Publications by authors named "Edythe Wiggs"

42 Publications

Neurodevelopmental Characterization of Young Children Diagnosed with Niemann-Pick Disease, Type C1.

J Dev Behav Pediatr 2020 Jun/Jul;41(5):388-396

Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD.

Objective: Niemann-Pick disease type C1 (NPC1) is a lysosomal storage disease characterized by progressive neurodegeneration, with the age of diagnosis ranging from the prenatal period through adulthood. Although neurological symptoms usually precede genetic diagnosis, they do not necessarily prompt diagnosis in the early years. Few prospective data are available to describe neurological onset, including neurodevelopmental delays, in children with NPC1. This dearth of information hinders the planning and implementation of adequate monitoring and treatment for the neurodevelopmental sequelae of NPC1.

Method: Twenty-nine infants, toddlers, and preschoolers younger than 6 years participated in a natural history study and were administered neurodevelopmental assessments using instruments commonly used for early intervention screening in the community.

Results: Twenty-two of 29 participants met the criteria for a significant delay of at least 1.5 SDs below the mean in at least one domain of development; the youngest children often met these criteria for a significant delay based on motor delays, but cognitive and language delays were also common. However, only 11 of the 22 participants were reported to receive early intervention services before study entry.

Conclusion: Although neurological symptoms may not prompt the genetic diagnosis of NPC1, the current findings support the use of a multimethod approach to repeated assessments for young children with the diagnosis because of the frequency of developmental delays or decline in multiple domains. The diagnosis of NPC1 alone should qualify children for evaluation for early intervention services and consideration of investigational therapeutic interventions.
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http://dx.doi.org/10.1097/DBP.0000000000000785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592416PMC
February 2020

Clinical evaluation of sibling pairs with gaucher disease discordant for parkinsonism.

Mov Disord 2020 02 30;35(2):359-365. Epub 2019 Nov 30.

Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Background: Although the association between mutations in GBA1 and parkinsonism is well established, most GBA1 mutation carriers never develop parkinsonism, implicating the contribution of other genetic, epigenetic, and/or environmental modifiers.

Objectives: To identify factors predisposing to or offering protection from parkinsonism among siblings with Gaucher's disease) discordant for Parkinson disease (PD).

Methods: This prospective, longitudinal study included nine sib pairs with Gaucher disease, but discordant for PD. Assessments included neurological, neuropsychological, olfactory, motor, nonmotor evaluations, and transcranial sonography. Validated mood and nonmotor questionnaires assessed fatigue, olfactory dysfunction, sleepiness, sleep disturbances, anxiety, and/or depression.

Results: There was no relationship between Gaucher treatments, genotype, or splenectomy and PD. Male sex predominance, younger age, and milder Gaucher disease symptoms were observed among the patients with PD. Substantia nigral echogenicity, olfactory dysfunction, serum triglycerides levels, and 9-hole peg scores, but not caffeine, alcohol, or tobacco use, environmental exposures, uric acid, or glucose levels, differed significantly between groups.

Conclusions: Longitudinal evaluation of discordant sib pairs may help identify PD risk factors. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27916DOI Listing
February 2020

Variation in cognitive function over time in Gaucher disease type 3.

Neurology 2019 12 12;93(24):e2272-e2283. Epub 2019 Nov 12.

From the Section on Molecular Neurogenetics (A.M.S., E.W., T.L., S.U., E.R., N.T., T.R.L.G.L., E.S.), Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD; and Kimberly H. Courtwright and Joseph W. Summers Institute of Metabolic Disease (R.S.), Baylor Scott & White Research Institute, Dallas, TX. The present address for Tamanna Roshan Lal is Lysosomal Storage and Treatment Program, George Washington University School of Medicine and Children's National Rare Disease Institute, Washington DC.

Objective: To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center.

Methods: Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator.

Results: Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ.

Conclusions: The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.
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http://dx.doi.org/10.1212/WNL.0000000000008618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937490PMC
December 2019

The neuropsychological phenotype of Chediak-Higashi disease.

Orphanet J Rare Dis 2019 05 6;14(1):101. Epub 2019 May 6.

National Human Genome Research Institute, Bethesda, MD, USA.

