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1.  Neurologist Consistency in interpreting information provided by an Interactive Visualization Software for Deep Brain Stimulation Post-Operative Programming Assistance 
Introduction
Post-operative programming in deep brain stimulation (DBS) therapy for movement disorders can be challenging and time consuming. Providing the neurologist with tools to visualize the electrode location relative to the patient’s anatomy along with models of tissue activation and statistical data can therefore be very helpful. In this study, we evaluate the consistency between neurologists in interpreting and using such information provided by our DBS programming assistance software.
Methods
Five neurologists experienced in DBS programming were each given a dataset of 29 leads implanted in 17 patients. For each patient, probabilistic maps of stimulation response, anatomical images, models of tissue activation volumes and electrode positions were presented inside a software framework called CRAVE. Consistency between neurologists in optimal contact selection using the software was measured.
Results
With only the efficacy map, the average consistency among the five neurologists with respect to the mode and mean of their selections was 97% and 95% respectively while these numbers were 93% and 89% respectively when both efficacy and an adverse effect map were used simultaneously. Fleiss’ kappa statistic also showed very strong agreement among the neurologists (0.87 when using one map and 0.72 when using two maps).
Conclusion
Our five neurologists demonstrated high consistency in interpreting information provided by the CRAVE interactive visualization software for DBS post-operative programming assistance. Three of our five neurologists had no prior experience with the software which suggests the software has a short learning curve and contact selection is not dependent on familiarity with the program tools.
doi:10.1111/ner.12061
PMCID: PMC4039015  PMID: 23647701
computer-assisted post-operative programming assistance; deep brain stimulation; electrophysiological statistical atlases; 3D anatomical structures; non-rigid image registration
2.  Pilot Study Assessing the Feasibility of Applying Bilateral Subthalamic Nucleus Deep Brain Stimulation in Very Early Stage Parkinson's Disease: Study design and rationale 
Journal of Parkinson's disease  2012;2(3):215-223.
Background
Deep brain stimulation provides significant symptomatic benefit for people with advanced Parkinson's disease whose symptoms are no longer adequately controlled with medication. Preliminary evidence suggests that subthalamic nucleus stimulation may also be efficacious in early Parkinson's disease, and results of animal studies suggest that it may spare dopaminergic neurons in the substantia nigra.
Objective
We report the methodology and design of a novel Phase I clinical trial testing the safety and tolerability of deep brain stimulation in early Parkinson's disease and discuss previous failed attempts at neuroprotection.
Methods
We recently conducted a prospective, randomized, parallel-group, single-blind pilot clinical trial of deep brain stimulation in early Parkinson's disease. Subjects were randomized to receive either optimal drug therapy or deep brain stimulation plus optimal drug therapy. Follow-up visits occurred every six months for a period of two years and included week-long therapy washouts.
Results
Thirty subjects with Hoehn & Yahr Stage II idiopathic Parkinson's disease were enrolled over a period of 32 months. Twenty-nine subjects completed all follow-up visits; one patient in the optimal drug therapy group withdrew from the study after baseline. Baseline characteristics for all thirty patients were not significantly different.
Conclusions
This study demonstrates that it is possible to recruit and retain subjects in a clinical trial testing deep brain stimulation in early Parkinson's disease. The results of this trial will be used to support the design of a Phase III, multicenter trial investigating the efficacy of deep brain stimulation in early Parkinson's disease.
doi:10.3233/JPD-2012-012095
PMCID: PMC4165487  PMID: 23938229
Parkinson's disease; deep brain stimulation; subthalamic nucleus; research design
3.  Validating an objective video-based dyskinesia severity score in Parkinson’s disease patients 
Parkinsonism & related disorders  2012;19(2):232-237.
