Publications by authors named "Maureen A Leehey"

45 Publications

Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study.

Cannabis Cannabinoid Res 2020 15;5(4):326-336. Epub 2020 Dec 15.

Department of Clinical Pharmacy, University of Colorado School of Medicine, Aurora, Colorado, USA.

Cannabis is increasingly used in Parkinson disease (PD), despite little information regarding benefits and risks. To investigate the safety and tolerability of a range of doses of cannabidiol (CBD), a nonintoxicating component of cannabis, and it's effect on common parkinsonian symptoms. In this open-label study Coloradans with PD, substantial rest tremor, not using cannabis received plant-derived highly purified CBD (Epidiolex; 100 mg/mL). CBD was titrated from 5 to 20-25 mg/kg/day and maintained for 10-15 days. Fifteen participants enrolled, two were screen failures. All 13 participants (10 male), mean (SD) age 68.15 (6.05), with 6.1 (4.0) years of PD, reported adverse events, including diarrhea (85%), somnolence (69%), fatigue (62%), weight gain (31%), dizziness (23%), abdominal pain (23%), and headache, weight loss, nausea, anorexia, and increased appetite (each 5%). Adverse events were mostly mild; none serious. Elevated liver enzymes, mostly a cholestatic pattern, occurred in five (38.5%) participants on 20-25 mg/kg/day, only one symptomatic. Three (23%) dropped out due to intolerance. Ten (eight male) that completed the study had improvement in total and motor Movement Disorder Society Unified Parkinson Disease Rating Scale scores of 7.70 (9.39, mean decrease 17.8%, =0.012) and 6.10 (6.64, mean decrease 24.7%, =0.004), respectively. Nighttime sleep and emotional/behavioral dyscontrol scores also improved significantly. CBD, in the form of Epidiolex, may be efficacious in PD, but the relatively high dose used in this study was associated with liver enzyme elevations. Randomized controlled trials are needed to investigate various forms of cannabis in PD.
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http://dx.doi.org/10.1089/can.2019.0068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759259PMC
December 2020

A Review of the Current Evidence Connecting Seborrheic Dermatitis and Parkinson's Disease and the Potential Role of Oral Cannabinoids.

Dermatology 2020 Dec 17:1-6. Epub 2020 Dec 17.

Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA,

Parkinson's disease (PD) is a neurodegenerative disorder associated with multiple comorbidities, including seborrheic dermatitis (SD), which develops in more than half of PD patients. SD in patients with PD can be severe and frequently intractable by traditional topical therapy. Cannabinoids possess anti-inflammatory and neuromodulatory properties working within the intrinsic endocannabinoid system, the activation of which may alleviate the motor symptoms of PD. The effect of cannabinoids on SD is unknown. Here we explore the pathophysiological mechanisms and possible therapeutic role of oral cannabinoids in PD patients with SD, and review speculative mechanisms underlying the association of PD and SD. Current data supporting the use of cannabinoids in both PD and SD, as well as oral cannabinoid safety and tolerability, are presented. Cannabinoids may provide the possibility of simultaneous treatment of both SD and PD. Specific SD studies and additional safety data on oral cannabinoids are needed.
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http://dx.doi.org/10.1159/000512189DOI Listing
December 2020

Eye Movements in Fragile X-Associated Tremor/Ataxia Syndrome.

J Neuroophthalmol 2020 Oct 23. Epub 2020 Oct 23.

Department of Neurological Sciences (DAH), Rush University, Chicago, Illinois; Department of Neurology (MAL, VSP), University of Colorado School of Medicine, Aurora, Colorado; and MIND Institute (RJH), University of California Davis, Sacramento, California.

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by ataxia, tremor, and parkinsonism. Eye motility abnormalities on the clinical examination of FXTAS patients have not been formally studied.

Methods: A case-control study with fragile X gene mutation carriers with and without FXTAS and normal controls was conducted and included a videotaping of ocular items of the International Cooperative Ataxia Rating Scale (ICARS). A neuro-ophthalmologist blinded to gene status rated nystagmus, ocular pursuit, and saccades.

Results: Forty-four cases and controls were recruited, with an average age of 55.2 years (±7.4) and 57% women. Gaze-evoked nystagmus was increased in fragile X gene carriers (odds ratio 1.44, 95% confidence interval: 0.33-7.36) but was not statistically significant. There was no difference in ocular pursuit nor saccade dysmetria between cases and controls.

