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1.  A quality dietary supplement: before you start and after it’s marketed—a conference report 
Consumers worldwide are turning to dietary supplements as one part of their personal goal to lead healthier and more active lives. In truth, the quality of life now supersedes the length of life as no one would trade living to one hundred (the last forty with compromised physical abilities and decreased mental acuity) for 80 years of travel, time with family, and intellectual pursuits. If there is the possibility of preventing a disease or debilitating condition through efficient lifestyle changes (additions, subtractions, modifications) and to also avoid the costly and escalating medical and pharmaceutical treatments that accompany having the disease/condition, then a sensible individual would focus on their overall health and wellness…proactively, instead of reactively. However, an important caveat is that over-regulation or inappropriate application of current regulations can increase the price of dietary supplements and nutritional products and thus cause underutilization of the potentially beneficial physiological attributes of these products. Conversely, strict adherence to regulatory guidelines could result in safer dietary supplements and fewer adverse reactions requiring medical attention. If new regulations or stricter interpretation/application of existing regulations result in certain dietary supplements being taken off the market, will continued demand create a completely unregulated, underground economy that will create unforeseen problems? More research should be supported by government agencies to determine the effectiveness of dietary supplements, nutritional products and complementary medicine in reducing personal and societal medical costs and further contribution to the overall health of the population.
PMCID: PMC4305087  PMID: 25579377
2.  Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease 
Neurology  2014;83(21):1906-1913.
The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort.
C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia.
A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low.
Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.
PMCID: PMC4248456  PMID: 25326098
3.  Role of Gα(olf) in familial and sporadic adult-onset primary dystonia 
Human Molecular Genetics  2013;22(12):2510-2519.
The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ∼10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.
PMCID: PMC3658169  PMID: 23449625
4.  Emerging Common Molecular Pathways for Primary Dystonia 
The dystonias are a group of hyperkinetic movement disorders whose principal cause is neuron dysfunction at one or more interconnected nodes of the motor system. The study of genes and proteins which cause familial dystonia provides critical information about the cellular pathways involved in this dysfunction which disrupts the motor pathways at systems level. In recent years study of the increasing number of DYT genes has implicated a number of cell functions which appear to be involved in the pathogenesis of dystonia.
Review of literature published in English language publications available on Pubmed relating to the genetics and cellular pathology of dystonia
Results and Conclusions
Numerous potential pathogenetic mechanisms have been identified. We describe those which fall into three emerging thematic groups: cell cycle and transcriptional regulation in the nucleus, endoplasmic reticulum and nuclear envelope function, and control of synaptic function.
PMCID: PMC3838975  PMID: 23893453
DYT genes; Cell cycle; endoplasmic reticulum; Nuclear envelope; synaptic function
5.  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.
PMCID: PMC4049367  PMID: 24936516
Dystonia; DYT6; intronic variant; minigene assay; THAP1
6.  Neural expression of the transcription factor THAP1 during development in rat 
Neuroscience  2012;231:282-295.
Loss of function mutations in THAP1 have been associated with primary generalized and focal dystonia in children and adults. THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and plays a critical role in G1-S cell cycle control. Current thinking suggests that dystonia may be a neurodevelopmental circuit disorder. Hence, THAP1 may participate in the development of the nervous system. Herein, we report the neurodevelopmental expression patterns of Thap1 transcript and THAP1 protein from the early postnatal period through adulthood in rat brain, spinal cord and dorsal root ganglia (DRG). We detected Thap1 transcript and THAP1-immunoreactivity (IR) in cerebral cortex, cerebellum, striatum, substantia nigra, thalamus, spinal cord and DRG. Thap1 transcript expression was higher in brain than in spinal cord and DRG at P1 and P7 and declined to similar levels at P14 and later time points in all regions except cerebellum, where it remained high through adulthood. In brain, THAP1 expression was highest in early development, particularly in cerebellum at P7. In addition to Purkinje cells in the cerebellum, THAP1-IR was also localized to pyramidal neurons in cerebral cortex, relay neurons in thalamus, medium spiny and cholinergic neurons in striatum, dopaminergic neurons in substantia nigra, and pyramidal and interneurons in hippocampus. In cerebellar cortex, THAP1-IR was prominently distributed in the perikarya and proximal dendrites of Purkinje cells at early time-points. In contrast, it was more diffusely distributed throughout the dendritic arbor of adult Purkinje cells producing a moderate diffuse staining pattern in the molecular layer. At all time points, nuclear IR was weaker than cytoplasmic IR. The prominent cytoplasmic and developmentally-regulated expression of THAP1 suggests that THAP1 may function as part of a cell surface-nucleus signaling cascade involved in terminal neural differentiation.
