Effect of MAPT and APOE on prognosis of progressive supranuclear palsy

To assess genetic influence on the clinical presentation of progressive supranuclear palsy (PSP), the genetic effect on disease course was examined for variants in the tau gene (MAPT) and the gene for apolipoprotein E (APOE) in 58 cases of pathologically confirmed PSP. Clinical indicators of disease course included age at symptomatic onset (AAO), age at death (AAD), and disease duration (DD) and the genetic effects examined included MAPT haplotypes and APOE genotypes. From linear regression analysis, the MAPT H1/H1 genotype was associated with significantly earlier AAO (P=0.038). The MAPT genotype did not significantly influence DD or AAD. The APOE epsilon4 allele did not significantly influence AAO, AAD, or DD. Male sex was a predictor for earlier AAO (P=0.015). The interaction between MAPT and APOE was not significant for AAD and DD, but a significant negative coefficient was found for AAO suggesting their combination does not have an additive effect. These results support the assertion that the H1/H1 genotype may contribute to the earlier occurrence of clinical symptoms.     

Inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia: recurrence of the VCP R155H mutation in an Italian family and implications for genetic counselling

The acronym IBMPFD denotes a syndrome including inclusion body myopathy, Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) as cardinal features, which is caused by missense mutations in the VCP gene. We studied the clinical characteristics and the histopathological features in two siblings and their mother who presented with adult-onset myopathy and presenile, rapidly progressive FTD. One sibling also showed PDB. Light and electron microscopy performed on muscle biopsies demonstrated degenerative changes with inclusion bodies and abnormal aggregates. Mutation analysis of the VCP gene on affected siblings revealed a heterozygous missense mutation (R155H) in a hot spot. This is the first Italian family with multiple individuals diagnosed as having IBMPFD and carrying the recurrent R155H mutation. The implications for genetic counselling were also discussed, with regard to the procedures that may be offered to families suffering from a multisystem disorder with high risk of cognitive decline.     

Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice

Mutations in p97/VCP cause the autosomal-dominant, inherited syndrome inclusion body myopathy (IBM) associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD) (Watts, G.D., Wymer, J., Kovach, M.J., Mehta, S.G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M.P. and Kimonis, V.E. (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. p97/VCP is a multi-functional protein with a role in the ubiquitin-proteasome system (UPS) (Wang, Q., Song, C. and Li, C.C. (2004) Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. To understand how mutations in this protein lead to a myopathy, we generated several lines of transgenic mice expressing p97/VCP-WT (TgVCP-WT) or the most common IBMPFD mutant, p97/VCP R155H (TgVCP-RH), under a muscle-specific promoter. TgVCP-RH animals, but not controls, became progressively weaker in a dose-dependent manner starting at 6 months of age. Abnormal muscle pathology, which included coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 expression at the sarcolemma developed coincident with the onset of weakness. These changes were not associated with alterations in sarcolemmal integrity as measured by muscle fiber uptake of Evan's blue dye. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high-molecular-weight ubiquitinated proteins, markers of UPS dysfunction. We suggest that this early and persistent increase in ubiquitinated proteins induced by IBMPFD mutations in p97/VCP may ultimately lead to animal weakness and the observed muscle pathology. TgVCP-RH animals will be a valuable tool for understanding the pathogenesis of IBM and the role of the UPS in skeletal muscle.     

Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9-60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy.     

H1 haplotype of the MAPT gene is associated with lower regional gray matter volume in healthy carriers

The microtubule-associated protein Tau (MAPT) gene codes for the protein Tau that is involved in the pathogenesis of neurodegenerative diseases. Recent studies have detected an over-representation of the H1 haplotype of the MAPT gene in neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Parkinson's disease (PD), whereas the H2 haplotype has been found to be related to familial FTD. We aimed to investigate the association between MAPT haplotype status and brain morphology in healthy adults. A total of 150 healthy subjects underwent 3D high-resolution magnetic resonance (MR). MR images were processed following an optimized protocol to perform the Voxel-based morphometry (VBM) comparisons of the gray matter (GM) in H1 carriers (n=141) in contrast to H2H2 homozygous (n=9), and H1H1 homozygous (n=85) in contrast to H2 carriers (n=65). The threshold for statistical significance was 0.005 uncorrected. Opposite comparisons were also carried out. The groups had similar demographic and cognitive features. Compared with H2H2, the H1 carriers showed up to 19% smaller GM volume in the head of the right caudate nucleus, in the right middle frontal gyrus, in the left insula and orbito-frontal cortex, and in the inferior temporal and inferior cerebellar lobes, bilaterally. Compared with all H2 carriers, H1H1 displayed lower GM in the same regions, but the effect was smaller (5%), possibly due to a dilution effect by H1 in the H2 carriers group. The data suggest that H1 haplotype is associated with a particular cerebral morphology that may increase the susceptibility of the healthy carriers to develop neurodegenerative diseases such as sporadic tauopathies.     

