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1.  Autosomal Dominant Familial Dyskinesia and Facial Myokymia: Single Exome Sequencing Identifies a Mutation in Adenylate Cyclase 5 
Archives of neurology  2012;69(5):630-635.
Background
Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a five-generation family of German ancestry we previously mapped FDFM to chromosome 3p21-3q21. The 72.5 Mbp linkage region was too large for traditional positional mutation identification.
Objective
To identify the gene responsible for FDFM by exome resequencing of a single affected individual.
Design, Setting and Participants
We performed whole exome sequencing in one affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or 1000 Genomes project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in three generations.
Results
The exome contained 23428 single nucleotide variants, of which 9391 were missense, nonsense or splice site alterations. The critical region contained 323 variants, five of which were not present in one of the sequence-databases. Adenylate cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control Caucasian exomes. This residue is highly conserved and the change is nonconservative and predicted to be damaging.
Conclusions
ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence in combination with linkage information to identify causative genes for rare autosomal dominant Mendelian diseases.
doi:10.1001/archneurol.2012.54
PMCID: PMC3508680  PMID: 22782511
2.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
3.  The N141I Mutation in PSEN2 
Archives of neurology  2010;67(5):631-633.
Objective
To connect a new family with early-onset Alzheimer disease (EOAD) in Germany to the American Volga German pedigrees.
Design
Pedigree molecular genetic analysis.
Setting
University Medical Centers in Fulda and Giessen, Germany, and in Seattle, Washington.
Results
The families from Fulda, Germany, and the American Volga German families with EOAD share the same N141I PSEN2 mutation on an identical haplotypic background. This establishes that the N141I mutation occurred prior to emigration of the families from the Hesse region to Russia in the 1760s, and documents that relatives of the original immigrant families are presently living in Germany with the mutation and the disease.
Conclusion
A family with the N141I mutation in PSEN2 that presently lives in Germany has been connected to the haplotype that carries the same mutation in pedigrees descended from the Volga Germans. This raises the possibility that the original patient with Alzheimer disease (Auguste D.), who had EOAD and lived in this same region of Germany, may also have had the PSEN2 N141I mutation.
doi:10.1001/archneurol.2010.87
PMCID: PMC3016011  PMID: 20457965
4.  The Spectrum of Mutations in Progranulin 
Archives of neurology  2010;67(2):161-170.
Background
Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations.
Objectives
To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants.
Design
Case-control study.
Setting
Clinical and neuropathology dementia research studies at 8 academic centers.
Participants
Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease.
Main Outcome Measures
Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays.
Results
We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history.
Conclusions
Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.
doi:10.1001/archneurol.2009.328
PMCID: PMC2901991  PMID: 20142524
5.  Glucocerebrosidase Gene Mutations 
Archives of neurology  2008;65(3):379-382.
Background
Mutations in the glucocerebrosidase (GBA) gene have been reported to modify risk for Parkinson disease (PD) and dementia with Lewy bodies (DLB). However, these findings have not been consistently replicated, and most studies have had substantial methodological shortcomings.
Objective
To better assess the role of GBA variants in altering risk for Lewy body disorders.
Design
Case-control study.
Setting
Four movement disorder clinics in the Seattle, Washington, area.
Participants
Seven hundred twenty-one patients with PD, 554 healthy control subjects, and 57 patients with DLB.
Main Outcome Measures
Disease status and presence or absence of the 2 most common GBA mutations (N370S and L444P).
Results
We observed a significantly higher heterozygote frequency for the 2 mutations in patients with PD (2.9%; P<.001) and those with DLB (3.5%; P=.045) compared with control subjects (0.4%).
Conclusion
Our findings suggest that GBA mutations exert a large effect on susceptibility for Lewy body disorders at the individual level but are associated with a modest (approximately 3%) population-attributable risk in individuals of European ancestry.
doi:10.1001/archneurol.2007.68
PMCID: PMC2826203  PMID: 18332251
6.  Clinical and neuropathological features of the Arctic APP mutation causing early onset Alzheimer's disease 
Archives of neurology  2008;65(4):499-505.
Background
A majority of mutations within the amyloid β (Aβ) region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral haemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-Aβ mutation to date causing the more typical clinical picture of Alzheimer's disease (AD).
Objective
To describe features of one Swedish and one American family with the previously reported Arctic APP mutation.
Subjects
Affected and non-affected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, one brain from each family was investigated neuropathologically.
Results
The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of AD and similar to the phenotype for other AD APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe, as demonstrated by magnetic resonance imaging and single photon emission computed tomography. One Swedish and one American case with the Arctic APP mutation have come to autopsy, neither of which showed any signs of haemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathology as well as abundant amyloid plaques. Intriguingly, a majority of plaques from both of these cases had a characteristic ring-like character.
Conclusions
Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with AD.
doi:10.1001/archneur.65.4.499
PMCID: PMC2723757  PMID: 18413473
Familial Alzheimer's disease; APP gene mutations; Arctic mutation; cerebral amyloid angiopathy; dementia; genealogy
7.  Lewy Body Pathology in Familial Alzheimer Disease 
Archives of neurology  2006;63(3):370-376.
Background
The origin and significance of Lewy bodies and neurites (Lewy body pathology [LBP]) in Alzheimer disease (AD) are poorly understood.
Objective
To examine LBP in the brainstem, limbic cortex, and neocortex of a large number of familial AD cases with mutations in 2 presenilin (PSEN) genes.
Methods
Twenty-five familial AD cases with 9 known PSEN 1 mutations and 14 familial AD cases with a single PSEN 2 mutation (N141I) were examined for LBP using α-synuclein immunohistochemistry and sampling of multiple brainstem and cortical regions.
Results
The amygdala was the most vulnerable site for LBP. In fact, virtually all (24 [96%] of 25 cases) of the PSEN 1 mutation cases had LBP in the amygdala. The PSEN 1 mutation cases also had more frequent LBP in the amygdala and neocortex than those with the PSEN 2 mutation. However, within families with a single mutation of either PSEN 1 or PSEN 2, there was frequent variability of the LBP.
Conclusion
These findings suggest that there are genetic influences on the presence of LBP in familial AD as demonstrated by the differences between PSEN 1 and PSEN 2 mutation cases.
doi:10.1001/archneur.63.3.370
PMCID: PMC1892620  PMID: 16533963

Results 1-7 (7)