PMCID: PMC3558550  PMID: 23219941
THAP1; Purkinje cells; cerebellum; dystonia; DYT6; transcription factor
7.  Non-Parkinson movement disorders 
Neurology. Clinical Practice  2013;3(1):22-29.
Solutions to the major riddles in movement disorders are appearing at a breathtaking pace: 1) loss-of-function mutations in PRRT2, which encodes a cell surface protein expressed in neurons, have been found in many patients with paroxysmal kinesigenic dyskinesias; 2) mutations in CIZ1, which encodes a protein involved in cell-cycle control at the G1-S checkpoint, have been identified in a small percentage of patients with cervical dystonia; and 3) finally, after many years of genetics and identification of more than 25 disease-associated genes, cellular studies related to the pathobiology of hereditary spastic paraplegia are converging on defects in modeling the endoplasmic reticulum and membrane trafficking. On the treatment front, the distinctive syndromes of faciobrachial dystonic seizures with anti-LRI1 antibodies and anti-N-methyl-d-aspartic acid encephalitis with orobuccolingual dyskinesias are becoming increasingly recognized by clinicians as imminently treatable conditions. Also on the treatment front, the first phase I trial of MRI-guided high-intensity focused ultrasound for essential tremor has been completed and intraoperative MRI is currently being used to place electrodes in the brains of patients with medically intractable dystonia. Definitive etiologies and efficacious treatments for non–Parkinson disease movement disorders are no longer wishful thinking.
PMCID: PMC3613216  PMID: 23634381
9.  Exome sequencing for gene discovery: time does not stand still 
Annals of neurology  2012;72(4):628-629.
PMCID: PMC3490435  PMID: 23109160
10.  Prevalence, predictors, and perceived effectiveness of complementary, alternative and integrative medicine in adult-onset primary dystonia 
Parkinsonism & related disorders  2012;18(8):936-940.
Complementary and Alternative Medicine (CAM) use is on the rise in both the US and Europe, despite questions about its safety, effectiveness and lack of national standards. We aimed to determine the prevalence and predictors of CAM and integrative medicine use (CAM-I) and perceived effectiveness compared to the standard treatment of botulinum toxin injections in patients with adult-onset primary dystonia.
This was a retrospective questionnaire study of 389 dystonia patients examining the effects age, gender, education level and number of anatomical regions affected on botulinum toxin and CAM-I use and their perceived effectiveness.
53% (208) of patients reported CAM-I use, while 90% (349) used the standard treatment (botulinum toxin), and 48% used both. Education was the only significant predictor of CAM-I use – individuals with bachelor’ s degrees were more likely to try CAM-I whereas those with high school diplomas were less likely. The mean effectiveness rate for botulinum toxin injections (59%) significantly exceeded that for and CAM-I (28%, p<0.0001).
Our work highlights the need for scientifically sound studies to determine the safety, effectiveness and expense of CAM-I treatments for dystonia and other neurological disorders given that CAM-I use is steadily increasing, there is great variability in what is classified as CAM-I, and the effectiveness of some modalities may be significantly less than conventional medical treatments.
PMCID: PMC3430825  PMID: 22633698
Dystonia; Complementary and Alternative Medicine (CAM); Botulinum toxin; Integrative medicine; Spasmodic dysphonia
11.  Dystonia, facial dysmorphism, intellectual disability and breast cancer associated with a chromosome 13q34 duplication and overexpression of TFDP1: case report 
BMC Medical Genetics  2013;14:70.
Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G1-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored.
Case presentation
Cytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2.
Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.
PMCID: PMC3722009  PMID: 23849371
Dystonia; Chromosome 13q34; Duplication; TFDP1; Breast cancer; G1-S Checkpoint pathway
12.  A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin®) in cervical dystonia 
Journal of Neural Transmission  2013;120(12):1699-1707.