Dyskinesia is a common side effect of prolonged dopaminergic therapy in Parkinson’s disease patients. Assessing the severity of dyskinesia can help develop better pharmacological and surgical interventions. We have developed a semi-automatic video-based objective dyskinesia quantifying measure called the severity score (SVS) that was evaluated on 35 patient videos. We present a study to evaluate the utility of our severity score and compare its performance to clinical ratings of neurologists. In addition to the Unified Dyskinesia Rating Scale (UDysRS) score for each video, four neurologists provided three sets of time lapsed ratings and rankings of the 35 videos using a specifically developed protocol. The statistical analysis of our data using Kendall’s tau-b and intra-class correlations shows that (a) ranking patient videos based on severity is suitable for studying the utility of the SVS, and (b) SVS exhibits moderate utility to quantify dyskinesia severity when compared to manual assessment of dyskinesia by neurologists using the UDysRS. These results support the effective use of SVS as an objective measure to quantify dyskinesia and the rationale for a ranking system that complements traditional rating scales.
doi:10.1016/j.parkreldis.2012.10.015
PMCID: PMC4105342  PMID: 23182314
Parkinson’s disease; rating scales; quantify dyskinesia; rater variability; severity ranking
4.  A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia 
Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia.
doi:10.1002/mgg3.67
PMCID: PMC4049367  PMID: 24936516
Dystonia; DYT6; intronic variant; minigene assay; THAP1
5.  Methods for Surgical Targeting of the STN in Early-Stage Parkinson’s Disease 
Patients with Parkinson’s disease (PD) experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn–Yahr Stage III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery, the ability to identify this nucleus in early-stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN in 15 patients with early PD (Hoehn–Yahr Stage II), using a combination of image guided surgery, microelectrode recordings, and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates and root mean squared activity) have previously been found to be lower than in later-stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson’s patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early-stage PD using traditional methods.
doi:10.3389/fneur.2014.00025
PMCID: PMC3958735  PMID: 24678307
Parkinson’s disease; subthalamic nucleus; surgical targeting; early stage; neurosurgery
6.  Hereditary spastic paraplegia-causing mutations in atlastin-1 interfere with BMPRII trafficking 
Disruption of the bone morphogenic protein (BMP)-linked signaling pathway has been suggested as an important factor in the development of hereditary spastic paraplegia (HSP). HSP-causing proteins spastin, spartin and NIPA1 were reported to inhibit the BMP pathway. We have previously shown a strong interaction of NIPA1 and atlastin-1 proteins. Hence, we investigated the role of another HSP-associated protein atlastin-1 in this signaling cascade. Endogenous and expressed atlastin-1 showed a strong interaction with BMP receptors II (BMPRII) and analyzed missense, HSP-causing mutations R239C and R495W disrupted BMPRII trafficking to the cell surface. BMPRII does not require the presence of atlastin-1 because knockdown expression of atlastin-1 did not alter endogenous BMPRII cellular distribution. Expression of mutant forms of atlastin-1 also interfered with the signaling response to BMP4 stimulation and reduced phosphorylation of Smad 1/5 proteins. Our results suggest that HSP-causing atlastin-1 mutations exhibit a dominant-negative effect on trafficking of BMPRII, which disrupts the BMP pathway in neurons. This, together with previously demonstrated inhibition of atlastin-1 of BMP pathway, further supports the role of this signaling cascade in axonal maintenance and axonal degeneration, which is seen in various types of HSP.
doi:10.1016/j.mcn.2012.10.005
PMCID: PMC3587122  PMID: 23079343
BMP pathway; Atlastin-1; Hereditary spastic paraplegia; BMPRII trafficking
7.  REEPing the benefits of an animal model of hereditary spastic paraplegia 
The Journal of Clinical Investigation  2013;123(10):4134-4136.
The hereditary spastic paraplegias (HSPs) are characterized by spasticity of the leg muscles due to axonal degeneration of corticospinal neurons. Beetz et al. report that the core motor phenotype and axonal pathology of HSPs are recapitulated in mice lacking the HSP-associated gene Reep1. REEP1 is shown to regulate ER structure in motor cortex neurons. The Reep1 knockout mouse should be a very useful model in which to study the mechanisms of progressive axon loss in HSPs and other disorders.
