Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) is an autosomal dominant neurodegenerative disorder characterized by adult onset of one or both of these features in an affected individual, with significant intrafamilial variation. The disorder is genetically and ... Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) is an autosomal dominant neurodegenerative disorder characterized by adult onset of one or both of these features in an affected individual, with significant intrafamilial variation. The disorder is genetically and pathologically heterogeneous (summary by Vance et al., 2006). Patients with C9ORF72 repeat expansions tend to show a lower age of onset, shorter survival, bulbar symptom onset, increased incidence of neurodegenerative disease in relatives, and a propensity toward psychosis or hallucinations compared to patients with other forms of ALS and/or FTD (summary by Harms et al., 2013). Patients with C9ORF72 repeat expansions also show psychiatric disturbances that may predate the onset of dementia (Meisler et al., 2013; Gomez-Tortosa et al., 2013). For a general phenotypic description of frontotemporal dementia, also known as frontotemporal lobar degeneration (FTLD), see 600274. For a general discussion of motor neuron disease (MND), see amyotrophic lateral sclerosis-1 (ALS1; 105400).
Pinsky et al. (1975) described amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) as an entity distinct from pure ALS because dementia is absent in the latter condition. They found considerable intrafamilial variability. Lesions in the cerebral cortex ... Pinsky et al. (1975) described amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) as an entity distinct from pure ALS because dementia is absent in the latter condition. They found considerable intrafamilial variability. Lesions in the cerebral cortex had a distinctive frontotemporal distribution. Another family was reported by Finlayson et al. (1973), and the families reported by Dazzi and Finizio (1969) and Robertson (1953) may have had the same condition. Hosler et al. (2000) described several families with ALS and FTD. In family F222, 1 patient was diagnosed with ALS and FTD, while 2 showed only motor neuron symptoms. For 3 other persons, the clinical records and other available information confirmed the diagnosis of ALS accompanied by dementia symptoms but were inconclusive as to the type of dementia. In family F17, 2 patients were diagnosed with ALS and FTD, while 2 had ALS alone. One patient had ALS accompanied by dementia symptoms. The mean age of onset for affected individuals in these 2 families was 53.8 +/- 8.2 years, with a range of 40 to 62 years, and an average duration of 3.8 +/- 4.0 years, with a range of 1.3 to 15 years. Most persons survived 4 years or less, and 1 patient survived 15 years. The dementia specified as FTD in these families was characterized by socially inappropriate, impulsive behavior and general deterioration in ability to perform routine daily tasks. These behavioral changes occurred months before any significant changes in memory. Examination of these patients documented a combination of corticospinal and lower motor neuron features in conjunction with signs of frontal release. Imaging studies were consistent with frontotemporal atrophy. Pathologic studies confirmed the presence of frontotemporal atrophy and also revealed frontotemporal gliosis, vacuolar changes in the corresponding cortex, rare Pick bodies, and a relative paucity of amyloid plaques and neurofibrillary tangles. Hosler et al. (2000) concluded that these combined findings fulfill the Lund-Manchester criteria for a diagnosis of FTD arising concurrently with motor neuron disease. Morita et al. (2006) reported a 4-generation Scandinavian kindred in which 5 individuals were diagnosed with amyotrophic lateral sclerosis and 9 with frontotemporal dementia. No individual had both diagnoses. Those with ALS presented with motor neuron symptoms, but 3 later developed subtle cognitive dysfunction. Those with dementia showed progressive cognitive deficits without significant memory loss and had no signs of motor impairment. Two individuals with FTD showed loss of spinal cord neurons at autopsy. Given the clinical and pathologic overlap of ALS and FTD and the observation that both disorders reflect neurodegenerative processes, Morita et al. (2006) concluded that the disorders in this family represent pleiotropic manifestations of a single gene defect. Vance et al. (2006) reported a large Dutch family in which 10 individuals had ALS. Five had bulbar onset, and 5 had limb onset. Age of onset ranged from 40 to 72 years with a mean survival of 3 years. Inheritance was autosomal dominant with reduced penetrance. Three individuals who presented with motor symptoms of ALS subsequently developed personality and behavioral changes, including apathy, social isolation, emotional lability, and hallucinations. Postmortem examination of 4 individuals showed significant upper and lower motor neuron degeneration. One female