Mutational analysis of VCP gene in familial amyotrophic lateral sclerosis

Mutations in valosin-containing protein (VCP) gene, already known to be associated with the multisystemic disorder, inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD), have been recently found also in familial cases of amyotrophic lateral sclerosis (ALS). To further define the frequency of VCP mutations in ALS Italian population, we screened a cohort of 166 familial ALS and 14 ALS-frontotemporal dementia (FTD) individuals. We identified a previously reported synonymous mutation (c.2093A>C; p.Q568Q), 2 intronic variants (c.1749-14C>T; c.2085-3C>T), and 1 nucleotide change (c.2814G>T) in the 3' untranslated region (UTR). Bioinformatical analyses predicted no changes in splicing process or microRNA binding sites. Our results do not confirm a main contribution of VCP gene to familial ALS in the Italian population.     

No association of common VCP variants with sporadic frontotemporal dementia

Mutations in the gene for valosin containing protein (VCP) cause autosomal dominant inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD). To investigate the role of this novel gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 27 single nucleotide polymorphisms covering the entire VCP genomic region in 198 patients with sporadic FTD and 184 matched controls from Germany. No significant association could be demonstrated. There is no evidence, that common variants in VCP confer a strong risk to the development of sporadic FTD.     

Role of ethnicity on the association of MAPT H1 haplotypes and subhaplotypes in Parkinson's disease

An association of the H1 haplotype and subhaplotypes in the microtubule-associated protein Tau (MAPT) gene with Parkinson's disease (PD) has been reported. To further evaluate their role in PD, we genotyped a sample set of 765 cases and controls consisting of two large European subgroups of German (n=418) and Serbian (n=347) origin for the MAPT haplotypes H1 and H2. The H1/H1 carriers were tested for three additional MAPT polymorphisms. In the Serbian sample, there was significant evidence (P=0.0108) of an association of the H1/H1 genotype and PD. Surprisingly, in the German sample, we did not find significant differences in genotype or haplotype frequencies between patients and controls. These results suggest that the role of H1 haplotypes in the etiology of PD may be ethnically dependent.     

Dose dependent effect of APOE epsilon4 on behavioral symptoms in frontal lobe dementia

To determine whether apolipoprotein alleles (APOE) influence behavioral and psychological signs and symptoms of dementia (BPSD), we initiated a prospective, longitudinal study. Patients with Alzheimer's disease (AD) (N=186), frontotemporal dementia (FTD) (N=29), mixed dementia (MXD) (N=28), dementia with Lewy bodies (DLB) (N=11) and Parkinson's disease dementia (PDD) (N=7) were included. Blood was collected for DNA extraction and APOE genotyping. Behavioral assessments were performed at baseline and semi-annually thereafter, using behavioral assessment scales (Middelheim frontality score, behavioral pathology in Alzheimer's disease rating scale (Behave-AD)). In FTD patients, we identified dose dependent effects of APOE epsilon4 on the Behave-AD total and cluster aggressiveness scores. APOE epsilon2 was associated with a higher score on the Behave-AD cluster delusions in PDD/DLB patients. No APOE effects on frequency or severity of BPSD in AD and MXD patients were found. In conclusion, APOE has disease-specific effects on BPSD in FTD and PDD/DLB patients, given the reported associations of APOE epsilon4 with aggression (FTD) and of APOE epsilon2 with delusions (PDD/DLB).     

A novel deletion in progranulin gene is associated with FTDP-17 and CBS

In the last decade familial frontotemporal dementia (FFTD) has emerged as a distinct clinical disease entity characterized by clinical and genetic heterogeneity. Here, we provide an extensive clinical and genetic characterization of two Italian pedigrees presenting with FFTD (FAM047: 5 patients, 5 unaffected; FAM071: 4 patients, 11 unaffected). Genetic analysis showed a conclusive linkage (LOD score for D17S791/D17S951: 4.173) to chromosome 17 and defined a candidate region containing MAPT and PGRN genes. Recombination analysis assigned two different disease haplotypes to FAM047 and FAM071. In affected subjects belonging to both families, we identified a novel 4 bp deletion mutation in exon 7 of PGRN gene (Leu271LeufsX10) associated with a variable clinical presentation ranging from FTDP-17 to corticobasal syndrome. The age-related penetrance was gender dependent. Both mutations in MAPT and PGRN genes are associated with highly variable clinical phenotypes. Despite the profound differences in the biological functions of the encoded proteins, it is not possible to define a clinical phenotype distinguishing the disease caused by mutations in MAPT and PGRN genes.     

Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis

No definite genetic risk factor of non-monogenic frontotemporal dementia (FTD) has yet been identified. Several groups have examined the potential association of FTD with the apolipoprotein E (APOE) gene, but the results are inconsistent. Our objective was to determine whether APOE is a risk factor of FTD, using the largest series of patients with FTD and controls analysed so far (94 unrelated patients and 392 age and sex-matched controls), and a meta-analysis. Homozygosity for the E2E2 genotype was significantly associated with FTD (odds ratio (OR)=11.3; P=0.033, exact test). After stratification on familial history (FH) for FTD, the OR for E2E2 was still found significant when analysing only patients with a positive FH (OR=23.8; P=0.019). The meta-analysis, using 10 case-control studies with available genotype or allele information, comprising a total of 364 FTD patients and 2671 controls, including the patients of the present study, did not reach statistical significance even if the E2E2 genotype was more frequent in patients than in controls (0.018 vs 0.006, respectively). Because of studies heterogeneity (Mantel-Haenszel statistics: P=0.004), we analysed on one hand the neuropathologically-confirmed studies, and on the other hand the clinical-based studies. In the neuropathologically-confirmed studies (Mantel-Haenszel statistics: P=ns), we found a significant increase of the E2 allele frequency in FTD patients (OR[E2 vs E3]=2.01; 95% CI=1.02-3.98; P=0.04). The same result was found in the clinical-based studies, but studies heterogeneity remained. No result was significant with the E4 allele. The E2 allele seems so to be a risk factor of FTD whereas this allele is associated with the lowest risk in Alzheimer's disease. If this finding was confirmed, it could provide new insights into the mechanisms of differential risk related to APOE in neurodegenerative diseases.     

Genotype–phenotype studies of VCP‐associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia

Valosin containing protein (VCP) disease associated with inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype–phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring 10 missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and noncarriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter‐familial variation; and significant genotype–phenotype correlations were difficult to establish because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with an earlier onset of myopathy and Paget (p = 0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p = 0.03).We identified amyotrophic lateral sclerosis (ALS) was diagnosed in 13 individuals (8.9%) and Parkinson's disease in five individuals (3%); however, there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of the natural history and provides genotype–phenotype correlations in this unique disease.     

The structure of the tau haplotype in controls and in progressive supranuclear palsy

The group of neurodegenerative diseases collectively known as tauopathies are characterized by hallmark lesions consisting of fibrillar aggregates of the microtubule-associated protein, tau (MAPT). Mutations of the tau gene (MAPT) are the cause of frontotemporal dementia with parkinsonism linked to chromosome 17, giving tau a central role in the pathogenic process. The chromosomal region containing MAPT has been shown to evolve into two major haplotypes, H1 and H2, which are defined by linkage disequilibrium (LD) between several polymorphisms over the entire MAPT gene. Studies to date suggest a complete absence of recombination between these two haplotypes. The more common haplotype H1 is over-represented in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration. Using single nucleotide polymorphisms, we mapped LD in the regions flanking MAPT and have established the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering approximately 2 Mb. This gene-rich region extends centromerically beyond the corticotrophin releasing hormone receptor 1 gene (CRHR1) to a region of approximately 400 kb, where there is a complete loss of LD. The telomeric end is defined by an approximately 150 kb region just beyond the WNT3 gene. We show that the entire, fully extended H1 haplotype is associated with PSP, which implicates several other genes in addition to MAPT, as candidate pathogenic loci.     

Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation

Mutations in the AAA+ protein (ATPase associated with a variety of cellular activities) p97/VCP (valosin-containing protein) cause a dominantly inherited syndrome of inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia (IBMPFD). p97/VCP is a ubiquitously expressed protein that participates in a number of cellular processes including endoplasmic reticulum-associated degradation (ERAD). p97/VCP aids in the extraction of ubiquitinated proteins from the endoplasmic reticulum (ER) and facilitates their delivery to the proteasome. This study focuses on the effects of disease-associated p97/VCP mutations on this pathway. We show that p97/VCP containing the most prevalent IBMPFD-associated mutation, R155H, has normal ATPase activity and hexameric structure. However, when expressed in cultured cells, both this and a second IBMPFD-associated p97/VCP mutant increase the overall level of ubiquitin-conjugated proteins and specifically impair degradation of mutant DeltaF508-CFTR handled by the ERAD pathway. These effects are similar to those previously described for an ATPase deficient p97/VCP mutant and suggest that IBMPFD mutations impair p97/VCP cellular function. In a subset of cells, IBMPFD mutations also promote formation of aggregates that contain p97/VCP, ubiquitin conjugates and ER-resident proteins. Undegraded mutant DeltaF508-CFTR also accumulates in these aggregates. We conclude that IBMPFD mutations in p97/VCP disrupt ERAD and that this may contribute to the pathogenesis of IBMPFD.     

