Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34–74 years) and disease duration (mean = 5.3, range = 1–16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia–amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with Mr 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.
frontotemporal dementia; frontotemporal lobar degeneration; amyotrophic lateral sclerosis; C9ORF72, TDP-43
Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4 %) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly-recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.
amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; C9ORF72; TDP-43; chromosome 9p
Describe the clinical features of a Brazilian
C9orf72 frontotemporal dementia – amyotrophic
lateral sclerosis (FTD-ALS) kindred, and compare them to other reported
C9orf72 families and FTD-ALS causing mutations.
Report of a kindred.
Dementia center at an University hospital.
One kindred encompassing 3 generations.
The presence of a hexanucleotide (GGGGCC) expansion in
C9orf72 was confirmed by repeat-primed PCR and Southern
blot. The observed phenotypes were behavioral variant FTD and ALS with
dementia, with significant variability in age of onset and duration of
disease. Parkinsonian features with focal dystonia, visual hallucinations
and more posterior atrophy on neuroimaging than is typical for FTD were
bvFTD due to C9orf72 expansions displays some
phenotypic heterogeneity, and may be associated with hallucinations,
parkinsonism, focal dystonia, and posterior brain atrophy. Personality
changes may precede by many years the diagnosis of dementia and may be a
distinguishing feature of this mutation.
The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism underlying many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72
Tertiary care academic medical center.
The members of the family affected by the mutation with features of FTD and/or ALS.
Main Outcome Measures
Clinical, neuropsychological, and neuroimaging assessments.
All three examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and one had ALS. MRI showed symmetric bilateral frontal, temporal, insular and cingulate atrophy.
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the clinico-neuroimaging-neuropathologic correlations.
Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.
Hexanucleotide expansion intronic to chromosome 9 open reading frame 72 (C9ORF72) has recently been identified as the most common genetic cause of both familial and sporadic amyotrophic lateral sclerosis and of frontotemporal dementia with or without concomitant motor neuron disease. Given the common frequency of this genetic aberration, clinicians seek to identify neuroimaging hallmarks characteristic of C9ORF72-associated disease, both to provide a better understanding of the underlying degenerative patterns associated with this mutation and to enable better identification of patients for genetic screening and diagnosis. A survey of the literature describing C9ORF72 neuroimaging thus far suggests that patients with this mutation may demonstrate symmetric frontal and temporal lobe, insular, and posterior cortical atrophy, although temporal involvement may be less than that seen in other mutations. Some studies have also suggested cerebellar and thalamic involvement in C9ORF72-associated disease. Diffuse cortical atrophy that includes anterior as well as posterior structures and subcortical involvement thus may represent unique features of C9ORF72.
Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.
amyotrophic lateral sclerosis; C9ORF72; dementia; neurodegeneration
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype.
To determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U.
We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings.
FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X).
Neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.
Frontotemporal dementia and parkinsonism linked to chromosome 17; Tau; Ubiquitin; TDP-43; Neuropathology
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one third of familial ALS cases of outbred European descent making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had >1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1149-y) contains supplementary material, which is available to authorized users.
ALS; Autophagy; C9ORF72; FTD; Hexanucleotide repeats; iPSCs; Neurodegeneration; Neurons; p62; RAN translation; RNA foci
To compare patterns of gray matter loss in subjects with mutations in the progranulin (PGRN) gene to subjects with mutations in the microtubule-associated protein tau (MAPT) gene.
We identified all subjects seen at the Mayo Clinic, Rochester, MN, who had screened positive for mutations in PGRN or MAPT and had a head MRI. Twelve cases with mutations in the PGRN gene were matched by time from disease onset to scan to 12 subjects with mutations in the MAPT gene. Voxel-based morphometry was used to assess patterns of gray matter loss in the PGRN and MAPT groups compared to a control cohort, and compared to each other. MAPT subjects were younger than the PGRN subjects; therefore, each group was also compared to a specific age-matched control group.
Both PGRN and MAPT groups showed gray matter loss in frontal, temporal, and parietal lobes compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT. The MAPT group had greater loss compared to healthy subjects of the same age than the PGRN subjects when compared to healthy subjects of the same age. The MAPT subjects showed greater gray matter loss in the medial temporal lobes, insula, and putamen than the PGRN subjects.
These results increase understanding of the biology of these disorders and suggest that patterns of atrophy on MRI may be useful to aid in the differentiation of groups of PGRN and MAPT mutation carriers.
= Alzheimer disease;
= Alzheimer's Disease Patient Registry;
= Alzheimer's Disease Research Center;
= behavioral variant frontotemporal dementia;
= bvFTD with parkinsonism;
= corticobasal syndrome;
= Clinical Dementia Rating scale sum of boxes;
= Dementia Rating Scale;
= frontotemporal lobar degeneration;
= microtubule-associated protein tau;
= mild cognitive impairment;
= Mini-Mental State Examination;
= primary progressive aphasia;
= Short Test of Mental Status;
= voxel-based morphometry.