individual presented at age 39 with progressive personality changes and dementia and subsequently developed muscle wasting and fasciculations consistent with ALS. She died of respiratory failure after 31 months, and postmortem examination showed frontal lobe atrophy and shrunken motor neurons. Valdmanis et al. (2007) reported 3 unrelated families with ALS and/or FTD. In a Canadian family, 5 individuals had ALS only, and 3 had FTD only. Five individuals from a family of Spanish origin had ALS; 1 of these patients had also shown early signs of FTD. A third family of French Canadian origin included 5 individuals with ALS only and 3 with ALS and FTD. Luty et al. (2008) reported a 3-generation Australian family of Anglo-Celtic origin in which 11 individuals had FTD and/or MND. Five presented with the behavioral variant of FTD, 2 presented with progressive bulbar and limb weakness consistent with MND, 2 presented with a combination of FTD and MND, and 2 had nonspecific dementia, diagnosed as Alzheimer disease (AD; 104300) in 1. The average age at onset was 53 years. Neuropathologic examination of 1 patient with FTD and the patient with a clinical diagnosis of AD showed abnormal TDP43 (TARDBP; 605078)-positive inclusions in neurons of the frontal cortex and hippocampus; examination of a patient with MND showed degeneration of the corticospinal tracts and TDP43-positive inclusions in anterior horn cells. Le Ber et al. (2009) identified 6 new families with FTD and/or motor neuron disease showing linkage to chromosome 9p. The mean age at onset was 57.9 years, and the mean disease duration was 3.6 years. The phenotype was heterogeneous both among and within families: 32% of patients presented with isolated FTD, 29% with isolated MND, and 39% with both disorders. Motor neuron disease presented as upper limb motor deficit and amyotrophy in most patients (68%), and bulbar symptoms were present in 32% of patients. FTD was consistent with a behavioral variant. Brain MRI showed bilateral predominantly frontotemporal atrophy, and neuropathologic examination of 3 patients showed neuronal loss in various brain regions and spinal cord. All patients had cytoplasmic neuronal ubiquitin (UBB; 191339)-positive, tau (MAPT; 157140)-negative cytoplasmic inclusions in the cortex and spinal cord. TDP43-positive neuronal inclusions were also found. Boxer et al. (2011) reported a large 4-generation family of Irish ancestry with FTD and/or ALS. Five individuals had the behavioral variant of FTD, 2 with mild parkinsonism, 2 had limb-onset ALS, and 3 had both disorders. One patient had apraxia and parkinsonism, consistent with a corticobasal syndrome. Age at onset ranged from 35 to 57 years, with a mean of 45.7, and the mean disease duration was 5.4 years. Brain imaging showed reduced cortical volume, particularly affecting the frontal lobes. Neuropathologic study of 3 patients showed chronic degenerative changes with neuronal loss, reactive gliosis, and superficial laminar spongiosis. The corticospinal tracts showed decreased myelin staining. Immunohistochemical studies showed TDP43-immunoreactive cytoplasmic inclusions in neurons, and to a lesser extent, in glial cells. Some neuronal inclusions and neurites stained for p62 (SQSTM1; 601530) and ubiquitin, but not TDP43. Pearson et al. (2011) reported a family originating from South Wales with this disorder. There were 9 affected individuals showing variable phenotypes. The average age at onset was 42.2 years, with a duration of 3.6 years. Five (62.5%) presented with ALS, with bulbar and/or limb onset; 1 also had FTD and 3 later developed FTD. Three (37.5%) patients presented with behavioral variant FTD and later developed ALS. Other variable features included psychosis, hallucinations, delusions, visuospatial dysfunction, extrapyramidal signs, and parkinsonism. One patient had cerebellar ataxia. Neuropathology showed many TDP43-positive neuronal cytoplasmic inclusions. Lindquist et al. (2013) identified a pathogenic C9ORF72 expansion in 14 (5%) of 280 unrelated hospitalized Danish patients referred for genetic testing for inherited dementia disorders. Ten patients had a diagnosis of FTD or FTD-ALS, 1 had ALS, and 3 had atypical diagnoses, including olivopontocerebellar degeneration, corticobasal syndrome, and atypical Parkinson syndrome with FTD-ALS. All except 1 patient had a family history of a similar disorder. The findings expanded the clinical spectrum associated with C9ORF72 mutations. Gomez-Tortosa et al. (2013) reported 9 Spanish FTD probands with expanded C9ORF72 repeats. Six of the patients had significant psychiatric symptoms, most commonly depression, as long as several decades before the onset of dementia. Brain MRI showed frontotemporal atrophy in 7 of 9 patients. Meisler et al. (2013) reported a parent and child of Northern European ancestry with bipolar disorder associated with a C9ORF72 repeat expansion. The proband was identified from a cohort of 89 patients with bipolar disorder who underwent screening for the C9ORF72 repeat expansion. The 