IncobotulinumtoxinA (Xeomin®, NT 201), a preparation without accessory (complexing) proteins, has shown comparable efficacy and safety to onabotulinumtoxinA in treating cervical dystonia (CD). This study evaluated the efficacy and safety of repeated incobotulinumtoxinA injections in subjects with CD. Following a ≤20-week placebo-controlled, randomized, double-blind, single-dose main period, subjects could enter a ≤68-week prospective, randomized, double-blind, repeated-dose, flexible-interval (minimum 6 weeks) extension period with 240 U or 120 U of incobotulinumtoxinA (≤5 injections). Outcome measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and adverse events (AEs). Of 219 subjects completing the main period, 214 were randomized in the extension period to receive incobotulinumtoxinA 240 U (n = 111) or 120 U (n = 103); 169 subjects completed the extension period, with 90 receiving five injection sessions. Both doses of incobotulinumtoxinA provided statistically significant and clinically relevant improvements in mean TWSTRS-Total, -Severity, -Disability, and -Pain scores, from each injection session to respective 4-week follow-up visits. The most frequently reported AE was dysphagia (240 U: 23.4 %; 120 U: 12.6 %), which did not result in any study withdrawals. There was no impact of injection interval on the incidence of AEs (post hoc analysis). A major limitation of this study was the fixed dose design requested by regulatory authorities, which does not reflect clinical practice. However, repeated incobotulinumtoxinA injections (240 or 120 U; flexible intervals) provided sustained efficacy and were well tolerated, with no unexpected safety risks following repeated injections. The incidence of AEs was similar in subjects requiring repeated injections at shorter intervals (≤12 weeks) compared with those treated using longer intervals (>12 weeks).
PMCID: PMC3834167  PMID: 23779062
Dystonia; Xeomin; IncobotulinumtoxinA; NT 201; Botulinum toxin
13.  Genotype-phenotype correlations in THAP1 dystonia: molecular foundations and description of new cases 
Parkinsonism & related disorders  2012;18(5):414-425.
An extensive variety of THAP1 sequence variants have been associated with focal, segmental and generalized dystonia with age of onset ranging from 3 to over 60 years. In previous work, we screened 1,114 subjects with mainly adult-onset primary dystonia (Neurology 2010;74:229-238) and identified 6 missense mutations in THAP1. For this report, we screened 750 additional subjects for mutations in coding regions of THAP1 and interrogated all published descriptions of THAP1 phenotypes (gender, age of onset, anatomical distribution of dystonia, family history and site of onset) to explore the possibility of THAP1 genotype-phenotype correlations and facilitate a deeper understanding of THAP1 pathobiology. We identified 5 additional missense mutations in THAP1 (p.A7D, p.K16E, p.S21C, p.R29Q, and p.I80V). Three of these variants are associated with appendicular tremors, which were an isolated or presenting sign in some of the affected subjects. Abductor laryngeal dystonia and mild blepharospasm can be manifestations of THAP1 mutations in some individuals. Overall, mean age of onset for THAP1 dystonia is 16.8 years and the most common sites of onset are the arm and neck, and the most frequently affected anatomical site is the neck. In addition, over half of patients exhibit either cranial or laryngeal involvement. Protein truncating mutations and missense mutations within the THAP domain of THAP1 tend to manifest at an earlier age and exhibit more extensive anatomical distributions than mutations localized to other regions of THAP1.
PMCID: PMC3358360  PMID: 22377579
Dystonia; THAP1; DYT6; Spasmodic dysphonia; Tremor
14.  JPH3 Repeat Expansions Cause a Progressive Akinetic-Rigid Syndrome with Severe Dementia and Putaminal Rim in a Five-Generation African-American Family 
Neurogenetics  2012;13(2):133-140.
We report the clinical, neuropsychological, genetic and radiological features of a large five-generation African-American kindred from the southern United States presenting with a progressive akinetic-rigid syndrome and severe dementia, but clinically insignificant chorea, due to mutations in JPH3. Overt disease onset was in the mid-twenties to late thirties with cognitive decline, REM sleep disturbance or psychiatric features, followed by development of a levodopa-unresponsive akinetic-rigid motor syndrome. Dystonia and myoclonus were present in some subjects. A bedridden, non-verbal severely akinetic-rigid state developed within 10 to 15 years after onset. CTG repeat expansions ranged from 47 to 53. Imaging revealed generalized cerebral atrophy with severe striatal involvement and putaminal rim hyperintensity. Analysis of our kindred indicates that JPH3 mutations should be considered in the differential diagnosis of early-onset dementia and hypokinetic-rigid syndromes in individuals of African descent. Moreover, chorea may not be overtly manifest at presentation or during significant parts of the disease course.
PMCID: PMC3370891  PMID: 22447335
Dementia; Parkinsonism; Chorea; Huntington disease; JPH3; Putaminal Rim; African-American
15.  Mutations in CIZ1 cause adult-onset primary cervical dystonia 
Annals of Neurology  2012;71(4):458-469.
Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult-onset, primary cervical dystonia.
Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult-onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult-onset cervical dystonia and matching controls for sequence variants in this mutant gene.
Exome sequencing led to the identification of an exonic splicing enhancer mutation in Exon 7 of CIZ1 (c.790A>G, p.S264G) which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21Cip1/Waf1-interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified two additional CIZ1 missense mutations (p.P47S and p.R672M).
Mutations in CIZ1 may cause adult-onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.
PMCID: PMC3334472  PMID: 22447717
16.  Dab2IP GTPase Activating Protein Regulates Dendrite Development and Synapse Number in Cerebellum 
PLoS ONE  2013;8(1):e53635.
DOC-2/DAB-2 interacting protein (Dab2IP) is a GTPase activating protein that binds to Disabled-1, a cytosolic adapter protein involved in Reelin signaling and brain development. Dab2IP regulates PI3K-AKT signaling and is associated with metastatic prostate cancer, abdominal aortic aneurysms and coronary heart disease. To date, the physiological function of Dab2IP in the nervous system, where it is highly expressed, is relatively unknown. In this study, we generated a mouse model with a targeted disruption of Dab2IP using a retrovirus gene trap strategy. Unlike reeler mice, Dab2IP knock-down mice did not exhibit severe ataxia or cerebellar hypoplasia. However, Dab2IP deficiency produced a number of cerebellar abnormalities such as a delay in the development of Purkinje cell (PC) dendrites, a decrease in the parallel fiber synaptic marker VGluT1, and an increase in the climbing fiber synaptic marker VGluT2. These findings demonstrate for the first time that Dab2IP plays an important role in dendrite development and regulates the number of synapses in the cerebellum.
PMCID: PMC3541190  PMID: 23326475
17.  Novel PRRT2 mutation in an African-American family with paroxysmal kinesigenic dyskinesia 
BMC Neurology  2012;12:93.
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.
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.
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.
Heterozygous PRRT2 gene mutations also cause paroxysmal kinesigenic dyskinesia in African-Americans. The c.649dupC hotspot mutation in PRRT2 is common across racial groups.
PMCID: PMC3460747  PMID: 22985072
PKD; PRRT2; African-American; ICCA; Hotspot mutation
18.  Altered Serotonin, Dopamine and Norepinepherine Levels in 15q Duplication and Angelman Syndrome Mouse Models 
PLoS ONE  2012;7(8):e43030.
Childhood neurodevelopmental disorders like Angelman syndrome and autism may be the result of underlying defects in neuronal plasticity and ongoing problems with synaptic signaling. Some of these defects may be due to abnormal monoamine levels in different regions of the brain. Ube3a, a gene that causes Angelman syndrome (AS) when maternally deleted and is associated with autism when maternally duplicated has recently been shown to regulate monoamine synthesis in the Drosophila brain. Therefore, we examined monoamine levels in striatum, ventral midbrain, frontal cerebral cortex, cerebellar cortex and hippocampus in Ube3a deficient and Ube3a duplication animals. We found that serotonin (5HT), a monoamine affected in autism, was elevated in the striatum and cortex of AS mice. Dopamine levels were almost uniformly elevated compared to control littermates in the striatum, midbrain and frontal cortex regardless of genotype in Ube3a deficient and Ube3a duplication animals. In the duplication 15q autism mouse model, paternal but not maternal duplication animals showed a decrease in 5HT levels when compared to their wild type littermates, in accordance with previously published data. However, maternal duplication animals show no significant changes in 5HT levels throughout the brain. These abnormal monoamine levels could be responsible for many of the behavioral abnormalities observed in both AS and autism, but further investigation is required to determine if any of these changes are purely dependent on Ube3a levels in the brain.
PMCID: PMC3420863  PMID: 22916201
19.  An African-American Family with Dystonia 
Parkinsonism & related disorders  2011;17(7):547-550.
