Publications by authors named "Lorraine Clark"

113 Publications

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease.

Ann Neurol 2021 May 2. Epub 2021 May 2.

23andMe, Inc., Sunnyvale, California, U.S.A.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genome-wide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these two proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value = 1.1E-07; age-at-onset top variant: P-value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26094DOI Listing
May 2021

Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia.

Neuron 2021 May 22;109(9):1465-1478.e4. Epub 2021 Mar 22.

Department of Computer Science, Columbia University, New York, NY 10027, USA; Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA. Electronic address:

The identification of rare variants associated with schizophrenia has proven challenging due to genetic heterogeneity, which is reduced in founder populations. In samples from the Ashkenazi Jewish population, we report that schizophrenia cases had a greater frequency of novel missense or loss of function (MisLoF) ultra-rare variants (URVs) compared to controls, and the MisLoF URV burden was inversely correlated with polygenic risk scores in cases. Characterizing 141 "case-only" genes (MisLoF URVs in ≥3 cases with none in controls), the cadherin gene set was associated with schizophrenia. We report a recurrent case mutation in PCDHA3 that results in the formation of cytoplasmic aggregates and failure to engage in homophilic interactions on the plasma membrane in cultured cells. Modeling purifying selection, we demonstrate that deleterious URVs are greatly overrepresented in the Ashkenazi population, yielding enhanced power for association studies. Identification of the cadherin/protocadherin family as risk genes helps specify the synaptic abnormalities central to schizophrenia.
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http://dx.doi.org/10.1016/j.neuron.2021.03.004DOI Listing
May 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Decision Support for Implantable Cardioverter-Defibrillator Replacement: A Pilot Feasibility Randomized Controlled Trial.

J Cardiovasc Nurs 2021 Mar-Apr 01;36(2):143-150

Background: Decision support can help patients facing implantable cardioverter-defibrillator (ICD) replacement understand their options and reach an informed decision reflective of their preferences.

Objective: The aim of this study was to evaluate the feasibility of a decision support intervention for patients faced with the decision to replace their ICD.

Methods: A pilot feasibility randomized trial was conducted. Patients approaching ICD battery depletion were randomized to decision support intervention or usual care. Feasibility outcomes included recruitment rates, intervention use, and completeness of data; secondary outcomes were knowledge, values-choice concordance, decisional conflict, involvement in decision making, and choice.

Results: A total of 30 patients were randomized to intervention (n = 15) or usual care (n = 15). The intervention was used as intended, with 2% missing data. Patients in the intervention arm had better knowledge (77.4% vs 51.1%; P = .002). By 12 months, 8 of 13 (61.5%) in the intervention arm and 10 of 14 (71.4%) in the usual care arm accepted ICD replacement; 1 per arm declined (7.7% vs 7.1%, respectively).

Conclusion: It was feasible to deliver the intervention, collect data, despite slow recruitment. The decision support intervention has the potential to improve ICD replacement decision quality.
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http://dx.doi.org/10.1097/JCN.0000000000000694DOI Listing
May 2020

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Acta Neuropathol Commun 2020 01 29;8(1). Epub 2020 Jan 29.

Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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http://dx.doi.org/10.1186/s40478-020-0879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990558PMC
January 2020

Whole genome sequencing and rare variant analysis in essential tremor families.

PLoS One 2019 12;14(8):e0220512. Epub 2019 Aug 12.

Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, United States of America.

Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns. In ET families with Mendelian inheritance patterns, WGS may lead to gene identification where WES analysis failed to identify the causative single nucleotide variant (SNV) or indel due to incomplete coverage of the entire coding region of the genome, in addition to accurate detection of larger structural variants (SVs) and copy number variants (CNVs). Alternatively, in ET families with complex disease inheritance patterns with gene x gene and gene x environment interactions enrichment of functional rare coding and non-coding variants may explain the heritability of ET. We performed WGS in eight ET families (n = 40 individuals) enrolled in the Family Study of Essential Tremor. The analysis included filtering WGS data based on allele frequency in population databases, rare SNV and indel classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test. A separate analysis of rare SV and CNVs segregating within ET families was also performed. Prioritization of candidate genes identified within families was performed using phenolyzer. WGS analysis identified candidate genes for ET in 5/8 (62.5%) of the families analyzed. WES analysis in a subset of these families in our previously published study failed to identify candidate genes. In one family, we identified a deleterious and damaging variant (c.1367G>A, p.(Arg456Gln)) in the candidate gene, CACNA1G, which encodes the pore forming subunit of T-type Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and has been previously implicated in neuronal autorhythmicity and ET. Other candidate genes identified include SLIT3 which encodes an axon guidance molecule and in three families, phenolyzer prioritized genes that are associated with hereditary neuropathies (family A, KARS, family B, KIF5A and family F, NTRK1). Functional studies of CACNA1G and SLIT3 suggest a role for these genes in ET disease pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220512PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690583PMC
March 2020

Current Opinions and Consensus for Studying Tremor in Animal Models.