Lack of association of APOE and tau polymorphisms with dementia in Parkinson's disease

Some APOE or tau gene polymorphisms have been associated with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Parkinson's disease (PD). The reports of a possible association between the APOE 4 allele and dementia in PD are controversial, and some studies suggest that the tau H1/H1 genotype may increase the risk of dementia in PD. Here we analysed these APOE and tau polymorphisms in 86 clinically diagnosed PD patients with dementia (PDD), in 138 clinically diagnosed non-demented PD (PDND) patients, and in 91 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. We examined the possible genetic association of these polymorphisms with dementia in PD, but found no differences in genotypic distributions between the PDND, PDD, and control groups. The effects of tau and APOE polymorphisms on the age at dementia onset were studied using Kaplan-Meier survival analysis but no significant association were found. The lack of association between the APOE 4 allele and PDD suggests that the pathological process involved in the development of dementia in PD is different from the one that occurs in AD.     

VCP mutations in familial and sporadic amyotrophic lateral sclerosis

Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause inclusion body myopathy (IBM) with Paget's disease (PDB) and frontotemporal dementia (FTD). The presence of VCP mutations in patients with sporadic ALS, sporadic ALS-FTD, and progressive muscular atrophy (PMA), a known clinical mimic of inclusion body myopathy, is not known. To determine the identity and frequency of VCP mutations we screened a cohort of 93 familial ALS, 754 sporadic ALS, 58 sporadic ALS-FTD, and 264 progressive muscular atrophy patients for mutations in the VCP gene. Two nonsynonymous mutations were detected; 1 known mutation (p.R159H) in a patient with familial ALS with several family members suffering from FTD, and 1 mutation (p.I114V) in a patient with sporadic ALS. Conservation analysis and protein prediction software indicate the p.I114V mutation to be a rare benign polymorphism. VCP mutations are a rare cause of familial ALS. The role of VCP mutations in sporadic ALS, if present, appears limited.     

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.     

Genetics of dementia: Update and guidelines for the clinician

With increased frequency, clinical geneticists are asked for genetic advice on the heredity of dementia in families. Alzheimer's disease is in most cases a complex disease, but may be autosomal dominant inherited. Mutations in the PSEN1 gene are the most common genetic cause of early onset Alzheimer's disease, whereas APP and PSEN2 gene mutations are less frequent. Familial frontotemporal dementia may be associated with a mutation in the MAPT or GRN gene, or with a repeat expansion in the C9orf72 gene. All these genes show autosomal dominant inheritance with a high penetrance. Although Alzheimer's disease and frontotemporal dementia are clinically distinguishable entities, phenotypical overlap may occur. Rarely, dementia is caused by mutations in other autosomal dominant genes or by genetic defects with autosomal recessive, X-linked dominant or mitochondrial inheritance. The inherited forms of frontotemporal dementia and Alzheimer's disease show a large phenotypic variability also within families, resulting in many remaining uncertainties for mutation carriers. Therefore, genetic counseling before performing genetic testing is essential in both symptomatic individuals and healthy at risk relatives. This review provides an overview of the genetic causes of dementia and discusses all aspects relevant for genetic counseling and testing. Furthermore, based on current knowledge, we provide algorithms for genetic testing in patients with early onset Alzheimer's disease or frontotemporal dementia. ? 2012 Wiley Periodicals, Inc.     

Apolipoprotein gene E4 allele promoter polymorphisms as risk factors for Alzheimer's disease

Alzheimer's disease is a complex neurodegenerative disorder, characterized by progressive cognitive decline and distinct neuropathology. The apolipoprotein gene E4 allele (APOE 4) is a major risk factor for the disease. Promoter polymorphisms at -491 and -427 may also contribute to the risk. We examined the two polymorphisms in 178 Alzheimer's patients and 141 controls. The -491AA genotype was overrepresented among the patients (68 versus 54%, P=0.01). However, in patients who were APOE4 carriers, the -491AA genotype more than doubled the risk [odds ratio (OR)=2.5; 95% confidence interval (CI)=1.2-5.4], especially in combination with -427TT [odds ratio (OR)=3.3; 95% confidence interval (CI)=1.5-7.7]. Moreover, the -491A/-427T/APOE4/APOC1A haplotype was threefold higher for patients. These results contribute to the evidence that regulation of APOE4 expression modulates risk for Alzheimer's disease.