Frontotemporal dementia (FTD) is a clinical syndrome with heterogeneous molecular basis. Until recently, our knowledge was limited to a minority of cases associated with abnormalities of the tau protein or gene (MAPT). However, in 2006, mutations in progranulin (GRN) were discovered as another important cause of familial FTD. That same year, TAR DNA binding protein 43 (TDP-43) was identified as the pathological protein in the most common subtypes of FTD and ALS. Since then, significant efforts have been made to understand the normal functions and regulation of GRN and TDP-43 and their roles in neurodegeneration. More recently, other DNA/RNA binding proteins (FUS, EWS and TAF15) were identified as pathological proteins in most of the remaining cases of FTD. And just six months ago, abnormal expansion of a hexanucleotide repeat in C9ORF72 was found to be the most common genetic cause of both FTD and ALS. With this remarkable progress, it appears that all the common FTD-causing genes have now been discovered and the major pathological proteins identified. This review highlights recent advances in the molecular aspects of FTD, which will provide the basis for improved patient care through the future development of more targeted diagnostic tests and therapies.
Mislocalization, aberrant processing and aggregation of TAR DNA-binding protein 43 (TDP-43) is found in the neurons affected by two related diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobe dementia (FTLD). These TDP-43 abnormalities are seen when TDP-43 is mutated, such as in familial ALS, but also in FTLD, caused by null mutations in the progranulin gene. They are also found in many patients with sporadic ALS and FTLD, conditions in which only wild type TDP-43 is present. The common pathological hallmarks and symptomatic cross over between the two diseases suggest that TDP-43 and progranulin may be mechanistically linked. In this study we aimed to address this link by establishing whether overexpression of mutant TDP-43 or knock-down of progranulin in zebrafish embryos results in motor neuron phenotypes and whether human progranulin is neuroprotective against such phenotypes. Mutant TDP-43 (A315T mutation) induced a motor axonopathy characterized by short axonal outgrowth and aberrant branching, similar, but more severe, than that induced by mutant SOD1. Knockdown of the two zebrafish progranulin genes, grna and grnb, produced a substantial decrease in axonal length, with knockdown of grna alone producing a greater decrease in axonal length than grnb. Progranulin overexpression rescued the axonopathy induced by progranulin knockdown. Interestingly, progranulin also rescued the mutant TDP-43 induced axonopathy, whilst it failed to affect the mutant SOD1-induced phenotype. TDP-43 was found to be nuclear in all conditions described. The findings described here demonstrate that progranulin is neuroprotective in vivo and may have therapeutic potential for at least some forms of motor neuron degeneration.
Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau (MAPT) or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.
corticobasal degeneration; TDP-43; frontotemporal lobar degeneration; progranulin
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients’ clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients’ delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.
frontotemporal lobar degeneration; clinical characteristics; motor neuron disease; psychosis; neuropathology
Frontotemporal dementia (FTD) comprises a group of behavioral, language, and movement disorders. On the basis of the nature of the characteristic protein inclusions, frontotemporal lobar degeneration (FTLD) can be subdivided into the common FTLD-tau and FTLD-TDP as well as the less common FTLD-FUS and FTLD-UPS. Approximately 10% of cases of FTD are inherited in an autosomal-dominant manner. Mutations in seven genes cause FTD, with those in tau (MAPT), chromosome 9 open reading frame 72 (C9ORF72), and progranulin (GRN) being the most common. Mutations in MAPT give rise to FTLD-tau and mutations in C9ORF72 and GRN to FTLD-TDP. The other four genes are transactive response–DNA binding protein-43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B). Mutations in TARDBP and VCP give rise to FTLD-TDP, mutations in FUS to FTLD-FUS, and mutations in CHMP2B to FTLD-UPS. The discovery that mutations in MAPT cause neurodegeneration and dementia has important implications for understanding Alzheimer disease.
Mutations in the tau (MAPT) gene account for ∼5% of frontotemporal dementia cases. They give rise to characteristic protein inclusions, providing insight into tau pathology in Alzheimer disease.
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 material
The online version of this article (doi:10.1007/s00401-013-1078-9) contains supplementary material, which is available to authorized users.
Frontotemporal dementia; Amyotrophic lateral sclerosis; Motor neuron disease; Corticobasal degeneration; Tau; TDP-43
Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau. The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases. Multiple IF gene mutations are pathogenic for Charcot–Marie–Tooth (CMT) disease and amyotrophic lateral sclerosis (ALS) — in addition to those in the copper/zinc superoxide dismutase-1 (SOD1) gene. Tau gene mutations are pathogenic for frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors for sporadic progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Thus, IF and tau abnormalities are linked directly to the aetiology and pathogenesis of neurodegenerative diseases. In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.