The genetic cause of late-onset focal and segmental dystonia remains unknown in most individuals. Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6 dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians. We are not aware of any previous descriptions of familial dystonia in African Americans or reports of THAP1 mutations in African Americans. Herein, we characterize an African-American (AA) kindred with late-onset primary dystonia, clinically and genetically. The clinical phenotype included cervical, laryngeal and hand-forearm dystonia. Symptoms were severe and disabling for several family members, whereas others only displayed mild signs. There were no accompanying motor or cognitive signs. In this kindred, age of onset ranged from 45 to 50 years and onset was frequently sudden, with symptoms developing within weeks or months. DYT1 was excluded as the cause of dystonia in this kindred. The entire genomic region of THAP1, including non-coding regions, was sequenced. We identified 13 sequence variants in THAP1, although none co-segregated with dystonia. A novel THAP1 variant (c.-237-3G>T/A) was found in 3/84 AA dystonia patient alleles and 3/212 AA control alleles, but not in 5,870 Caucasian alleles. In summary, although previously unreported, familial primary dystonia does occur in African Americans. Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African Americans. Therefore, genetic testing for dystonia and future studies of candidate genes must take genetic background into consideration.
PMCID: PMC3137742  PMID: 21601506
Dystonia; Genetics; African American; DYT6; THAP1; Adult-Onset Dystonias; Dystonia, Hereditary; Focal Dystonia
Neurobiology of disease  2010;42(2):152-161.
Dystonia is a motor sign characterized by involuntary muscle contractions which produce abnormal postures. Genetic factors contribute significantly to primary dystonia. In comparison, secondary dystonia can be caused by a wide variety of metabolic, structural, infectious, toxic and inflammatory insults to the nervous system. Although classically ascribed to dysfunction of the basal ganglia, studies of diverse animal models have pointed out that dystonia is a network disorder with important contributions from abnormal olivocerebellar signaling. In particular, work with the dystonic (dt) rat has engendered dramatic paradigm shifts in dystonia research. The dt rat manifests generalized dystonia caused by deficiency of the neuronally-restricted protein caytaxin. Electrophysiological and biochemical studies have shown that defects at the climbing fiber-Purkinje cell synapse in the dt rat lead to abnormal bursting firing patterns in the cerebellar nuclei, which increases linearly with postnatal age. In a general sense, the dt rat has shown the scientific and clinical communities that dystonia can arise from dysfunctional cerebellar cortex. Furthermore, work with the dt rat has provided evidence that dystonia (1) is a neurodevelopmental network disorder and (2) can be driven by abnormal cerebellar output. In large part, work with other animal models has expanded upon studies in the dt rat and shown that primary dystonia is a multi-nodal network disorder associated with defective sensorimotor integration. In addition, experiments in genetically-engineered models have been used to examine the underlying cellular pathologies that drive primary dystonia.
PMCID: PMC3171987  PMID: 21081162
Dystonia; Inferior olive; Purkinje cell; Caytaxin; TorsinA; Basal ganglia
Neuroscience  2011;177:183-194.
DYT1 dystonia is caused by a GAG deletion in TOR1A, the gene which encodes torsinA. Gene expression studies in rodents and functional imaging studies in humans suggest that DYT1 dystonia may be a network disorder of neurodevelopmental origin. To generate high resolution metabolic maps of DYT1 dystonia and pinpoint dysregulated network elements, we performed 2-deoxyglucose autoradiography and cytochrome oxidase (CO) histochemistry in transgenic mice expressing human mutant (hMT1) torsinA and wild-type littermates. In comparison with controls, hMT1 mice showed increased glucose utilization (GU) in the inferior olive (IO) medial nucleus (IOM), IO dorsal accessory nucleus and substantia nigra compacta, and decreased GU in the medial globus pallidus (MGP) and lateral globus pallidus. The hMT1 mice showed increased CO activity in the IOM and Purkinje cell layer of cerebellar cortex, and decreased CO activity in the caudal caudate-putamen, substantia nigra reticulata and MGP. These findings suggest that (1) the DYT1 carrier state increases energy demand in the olivocerebellar network and (2) the IO may be a pivotal node for abnormal basal ganglia-cerebellar interactions in dystonia.
PMCID: PMC3171990  PMID: 21241782
dystonia; globus pallidus; glucose utilization; cytochrome oxidase histochemistry; inferior olive; Purkinje cells
22.  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.
PMCID: PMC3171986  PMID: 21370264
dystonia; DYT6; high-resolution melting; untranslated region; THAP1
23.  Blepharospasm plus Cervical Dystonia with Predominant Anterocollis: A Distinctive Subphenotype of Segmental Craniocervical Dystonia? 
Dystonia of the eyelids often spreads to affect other muscles in the craniocervical region. Certain blepharospasm-plus subphenotypes may be clinically unique.
Seven subjects with the subphenotype of late-onset blepharospasm with apraxia of eyelid opening and cervical dystonia with predominant anterocollis were identified from a database of over 1800 patients with primary dystonia.