Background/objectives: Chediak-Higashi Disease (CHD) is a rare autosomal disorder, purported to have cognitive and neurological impairments. Prior descriptions of cognitive impairment, however, are solely based on subjective, unstructured observations rather than on formal neuropsychological measures.

Methods: Four pediatric and 14 adult patients with diagnostically confirmed CHD were administered a neuropsychological battery assessing memory, attention, processing speed, psychomotor speed, language fluency, executive function, and general intelligence. Nine of the adult patients received follow-up evaluations to elucidate the longitudinal progression or stability of cognition over time.

Results: Pediatric CHD patients performed within the average range. Adult patients, however, performed below average on nearly all measures administered, and endorsed subjective reports of learning difficulties and poor academic performance in childhood. In particular, patients struggled with memory and psychomotor speed tasks, with 75% or more of patients scoring in the bottom 2.3 percentile in these two domains. No significant declines in cognition were observed among the patients who completed follow-up evaluations (M = 39.90, SD = 8.03 months between visits). Exploratory analyses suggested that adult patients who had classic CHD and previously received bone marrow transplants (BMTs; n = 3) exhibited moderately greater cognitive impairment than adult patients who had atypical CHD and had not received BMTs (n = 10).

Conclusions: Adult patients with CHD uniformly exhibit deficits in multiple domains, but in psychomotor speed and memory, in particular. Based on their neuropsychological profile, their ability to hold jobs and succeed in school may require support and special accommodations. The source of cognitive deficits is probably multifactorial including central nervous system involvement in CHD, and, for those transplanted, BMT-related side effects and complications. Absence of cognitive decline at three-year follow-up is encouraging but does not exclude progression at a slower time-scale. Future work should elucidate the possible effects and timing of BMT on cognition, as well as the mechanisms driving neuropsychological impairment in CHD.
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http://dx.doi.org/10.1186/s13023-019-1049-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503440PMC
May 2019

Functional MRI and direct cortical stimulation: Prediction of postoperative language decline.

Epilepsia 2019 03 11;60(3):560-570. Epub 2019 Feb 11.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Objective: To assess the ability of functional MRI (fMRI) to predict postoperative language decline compared to direct cortical stimulation (DCS) in epilepsy surgery patients.

Methods: In this prospective case series, 17 patients with drug-resistant epilepsy had intracranial monitoring and resection from 2012 to 2016 with 1-year follow-up. All patients completed preoperative language fMRI, mapping with DCS of subdural electrodes, pre- and postoperative neuropsychological testing for language function, and resection. Changes in language function before and after surgery were assessed. fMRI activation and DCS electrodes in the resection were evaluated as potential predictors of language decline.

Results: Four of 17 patients (12 female; median [range] age, 43 [23-59] years) experienced postoperative language decline 1 year after surgery. Two of 4 patients had overlap of fMRI activation, language-positive electrodes in basal temporal regions (within 1 cm), and resection. Two had overlap between resection volume and fMRI activation, but not DCS. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to DCS (50% and 85%, respectively). When fMRI and DCS language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Seizure-onset age, resection side, type, volume, or 1 year seizure outcome did not predict language decline.

Significance: Language localization overlap of fMRI and direct cortical stimulation in the resection influences postoperative language performance. Our preliminary study suggests that fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone.
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http://dx.doi.org/10.1111/epi.14666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467056PMC
March 2019

fMRI prediction of naming change after adult temporal lobe epilepsy surgery: Activation matters.

Epilepsia 2019 03 11;60(3):527-538. Epub 2019 Feb 11.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.

Objective: We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability.

Method: Thirty-five adults (mean age 37.5 ± 10.9 years, 13 male) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative MRI tissue map comparison. This mask provided the following: (a) resection volume; (b) overlap between resection and preoperative activation; and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance.

Results: Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r = 0.28, P = 0.012). The percentage of top 10% fMRI activation resected (P = 0.017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality).

Significance: Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection.
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http://dx.doi.org/10.1111/epi.14656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401285PMC
March 2019

One-year pilot study on the effects of nitisinone on melanin in patients with OCA-1B.

JCI Insight 2019 Jan 24;4(2). Epub 2019 Jan 24.

National Eye Institute and.