Cerebellum 2019 Dec;18(6):1036-1063

Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL, USA.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.
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http://dx.doi.org/10.1007/s12311-019-01037-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872927PMC
December 2019

Heritability and genetic variance of dementia with Lewy bodies.

Neurobiol Dis 2019 07 3;127:492-501. Epub 2019 Apr 3.

Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
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http://dx.doi.org/10.1016/j.nbd.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588425PMC
July 2019

Copy number variation of in familial dystonic tremor.

Neurol Genet 2019 Feb 4;5(1):e307. Epub 2019 Feb 4.

Medical Research (Level 4) (V.A., B.A.C., G.V.H., H.H., A.S.-N., J.K.C., E.L.B., A.H.C.), University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, United Kingdom; Reta Lila Weston Institute of Neurological Studies (V.A., T.T.W.), UCL Institute of Neurology, London, United Kingdom; Department of Neurology (T.I.), Government Medical College, Thiruvananthapuram, Kerala, India; Department of Anatomy and Microbiology (R.S.), Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India; Clinical Neuroscience (C.P.), Royal Free Campus, UCL Institute of Neurology, London, United Kingdom; Institute of Psychological Medicine and Clinical Neurosciences (K.P.), Cardiff University, Cardiff, United Kingdom; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (L.N.C.), Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY; Institute of Biomedical and Clinical Science (R.C., H.L.A., M.W.), University of Exeter Medical School, United Kingdom; and Departments of Neurology and Chronic Disease Epidemiology and Center for Neuroepidemiology and Clinical Neurological Research (E.D.L.), Yale School of Medicine and Yale School of Public Health, Yale University, New Haven, CT.

Objective: To elucidate the genetic cause of a large 5 generation South Indian family with multiple individuals with predominantly an upper limb postural tremor and posturing in keeping with another form of tremor, namely, dystonic tremor.

Methods: Whole-genome single nucleotide polymorphism (SNP) microarray analysis was undertaken to look for copy number variants in the affected individuals.

Results: Whole-genome SNP microarray studies identified a tandem duplicated genomic segment of chromosome 15q24 present in all affected family members. Whole-genome sequencing demonstrated that it comprised a ∼550-kb tandem duplication encompassing the entire gene.

Conclusions: The identification of a genomic duplication as the likely molecular cause of this condition, resulting in an additional gene copy in affected cases, adds further support for a causal role of this gene in tremor disorders and implicates increased expression levels of as a potential pathogenic mechanism.
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http://dx.doi.org/10.1212/NXG.0000000000000307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384021PMC
February 2019

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

Mov Disord 2019 04 20;34(4):526-535. Epub 2019 Feb 20.

Montreal Neurological Institute, McGill University, Montréal, QC, Canada.

Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD.

Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed.

Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome.

Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469643PMC
April 2019

SCAPER-associated nonsyndromic autosomal recessive retinitis pigmentosa.

Am J Med Genet A 2019 02 18;179(2):312-316. Epub 2018 Dec 18.

Department of Ophthalmology, New York-Presbyterian Hospital, New York, New York.

Mutations in the gene SCAPER (S-phase CyclinA Associated Protein residing in the Endoplasmic Reticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention-deficit/hyperactivity disorder. We present the case of an 11-year-old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa. Genetic testing of the patient and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Unique to our patient's presentation is the absence of intellectual disability and attention-deficit/hyperactivity disorder, suggesting that SCAPER-associated retinitis pigmentosa can also present without systemic manifestations.
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http://dx.doi.org/10.1002/ajmg.a.61001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349500PMC
February 2019

A comprehensive screening of copy number variability in dementia with Lewy bodies.

Neurobiol Aging 2019 03 24;75:223.e1-223.e10. Epub 2018 Oct 24.

Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541211PMC
March 2019

Validity of probands' reports and self-reports of essential tremor: Data from a large family study in North America.

J Neurol Sci 2018 10 6;393:45-50. Epub 2018 Aug 6.

G.H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA; Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.

The search for genes for essential tremor (ET) is active. Researchers often depend on probands' reports or self-reports to assign disease status to relatives. Yet there are surprisingly few data on the validity of these reports. In two prior studies, with small sample sizes, validity was poor (sensitivity = 16.7-43.3%). In the current study, ET probands and their relatives were screened for tremor and then underwent a videotaped in-person neurological examination. One investigator then assessed the screening questionnaires and videotapes to assign diagnoses of ET, borderline tremor or other diagnosis. There were 98 probands and 243 relatives (105 with ET, 34 with borderline tremor). Educational attainment was high (15.6 ± 2.7 years). Probands failed to report tremor in 39/139 relatives with ET or borderline tremor; conversely, they reported tremor in 32/104 relatives without ET or borderline tremor. Thus, in total, there were 71/243 (29.2%) mis-identifications. Thirty six of 139 ET and borderline ET cases failed to self-report tremor; conversely, 30/104 relatives without ET or borderline tremor self-reported tremor. Thus, in total, there were 66/243 (27.2%) mis-identifications. In summary, in individuals with greater educational attainment, the validity of reported information on ET was considerably higher than previously reported. Despite this, even among well-educated individuals in North America, probands' reports and self-reports misclassified approximately 30% (i.e., one-in-three) of relatives.
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http://dx.doi.org/10.1016/j.jns.2018.08.006DOI Listing
October 2018

Transient, Isolated Head Tremor in "Unaffected" Individuals: Is Essential Tremor an Even More Prevalent Disease Than We Suppose?

Front Neurol 2018 13;9:570. Epub 2018 Jul 13.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States.

Mild and transient head tremor may sometimes be observed in otherwise tremor-free relatives of essential tremor (ET) cases, although its prevalence is unclear. A diagnostic question is whether this transient, isolated head tremor, often observed as no more than a wobble, is an early manifestation of ET or whether it is a normal finding. A direct comparison with controls is needed. Two hundred and forty-one first-degree relatives of ET cases (FD-ET) and 77 spousal controls (Co) were enrolled in a study of ET. Each underwent a detailed evaluation that included a tremor history and videotaped neurological examination. None of the enrollees reported tremor, had a prior diagnosis of ET, or had significant tremor on screening spirals. All videotaped examinations were initially reviewed by a movement disorder neurologist blinded to subject type, and among those with head tremor on examination, co-reviewed by two additional movement disorders neurologists. Twenty-six (10.8, 95% Confidence interval [CI] = 7.5-15.3%) of 241 FD-ET vs. 2 (2.6, 95% CI = 0.7-9.0%) of 77 Co had isolated, transient head tremor (odds ratio = 4.54, 95% CI = 1.05-19.57, p = 0.04). No enrollee had significant upper extremity tremor and none met inclusion criteria for ET based on the presence of upper extremity tremor. With one exception, head tremor occurred during or after phonation. It was always transient (generally a single back and forth wobble) and rare (observed briefly on one or two occasions during the videotaped examination) and had a faster frequency, lower amplitude and a different quality than voluntary head shaking. The basis for the observed isolated head tremor is unknown, but it could be an early feature of ET in ET families.Indeed, one-in-ten otherwise unaffected first-degree relatives of ET cases exhibited such tremor. To a far lesser extent it was also observed in "unaffected" controls. In both, it is likely a sign of early, emerging, undiagnosed ET, although follow-up studies are needed to confirm this. If it were ET, it would indicate that the prevalence of ET may be considerably higher than previously suspected.
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http://dx.doi.org/10.3389/fneur.2018.00570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053923PMC
July 2018

A Drosophila Model of Essential Tremor.

Sci Rep 2018 05 16;8(1):7664. Epub 2018 May 16.

Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.

Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.
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http://dx.doi.org/10.1038/s41598-018-25949-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955955PMC
May 2018

High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation.

Hum Genet 2018 Apr 28;137(4):343-355. Epub 2018 Apr 28.

Department of Computer Science, Columbia University, 500 W 120th St, New York, NY, 10027, USA.

While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.
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http://dx.doi.org/10.1007/s00439-018-1886-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954822PMC
April 2018

Genetic Testing Preferences of Individuals in Families with Essential Tremor.