doi:10.1172/JCI72324
PMCID: PMC3784552  PMID: 24051371
8.  Pharmacotherapy of Essential Tremor 
Essential tremor (ET) is a common movement disorder but its pathogenesis remains poorly understood. This has limited the development of effective pharmacotherapy. The current therapeutic armamentaria for ET represent the product of careful clinical observation rather than targeted molecular modeling. Here we review their pharmacokinetics, metabolism, dosing, and adverse effect profiles and propose a treatment algorithm. We also discuss the concept of medically refractory tremor, as therapeutic trials should be limited unless invasive therapy is contraindicated or not desired by patients.
doi:10.4137/JCNSD.S6561
PMCID: PMC3873223  PMID: 24385718
essential tremor; pathogenesis; propranolol; primidone; topiramate; gabapentin; pregabalin
9.  Novel polymerase gamma (POLG1) gene mutation in the linker domain associated with parkinsonism 
BMC Neurology  2013;13:92.
Background
Mutations in the POLG1 gene have variable phenotypic presentations and a high degree of clinical suspicion is necessary for their recognition. Parkinsonism and ataxia are the most common movement disorders associated with POLG1 mutations but no phenotype-genotype correlation has been established.
Case presentation
We identified a male patient with progressive external ophthalmoplegia who also developed a progressive bradykinesia, rigidity and camptocormia in the third decade. Parkinsonism was partially responsive to dopaminegic replacement. His father and brother had reportedly similar clinical problems. Genetic analysis identified a novel mutation p.K512M in the POLG1 gene.
Conclusion
This report further expands the spectrum of POLG1-associated neurologic problems with the report of a novel mutation in the linker region of the gene, which are rarely associated with parkinsonism.
doi:10.1186/1471-2377-13-92
PMCID: PMC3728152  PMID: 23865558
Mitochondrial DNA polymerase gamma (POLG1); Parkinsonism; Progressive external ophthalmoplegia; Ataxia; Sensory neuropathy
10.  Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia 
BMC Neurology  2012;12:93.
Background
Recently, heterozygous mutations in PRRT2 (Chr 16p11.2) have been identified in Han Chinese, Japanese and Caucasians with paroxysmal kinesigenic dyskinesia. In previous work, a paroxysmal kinesigenic dyskinesia locus was mapped to Chr 16p11.2 - q11.2 in a multiplex African-American family.
Methods
Sanger sequencing was used to analyze all four PRRT2 exons for sequence variants in 13 probands (9 Caucasian, 1 Caucasian-Thai, 1 Vietnamese and 2 African-American) with some form of paroxysmal dyskinesia.
Results
One patient of mixed Caucasian-Thai background and one African-American family harbored the previously described hotspot mutation in PRRT2 (c.649dupC, p.R217Pfs*8). Another African-American family was found to have a novel mutation (c.776dupG, p.E260*). Both of these variants are likely to cause loss-of-function via nonsense-mediated decay of mutant PRRT2 transcripts. All affected individuals had classic paroxysmal kinesigenic dyskinesia phenotypes.
Conclusions
Heterozygous PRRT2 gene mutations also cause paroxysmal kinesigenic dyskinesia in African-Americans. The c.649dupC hotspot mutation in PRRT2 is common across racial groups.
doi:10.1186/1471-2377-12-93
PMCID: PMC3460747  PMID: 22985072
PKD; PRRT2; African-American; ICCA; Hotspot mutation
11.  Metabolic Hyperactivity of the Medial Posterior Parietal Lobes in Psychogenic Tremor 
Background
The pathophysiology of psychogenic movement disorders, including psychogenic tremor (PT), is only emerging.
Case Report
This is a single case report of a patient who met diagnostic criteria for PT. He underwent positron emission tomography (PET) of brain with 18F-deoxyglucose at resting state. His PET study showed symmetrically increased 18F-deoxyglucose uptake in both posterior medial parietal lobes. There was no corresponding abnormality on structural imaging.
Discussion
Hypermetabolism of the medial aspects of posterior parietal lobes bilaterally may reflect abnormal activity of sensory integration that is important in the pathogenesis of PT. This further supports the idea that non-organic movement disorders may be associated with detectable functional brain abnormalities.
PMCID: PMC3379878  PMID: 23440006
Psychogenic tremor; positron emission tomography; parietal lobe; conversion reaction
12.  Metabolic Hyperactivity of the Medial Posterior Parietal Lobes in Psychogenic Tremor 
Tremor and Other Hyperkinetic Movements  2012;2:tre-02-50-441-1.