Background: Oculocutaneous albinism (OCA) results in reduced melanin synthesis, skin hypopigmentation, increased risk of UV-induced malignancy, and developmental eye abnormalities affecting vision. No treatments exist. We have shown that oral nitisinone increases ocular and fur pigmentation in a mouse model of one form of albinism, OCA-1B, due to hypomorphic mutations in the Tyrosinase gene.

Methods: In this open-label pilot study, 5 adult patients with OCA-1B established baseline measurements of iris, skin, and hair pigmentation and were treated over 12 months with 2 mg/d oral nitisinone. Changes in pigmentation and visual function were evaluated at 3-month intervals.

Results: The mean change in iris transillumination, a marker of melanin, from baseline was 1.0 ± 1.54 points, representing no change. The method of iris transillumination grading showed a high intergrader reliability (intraclass correlation coefficient ≥ 0.88 at each visit). The number of letters read (visual acuity) improved significantly at month 12 for both eyes (right eye, OD, mean 4.2 [95% CI, 0.3, 8.1], P = 0.04) and left eye (OS, 5 [1.0, 9.1], P = 0.003). Skin pigmentation on the inner bicep increased (M index increase = 1.72 [0.03, 3.41], P = 0.047). Finally, hair pigmentation increased by both reflectometry (M index [17.3 {4.4, 30.2}, P = 0.01]) and biochemically.

Conclusion: Nitisinone did not result in an increase in iris melanin content but may increase hair and skin pigmentation in patients with OCA-1B. The iris transillumination grading scale used in this study proved robust, with potential for use in future clinical trials.

Trial Registration: ClinicalTrials.gov NCT01838655.

Funding: Intramural program of the National Eye Institute.
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http://dx.doi.org/10.1172/jci.insight.124387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413781PMC
January 2019

The Feasibility and Impact of the EMOVE Intervention on Self-efficacy and Outcome Expectations for Exercise in Epilepsy.

J Neurosci Nurs 2019 Apr;51(2):95-100

Questions or comments about this article may be directed to Irene H. Dustin, PhD CRNP, at She is a Senior Nurse Consultant, National Institutes of Health, Bethesda, MD. Barbara Resnick, PhD CRNP FAAN FAANP, is Professor, University of Maryland, Baltimore, Baltimore, MD. Elizabeth Galik, PhD CRNP FAAN FAANP, is Professor, University of Maryland, Baltimore, Baltimore, MD. N. Jennifer Klinedinst, PhD MPH MSN FAHA, is Assistant Professor, University of Maryland, Baltimore, Baltimore, MD. Kathleen Michael, PhD CRRN, is Associate Professor, University of Maryland, Baltimore, Baltimore, MD. Edythe Wiggs, PhD, is Clinical Neuropsychologist, National Institutes of Health, Bethesda, MD. William H. Theodore, MD, is Chief, Clinical Epilepsy Section, National Institutes of Health, Bethesda, MD.

The purpose of this pilot study was to evaluate the feasibility of the self-efficacy based Epilepsy-Motivate and Outcome Expectations for Vigorous Exercise (EMOVE) intervention and report on the preliminary efficacy of this intervention aimed at improving exercise behaviors in adults with epilepsy. Methods: A single-group, repeated-measures design was used in 30 outpatients. Data were collected at baseline and 12 weeks after the intervention. Participant outcomes included Self-Efficacy and Outcome Expectations for Exercise in Epilepsy, Beck Depression Inventory-II, Quality of Life in Epilepsy Inventory-31, seizure frequency, average daily steps, and body mass index. Daily number of steps was measured using a wrist-worn activity monitor. Feasibility data were assessed using evidence of treatment fidelity including intervention delivery, receipt, and enactment. Results: Participants were single (63%), white (53%), female (63%), had a mean (SD) age of 46.7 (13) years (range, 26-68 years), had low levels of self-efficacy (mean, 5.10; range, 0-10) and high outcome expectations (mean, 3.90; range, 0-5), took under the recommended 10 000 steps per day (mean, 5107), and had an average of 6 seizures per month. Postintervention testing showed statistical improvement in depressive symptoms (mean [SD], 9.95 [9.47]; P < .05). There were no significant differences found for the other study outcomes. Our study showed the EMOVE intervention was feasible. Study participants had improved depressive symptoms. Future research should focus on increasing the sample size, improving exercise performance through group or individualized exercise sessions, and adding a control group to better evaluate the relationship between the intervention and improved depressive symptoms.
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http://dx.doi.org/10.1097/JNN.0000000000000425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399022PMC
April 2019

In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics.