Conclusion: The results show that clinical examination findings of ocular abnormalities, using the ICARS oculomotor disorders movement subscale, are not more common in FXTAS or FMR1 premutation carriers than normal controls on examination in the clinic. Examining a larger cohort of patients with FXTAS would be an ideal next step.
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http://dx.doi.org/10.1097/WNO.0000000000001082DOI Listing
October 2020

Novel clinical features of glycine receptor antibody syndrome: A series of 17 cases.

Neurol Neuroimmunol Neuroinflamm 2019 09 1;6(5):e592. Epub 2019 Jul 1.

Department of Neurology (A.L.P., M.K., M.P.W., J.L.B., M.A.L., L.S., T.L.S.), University of Colorado, Aurora; Department of Neurology (A.L.P., J.E.A.W., M.M.P.S., S.L.C.), University of Utah; Department of Ophthalmology (J.E.A.W.), Moran Eye Center, University of Utah, Salt Lake City; Department of Ophthalmology and Program in Neuroscience (J.L.B.), University of Colorado; Department of Neurology (T.L.S.), Children's Hospital Colorado, Aurora; and Department of Veterans Affairs (M.M.P.S., S.L.C.), George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT.

Objective: To describe novel clinical features of GlyRα1-IgG-positive patients.

Methods: Patients with a positive serum GlyRα1-IgG were identified during a 2-year period from July 2016 to December 2018 at 2 academic centers and followed prospectively. All patients in this series were evaluated in the Neuroimmunology and Autoimmune Neurology clinics at the University of Utah or the University of Colorado.

Results: Thirteen of 17 patients had phenotypes more typically associated with glutamic acid decarboxylase (GAD65) antibody syndromes, consisting of stiff-person syndrome (SPS) with parkinsonism or cerebellar signs. One patient with parkinsonism had a presentation similar to rapidly progressive multiple system atrophy with severe dysautonomia. Ten of 17 patients had various visual symptoms including visual snow, spider web-like images forming shapes and 3-dimensional images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia. Three of 17 patients presented with primarily autoimmune epilepsy accompanied by psychiatric symptoms.

Conclusions: Clinicians should consider testing for GlyR antibodies in GAD65 antibody-negative or low-positive GAD65 antibody patients with SPS-like presentations, especially in the setting of atypical features such as visual disturbances, parkinsonism, or epilepsy.
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http://dx.doi.org/10.1212/NXI.0000000000000592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624144PMC
September 2019

Clinimetric Properties of the Fragile X-associated Tremor Ataxia Syndrome Rating Scale.

Mov Disord Clin Pract 2019 Feb 22;6(2):120-124. Epub 2019 Jan 22.

Department of Neurology University of Colorado School of Medicine Aurora Colorado United States.

Background: There are currently no proven treatments for fragile X-associated tremor and ataxia syndrome (FXTAS). Validated outcome measures are needed in order to plan and conduct clinical trials to aid in the development of therapy.

Methods: This study examined the reliability and construct validity of the FXTAS Rating Scale. The study was conducted by using ratings from movement disorder specialists, who were blinded to gene status, on the FXTAS Rating Scale.

Results: In 295 premutation carriers with and without FXTAS, 33 scale items showed a high level of overall reliability, adequate item-to-total correlations and construct validity. Factor analysis revealed four components.

Conclusions: The result demonstrates that many items in the scale meet standard clinimetric criteria, but modification of the scale improved the overall utility.
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http://dx.doi.org/10.1002/mdc3.12708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384171PMC
February 2019

An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

Ther Drug Monit 2017 10;39(5):556-564

*Department of Anesthesiology, University of Colorado, Aurora; †Division of Substance Dependence, Department of Psychiatry, University of Colorado, Aurora; ‡Department of Neurology, University of Colorado, Aurora; §Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora; ¶Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora; and ‖Division of Pulmonary Medicine, National Jewish Health, Denver, Colorado.

Background: Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids.

Methods: To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma.

Results: In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy.

Conclusions: This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.
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http://dx.doi.org/10.1097/FTD.0000000000000427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600652PMC
October 2017

Long-term follow-up of a randomized AAV2- gene therapy trial for Parkinson's disease.