Background
The pathophysiology of psychogenic movement disorders, including psychogenic tremor (PT), is only emerging.
Case Report
This is a single case report of a patient who met diagnostic criteria for PT. He underwent positron emission tomography (PET) of brain with 18F-deoxyglucose at resting state. His PET study showed symmetrically increased 18F-deoxyglucose uptake in both posterior medial parietal lobes. There was no corresponding abnormality on structural imaging.
Discussion
Hypermetabolism of the medial aspects of posterior parietal lobes bilaterally may reflect abnormal activity of sensory integration that is important in the pathogenesis of PT. This further supports the idea that non-organic movement disorders may be associated with detectable functional brain abnormalities.
PMCID: PMC3379878  PMID: 23440006
Psychogenic tremor; positron emission tomography; parietal lobe; conversion reaction
13.  The c.-237_236GA>TT THAP1 Sequence Variant Does Not Increase Risk for Primary Dystonia 
Sequence variants in coding and non-coding regions of THAP1 have been associated with primary dystonia. In this study, 1446 Caucasian subjects with mainly adult-onset primary dystonia and 1520 controls were genotyped for a variant located in the 5’-untranslated region of THAP1 (c.-237_236GA>TT). Minor allele frequencies were 62/2892 (2.14%) and 55/3040 (1.81%) in subjects with dystonia and controls, respectively (P = 0.202). Subgroup analyses by gender and anatomical distribution also failed to attain statistical significance. In addition, there was no effect of the TT variant on expression levels of THAP1 transcript or protein. Our findings indicate that the c.-237_236GA>TT THAP1 sequence variant does not increase risk for adult-onset primary dystonia in Caucasians.
doi:10.1002/mds.23551
PMCID: PMC3171986  PMID: 21370264
dystonia; DYT6; high-resolution melting; untranslated region; THAP1
14.  The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1 
Despite its genetic heterogeneity, hereditary spastic paraplegia (HSP) is characterized by similar clinical phenotypes, suggesting that a common biochemical pathway underlies its pathogenesis. In support of this hypothesis, we used a combination of immunoprecipitation, confocal microscopy, and flow cytometry to demonstrate that two HSP-associated proteins, atlastin-1 and NIPA1, are direct binding partners, and interestingly, that the endogenous expression and trafficking of these proteins is highly dependant upon their coexpression. In addition, we demonstrated that the cellular distribution of atlastin-1:NIPA1 complexes was dramatically altered by HSP-causing mutations, as missense mutations in atlastin-1 (R239C and R495W) and NIPA1 (T45R and G106R) caused protein sequestration in the Golgi complex (GC) and endoplasmic reticulum (ER), respectively. Moreover, we demonstrated that HSP-causing mutations in both atlastin-1 and NIPA1 reduced axonal and dendritic sprouting in cultured rat cortical neurons. Together, these findings support the hypothesis that NIPA1 and atlastin-1 are members of a common biochemical pathway that supports axonal maintenance, which may explain in part the characteristic degeneration of long spinal pathways observed in patients with HSP.
doi:10.1016/j.mcn.2010.08.012
PMCID: PMC3010260  PMID: 20816793
15.  Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations 
Human mutation  2010;31(10):1142-1154.
A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining ninety-three probands here. This includes nineteen probands (twelve mutations) who fulfilled clinical criteria for GCPS or PHS, forty-eight probands (sixteen mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), twenty-one probands (six mutations) with features of PHS or GCPS and oral-facial-digital syndrome and five probands (one mutation) with non-syndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the phenotype-genotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.
doi:10.1002/humu.21328
PMCID: PMC2947617  PMID: 20672375
GLI3; Greig syndrome; Pallister-Hall syndrome; Oral-facial-digital syndrome
16.  Clustering of dystonia in some pedigrees with autosomal dominant essential tremor suggests the existence of a distinct subtype of essential tremor 
BMC Neurology  2010;10:66.