Tremor Other Hyperkinet Mov (N Y) 2018 27;8:545. Epub 2018 Mar 27.

Division of Movement Disorders, Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.

Background: The search for essential tremor (ET) genes is active, and it is only a matter of time before genetic tests become available. Genetic testing preferences in families have been studied in numerous other neurological disorders but there are no published data about ET.

Methods: We surveyed 34 ET probands and their relatives (43 affected, 28 unaffected) enrolled in our Family Study of Essential Tremor to assess their interest in genetic testing. We examined whether clinical factors influenced their interest in testing. Clinical utility ("Your physician will be able to use the information obtained to improve your care") and penetrance ("How likely an individual who carries an ET gene is to develop ET") were defined for participants.

Results: Interest in genetic testing was high in ET families (90/105 [85.7%]). There was a significant difference between affected (including probands and affected relatives) and unaffected relatives in terms of their interest in genetic testing, with the former being more interested (70/77 [90.9%] vs. 20/28 [71.4%] p = 0.04). Participants were more likely to want testing in the scenarios with high clinical utility; disease penetrance was not a determining factor (all p < 0.05). Sixteen hypothetical factors were identified that might influence a participant's decision to undergo genetic testing for ET.

Discussion: Interest in genetic testing was high in ET families. While genetic testing is not currently available for ET, the hunt for ET genes is ongoing, and this is a highly familial disorder. Understanding genetic testing preferences will greatly aid clinicians once a genetic test becomes available.
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http://dx.doi.org/10.7916/D8B296RKDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876471PMC
November 2018

Application of the Movement Disorder Society prodromal criteria in healthy G2019S-LRRK2 carriers.

Mov Disord 2018 Jul 30;33(6):966-973. Epub 2018 Mar 30.

Movement Disorders Unit, Neurological Institute, Tel Aviv Medical Center, Tel-Aviv, Israel.

Background: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD.

Objectives: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters.

Methods: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point.

Results: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers.

Conclusions: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105406PMC
July 2018

User-centered Development of a Decision Aid for Patients Facing Implantable Cardioverter-Defibrillator Replacement: A Mixed-Methods Study.

J Cardiovasc Nurs 2018 Sep/Oct;33(5):481-491

Krystina B. Lewis, MN, RN PhD candidate, School of Nursing, University of Ottawa, and Registered Nurse, University of Ottawa Health Institute, Ontario, Canada. David Birnie, MD Director of Arrhythmia Service, University of Ottawa Heart Institute, Ontario, Canada. Sandra L. Carroll, PhD, RN Associate Professor, School of Nursing, McMaster University, Hamilton, Ontario, Canada. Lorraine Clark, MHS, RN Clinical Manager, Clinical Services, University of Ottawa Heart Institute, Ontario, Canada. Freya Kelly, MN, RN Registered Nurse, University of Ottawa Heart Institute, Ontario, Canada. Paul Gibson Patient Partner, Health Consumer, Ottawa, Canada. Lloyd Rockburn Patient Partner, Health Consumer, Ottawa, Canada. Louise Rockburn Patient Partner, Health Consumer, Ottawa, Canada. Dawn Stacey, PhD, RN Professor, School of Nursing, University of Ottawa, and Senior Scientist, Ottawa Hospital Research Institute, Ontario, Canada.

Background: Because of battery depletion, an implantable cardioverter-defibrillator (ICD) generator requires surgical replacement every 5 to 7 years. Routine replacement is the norm without discussion with patients about whether or not to proceed.

Objective: The aim of this study was to develop a patient decision aid (PDA) for patients facing ICD replacement and plan for its implementation.

Methods: An embedded mixed-methods study was conducted using questionnaires and semistructured interviews focused on current ICD replacement practices; PDA acceptability, usability, and content; and PDA implementation. Transcripts were analyzed using constant comparative analysis.

Results: Eighteen PDA end users in 16 interviews characterized the current ICD replacement approach as automatic without consideration for patient preferences. The PDA was positively received, and the content was iteratively revised 4 times during the interviews. Changes were related to missing and excess information, language, and wording. The PDA was identified as a means to support a shared decision-making (SDM) process, not to be used as a standalone instrument. To shift current practices to an SDM process, participants identified that an invitation to discuss the option of ICD replacement is required-whether initiated by the patient or the clinician.