JCI Insight 2017 04 6;2(7):e90133. Epub 2017 Apr 6.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2- delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and F-fluorodeoxyglucose (FDG) PET imaging. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2- group compared with the sham group continued at 12 months [time effect: (4,138) = 11.55, < 0.001; group effect: (1,35) = 5.45, < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2- group ( = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines ( < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2- group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2- group ( < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. These findings show that clinical benefits after gene therapy with STN AAV2- in PD patients persist at 12 months. ClinicalTrials.gov NCT00643890. Neurologix Inc.
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http://dx.doi.org/10.1172/jci.insight.90133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374069PMC
April 2017

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series.

Cerebellum 2016 10;15(5):623-31

Department of Neurological Sciences, Rush University, 1725 West Harrison Street, Suite 755, Chicago, IL, 60612, USA.

Considerable research has focused on patients with trinucleotide (CGG) repeat expansions in the fragile X mental retardation 1 (FMR1) gene that fall within either the full mutation (>200 repeats) or premutation range (55-200 repeats). Recent interest in individuals with gray zone expansions (41-54 CGG repeats) has grown due to reported phenotypes that are similar to those observed in premutation carriers, including neurological, molecular, and cognitive signs. The purpose of this manuscript is to describe a series of adults with FMR1 alleles in the gray zone presenting with movement disorders or memory loss. Gray zone carriers ascertained in large FMR1 screening studies were identified and their clinical phenotypes studied. Thirty-one gray zone allele carriers were included, with mean age of symptom onset of 53 years in patients with movement disorders and 57 years in those with memory loss. Four patients were chosen for illustrative case reports and had the following diagnoses: early-onset Parkinson disease (PD), atypical parkinsonism, dementia, and atypical essential tremor. Some gray zone carriers presenting with parkinsonism had typical features, including bradykinesia, rigidity, and a positive response to dopaminergic medication. These patients had a higher prevalence of peripheral neuropathy and psychiatric complaints than would be expected. The patients seen in memory clinics had standard presentations of cognitive impairment with no apparent differences. Further studies are necessary to determine the associations between FMR1 expansions in the gray zone and various phenotypes of neurological dysfunction.
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http://dx.doi.org/10.1007/s12311-016-0809-6DOI Listing
October 2016

Association Between Change in Body Mass Index, Unified Parkinson's Disease Rating Scale Scores, and Survival Among Persons With Parkinson Disease: Secondary Analysis of Longitudinal Data From NINDS Exploratory Trials in Parkinson Disease Long-term Study 1.

JAMA Neurol 2016 Mar;73(3):321-8

Department of Neurological Sciences, University of Vermont College of Medicine, Burlington.

Importance: Greater body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) is associated with improved survival among persons with Huntington disease or amyotrophic lateral sclerosis. Weight loss is common among persons with Parkinson disease (PD) and is associated with worse quality of life.

Objective: To explore the association between change in BMI, Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores, and survival among persons with PD and to test whether there is a positive association between BMI at randomization and survival.

Design, Setting, And Participants: Secondary analysis (from May 27, 2014, to October 13, 2015) of longitudinal data (3-6 years) from 1673 participants who started the National Institute of Neurological Disorders and Stroke Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1). This was a double-blind randomized placebo-controlled clinical trial of creatine monohydrate (10 g/d) that was performed at 45 sites throughout the United States and Canada. Participants with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) PD were enrolled from March 2007 to May 2010 and followed up until September 2013.

Main Outcomes And Measures: Change across time in motor UPDRS score, change across time in total UPDRS score, and time to death. Generalized linear mixed models were used to estimate the effect of BMI on the change in motor and total UPDRS scores after controlling for covariates. Survival was analyzed using Cox proportional hazards models of time to death. A participant's BMI was measured at randomization, and BMI trajectory groups were classified according to whether participants experienced weight loss ("decreasing BMI"), weight stability ("stable BMI"), or weight gain ("increasing BMI") during the study.

