J Hardy

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype

Objective: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). Background: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. Methods: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. Results: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X2 = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X2 = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). Conclusions: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Predisposing locus for Alzheimer's disease on chromosome 21

Linkage between Alzheimers disease and markers on the long arm of chromosome 21 was investigated in six families affected by disease of early onset. Linkage was confirmed and the disease locus shown to be centromeric to the locus D21S1/S11 on the long arm of the chromosome. It is argued that the data are consistent with the notion that all patients with Alzheimers disease of genetic aetiology have a predisposing locus on chromosome 21.

The heritability and genetics of frontotemporal lobar degeneration

Background: Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder. Methods: We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease. Results: A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia–motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1). Conclusion: These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.

Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.

Background: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). Objective: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. Methods: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation. Results: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. Conclusion: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.

GLUCOCEREBROSIDASE MUTATIONS IN 108 NEUROPATHOLOGICALLY CONFIRMED CASES OF MULTIPLE SYSTEM ATROPHY

Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA) are synucleinopathies whose primary pathogenic event is the deposition of inclusions composed of aberrantly fibrillized α-synuclein.1 In PD and LBD, Lewy bodies are the key aggregate, whereas in MSA, α-synuclein accumulates in the form of oligodendroglial and neuronal cytoplasmic inclusions (GCIs and NCIs).2,3 Parkinsonian manifestations have been noted in a subset of patients with Gaucher disease and there is evidence that parkinsonism is more frequent among carrier relatives of patients with Gaucher disease.4 In a remarkable study, the glucocerebrosidase (GBA) gene was sequenced in an American PD brain bank series where GBA mutations were detected at a much higher frequently than in controls (PD 21% vs control 4.5%).5 These findings have since been replicated, mainly in Ashkenazi patient groups who have a higher mutation frequency but also in patients with clinically and pathologically diagnosed PD and LBD in a number of studies in different populations.4 In a study of 75 neuropathologically confirmed synucleinopathies, GBA mutations were found in 23% of the cases with Lewy bodies.6 The frequency of GBA mutations around the world between 2.3 and 31% (depending on population) indicates that GBA mutations are one of the commonest genetic risk factors for PD. GBA mutation carriers have a wide spectrum of phenotypes, ranging from classic l-dopa-responsive PD to LBD. In neuropathologic studies of PD/LBD cases, GBA mutations, α-synuclein inclusions, and Lewy bodies have been seen. This spectrum of clinical and pathologic features would suggest that MSA should also be a candidate to have GBA mutation.3 Only 12 cases of MSA have been analyzed for GBA mutations and defects were seen in this handful of cases.6 We extracted DNA from the brain tissue of 108 neuropathologically confirmed British MSA cases that had been diagnosed according to brain bank criteria and 257 normal British controls. Mean age at onset was 58.2 ± 10.7 years (range 34–83), mean age at death 64.5 ± 10.2 years (39–87), mean disease duration 6.8 ± 2.9 years (2–16), and 48% were men. All exons and flanking intronic regions of the GBA gene were sequenced in MSA and control cases. To avoid amplifying and sequencing the GBA pseudogene we employed long range GBA PCR and then BigDye sequencing as previously described.7 In our MSA study group of 108 cases, we identified one heterozygous GBA mutation (c.904C>T; R262H), giving a mutation frequency of 0.92%. In the British controls, three heterozygous mutations (V497L, N409S, and R269Q) out of 257 cases were identified (1.17%). There was no significant difference between the two groups (p = 0.66). The single MSA case with the heterozygous R262H mutation was a woman with an age at onset of 44 years. She had parkinsonian, cerebellar, and autonomic features (MSA–mixed type) with no family history. She died at age 51 years and the neuropathology revealed widespread GCIs and NCIs with a predominance in striatonigral structures. There were no Lewy bodies. One limitation of our study is the small sample size. Our study has a power of 80% to detect variants with an OR >1.61 or <0.63 at a significance level of 0.05. The results of this study indicate that GBA mutations are not common etiologic players in Caucasian patients with MSA. We cannot exclude that GBA mutations confer modest or low risk to disease. Furthermore, we did not sequence risk variants in regulatory regions (such as the promotor region or untranslated regions). Mutations in these regions would therefore have been missed. The unexpected role of GBA mutations has been demonstrated in several populations and is undoubtedly a highly significant risk factor for PD and LBD. More importantly, GBA mutations reveal a direct link between the lysosomal protein pathway and the clearance or the development of α-synuclein aggregates into Lewy bodies. Our study indicates that GBA mutations are not associated with MSA in the population that we analyzed, and that this branch of the ceramide pathway is unlikely to be associated with all types of primary α-synuclein deposition.

