E. Rogaeva

Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations

Background: Mutations in the presenilin-1 gene (PS1) account for a majority of patients with early-onset familial AD. However, the clinical indications and algorithms for genetic testing in dementia are still evolving. Methods: The entire open reading frame of the PS1 gene was sequenced in a series of 414 consecutive patients referred for diagnostic testing, including 372 patients with AD and 42 asymptomatic persons with a strong family history of AD. Results: Forty-eight independent patients screened had a PS1 mutation including 21 novel mutations. In addition, 3% of subjects (11/413) had a known polymorphism, the Glu318Gly substitution. The majority of the mutations were missense substitutions but there were three insertions and Δexon 10 mutation. With six exceptions (codons 35, 178, 352, 354, 358, and 365) most of the mutations occurred at residues conserved in the homologous PS2 gene or in PS1 of other species. Conclusions: Eleven percent of a referral-based series of patients with AD can be explained by coding sequence mutations in the PS1 gene. The high frequency of PS1 mutations in this study indicates that screening for PS1 mutations in AD is likely to be successful, especially when directed at patients with a positive family history with onset before 60 years (90% of those with PS1 mutations were affected by age 60 years). This will also have significance for the secondary identification of at-risk relatives who might be candidates for future prophylactic therapies for AD.

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinsons Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667

Familial Alzheimer disease: Decreases in CSF Aβ42 levels precede cognitive decline

CSF amyloid β-peptide 42 (Aβ42) levels in presymptomatic subjects with pathogenic mutations in the PS1 gene are significantly lower than in an age-matched control group. Consequently, in these subjects, there is a window of opportunity estimated as at least 4 to 12 years to evaluate the ability of any putative prophylactic therapy to decrease, arrest, or reverse abnormalities in Aβ42 metabolism many years before clinical symptoms of Alzheimer disease are otherwise likely to occur.

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.

The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter

Pathological expansion of a G4C2 repeat, located in the 5 regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD–ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45–78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5 flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent–child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5 CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7–24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2–6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.

Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism

Objectives: To study the frequency of different gene mutations in patients with early-onset parkinsonism and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and the short- and long-term surgical outcome in mutation-positive (MUT+) and -negative (MUT−) patients. Methods: Eighty patients with disease onset at age ≤ 45 years and bilateral STN-DBS were screened for mutations in the Parkin gene and PINK1 gene and for the recurrent p.G2019S mutation in the LRRK2 gene. The Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr (H-Y) scale were used to compare the on- and off-medication conditions preoperatively and in the off-medication/on-stimulation condition postoperatively. Results: We identified 12 mutation carriers (11 Parkin [6 with 2 mutated alleles, 5 with 1 mutated allele], 1 homozygous PINK1). There were no clinical differences between the MUT− and MUT+ patients preoperatively, except for more severe H-Y stage and postural and gait scores in the on-medication state in the MUT+ group. During the first year after surgery, MUT− patients showed better clinical improvement (56% motor UPDRS improvement) compared with MUT+ patients (36%). However, in the long-term follow-up (3–6 years), both groups presented with the same degree of clinical improvement (MUT−: 44% vs MUT+: 42%). Although the MUT+ group showed more severe axial signs preoperatively, MUT− patients developed levodopa– and deep brain stimulation–resistant axial signs within the first 3 to 6 years postoperatively, which diminished the initial benefit soon after surgery. Conclusions: Patients with Parkin or PINK1 mutations benefit from subthalamic nucleus deep brain stimulation. However, the clinical response is not superior to non–mutation carriers and might be limited by more advanced axial motor symptoms at a relatively early disease stage.

Clinical and genetic study of a large Italian family linked to SPG12 locus

Background: Seven loci for autosomal dominant hereditary spastic paraplegia (ADHSP) have been mapped. To date, two families of SPG12 (chromosome 19q13) have been analyzed; however, there is not enough clinical information on SPG12 to establish locus-phenotype correlations. Methods: The authors studied 60 individuals from a large Italian family with ADHSP, in which 16 members in four generations were affected. They performed genetic linkage analysis with DNA markers from currently known ADHSP loci. After database searching, one candidate gene for SPG12 was analyzed by sequencing. Results: The patients in this family showed an early onset and rapid progression of symptoms, resulting in severe disability, with a large proportion of affected members requiring use of a wheelchair. By age 16, most patients had sensory disturbance. Evidence for linkage to the SPG12 locus was obtained. Obligate recombination events observed in this family have narrowed the SPG12 locus from the 16.1 cM to 11.3 cM region between markers D19S416 and D19S412. In combination with previous genetic studies, the SPG12 locus was further narrowed to the 3.3 cM region between D19S416 and D19S220. A homologue of the AAA (ATPases associated with a variety of cellular activities) protein family, proteasome 26S subunit ATPase mapped near D19S220, was excluded by sequencing. Conclusions: This study refined the SPG12 region between D19S416 and D19S220 and revealed several clinical characteristics—early onset, rapid progression, and involvement of sensory disturbance—that may be unique to SPG12. Suggestive evidence of genetic anticipation was obtained, but should be confirmed in other SPG12 families.

PS1 Alzheimer’s disease family with spastic paraplegia: The search for a gene modifier

PS1 mutations are associated with classic Alzheimer’s disease (AD); however, some families develop AD and spastic paraplegia (SP) with brain pathology characterized by Aβ cotton wool plaques. The authors report a variant AD family with the E280Q PS1 mutation. The fact that the same PS1 mutation can be found in patients with either variant or classic AD argues in favor of the presence of a genetic modifier. The authors have excluded that this modifier effect originates from coding sequence variations in three SP genes or from a second mutation in the other AD genes.

Parkin-proven disease Common founders but divergent phenotypes

Objective: To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3Δ40) to search for evidence of a common founder. Method: Clinical review, parkin gene sequencing, dosage studies, and high-resolution genotype/haplotype analysis were performed. Results: All subjects had two or more signs consistent with a diagnosis of possible or probable PD with age at onset younger than 45 years (mean ± SD 29.3 ± 10.2 years, range 16 to 42 years). Affected individuals were either homozygotes, compound heterozygotes, or Ex3Δ40 carriers with one normal parkin allele. Haplotype analysis revealed both Ex3Δ40 and Ex7 924 C→T (R275W) mutations originated from common founders, the former most probably of Irish descent. Although three cases had Ex7 924 C→T (R275W) and Ex3Δ40 mutations, their clinical presentation and mode of inheritance were variable. Conclusion: Parkin mutations on common parkin haplotypes provide testable hypotheses of parkin function in genetically defined parkinsonism.

Characterization of the kindred of Alois Alzheimer's patient with plaque-only dementia

We describe the kindred of Alois Alzheimers second published patient (Johann F.) with the brain pathology typical of a subgroup of Alzheimer disease called “plaque-only type.” The genealogic records of the kindred extend back to 1670. We constructed a family tree of 1403 individuals and identified 4 living demented members of the Johann F. kindred. The pedigree is consistent with an autosomal dominant trait. The analyses of known dominant dementia genes (APP, PS1, PS2, PRNP, and BRI) failed to reveal mutations in the proband. Further examination of this family might yield new insights into the genetics of Alzheimer disease.