Results: Of the 1673 participants (mean [SD] age, 61.7 [9.6] years; 1074 [64.2%] were male), 158 (9.4%) experienced weight loss (decreasing BMI), whereas 233 (13.9%) experienced weight gain (increasing BMI). After adjusting for covariates, we found that the weight-loss group's mean (SE) motor UPDRS score increased by 1.48 (0.28) (P < .001) more points per visit than the weight-stable group's mean (SE) motor UPDRS score. The weight-gain group's mean (SE) motor UPDRS score decreased by -0.51 (0.24) (P = .03) points per visit, relative to the weight-stable group. While there was an unadjusted difference in survival between the 3 BMI trajectory groups (log-rank P < .001), this was not significant after adjusting for covariates.

Conclusions And Relevance: Change in BMI was inversely associated with change in motor and total UPDRS scores in the NET-PD LS-1. Change in BMI was not associated with survival; however, these results were limited by the low number of deaths in the NET-PD LS-1.

Trial Registration: clinicaltrials.gov Identifier: NCT00449865.
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http://dx.doi.org/10.1001/jamaneurol.2015.4265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469290PMC
March 2016

Erratum: Emerging topics in FXTAS.

J Neurodev Disord 2015 8;7(1):13. Epub 2015 Apr 8.

Department of Neurology, University of Colorado at Denver, Denver, CO USA.

[This corrects the article DOI: 10.1186/1866-1955-6-31.].
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http://dx.doi.org/10.1186/s11689-015-9108-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387583PMC
April 2015

Emerging topics in FXTAS.

J Neurodev Disord 2014 30;6(1):31. Epub 2014 Jul 30.

Department of Neurology, University of Colorado at Denver, Denver, CO, USA.

This paper summarizes key emerging issues in fragile X-associated tremor/ataxia syndrome (FXTAS) as presented at the First International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2013.
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http://dx.doi.org/10.1186/1866-1955-6-31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141265PMC
February 2015

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

JAMA Neurol 2014 May;71(5):543-52

Columbia University Medical Center, Neurological Institute, New York, New York.

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective: To examine whether CoQ10 could slow disease progression in early PD.

Design, Setting, And Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation.

Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E.

Main Outcomes And Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo.

Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo).

Conclusions And Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit.

Trial Registration: clinicaltrials.gov Identifier: NCT00740714.
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http://dx.doi.org/10.1001/jamaneurol.2014.131DOI Listing
May 2014

Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): revisited.

Parkinsonism Relat Disord 2014 Apr 18;20(4):456-9. Epub 2014 Jan 18.

Department of Neurology, University of California Davis, Sacramento, CA, USA. Electronic address:

Background: Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures.

Methods: Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS).

Results: The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor.

Interpretation: Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS.
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http://dx.doi.org/10.1016/j.parkreldis.2014.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019503PMC
April 2014

Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial.

J Clin Psychiatry 2014 Mar;75(3):264-71

2230 Stockton Blvd, Sacramento, CA 95817

Objective: Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, is currently approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. Anecdotal reports have suggested that memantine may improve neurologic and cognitive symptoms of individuals with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial.

Method: Individuals with FXTAS aged 34-80 years were enrolled in a randomized, double-blind, placebo-controlled, 1-year trial between September 2007 and August 2012. Inclusion required definite, probable, or possible FXTAS in clinical stages 1-5 according to previously published criteria. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity.

Results: Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started treatment with memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants receiving memantine and 36 receiving placebo completed the 1-year endpoint assessment (n = 70). Intention-to-treat analysis showed no improvement with respect to intention tremor severity (mean [SD] values with memantine vs placebo: 1.05 [0.73] vs 1.89 [2.19], P = .047) or BDS score (16.12 [5.43] vs 15.72 [3.93], P = .727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), those with late FXTAS (stage > 3), and those in different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events were observed in the placebo group, while more frequent moderate adverse events occurred in the memantine group (P = .007).

Conclusion: This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit compared to placebo with respect to the selected outcome measures.

Trial Registration: ClinicalTrials.gov identifier: NCT00584948.
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http://dx.doi.org/10.4088/JCP.13m08546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296896PMC
March 2014

Fibromyalgia in fragile X mental retardation 1 gene premutation carriers.

Rheumatology (Oxford) 2011 Dec 16;50(12):2233-6. Epub 2011 Sep 16.

Department of Neurology, University of Colorado, Denver, CO,USA.