neuronal intermediate filament; tau; cytoskeleton; mutation; neurodegenerative disease; peripheral neuropathy
An intronic expansion of a hexanucleotide GGGGCC repeat in the C9ORF72 gene has recently been shown to be an important cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in familial and sporadic cases. The frequency has only been defined in a small number of populations where the highest sporadic rate was identified in Finland (21.1%) and the lowest in mainland Italy (4.1%). We examined the C9ORF72 expansion in a series of 146 Greek ALS cases, 10.95% (n = 16) of cases carried the pathological expansion defined as greater than 30 repeats. In the 10 familial ALS probands, 50% (n = 5) of them carried a pathologically large expansion. In the remaining 136 sporadic ALS cases, 11 were carriers (8.2%). None of the 228 Greek controls carried an expanded repeat. The phenotype of our cases was spinal (13/16) or bulbar (3/16) ALS, the familial cases were all spinal ALS and none of our cases had behavioral frontotemporal dementia. Expansions in the C9ORF72 gene therefore represent a common cause of ALS in Greece and this test will be diagnostically very important to implement in the Greek population. The frequency is higher than other populations with the exception of Finland and this may be due to Greece being a relatively isolated population.
ALS; C9ORF72; Expansion; Hexanucleotide; Greek population
Chromosome 9 open reading frame 72 (C9orf72) is an evolutionarily conserved protein with unknown function, expressed at high levels in the brain. An expanded hexanucleotide GGGGCC repeat located in the first intron of the C9orf72 gene represents the most common genetic cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Previous studies by immunohistochemistry with two different anti-C9orf72 antibodies named sc-138763 and HPA023873 showed that C9orf72 is expressed chiefly in the cytoplasm of neurons, and is concentrated in the synaptic terminals in the brains of FTD/ALS with or without C9orf72 repeat expansion as well as those of controls. At present, a pathological role of C9orf72 in the process of neurodegeneration remains unknown.
Using immunohistochemistry we studied C9orf72 expression in the frontal cortex and the hippocampus of six Alzheimer's disease (AD) and 13 control cases, including ALS, Parkinson's disease, multiple system atrophy, and non-neurological cases.
The HPA023873 antibody showed a cross-reactivity to glial fibrillary acidic protein, and therefore stained intensely reactive astrocytes in AD and non-AD brains. Both sc-138763 and HPA023873 antibodies labeled the neuronal cytoplasm and the neuropil with variable intensities, and intensely stained a cluster of p62-negative, UBQLN1-positive swollen neurites, which were distributed in the CA1 region and the molecular layer in the hippocampus of both AD and non-AD brains. Most notably, both of these antibodies reacted strongly with dystrophic neurites accumulated on senile plaques in AD brains.
These results suggest a general role of C9orf72 in the process of neurodegeneration in a range of human neurodegenerative diseases.
Frontotemporal dementia and parkinsonism (FTDP) is a major neurodegenerative syndrome, particularly for those with symptoms beginning before age 65. A spectrum of degenerative disorders can present as sporadic or familial FTDP. Mutations in the gene encoding the microtubule associated protein tau (MAPT) on chromosome 17 have been found in many kindreds with familial FTDP. Several other kindreds with FTDP had been linked to chromosome 17, but they had ubiquitin-positive inclusions rather than tauopathy pathology, and no mutations in MAPT. This conundrum was solved over this past year with the identification of mutations in the gene encoding progranulin (PGRN), which is only 1.7 Mb centromeric to MAPT on chromosome 17. In this review, we compare and contrast the demographic, clinical, radiologic, neuropathologic, genetic, and pathophysiologic features in patients with FTDP linked to mutations in MAPT and PGRN, highlighting the many similarities but also a few important differences. The findings provide an intriguing oddity of nature in which two genes can cause a similar phenotype through apparently different mechanisms yet reside so near to each other on the same chromosome.
frontotemporal dementia; parkinsonism; progranulin; tau; PGRN; MAPT
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.
It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (familial ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1,757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1,523 from mainland Italy. Sixty (3.7%) of 1,624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally-matched control samples (1,238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived one year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucloetide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the commonest mutation in Italy and the second more common in Sardinia.
Amyotrophic lateral sclerosis; C9ORF72; frontotemporal dementia; survival
To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubule-associated protein tau (MAPT) gene mutations.
In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline.
The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9–2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8–4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9–12], GRN = 6.5% [95% CI 1.7–11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p < 0.001).
Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure.
Frontotemporal lobar degeneration (FTLD), the most frequent neurodegenerative disorder with a presenile onset, presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. Familial aggregation is frequently reported, and about 10% of cases have an autosomal dominant transmission. Microtubule associated protein tau (MAPT) gene mutations have been the first ones identified and are associated with early onset behavioral variant frontotemporal dementia phenotype. More recently, progranulin gene (GRN) mutations were recognized in association with familial form of FTLD. In addition, other genes are linked to rare cases of familial FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified. In this review, current knowledge about mutations at the basis of familial FTLD will be described, together with genetic risk factors influencing the susceptibility to FTLD.
genetics; frontotemporal lobar degeneration; autosomal dominant; mutation; risk factor