Conclusion: Currently, the option of ICD replacement is rarely offered, and patient preferences are seldom elicited. Participants believed the PDA to be a useful intervention that could help facilitate an SDM process for patients facing ICD replacement. Preparing for implementation during the development phase will allow us to strategize effectively to overcome perceived barriers and capitalize on perceived facilitators during actual implementation.
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http://dx.doi.org/10.1097/JCN.0000000000000477DOI Listing
November 2019

Knowledge about Essential Tremor: A Study of Essential Tremor Families.

Front Neurol 2018 26;9:27. Epub 2018 Jan 26.

Division of Movement Disorders, Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, United States.

Background: Essential tremor (ET) is among the most common neurological diseases and it often runs in families. How knowledgeable ET patients and their families are about their disease has been the subject of surprisingly little scholarship.

Methods: To fill this gap in knowledge, we administered a comprehensive 32-item survey (i.e., questions about etiology, pathophysiology, symptoms and signs, natural history, and treatments) to 427 participants, including 76 ET probands, 74 affected relatives (AFRs), 238 unaffected relatives, and 39 spouses of unaffected relatives, all of whom were participating in two ET family studies. We hypothesized that there would be gaps in knowledge about ET and furthermore, that probands and AFRs would be the most knowledgeable, followed by unaffected relatives and then spouses of unaffected relatives, who would be the least knowledgeable.

Results: Overall, ET patients lacked knowledge about their disease. Nearly one-third of probands answered "yes" or "do not know" to the question, "is ET the same or different from the type of tremor that many normal people can get when they become old and frail?" A similar proportion did not know whether children could get ET or they responded "no." Nearly one-fourth of affecteds (i.e., probands and AFRs) did not know whether or to what degree (e.g., very well, moderately well, not well) the symptoms of ET could be medically controlled, and 38.0% either reported that there was no brain surgery for ET or reported that they did not know. Nearly 17% of affecteds did not endorse genes as a cause for ET, which was surprising given the fact that this was a family study of ET. Probands and AFRs were the most knowledgeable, followed by unaffected relatives. Spouses of unaffected relatives were the least knowledgeable.

Conclusion: We targeted a large group of ET patients and their families, as this group is perhaps most likely to be informed about the disease. ET patients and their AFRs were more knowledgeable about the features of ET than their family members without ET. Overall, however, knowledge of ET was very limited and this lack of knowledge encompassed all aspects of the disease including its underlying causes, the nature of the symptoms and signs, its natural history and its treatment. Further ET awareness education and programs targeting both families of ET patients and the public would help alleviate this gap in knowledge.
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http://dx.doi.org/10.3389/fneur.2018.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790790PMC
January 2018

Essential tremor.

Handb Clin Neurol 2018 ;147:229-239

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York; and Departments of Neurology and of Chronic Disease Epidemiology and Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, New Haven, CT, United States. Electronic address:

Essential tremor (ET) is one of the most common neurologic disorders, and genetic factors are thought to contribute significantly to disease etiology. There has been a relative lack of progress in understanding the genetic etiology of ET. This could reflect a number of factors, including the presence of substantial phenotypic and genotypic heterogeneity. Thus, a meticulous approach to phenotyping is important for genetic research. A lack of standardized phenotyping across studies and patient centers likely has contributed to the relative lack of success of genomewide association studies in ET. To dissect the genetic architecture of ET, whole-genome sequencing will likely be of value. This will allow specific hypotheses about the mode of inheritance and genetic architecture to be tested. A number of approaches still remain unexplored in ET genetics, including the contribution of copy number variants, uncommon moderate-effect alleles, rare variant large-effect alleles (including Mendelian and complex/polygenic modes of inheritance), de novo and gonadal mosaicism, epigenetic changes, and noncoding variation.
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http://dx.doi.org/10.1016/B978-0-444-63233-3.00015-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898616PMC
July 2018

Functional variants in the gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

Sci Transl Med 2018 01;10(423)

New York University School of Medicine, New York City, NY 10016, USA.

Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the gene that conferred risk for CD (N2081D variant, = 9.5 × 10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, = 3.3 × 10). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated in CD pathogenesis. Analysis of the extended locus in 24,570 CD cases, patients with Parkinson's disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.
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http://dx.doi.org/10.1126/scitranslmed.aai7795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028002PMC
January 2018

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study.

Lancet Neurol 2018 01 16;17(1):64-74. Epub 2017 Dec 16.

Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder.

Methods: In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage.

Findings: This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14-2·70; p=1·05 × 10), SNCA (rs7681440; OR 0·73, 0·66-0·81; p=6·39 × 10), an GBA (rs35749011; OR 2·55, 1·88-3·46; p=1·78 × 10). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27-1·79; p=2·32 × 10); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%.

Interpretation: Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.

Funding: The Alzheimer's Society and the Lewy Body Society.
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http://dx.doi.org/10.1016/S1474-4422(17)30400-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805394PMC
January 2018

Frequency of variants in autopsy-proven multiple system atrophy.

Mov Disord Clin Pract 2017 Jul-Aug;4(4):574-581. Epub 2017 Apr 3.

Columbia University Medical Center, New York, New York.

Background: Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA.

Objectives: To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City.

Methods: The glucocerebrosidase gene was fully sequenced in the 17 autopsy-proven MSA cases with extractable DNA at the Columbia University New York Brain Bank from 2002 to 2016. To test if the MSA cases in the brain bank are enriched for variants, we compared the variant frequency in MSA to all brain bank cases with pure Alzheimer's disease (AD) at Columbia University for whom genotype was available (n=82).

Results: 4/17 (23.5%) MSA cases carried glucocerebrosidase gene variants, including an individual homozygous for N370S, and one each who were heterozygous carriers of N370S, T369M and R496H. Among the comparator cases with pure AD, 3 of the 82 autopsies (3.7%) carried variants (P = 0.0127, Fisher exact test), including one case each of N370S homozygote, and R496H and T369M heterozygous variant.

Conclusion: We found a higher frequency of glucocerebrosidase variants among pathologically diagnosed MSA cases in our brain bank compared to AD autopsies. This study demonstrates the need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.
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http://dx.doi.org/10.1002/mdc3.12481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614491PMC
April 2017

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome.

Neurobiol Aging 2017 08 3;56:150-158. Epub 2017 May 3.

Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Taub Institute, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA.

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid β levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603247PMC
August 2017

Action Tremor Asymmetry Profile Does Not Aggregate in Families with Essential Tremor.

Front Neurol 2017 19;8:148. Epub 2017 Apr 19.

G.H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Background: Action tremor is the hallmark feature of essential tremor (ET). While the tremor typically is mildly asymmetric, in some patients, it is markedly asymmetric. There are few data on factors that influence this asymmetry. ET is also a highly familial disease. Whether the tremor asymmetry profile (i.e., differential expression of tremor in each arm in a given patient) is similar across family members is not known. The alternative possibility is that this feature is not heritable. There are no published data addressing this issue. The aim of this study was to determine whether the extent of action tremor asymmetry ran in ET families.

Methods: ET probands and relatives were enrolled in a genetic study at Yale and Columbia Universities. An in-person evaluation included a videotaped neurological examination, including a detailed assessment of tremors. A senior movement disorders neurologist reviewed all videotaped examinations, and the severity of postural and kinetic arm tremors was rated on 12 examination items using a reliable rating scale. The tremor asymmetry index = right arm tremor score - left arm tremor score. We used a bivariate linear regression model to assess the predictors of the tremor asymmetry index in relatives; this model used the tremor asymmetry index in the proband as a primary predictor of interest. In an analysis of variance (ANOVA), we tested for heterogeneity across families in the tremor asymmetry index (i.e., to see whether there was a significant family effect).

Results: There were 187 enrollees (59 probands, 128 affected relatives). In a bivariate linear regression model, the tremor asymmetry index in the proband was not a predictor of the tremor asymmetry index in their relatives ( = 0.66). In an ANOVA, family grouping did not explain a significant proportion of the total variance in the tremor asymmetry index ( = 0.56).

Conclusion: Tremor asymmetry did not aggregate in families with ET. Therefore, this does not seem to be a disease feature that is heritable. These data will provide added value to the clinical dialog, giving patients one more piece of information about the way the disease manifests within families.
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http://dx.doi.org/10.3389/fneur.2017.00148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395646PMC
April 2017

Early Head Tremor in Essential Tremor: A Case Series and Commentary.

Tremor Other Hyperkinet Mov (N Y) 2017 25;7:453. Epub 2017 Mar 25.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.