Objective: FM is a disorder of altered pain regulation and is characterized by pain, fatigue, poor sleep and psychological impairments; thus, it is classified as a central sensitivity syndrome. Female carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene frequently have widespread musculoskeletal pain and sometimes have been diagnosed with FM, especially if they have the motor signs of fragile X-associated tremor ataxia syndrome (FXTAS). Studies suggest that FM occurs in persons with a genetic predisposition. We describe the clinical features of female FMR1 premutation carriers with symptoms of FM.

Methods: A sample of patients was selected that participated in studies at two tertiary referral academic centres on the phenotype and therapy of FXTAS.

Results: This selected sample of patients, five female premutation carriers, has FM symptoms or diagnoses and other central sensitivity syndromes.

Conclusion: Since FM affects 2-4% of the world's population and about 1 in 250 females are FMR1 carriers, a study screening females with FM for the presence of the FMR1 premutation is worthwhile. A finding of increased prevalence of FMR1 carriers among females with FM would impact the standard evaluation of FM. Presently, guidelines for FMR1 genetic testing includes early menopause, congenital intellectual disability, autism spectrum disorder, tremor or ataxia, and a family history of FXTAS or fragile X syndrome. The latter is a common cause of autism and developmental delay. Such testing is important because female carriers are at risk of having a child with fragile X syndrome.
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http://dx.doi.org/10.1093/rheumatology/ker273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222847PMC
December 2011

Fragile X-associated tremor/ataxia syndrome.

Handb Clin Neurol 2012 ;103:373-86

Department of Neurology, University of Colorado at Denver Health Sciences Center, Denver, CO, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an under-recognized disorder that is a significant cause of late-adult-onset ataxia. The etiology is expansion of a trinucleotide repeat to the premutation range (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. Expansion to >200 CGGs causes fragile X syndrome, the most common heritable cause of cognitive impairment and autism. Core features of FXTAS include progressive action tremor and gait ataxia; with frequent, more variable features of cognitive decline, especially executive dysfunction, parkinsonism, neuropathy, and autonomic dysfunction. MR imaging shows generalized atrophy and frequently abnormal signal in the middle cerebellar peduncles. Autopsy reveals intranuclear inclusions in neurons and astrocytes and dystrophic white matter. FXTAS is likely due to an RNA toxic gain-of-function of the expanded-repeat mRNA. The disorder typically affects male premutation carriers over age 50, and, less often, females. Females also are at increased risk for primary ovarian insufficiency, chronic muscle pain, and thyroid disease. Treatment targets specific symptoms, but progression of disability is relentless. Although the contribution of FXTAS to the morbidity and mortality of the aging population requires further study, the disorder is likely the most common single-gene form of tremor and ataxia in the older adult population.
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http://dx.doi.org/10.1016/B978-0-444-51892-7.00023-1DOI Listing
December 2011

FMR1 gray-zone alleles: association with Parkinson's disease in women?

Mov Disord 2011 Aug 12;26(10):1900-6. Epub 2011 May 12.

Department of Neurological Sciences, Rush University, 1725 West Harrison St., Suite 755, Chicago, IL 60611, USA.

Carriers of fragile X mental retardation 1 repeat expansions in the premutation range (55-200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism. These neurological signs are believed to be a result of elevated levels of expanded CGG-repeat fragile X mental retardation 1 mRNA. The purpose of this study was to determine the prevalence of fragile X mental retardation 1 repeat expansions in a movement disorder population comprising subjects with all types of tremor, ataxia, and parkinsonism. We screened 335 consecutive patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders. There was no difference in fragile X mental retardation 1 premutation size expansions in the cases compared with controls. Eleven percent of the women with Parkinson's disease had fragile X mental retardation 1 gray-zone expansions compared with 4.4% of female controls (odds ratio of 3.2; 95% confidence interval, 1.2-8.7). Gray-zone expansions in patients with other phenotypes were not overrepresented in comparison with controls. Fragile X mental retardation 1 premutation range expansions are not more common in a mixed movement disorder population compared with controls. Our results, however, suggest that fragile X mental retardation 1 gray-zone alleles may be associated with Parkinson's disease in women.
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http://dx.doi.org/10.1002/mds.23755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934001PMC
August 2011

AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial.

Lancet Neurol 2011 Apr;10(4):309-19

Wayne State University School of Medicine, Parkinson's Disease and Movement Disorders Program, Henry Ford West Bloomfield Hospital, MI, USA.