Background
There is an ongoing debate whether essential tremor (ET) represents a monosymptomatic disorder or other neurologic symptoms are compatible with the diagnosis of ET. Many patients with clinically definite ET develop dystonia. It remains unknown whether tremor associated with dystonia represent a subtype of ET. We hypothesized that ET with dystonia represents a distinct subtype of ET.
Methods
We studied patients diagnosed with familial ET and dystonia. We included only those patients whose first-degree relatives met diagnostic criteria for ET or dystonia with tremor. This cohort was ascertained for the presence of focal, segmental, multifocal, hemidystonia or generalized dystonia, and ET.
Results
We included 463 patients from 97 kindreds with autosomal dominant mode of inheritance (AD), defined by the vertical transmission of the disease. ET was the predominant phenotype in every ascertained family and each was phenotypically classified as AD ET. "Pure" ET was present in 365 individuals. Focal or segmental dystonia was present in 98 of the 463 patients; 87 of the 98 patients had ET associated with dystonia, one had dystonic tremor and ten had isolated dystonia. The age of onset and tremor severity did not differ between patients with "pure" ET and ET associated with dystonia. We did not observe a random distribution of dystonia in AD ET pedigrees and all patients with dystonia associated with ET were clustered in 28% of all included pedigrees (27/97, p < 0.001).
Conclusions
Our results suggest that familial ET associated with dystonia may represent a distinct subtype of ET.
doi:10.1186/1471-2377-10-66
PMCID: PMC2918572  PMID: 20670416
17.  Evaluation of SCN8A as a Candidate Gene for Autosomal Dominant Essential Tremor 
Parkinsonism & related disorders  2008;15(4):321-323.
Objectives
Essential tremor (ET) is a common inherited movement disorder whose causes remain unknown. The presence of spontaneous tremor in murine mutants may provide clues into the pathogenesis of ET. SCN8A encodes the neuronal voltage gated sodium channel Nav1.6 that is widely expressed in the central nervous system. Several mutations Scn8a in the mouse result in congenital postural tremor of the extremities and head.
Methods
We screened SCN8A as a candidate gene in a cohort of 95 Caucasian patients with ET and a positive family history, including 48 patients with early onset in the first two decades of life. Early and adult onset ET subgroups did not differ in disease severity, but early onset patients had longer disease duration. Observed sequence variants were also screened in an ethnically matched control group.
Results
We did not detect SCN8A mutations affecting amino acid sequence or splice sites in our cohort of ET patients.
Conclusions
Although mutations Scn8a cause congenital tremor in mice, mutations in the sequence of the exons and splice sites of human SCN8A do not appear to be a common cause of autosomal dominant essential tremor in Caucasian patients.
doi:10.1016/j.parkreldis.2008.06.010
PMCID: PMC2877193  PMID: 18718804
SCN8A; essential tremor; genetics; mouse mutants
18.  Reappraisal of the role of the DRD3 gene in essential tremor 
Parkinsonism & related disorders  2008;14(6):471-475.
Objectives
Analyze the distribution of polymorphism in the dopamine receptor D3 (DRD3) gene, which was previously reported as a susceptibility risk for essential tremor (ET), in a large cohort of ET.
Methods
The role of 312G>A DRD3 polymorphism was analyzed using linkage analysis, association study and transmission disequilibrium test in a group of 433 ET patients, and two unrelated control groups with 121 and 151 individuals.
Results
Allelic frequencies of glycine and serine forms of the DRD3 gene did not differ between patients and both control groups, and were in Hardy-Weinberg equilibrium. Linkage analysis identified obligatory recombinants in every large pedigree, even in those with relatively high frequency of glycine allele, thus excluding the linkage to this locus. Both alleles were transmitted with an equal likelihood to affected offspring. We also failed to replicate the relationship between glycine homozygosity and an earlier age of onset or more severe tremor course.
