Abstract
Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1–16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1078-9) contains supplementary material, which is available to authorized users.
Highlights
Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous group of disorders that can present with personality and behavioural changes or language deficits [33]
Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration
Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent amyotrophic lateral sclerosis (ALS) family, indicating that this region may harbour a second major locus for frontotemporal dementia (FTD)-ALS
Summary
Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous group of disorders that can present with personality and behavioural changes or language deficits [33]. The discovery of MAPT mutations in families with hereditary dementia with parkinsonism [16] allowed the unified classification of a group of families with a wide spectrum of clinical and pathological diagnoses Dementia in these families was often atypical but most resembled FTD [27], with changes in personality, behaviour and insight, together with extrapyramidal motor features. Families with hereditary dementia and ALS have been linked to a C9ORF72 hexanucleotide repeat expansion [9, 31] These families usually include some affected members with pure ALS, while the majority of affected members develop a dementia syndrome that is often atypical or difficult to diagnose, but in most cases eventually resembles FTD. As well as MAPT, GRN and C9ORF72, other genes have been found to harbour mutations in families with FTD (e.g., VCP, CHMP2B) or ALS (e.g., SOD1, TARDBP, FUS) [3, 35]
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