Background: Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease.

Methods: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890.

Findings: Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two).

Interpretation: The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders.

Funding: Neurologix.
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http://dx.doi.org/10.1016/S1474-4422(11)70039-4DOI Listing
April 2011

Aging in fragile X syndrome.

J Neurodev Disord 2010 Jun 12;2(2):70-76. Epub 2010 May 12.

Many studies have focused on the behavior and cognitive problems in young patients with fragile X syndrome (FXS), but there are no studies about the problems in aging for those with FXS. The discovery of the fragile X-associated tremor ataxia syndrome (FXTAS), a neurodegenerative disorder related to elevated FMR1-mRNA, in elderly men and some women with the premutation, intensified the need for aging studies in FXS. Approximately 40% of males with FXS have repeat size mosaicism and as a result, some of these individuals also have elevated levels of FMR1-mRNA which theoretically puts them at risk for FXTAS. Here, we have surveyed all of the aging patients with FXS that we have followed over the years to clarify the medical complications of aging seen in those with FXS. Data was collected from 62 individuals with the FXS full mutation (44 males; 18 females) who were at least 40 years old at their most recent clinical examination. We found that the five most frequent medical problems in these patients were neurological problems (38.7%), gastrointestinal problems (30.6%), obesity (28.8%), hypertension (24.2%) and heart problems (24.2%). Movement disorders were significantly different between males and females (38.6% vs.10.2%, p = 0.029). We did not find any differences in medical problems between those with a full mutation and those with mosaicism. Identification of medical problems associated with aging in FXS is important to establish appropriate recommendations for medical screening and treatment considerations.
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http://dx.doi.org/10.1007/s11689-010-9047-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882562PMC
June 2010

Conversion disorder in women with the FMR1 premutation.

Am J Med Genet A 2009 Nov;149A(11):2501-6

Department of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, California, USA.

Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until recently believed to be unaffected. It is now known that up to 8% of older female FMR1 premutation carriers develop fragile X-associated tremor/ataxia syndrome (FXTAS). Female carriers may also develop primary ovarian insufficiency, thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. We present a 60-year-old woman with FMR1 premutation who had depression, anxiety, and conversion disorder with seizures. The FMR1 premutation with its associated mRNA toxicity is postulated as an underlying neurobiological mechanism of conversion symptoms, through functional and structural neural dysconnectivity.
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http://dx.doi.org/10.1002/ajmg.a.33054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783547PMC
November 2009

Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment.

Authors:
Maureen A Leehey

J Investig Med 2009 Dec;57(8):830-6

Department of Neurology, University of Colorado Denver, Aurora, CO 80045, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG repeat expansion in the premutation range (55-200) in the fragile X mental retardation 1 gene. Onset is typically in the early seventh decade, and men are principally affected. The major signs are cerebellar gait ataxia, intention tremor, frontal executive dysfunction, and global brain atrophy. Other frequent findings are parkinsonism (mild), peripheral neuropathy, psychiatric symptoms (depression, anxiety, and agitation), and autonomic dysfunction. The clinical presentation is heterogeneous, with individuals presenting with varied dominating signs, such as tremor, dementia, or neuropathy. Magnetic resonance imaging shows atrophy and patchy white matter lesions in the cerebral hemispheres and middle cerebellar peduncles. The latter has been designated the middle cerebellar peduncle sign, which occurs in about 60% of affected men, and is relatively specific for FXTAS. Affected females generally have less severe disease, less cognitive decline, and some symptoms different from that of men, for example, muscle pain. Management of FXTAS is complex and includes assessment of the patient's neurological and medical deficits, treatment of symptoms, and provision of relevant referrals, especially genetic counseling. Treatment is empirical, based on anecdotal experience and on knowledge of what works for symptoms of other disorders that also exist in FXTAS. Presently, the disorder is underrecognized because the first published report was only in 2001 and because the presentation is variable and mainly consists of a combination of signs common in the elderly. However, accurate diagnosis is critical for the patient and for the family because they need education regarding their genetic and health risks.
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http://dx.doi.org/10.2310/JIM.0b013e3181af59c4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787702PMC
December 2009

Functional status of men with the fragile X premutation, with and without the tremor/ataxia syndrome (FXTAS).