Compound heterozygous PANK2 mutations confirm HARP and Hallervorden-Spatz syndromes are allelic

The authors describe a patient with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) who has two compound heterozygote mutations of the PANK2 gene. IVS4–1 G>T segregates with the lipid and erythrocyte changes in the mother and sister. No other family members have the lipid, erythrocyte, or clinical abnormalities. The father and two brothers are heterozygous for Met327Thr. One other mutation has been found in this PANK2 region associated with the HARP phenotype, suggesting a local genotype effect.

Genome-wide scan linkage analysis for Parkinson's disease: The European genetic study of Parkinson's disease

Objective: To undertake a full genome-wide screen for Parkinson’s disease susceptibility loci. Methods: A genome-wide linkage study was undertaken in 227 affected sibling pairs from 199 pedigrees with Parkinson’s disease. The pedigree sample consisted of 188 pedigrees from five European countries, and 11 from the USA. Individuals were genotyped for 391 microsatellite markers at ∼10 cM intervals throughout the genome. Multipoint model-free affected sibling pair linkage analyses were carried out using the MLS (maximum LOD score) test. Results: There were six chromosomal regions with maximum MLS peaks of 1 or greater (pointwise p<0.018). Four of these chromosomal regions appear to be newly identified regions, and the highest MLS values were obtained on chromosomes 11q (MLS = 1.60, at 91 cM, D11S4175) and 7p (MLS = 1.51, at 5 cM, D7S531). The remaining two MLS peaks, on 2p11–q12 and 5q23, are consistent with excess sharing in regions reported by other studies. The highest MLS peak was observed on chromosome 2p11–q12 (MLS = 2.04, between markers D2S2216 and D2S160), within a relatively short distance (∼17 cM) from the PARK3 region. Although a stronger support of linkage to this region was observed in the late age of onset subgroup of families, these differences were not significant. The peak on 5q23 (MLS = 1.05, at 130 cM, D5S471) coincides with the region identified by three other genome scans. All peak locations fell within a 10 cM distance. Conclusions: These stratified linkage analyses suggest linkage heterogeneity within the sample across the 2p11–q12 and 5q23 regions, with these two regions contributing independently to Parkinson’s disease susceptibility.

The BDNF val66met polymorphism is not associated with late onset Alzheimer's disease in three case–control samples

The BDNF val66met polymorphism is not associated with late onset Alzheimers disease in three case–control samples

Disentangling the role of the tau gene locus in sporadic tauopathies.

Fibrillar aggregates of abnormally hyperphosphorylated tau protein are the major component of the pathological entities, including intraneuronal neurofibrillary tangles that define the broad class of late-onset neurodegenerative disorders called the tauopathies. Mutations in the tau gene (MAPT) causing familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) confirm that tau protein dysfunction could be a primary cause of neuronal loss. However, in the sporadic tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) where MAPT mutation is absent, common variation in MAPT that defines the H1 and H2 haplotype clades strongly influences disease risk. Surprisingly, this influence on risk extends to sporadic Parkinsons disease (PD), traditionally not defined as a tauopathy. This review will focus on recent work aimed at elucidating the mechanistic basis of this haplotype-specific effect on disease risk, implicating elevated levels of MAPT expression, particularly via increased transcription and/or alterations in splicing. This conforms to an emerging picture of a shared mechanism that underlies the fundamental process(es) leading to neuronal death. Increased availability of the fibrillogenic protein substrates of the pathological aggregates that define several neurodegenerative proteopathies, eg α-synuclein in PD, β-amyloid in AD and tau in the tauopathies, contributes to causation and risk in the familial and sporadic forms of these disorders, respectively.

Review: Genetics and neuropathology of primary pure dystonia

R. Paudel, J. Hardy, T. Revesz, J. L. Holton and H. Houlden (2012) Neuropathology and Applied Neurobiology38, 520–534