35-year-old proband developed typical bipolar disorder at age 25 years and showed normal executive function and memory ability at age 35. The affected parent developed bipolar disorder and mood irregularities at age 62, and was subsequently diagnosed with FTD. The parent also developed a gait disorder and had parkinsonian features at age 66; the parent died at age 69. Postmortem examination showed frontotemporal atrophy and some neuropathologic changes consistent with Alzheimer disease, including tau pathology and ubiquitinated cytoplasmic inclusions. Southern blot analysis of peripheral blood from the proband identified a 2,600 repeat expansion (between 14 and 20 kb), whereas the parent carried shorter expansions (8.5 to 20 kb). Cultured lymphoblast cell lines from the parent were enriched for the shorter 8.5-kb expansion length, suggesting that there may be selection for the shorter repeat in cultured cells. The genetic and clinical findings were suggestive of genetic anticipation, as well as etiologic relationship between the C9ORF72 expansion and disease progression from bipolar disorder to FTD.
In affected members of large families with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis (FTD/ALS) mapping to chromosome 9p21, DeJesus-Hernandez et al. (2011) and Renton et al. (2011) simultaneously and independently identified a heterozygous expanded hexanucleotide repeat ... In affected members of large families with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis (FTD/ALS) mapping to chromosome 9p21, DeJesus-Hernandez et al. (2011) and Renton et al. (2011) simultaneously and independently identified a heterozygous expanded hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene (614260.0001). The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded to 700 to 1,600 (DeJesus-Hernandez et al., 2011) or 250 repeats (Renton et al., 2011) in patients. DeJesus-Hernandez et al. (2011) identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat. Renton et al. (2011) found the expanded repeat in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases from Finland, as well as in 38.1% of 268 familial ALS probands of European origin. Both DeJesus-Hernandez et al. (2011) and Renton et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. In the study of DeJesus-Hernandez et al. (2011), transcript-specific cDNA amplified from frozen frontal cortex brain tissue from an affected individual showed absence of the variant 1 transcribed from the mutant RNA, whereas transcription of variants 2 and 3 was normal. mRNA expression analysis of variant 1 was decreased to about 50% in lymphoblast cells from a patient and in frontal cortex samples from other patients. These findings were consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. Millecamps et al. (2012) identified expanded repeats in intron 1 of the C9ORF72 gene in 46% of 225 French patients with familial ALS, 7% of 725 French patients with sporadic ALS, and in none of 580 controls. The expanded repeat was shown to segregate with the disorder in 16 families, although there were some unaffected obligate carriers, suggesting incomplete penetrance. An expanded C9ORF72 repeat was defined as greater than 50 repeats. Compared to ALS patients with mutations in other genes, those with the C9ORF72 repeat had later age at onset, showed more frequent bulbar involvement, more often had FTD, and showed shorter disease duration. The findings confirmed that the C9ORF72 repeat expansion plays a major role in ALS. Belzil et al. (2013) identified a hexanucleotide repeat expansion in the C9ORF72 gene in 13 (52%) of 25 patients of Caucasian origin with ALS who had a family history of cognitive impairment. Gomez-Tortosa et al. (2013) identified expanded C9ORF72 repeats in 9 (8.2%) of 109 Spanish probands with FTD. Four patients had more than 30 repeats, whereas 4 had 20 repeats and 1 had 22 repeats. None of the other 100 cases had greater than 13 repeats, and none of 216 controls had more than 14 repeats. In 4 families, the expanded 20- or 22-repeat alleles segregated consistently in all affected sibs, with the unaffected sibs having wildtype alleles (2-9 repeats). The 20- or 22-repeat allele was associated with the surrogate marker of the founder haplotype in all cases. Most of the 9 expansion carriers had extended periods with psychiatric symptoms and subjective cognitive complaints before clear neurologic deterioration, and there was no phenotypic difference between those with longer or shorter expansions. These findings suggested that short C9ORF72 hexanucleotide expansions in the 20- to 22-repeat range are also related to FTD. Harms et al. (2013) found C9ORF72 hexanucleotide expansions in 55 (6.9%) of 797 patients with sporadic ALS from the United States. The frequency of expansions was significantly higher in the Midwest (9.2%) compared to the Pacific Northwest (3.0%). Mutation carriers had an earlier age at onset compared to nonmutation carriers (55.9 versus 59.2 years), and were more likely than noncarriers to have a family