Int J Geriatr Psychiatry 2009 Oct;24(10):1101-9

Department of Medicine, University of Colorado Denver, Aurora, CO 80217-3364, USA.

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in some premutation carriers of the fragile X mental retardation 1 (FMR1) gene, is a neurodegenerative disorder characterized by action tremor, gait ataxia, and impaired executive cognitive functioning.

Objective: To evaluate the nature and severity of functional limitations among male carriers of the fragile X premutation, both with and without FXTAS.

Methods: Forty-two subjects with FXTAS and 24 asymptomatic premutation carriers were compared to 32 control subjects on measures of physical functioning, activities of daily living (ADLs; e.g. eating, bathing), and instrumental activities of daily living (IADLs; e.g. shopping, managing medications). Ordinary least squares regression, controlling for age, education, medical comorbidity, and pain, was used to examine group differences in physical and functional performance.

Results: Men with FXTAS performed significantly worse than control subjects on all dependent measures, showing greater limitations in physical functioning, as well as ADL and IADL performance (p < 0.05). Subsequent analyses suggested that physical and functional impairments among men with FXTAS result largely from deficits in motor and executive functioning and that CGG repeat length is associated with functional impairment. Asymptomatic carriers of the fragile X premutation performed similarly to control subjects on all measures.

Conclusions: This study provides the first comprehensive evaluation of functional status among male premutation carriers. Although carriers without FXTAS performed similarly to control subjects, men with FXTAS showed evidence of significant physical and functional impairment, which appears to result largely from motor and executive deficits characteristic of the syndrome.
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http://dx.doi.org/10.1002/gps.2231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414034PMC
October 2009

The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome.

J Clin Exp Neuropsychol 2008 Nov 15;30(8):853-69. Epub 2008 Feb 15.

Department of Medicine, University of Colorado, Denver, Aurora, CO, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation trinucleotide repeat expansion in the fragile X mental retardation 1 gene. Symptoms include gait ataxia, action tremor, and cognitive impairment. The objectives of the study were to clarify the nature of the dysexecutive syndrome observed in FXTAS and to assess the contribution of executive impairment to deficits in nonexecutive cognitive functions. Compared to controls, men with FXTAS demonstrated significant executive impairment, which was found to mediate group differences in most other cognitive abilities. Asymptomatic premutation carriers performed similarly to controls on all but two measures of executive functioning. These findings suggest that the impairment of nonexecutive cognitive skills in FXTAS is in large part secondary to executive dysfunction.
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http://dx.doi.org/10.1080/13803390701819044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098148PMC
November 2008

Parkinsonism in FMR1 premutation carriers may be indistinguishable from Parkinson disease.

Parkinsonism Relat Disord 2009 Feb 20;15(2):156-9. Epub 2008 Jun 20.

Department of Neurology, University of Colorado at Denver and Health Sciences Center, Denver, CO, USA.

Premutation carriers of repeat expansions in the fragile X mental retardation (FMR1) gene develop kinetic tremor and ataxia or the 'fragile X associated tremor/ataxia syndrome' (FXTAS). Affected FMR1 premutation carriers also have parkinsonism, but have not been reported to meet criteria for Parkinson disease. This case series illustrates that some patients who are FMR1 premutation carriers may appear by history and examination to have idiopathic Parkinson disease. Based on previous studies, it is likely that the genetic mutation and parkinsonism are associated. Although screening all PD patients is likely to be low yield, genetic testing of FMR1 in individuals with PD and a family history of fragile X syndrome, autism or developmental delay, or other related FMR1 phenotypes is warranted.
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http://dx.doi.org/10.1016/j.parkreldis.2008.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685192PMC
February 2009

Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Neuropsychology 2008 Jan;22(1):48-60

Children's Hospital.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.
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http://dx.doi.org/10.1037/0894-4105.22.1.48DOI Listing
January 2008

Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome.

Am J Med Genet A 2007 Oct;143A(19):2256-60

Department of Pediatrics, University of California at Davis Medical Center, Sacramento, California 95817, USA.

