial ALS FTD"} {"#name":"keyword" "$":{"id":"kw0085"} "$$":[{"#name":"text" "_":"FrontoTemporal Dementia HSP"} {"#name":"keyword" "$":{"id":"kw0095"} "$$":[{"#name":"text" "_":"Hereditary Spastic Paraplegia IBMPFD"} {"#name":"keyword" "$":{"id":"kw0105"} "$$":[{"#name":"text" "_":"Inclusion body myopathy with early-onset Paget disease and/or frontotemporal dementia PDB"} {"#name":"keyword" "$":{"id":"kw0115"} "$$":[{"#name":"text" "_":"Paget's disease of bone SALS"} {"#name":"keyword" "$":{"id":"kw0125"} "$$":[{"#name":"text" "_":"sporadic ALS SMA"} {"#name":"keyword" "$":{"id":"kw0135"} "$$":[{"#name":"text" "_":"spinal muscular atrophy VUS"} {"#name":"keyword" "$":{"id":"kw0145"} "$$":[{"#name":"text" "_":"variant of unknown significance WES"} {"#name":"keyword" "$":{"id":"kw0155"} "$$":[{"#name":"text" "_":"whole exome sequencing WGS"} {"#name":"keyword" "$":{"id":"kw0165"} "$$":[{"#name":"text" "_":"whole genome sequencing |
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