Background: Classically, the onset of head tremor in essential tremor (ET) patients follows that of hand tremor, such that there is a somatotopic spread of involved areas. Here we present a series of seven self-reportedly "unaffected" relatives of ET cases. These seven were clinically asymptomatic and had normal levels of arm tremor on examination, yet each evidenced a transient head wobble on examination. We estimate the prevalence of this phenotype within the two studies from which cases were ascertained.

Methods: ET cases and their self-reportedly affected and unaffected relatives, enrolled in two family studies, underwent a medical history and videotaped neurological examination.

Results: In seven self-reportedly "unaffected" relatives, a transient and subtle head wobble was seen, always during sustained phonation, speech, or reading aloud. Total tremor score (a measure of arm tremor) ranged from 5 to 12 (i.e., mild tremor within the range of normal). The prevalence of this phenotype of early head tremor was 3.7% in one study and 23.1% in the other.

Discussion: We present a series of seven individuals who had early head tremor in an evolving transition state from normal to ET. These cases raise a number of broad clinical, phenotypic, and pathophysiological issues about ET.
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http://dx.doi.org/10.7916/D8KW5MRGDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374515PMC
March 2017

Familial Aggregation of the Cerebellar Signs in Familial Essential Tremor.

Tremor Other Hyperkinet Mov (N Y) 2017 13;7:439. Epub 2017 Jan 13.

G.H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA; Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.

Background: Although the hallmark feature of essential tremor (ET) is kinetic tremor, patients may exhibit additional motor features (e.g., intention tremor and mild gait ataxia) that are markers of an underlying abnormality of cerebellar function. ET is also a highly familial disorder, but we do not know whether the presence and expression of cerebellar signs are similar across family members. There are simply no published data. The alternative possibility is that these features are not heritable. We tested the specific hypothesis that the presence of cerebellar signs (i.e., intention tremor, tandem gait difficulty) ran in ET families.

Methods: ET probands and relatives enrolled in a genetic study at Yale and Columbia universities underwent a detailed videotaped neurological examination.

Results: There were 187 enrollees (59 probands, 128 affected relatives). In a bivariate logistic regression model, the presence of intention tremor in the proband was not a predictor of the presence of intention tremor in the relatives (odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.28-1.27, p = 0.18). In a similar model, the presence of greater tandem gait difficulty (i.e., a tandem gait score in the upper quartile) in the proband was not a predictor of the presence of such difficulty in the relatives (OR = 1.22, 95% CI = 0.41-3.66, p = 0.73).

Discussion: The presence of cerebellar signs did not aggregate in families with ET. In the current dataset, these did not seem to be disease features that were heritable.
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http://dx.doi.org/10.7916/D8KK9C8QDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288993PMC
January 2017

Genome-wide association study in essential tremor identifies three new loci.

Brain 2016 12 20;139(Pt 12):3163-3169. Epub 2016 Oct 20.

15 Neurogenetics, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, CIBERNED, Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
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http://dx.doi.org/10.1093/brain/aww242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382938PMC
December 2016

Genetic and Clinical Predictors of Deep Brain Stimulation in Young-Onset Parkinson's Disease.

Mov Disord Clin Pract 2016 Sep-Oct;3(5):465-471. Epub 2016 Jan 18.

Department of Neurology and the Taub Institute, Columbia University Medical Center, New York, NY, USA.

Objective: In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment.

Methods: Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years. The analyses presented here focus on (), (), and () mutation carriers. Mutation carrier status, demographic data, and disease characteristics in individuals who did and did not enroll in DBS were analyzed. The association between mutation status and DBS placement was assessed in logistic regression models.

Results: Patients who had PD with either , , or mutations were more common in the DBS group (n = 99) compared with the non-DBS group (n = 684; 26.5% vs. 16.8%, respectively; = 0.02). In a multivariate logistic regression model, mutation status (odds ratio, 2.1; 95% confidence interval, 1.0-4.3; = 0.05) was associated with DBS surgery enrollment. However, when dyskinesia was included in the multivariate logistic regression model, dyskinesia had a strong association with DBS placement (odds ratio, 3.8; 95% confidence interval, 1.9-7.3; < 0.0001), whereas the association between GBA mutation status and DBS placement did not persist ( = 0.25).

Conclusions: DBS populations are enriched with genetic mutation carriers. The effect of genetic mutation carriers on DBS outcomes warrants further exploration.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047521PMC
http://dx.doi.org/10.1002/mdc3.12309DOI Listing
January 2016