Conclusions
Our comprehensive genetic analysis in a large ET cohort strongly argues against the role of the DRD3 gene in ET pathogenesis.
doi:10.1016/j.parkreldis.2007.11.002
PMCID: PMC2576470  PMID: 18316228
Essential tremor; DRD3; Genetics
19.  Hereditary spastic paraplegia-associated mutations in the NIPA1 gene and itC. elegans homolog trigger neural degeneration in vitro and in vivo through a gain of function mechanism 
We studied the consequences of expression of wildtype (WT) human NIPA1 and two mutant forms of NIPA1 with known HSP-associated mutations (T45R and G106R) on cultured rat cortical neurons and using equivalent substitutions in the Caenorhabditis elegans NIPA1 homolog CeNIPA. WT NIPA1 localized in transfected neuronal and non-neuronal cells to the Golgi complex, a subset of synaptic vesicles, to a subset of early endosomes, and plasma cell membrane. Mutant NIPA1 accumulated in the endoplasmic reticulum (ER) triggering ER stress and features of apoptotic cell death. Flow cytometric analysis of NIPA1 surface expression demonstrated relatively intact trafficking of mutant forms and only the T45R mutant exhibited modestly reduced patterns of surface expression without evidence for a dominant-negative effect. In vivo panneuronal expression of the WT C. elegans NIPA1 homolog (CeNIPA) was well tolerated, with no obvious impact on neuronal morphology or behavior. In striking contrast, expression of CeNIPA bearing HSP-associated mutations caused a progressive neural degeneration and a clear motor phenotype. Neuronal loss in these animals began at day 7 and by day 9 animals were completely paralyzed. These effects appeared to arise from activation of the apoptotic program triggered by unfolded protein response (UPR), as we observed marked modifications of motor and cellular phenotype when mutant NIPA1 was expressed in caspase (ced-3) and UPR (xbp-1) deficient backgrounds. We propose that HSP-associated mutations in NIPA1 lead to cellular and functional deficits through a gain-of-function mechanism supporting the ER-accumulation of toxic NIPA1 proteins.
doi:10.1523/JNEUROSCI.4668-08.2008
PMCID: PMC2660329  PMID: 19091982
hereditary spastic paraplegia; NIPA1; Caenorhabditis elegans; flow cytometry; animal model; unfolded protein response
20.  High-throughput mutational analysis of TOR1A in primary dystonia 
BMC Medical Genetics  2009;10:24.
Background
Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some ΔGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify TOR1A Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia.
Methods
High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known ΔGAG DYT1 dystonia and 88 subjects with ΔGAG-negative dystonia.
Results
HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A ΔGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic ΔGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia.
Conclusion
First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia.
doi:10.1186/1471-2350-10-24
PMCID: PMC2661056  PMID: 19284587
21.  The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures 
BMC Medical Genetics  2005;6:13.
Background
Polymorphism G1465A in the GABBR1 gene has been suggested as a risk factor for non-lesional temporal lobe epilepsy (TLE); however, this genetic association study has not been independently replicated. We attempted to replicate this study in our cohort of patients with TLE. Furthermore, we also analyzed the coding sequence of this gene and searched for disease-causing mutations.
Methods
We included 120 unrelated individuals with TLE that was preceded by febrile seizures (FS) who did not have any evidence of structural lesions suggesting secondary epilepsy. 66 individuals had positive family history of TLE epilepsy and 54 were sporadic. Each patient was genotyped for the presence of G1465A polymorphism. All exons of the GABBR1 gene were screened by single strand confirmation polymorphism method. Genotypes were compared with two independent matched control groups.
Results
We detected two A alleles of the G1465A polymorphism in one homozygous control subject (0.87% of all alleles) and one A allele in a patient with TLE (0.45%, not significant). Other detected polymorphisms in coding regions had similar frequencies in epilepsy patients and control groups. No disease causing mutations in the GABBR1 gene were detected in patients with sporadic or familial TLE.
Conclusion
Our results indicate that TLE preceded by FS is not associated with the polymorphisms or mutations in the GABBR1 gene, including the G1465A polymorphism. The proportion of TLE patients with FS in the original study, reporting this positive association, did not differ between allele A negative and positive cases. Thus, our failure to reproduce this result is likely applicable to all non-lesional TLE epilepsies.
doi:10.1186/1471-2350-6-13
PMCID: PMC1079842  PMID: 15799783

Results 1-21 (21)