history of dementia. Two (0.4%) of 526 neurologically normal Caucasian controls also carried an expansion. Repeat expansions were also found in 22 (43%) of 51 patients with familial ALS. Fibroblast cell lines available from 9 patients showed expanded repeats between 600 and 800 units. Two individuals had additional smaller expanded alleles, suggesting somatic instability. DNA derived from occipital cortex was available for 2 additional patients and showed much larger expansions (1,600 repeat units), suggesting that expansions are larger within neuronal tissues. Sequencing of the coding exons of the C9ORF72 gene in 389 ALS patients yielded no pathogenic mutations, suggesting a gain-of-function mechanism rather than a loss-of-function mechanism. Van Blitterswijk et al. (2013) detected C9ORF72 repeat expansions in 4 (1.2%) of 334 individuals who carried pathogenic mutations in genes associated with a neurodegenerative disease. Three of the patients carried mutations in the GRN gene (138945) and 1 had a mutation in the MAPT gene (157140). All 4 patients had the behavioral variant of FTD. Postmortem examination of 1 of the patients who carried both a GRN mutation and a C9ORF72 expansion showed mixed neuropathology with characteristics of both genetic defects. The findings indicated that some cases of FTD may be due to an oligogenic effect, and suggested that the cooccurrence of 2 pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. Van Blitterswijk et al. (2013) concluded that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members. - Associations Pending Confirmation In affected members of the family with FTD and/or MND reported by Luty et al. (2008), Luty et al. (2010) identified a putative pathogenic heterozygous G-to-T transversion (672*51G-T) in the 3-prime untranslated region (UTR) of the SIGMAR1 gene (601978) on chromosome 9p13. In vitro functional expression studies in human neuroblastoma, HEK293 cells, and patient lymphocytes showed that the substitution resulted in about 2-fold increased expression of SIGMAR1 compared to wildtype, and neuropathologic study of affected individuals showed increased SIGMAR1 protein in frontal cortex tissue. Studies of brain tissue from controls and from individuals with unrelated form of FTLD showed that sigma-1 was localized on membranes within the cytoplasm of most neurons, astrocytes, and oligodendroglia, whereas in 2 patients with the 672*51G-T mutation, it was concentrated within the nucleus of degenerating neurons. Patients with the SIGMAR1 mutation also had TDP43- and FUS-positive inclusions in affected brain regions, although in different neuronal populations. Overexpression of SIGMAR1 in cell lines resulted in increased levels of TDP43 protein, but not TDP43 transcripts, and caused a change in localization of TDP43 from the nucleus to the cytoplasm. Luty et al. (2010) postulated that the 672*51G-T transversion, which occurs in the 3-prime UTR of the SIGMAR1 gene, alters transcript stability and increases gene expression, resulting in increased pathogenic alterations of TDP43 and FUS. However, the authors noted that SIGMAR1 gene may not represent the major locus for FTLD/MND that maps to chromosome 9p. Belzil et al. (2013) did not identify any coding or noncoding variants in the SIGMAR1 gene among 25 patients with ALS and a family history of dementia. A G-to-T transversion (672*43G-T) in the 3-prime untranslated region was found in 1 patient, but this was also found in 1 of 190 controls. Moreover, the C9ORF72 repeat expansion was subsequently identified in this patient and in 52% of the entire cohort. Belzil et al. (2013) suggested that the SIGMAR1 variants identified by Luty et al. (2010) actually segregated with C9ORF72 expansions, and that SIGMAR1 variants are not a cause of ALS with dementia.
In a genomewide association analysis of 442 Finnish ALS patients and 521 controls, Laaksovirta et al. (2010) identified a disease association with SNP dbSNP rs3849942 on chromosome 9p21 (p = 9.11 x 10(-11)). A 42-SNP haplotype was associated ... In a genomewide association analysis of 442 Finnish ALS patients and 521 controls, Laaksovirta et al. (2010) identified a disease association with SNP dbSNP rs3849942 on chromosome 9p21 (p = 9.11 x 10(-11)). A 42-SNP haplotype was associated with a significantly increased risk of ALS (odds ratio of 21.0, p = 7.47 x 10(-33)) when those with familial ALS were compared to controls. For familial ALS, the population attributable risk for the chromosome 9p21 locus was 37.9%. About 3% of the patients with this risk haplotype developed FTD. The findings were consistent with a founder effect in this homogeneous population. Mok et al. (2012) found that a smaller founder disease haplotype, located within that identified in the Finnish population by Laaksovirta et al. (2010), was present in ALS families from other populations of northern European descent, including Irish, UK, and US, but not in Italians. The findings suggested that most individuals with the disease carry the same pathogenic