Peripheral neuropathy is common among patients with fragile X-associated tremor ataxia syndrome (FXTAS). Four patients with FXTAS are described with neuropathy as the presenting feature, two having received a prior diagnosis of Charcot-Marie-Tooth (CMT) disease. A fifth is described with neuropathy as the only clinical feature. A functional connection between FXTAS and neuropathy has been suggested by the presence of lamin A/C in the intranuclear, neuronal and astrocytic inclusions of FXTAS, since mutations in lamin A/C are known to give rise to an axonal form of CMT.
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http://dx.doi.org/10.1002/ajmg.a.31920DOI Listing
October 2007

Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines.

Mov Disord 2007 Oct;22(14):2018-30, quiz 2140

Department of Pediatrics, Rush University Medical Center, Chicago, Illinois 60612, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated findings include parkinsonism, executive function deficits and dementia, neuropathy, and dysautonomia. Magnetic Resonance Imaging studies in FXTAS demonstrate increased T2 signal intensity in the middle cerebellar peduncles (MCP sign) in the majority of patients. Similar signal alterations are seen in deep and subependymal cerebral white matter, as is general cortical and subcortical atrophy. The major neuropathological feature of FXTAS is the presence of intranuclear, neuronal, and astrocytic, inclusions in broad distribution throughout the brain and brainstem. FXTAS is caused by moderate expansions (55-200 repeats; premutation range) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene, the same gene which causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA per se. Although only recently discovered, and hence currently under-diagnosed, FXTAS is likely to be one of the most common single-gene disorders leading to neurodegeneration in males. In this report, we review information available on the clinical, radiological, and pathological features, and prevalence and management of FXTAS. We also provide guidelines for the practitioner to assist with identifying appropriate patients for DNA testing for FXTAS, as well as recommendations for genetic counseling once a diagnosis of FXTAS is made.
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http://dx.doi.org/10.1002/mds.21493DOI Listing
October 2007

CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS).

Am J Med Genet B Neuropsychiatr Genet 2007 Jun;144B(4):566-9

Department of Biochemistry and Molecular Medicine, University of California, School of Medicine, Davis, California 95616, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurological disorder among carriers of premutation CGG-repeat expansions within the FMR1 gene. Principal features of FXTAS include progressive action tremor and gait ataxia, with associated features of parkinsonism, peripheral neuropathy, dysautonomia, and cognitive decline. Although both clinical and neuropathologic features of FXTAS are known to be highly associated with CGG repeat length, the relationship between repeat length and age-of-onset is not known. To address this issue, the ages of onset of action tremor and gait ataxia were documented by history for 93 male carriers. For this cohort, the mean ages of onset were 62.6 +/- 8.1 years (range, 39-78 years) for tremor, and 63.6 +/- 7.3 years (range, 47-78 years) for ataxia; the mean CGG repeat number was 88.5 +/- 14 (range, 60-133). Analysis of the relationship between clinical onset and molecular measures revealed significant correlations between CGG repeat number and onset of both tremor (P = 0.001) and ataxia (P = 0.002), as well as overall onset (P < 0.0001). Our findings indicate that the CGG repeat number is a potential predictor of the age of onset of core motor features of FXTAS.
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http://dx.doi.org/10.1002/ajmg.b.30482DOI Listing
June 2007

MS vs. HD: can white matter and subcortical gray matter pathology be distinguished neuropsychologically?

J Clin Exp Neuropsychol 2007 Feb;29(2):142-54

Regis University, Department of Psychology and Neuroscience Program, Denver, CO 80221-1099, USA.

This study was conducted to examine the neuropsychological effects of white matter and subcortical gray matter pathology. Nineteen patients with multiple sclerosis (MS), 16 with Huntington's disease (HD), and 17 normal controls (NC) participated. Participants completed the California Verbal Learning Test (CVLT), Rotary Pursuit (RP) and Mirror Tracing (MT) tasks, and the Symbol Digit Modalities Test (SDMT). The principal findings pertain to a dissociation in procedural memory: on RP, the HD group demonstrated impaired sequence learning compared to the MS group, which performed similarly to the NC group, yet on MT, the MS and HD groups demonstrated normal perceptual-motor integration learning. On the CVLT, both patient groups performed better on recognition than on recall. On the SDMT, both patient groups performed worse than the NC group, with the HD group performing more poorly than the MS and NC groups. These results suggest that involvement of white and subcortical gray matter may produce different neuropsychological effects.
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http://dx.doi.org/10.1080/13803390600582438DOI Listing
February 2007