RESULTS: The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAP tau. MAIN OUTCOME MEASURES: Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS). The chromosome 9-linked ALS-FTD mutation is a hexanucleotiderepeat expansion in which a “six-letter” string of nucleotides coded GGGGCC is repeated far more times in people with ALS, FTD or A… Kindreds with a phenotype encompassing features of FTD, parkinsonism and ALS have been linked to 17q21 and mutations have been identified in the microtubule associated protein tau (MAPT) (OMIM 157041) (Hutton et al., 1998). Identification de nouveaux gènes 2. Plusieurs voies biologiques impliquées Cytosquelette & transport axonal TAU, DCTN1 Métabolisme des ARNs TDP-43 , FUS, MATR3, hnRNPA2/B1 … Caractérisation des formes génétiques connues Caractérisation des troubles psychiatriques associés aux expansions C9orf72 (Dr Guilhem Carle) Identification des facteurs modificateurs de l [âge de début des DFT-GRN et C9orf72 (M Barbier) 3. Sapp PC, Hosler BA, McKenna-Yasek D, Chin W, Gann A, Genise H, et al. In ALS, motoneurons in the motor cortex, brainstem and spinal cord degenerate. In ∼40% of FTD cases, there is a family history of dementia, indicating a significant genetic contribution (Rosso, 2003). Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport. Ages were defined as the age at onset in affecteds and the age at last review of asymptomatic individuals. Familial ALS (FALS) share many common clinical characteristics with sporadic ALS (SALS), which makes it difficult to distinguish between the two forms. Anti-neuronal autoantibody screen was negative but MRI of the brain revealed striking frontal lobe atrophy (Fig. Inheritance is usually autosomal dominant with variable penetrance. Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis. The pathological hallmark of ALS is the presence of ubiquitinated inclusions in the perikaryon and proximal axon of surviving motoneurons, but the underlying disease mechanisms are poorly understood (Leigh, 1989). Prevention and treatment information (HHS). Clinical features and investigation results of affected individuals from Family F2 with ALS–FTD. Graphical representation of multipoint LOD scores from an affecteds-only analysis of the kindred comparing non-parametric (NPL) and parametric linkage data generated by Merlin. He presented with fearfulness, irascibility and violent behaviour, leading to his admission to a psychiatric hospital. There is increasing evidence that the two conditions can exist in a phenotypic spectrum within individuals and within autosomal dominant kindreds (Lipton, 2004). The maximum NPL LOD score of 1.21 was detected at 9p (with a maximum potential LOD score of 1.43) and a parametric peak of 2.4. Jonsson PA, Ernhill K, Andersen PM, Bergemalm D, Brannstrom T, Gredal O, et al. Abecasis G, Cherny S, Cookson W, Cardon L. MERLIN—Rapid analysis of dense genetic maps using sparse gene flow trees. In our initial report we described a second family (F2), which showed weaker linkage to the same region with a two-point LOD score of 1.84 (Ruddy et al., 2003). 2021 Feb 18;15:637548. doi: 10.3389/fncel.2021.637548. Thanks are due to Dr G. A. Hoffland, Radiologist (VieCuri Hospitals, Venlo, Netherlands), for allowing us to reproduce the MRI scans. ), Guy's and St Thomas' Charity and ALS Centrum Nederland, which supports the ALS Tissue Bank. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Nishimura AL, Mitne-Neto M, Silva HC, Oliveira JR, Vainzof M, Zatz M. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13. Alzheimer Dis Assoc Disord. Both PD and FTD/ALS are defined at post mortem by the presence of protein aggregates and the loss of specific subsets of neurons. Ince PG, Tomkins J, Slade JY, Thatcher NM, Shaw PJ. Hentati A, Ouahchi K, Pericak-Vance MA, Nijhawan D, Ahmad A, Yang Y, et al. Ethical committees in both clinical centres have approved genetic research on ALS. People with FTD develop erratic behavior, emotional problems, trouble communicating, or difficulty with walking and other basic movements. In an outbred European population they found that one third of ALS patients have an expanded GGGGCC repeat. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. The fluorescent dideoxy sequencing products were run out on an ABI 3100 and analysed for base pair changes by Sequencher v4.5 (GeneCodes Corp., Ann Arbor, MI, USA). Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, et al. Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases. Mutations in copper/zinc superoxide dismutase 1 (SOD1) are found in approximately 20% of familial and approximately 3% of sporadic ALS cases but are not associated with dementia. The identification of a hexanucleotide repeat expansion in a noncoding region of the chromosome 9 open reading frame 72 (C9ORF72) gene as a common cause of FTD/ALS, familial FTD, and familial ALS marks the culmination of many years of investigation. Inheritance is usually autosomal dominant with variable penetrance. Death due to respiratory failure occurs on average only 3 years after symptom onset and there is no therapy that significantly alters the course of the disease (Shaw et al., 2001). The average SNP genotype call rate was 99.1% (range 98.09–99.88%), providing on average 9957 genotypes per individual. Concurrently, two other unrelated families were published demonstrating linkage to an overlapping region on 16q12 with multipoint LOD scores of 3.29 (Sapp et al., 2003) and 2.06 (Abalkhail, 2003), and the locus has been designated ALS6 (OMIM 608030). Mutant dynactin in motor neuron disease. Introduction to the special topic papers: part I. Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, et al. The peak multipoint LOD score of 3.02 occurred between D9S52 and D9S1805 (Table 2). (A) Axial T2-weighted image showing symmetrical widening of the frontal lobe sulci, sylvian fissures and anterior horns of the lateral ventricles with relative sparing of the posterior cerebrum. Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J, Jongjaroenprasert W, Horvitz HR, Gunnarsson LG, Brown RH Jr. Neurology. DLFT-TAU 30% DLFT-TDP 60% GRN/PGRN C9orf72 VCP SQSTM1 etc… MAPT TDP-43 TAU FUS P62-c9orf72 TDP-43 TAU FUS Corrélations génétique-neuropathologie. Familial ALS and FTD, the targets of his research, constitute a very narrow subset of neurodegenerative disease. Repeat expansion on the C9orf72 gene on the chromosome are causally linked to classical ALS and frontotemporal dementia (FTD). Bioinformatic analysis of the region has identified 103 known genes. Main Outcome Measures Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS). Caroline Vance, Ammar Al-Chalabi, Deborah Ruddy, Bradley N. Smith, Xun Hu, Jemeen Sreedharan, Teepu Siddique, H. Jurgen Schelhaas, Benno Kusters, Dirk Troost, Frank Baas, Vianney de Jong, Christopher E. Shaw, Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3, Brain, Volume 129, Issue 4, April 2006, Pages 868–876, https://doi.org/10.1093/brain/awl030. All rights reserved. In Asian FALS patients, pathogenic variants in the C9orf72, SOD1, FUS, TARDBP genes account for 2%, 30%, 6% and 1.5% cases (Zou et al. Introduction. Epub 2003 Jul 1. Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. The newly discovered mutation belongs to a class of mutations called repeat expansion mutations. FTD FTD-ALS FTD-ALS FTD ALS www.cref-demrares . From this analysis, five mutations were found in the PXX domain and all consisted of substituted proline residues (P497H, P497S, P506T, P509S and P525S). eCollection 2021 Feb. Castellanos-Montiel MJ, Chaineau M, Durcan TM. Although dividing the family was essential if we were to analyse data from all 27 individuals genotyped, we also analysed the data as a single core pedigree as an affected-only study of 18 individuals, which permitted NPL and parametric analyses. The maximum LOD score detected was 1.34 and no other region had a LOD score > 0.8 (maximum achievable = 1.54). Similar early clinical presentations in familial and non-familial frontotemporal dementia. 8600 Rockville Pike Linkage analysis of single nucleotide polymorphism (SNP) data identified consistently positive log of the odds (LOD) scores across chromosome 9p (maximal LOD score of 2.4). With few exceptions, familial and sporadic ALS are indistinguishable on clinical and pathological grounds (Shaw et al., 1997; Ince et al., 1998). Shaw CE, Enayat ZE, Powell JF, Anderson VE, Radunovic A, al-Sarraj S, et al. Recombination has narrowed the region shared between the families to 11 Mb containing 103 known genes in this region. We have previously published the results of a genome-wide microsatellite marker scan in a large English family (F1), which demonstrated linkage to chromosome 16q12 with a two-point LOD score of 3.61 (Ruddy et al., 2003). Five individuals underwent detailed pathological assessment; at post-mortem significant upper and lower motoneuron degeneration was detected in all four cases who presented with ALS. Only 10% of cases are familial, a subset of which overlaps with frontotemporal dementia (FTD). These will be screened for mutations and prioritized on the basis of their expression in the central nervous system and potential role in the pathogenesis of ALS. Alberti S, Esser C, Hohfeld J. BAG-1—a nucleotide exchange factor of Hsc70 with multiple cellular functions. Phenotypic overlap between ALS and FTD can occur within the same kindred. One individual, IV:1, the offspring of the affected III:2, presented at the age of 39 with a progressive dementia and died of respiratory failure after 31 months. Examination 6 months later revealed an emaciated woman with little spontaneous speech. Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, et al. 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