Blepharospasm was the first affected site in 6/7 subjects, followed by spread of the disease to the cervical muscles. Although four patients also had other forms of dystonia (laryngeal, lower face), none showed spread outside the craniocervical region. A family history of dystonia was present in 4/7. No mutations were identified in THAP1 or TOR1A. Overall, blepharospasm was difficult to treat, typically requiring both myectomy and substantial doses of botulinum toxin into the pretarsal orbicularis oculi muscles. In one subject, anterocollis markedly improved after deep brain stimulation.
Delineation and characterization of craniocervical dystonia subphenotypes may serve to guide genetic and therapeutic studies, in addition to clinical interventions. The blepharospasm with apraxia of eyelid opening and anterocollis subphenotype can be therapeutically challenging.
PMCID: PMC3253013  PMID: 22229127
anterocollis; blepharospasm; craniocervical dystonia; THAP1; TOR1A
24.  Projections from the Hypothalamic Paraventricular Nucleus and the Nucleus of the Solitary Tract to Prechoroidal Neurons in the Superior Salivatory Nucleus: Pathways Controlling Rodent Choroidal Blood Flow 
Brain research  2010;1358:123-139.
Using intrachoroidal injection of the transneuronal retrograde tracer pseudorabies virus (PRV) in rats, we previously localized preganglionic neurons in the superior salivatory nucleus (SSN) that regulate choroidal blood flow (ChBF) via projections to the pterygopalatine ganglion (PPG). In the present study, we used higher order transneuronal retrograde labeling following intrachoroidal PRV injection to identify central neuronal cell groups involved in parasympathetic regulation of ChBF via input to the SSN. These prominently included the hypothalamic paraventricular nucleus (PVN) and the nucleus of the solitary tract (NTS), both of which are responsive to systemic BP, and are involved in systemic sympathetic vasoconstriction. Conventional pathway tracing methods were then used to determine if the PVN and/or NTS project directly to the choroidal subdivision of the SSN. Following retrograde tracer injection into SSN (biotinylated dextran amine 3K or Fluorogold), labeled perikarya were found in PVN and NTS. Injection of the anterograde tracer, biotinylated dextran amine 10K (BDA10K) into PVN or NTS resulted in densely packed BDA10K+ terminals in prechoroidal SSN (as defined by its enrichment in nitric oxide synthase-containing perikarya). Double-label studies showed these inputs ended directly on prechoroidal nitric oxide synthase-containing neurons of SSN. Our study thus establishes that PVN and NTS project directly to the part of SSN involved in parasympathetic vasodilatory control of the choroid via the PPG. These results suggest that control of ChBF may be linked to systemic blood pressure and central control of the systemic vasculature.
PMCID: PMC2949519  PMID: 20801105
biotinylated dextran amine (BDA); pseudorabies virus (PRV); choroidal blood flow (ChBF); superior salivatory nucleus (SSN); paraventricular nucleus (PVN); nucleus of solitary tract (NTS)
25.  Blepharospasm plus Cervical Dystonia with Predominant Anterocollis: A Distinctive Subphenotype of Segmental Craniocervical Dystonia 
Tremor and Other Hyperkinetic Movements  2011;1:tre-01-33-140-2.
Dystonia of the eyelids often spreads to affect other muscles in the craniocervical region. Certain blepharospasm-plus subphenotypes may be clinically unique.
Seven subjects with the subphenotype of late-onset blepharospasm with apraxia of eyelid opening and cervical dystonia with predominant anterocollis were identified from a database of over 1800 patients with primary dystonia.
Blepharospasm was the first affected site in 6/7 subjects, followed by spread of the disease to the cervical muscles. Although four patients also had other forms of dystonia (laryngeal, lower face), none showed spread outside the craniocervical region. A family history of dystonia was present in 4/7. No mutations were identified in THAP1 or TOR1A. Overall, blepharospasm was difficult to treat, typically requiring both myectomy and substantial doses of botulinum toxin into the pretarsal orbicularis oculi muscles. In one subject, anterocollis markedly improved after deep brain stimulation.
Delineation and characterization of craniocervical dystonia subphenotypes may serve to guide genetic and therapeutic studies, in addition to clinical interventions. The blepharospasm with apraxia of eyelid opening and anterocollis subphenotype can be therapeutically challenging.
PMCID: PMC3253013  PMID: 22229127
anterocollis; blepharospasm; craniocervical dystonia; THAP1; TOR1A

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