Genet Med 2018 01 22;20(1):14-23. Epub 2017 Jun 22.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.
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http://dx.doi.org/10.1038/gim.2017.68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763157PMC
January 2018

Disease progression in mutation carriers.

Neurology 2017 Jul 14;89(3):234-241. Epub 2017 Jun 14.

From the National Institute of Neurological Disorders and Stroke (M.K.F., J.F., L.E.B., M.T., E.A.W., T.W.) and National Institute of Aging (B.J.T.), NIH, Bethesda, MD.

Objective: To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in mutation carriers (C9+) with varied clinical phenotypes.

Methods: Thirty-four unrelated participants with mutations in were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS-familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria. Diagnostic cognitive and motor tests were repeated at 6 and 18 months. The ALSFRS-R, letter fluency, and FBI were administered at baseline and follow-up visits at 6, 12, and 18 months.

Results: The clinical diagnosis of most patients did not change over the follow-up. ALSFRS-R scores correlated with measures of motor function. Letter fluency correlated with FBI and cognitive tests. ALSFRS-R, letter fluency, and FBI differed among the C9+ diagnostic subgroups at enrollment and worsened over follow-up in symptomatic patients, with different slopes among the subgroups. Most patients survived to the 6-month time point after enrollment. Survival of C9+ patients with ALS and C9+ patients with ALS-FTD declined over the 12- and 18-month follow-up.

Conclusions: The pattern of scores of the ALSFRS-R, letter fluency, and FBI distinguished between ALS, ALS-FTD, and FTD presentations of mutation carriers and asymptomatic carriers. Longitudinal changes in these measures occurred with disease progression in a manner consistent with presenting phenotype.
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http://dx.doi.org/10.1212/WNL.0000000000004115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513817PMC
July 2017

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center.

Am J Med Genet A 2017 Jul 12;173(7):1796-1812. Epub 2017 May 12.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M = 64.3 ± 15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n = 15; M = 50.7 ± 12.9) compared to participants with normal EEG (n = 39; M = 64.7 ± 16.3; p = .004). Participants taking psychiatric medications manifested a lower FSIQ (n = 20; M = 54.8 ± 13.2) than those not taking them (n = 42; M = 65.0 ± 17.2; p = .022). These correlations were also present in the TMEM67-related JS sub-cohort (n = 14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p < .004 for all). The majority (65%) of individuals with JS have some degree of intellectual disability. Abnormal EEG is associated with lower neuropsychological function. Processing speed is a weakness, while verbal comprehension and receptive language are relative strengths. These findings may guide parents, teachers, therapists, and doctors to determine appropriate therapies, accommodations, and academic goals for individuals with JS.
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http://dx.doi.org/10.1002/ajmg.a.38272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682233PMC
July 2017

Reliability and Validity of the Self-Efficacy for Exercise in Epilepsy and the Outcome Expectations for Exercise in Epilepsy Scales.

J Nurs Meas 2017 04;25(1):22-40

Purpose: The purpose of this study was to test the psychometric properties of the revised Self-Efficacy for Exercise With Epilepsy (SEE-E) and Outcome Expectations for Exercise with Epilepsy (OEE-E) when used with people with epilepsy.

Methods: The SEE-E and OEE-E were given in face-to-face interviews to 26 persons with epilepsy in an epilepsy clinic.

Results: There was some evidence of validity based on Rasch analysis INFIT and OUTFIT statistics. There was some evidence of reliability for the SEE-E and OEE-E based on person and item separation reliability indexes.

Conclusions: These measures can be used to identify persons with epilepsy who have low self-efficacy and outcome expectations for exercise and guide design of interventions to strengthen these expectations and thereby improve exercise behavior.
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http://dx.doi.org/10.1891/1061-3749.25.1.22DOI Listing
April 2017

Poly(GP) proteins are a useful pharmacodynamic marker for -associated amyotrophic lateral sclerosis.

Sci Transl Med 2017 03;9(383)

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a GC repeat expansion in the gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. GC repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in -associated ALS (c9ALS). Therapeutics that target GC RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from GC RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target GC RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in GC RNA and downstream GC RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of GC RNA-based therapies in symptomatic repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.
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http://dx.doi.org/10.1126/scitranslmed.aai7866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576451PMC
March 2017

Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency.