variant. Garcia-Redondo et al. (2013) identified a pathogenic intron 1 C9ORF72 hexanucleotide repeat expansion (defined as more than 30 repeats) (614260.0001) in 42 (27.1%) of 155 Spanish patients with familial ALS and in 25 (3.2%) of 781 Spanish patients with sporadic ALS. Thus, this mutation was the most common genetic cause of ALS in the Spanish population, followed by SOD1 (147450) mutations, which account for 18% of familial ALS and 1% of sporadic ALS. Haplotype analysis indicated a founder effect for the pathogenic expansion allele. One ALS patient with 28 repeats was identified, and his allele was on the founder disease haplotype. The most common nonpathogenic allele in both patients and controls was 2 repeats; none of 248 controls carried the expansion mutation. C9ORF72 mutation carriers had a lower age at onset, frequent concurrence with FTD, and shorter survival when compared to ALS patients without the expansion. Analysis of other ethnic populations showed that this haplotype was present in 5.6% Yoruba African, 8.9% European CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes. Van der Zee et al. (2013) assessed the distribution of C9ORF72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort of 1,205 individuals ascertained by the European Early-Onset Dementia (EOD) consortium. A metaanalysis of the data and that of other European studies, including a total of 2,668 patients from 15 countries, showed that the frequency of C9ORF72 expansions in Western Europe was 9.98% in FTLD, with 18.52% in familial and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of 29.33% and 20.73%, respectively, consistent with the hypothesis of a Scandinavian founder effect. However, Spain also showed a high frequency of the expansion, at 25.49%. In contrast, the prevalence in Germany was low, at 4.82%. The phenotype was most often characterized by behavioral disturbances (95.7%). Postmortem examination of a small number of cases showed TDP43 (605078) and p62 (601530) deposits in the brain. Intermediate repeats (7 to 24 repeat units) were found to be strongly correlated with the risk haplotype tagged by a T allele of SNP dbSNP rs2814707. In vitro reporter gene expression studies showed significantly decreased transcriptional activity of C9ORF72 with increasing number of normal repeat units, consistent with a loss of function. This was also observed with intermediate repeats, suggesting that they might act as predisposing alleles. There was also a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the expanded repeat in expansion carriers, suggesting that pathologic expansion may be due to replication slippage. Smith et al. (2013) identified the expanded hexanucleotide repeat in C9ORF72 in 226 (17%) of 1,347 patients with ALS with or without FTD collected from 5 European populations in whom known ALS genes had been excluded. The expansion was also observed in 3 (0.3%) of 856 controls, yielding an odds ratio (OR) of 57 (p = 4.12 x 10(-47)), but also indicating incomplete penetrance. The highest frequency of the mutation was in familial cases of ALS+FTD (48/67, 72%), but it was also prevalent in pure ALS families (89/228, 39%), with the total familial frequency being 46% (OR of 244, p = 6.13 x 10(-89)). Frequencies of the expansion in familial ALS+FTD showed variation by country: 19/22 (86%) in Belgium, 30/41 (73%) in Sweden, 10/27 (37%) in the Netherlands, 73/185 (39%) in England, and 4/20 (20%) in Italy. Haplotype analysis identified a common 82-SNP disease haplotype in the majority of 137 cases studied, indicating a single common founder in these European populations. The mutation was estimated to have arisen 6,300 years ago. The disease haplotype was found in almost 15% of European controls. The average number of pathogenic repeats on the disease haplotype was 8, with a spread of expanded alleles up to 26. The most prevalent number of repeats on other haplotypes was 2. The findings suggested that the background disease haplotype is intrinsically unstable, tending to generate longer repeats. In a subset of 296 ALS patients with or without FTD from London, the C9ORF72 expanded repeat was found in 26%, followed by mutations in SOD1 (147450) (24%), FUS (137070) (4%), and TARDPB (605078) (1%). Overall, the findings showed that the C9ORF72 expanded repeat is the most common genetic cause of ALS with or without FTD across Europe. Using repeat-primed PCR, Beck et al. (2013) identified 96 repeat-primed PCR expansions in a large population- and patient-based cohort: there were 85 (2.9%) expansions among 2,974 patients with various neurodegenerative diseases and 11 (0.15%) expansions among 7,579 controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in patients was 800 to 4,400. Large expansions were also detected in the population controls. There were some differences in expansion size and morphology between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. The findings suggested that there may be a higher prevalence of expanded C9ORF72 repeat carriers than previously thought.