JIMD Rep 2016 24;30:81-87. Epub 2016 Jun 24.

Clinical Epilepsy Section, Bethesda, MD, USA.

Aim: We tested the hypothesis that patients with succinic semialdehyde dehydrogenase (SSADH) deficiency on taurine would have decreased cortical excitability as measured by transcranial magnetic stimulation (TMS) and improved cognition, due to taurine's partial GABA(A and B) receptor agonist effects and rescue in the null mouse model from status epilepticus and premature lethality.

Method: Biomarkers including neuropsychological testing, TMS, and CSF metabolites were studied in a cohort of patients on and off three months' taurine treatment.

Results: Seven patients (5M/2F; age range 12-33 years) were enrolled in this open-label crossover study. Baseline average full-scale IQ (FSIQ) was 44.1 (range 34-55). Of six who returned at 6-month follow-up, five completed cognitive testing (3M/2F) on therapy; average FSIQ = 43.4 (range 33-51). CSF biomarkers (n = 4 subjects) revealed elevation in taurine levels but no change in free or total GABA. Baseline cortical excitability measured with TMS agreed with previous findings in this population, with a short cortical silent period and lack of long-interval intracortical inhibition. Patients on taurine showed a decrease in cortical silent period and short-interval intracortical inhibition compared to their off taurine study.

Interpretation: TMS demonstrated decreased inhibition in patients on taurine, in contrast to the study hypothesis, but consistent with its failure to produce clinical or cognitive improvement. TMS may be a useful biomarker for therapy in pediatric neurotransmitter disorders.
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http://dx.doi.org/10.1007/8904_2015_524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110443PMC
June 2016

Clinical course and prognosis in patients with Gaucher disease and parkinsonism.

Neurol Genet 2016 Apr 4;2(2):e57. Epub 2016 Mar 4.

Section on Molecular Neurogenetics (G.L., J.K., E.W., D.C., C.G., N.T., O.G.-A., E.S.), Medical Genetics Branch, NHGRI, NIH, Bethesda, MD; Yale School of Medicine (P.K.M.), New Haven, CT; Mater Misericordiae University Hospital (G.M.P.), Dublin, Ireland; Gaucher Clinic (A.Z.), Shaare Zedek Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel; and Lysosomal Disorders Research & Treatment Unit (O.G.-A.), O & O Alpan LLC, Fairfax, VA.

Objective: The goal of this study was to characterize the parkinsonian phenotype in patients with Gaucher disease (GD) who developed parkinsonism in order to evaluate clinical course and prognosis.

Methods: This is a retrospective observational study conducted at the Clinical Center of the NIH, Bethesda, MD, over a period of 10 years. The study included 19 patients with GD and parkinsonism. The severity of Gaucher and parkinsonian symptoms was determined from clinical data including physical, neurologic, pathologic, and neurocognitive evaluations, family histories, imaging studies, olfactory testing, and validated questionnaires.

Results: We found an earlier age at onset of parkinsonism and evidence of mild cognitive dysfunction in our cohort. Although the clinical course in some patients was similar to that of idiopathic Parkinson disease with a favorable levodopa response, others exhibited features characteristic of dementia with Lewy bodies. When we examined the patients as a group, we did not observe a uniformly aggressive form of parkinsonism after the initial onset of symptoms, contrary to other published reports.

Conclusions: Appreciable clinical variation was seen in this cohort with GD and parkinsonism. Although some patients had early onset and prominent cognitive changes, others had a later, slower course, indicating that GBA1 mutations may not be a reliable prognostic indicator in Parkinson disease in clinical settings.
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http://dx.doi.org/10.1212/NXG.0000000000000057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830189PMC
April 2016

Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects.

J Med Genet 2016 05 13;53(5):318-29. Epub 2016 Jan 13.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: Laminins are heterotrimeric complexes, consisting of α, β and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions.

Methods: Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells.

Results: In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery.

Conclusion: This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1 000 000.

Trial Registration Number: NCT00068224.
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http://dx.doi.org/10.1136/jmedgenet-2015-103416DOI Listing
May 2016

MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis.

Am J Med Genet A 2016 Mar 8;170(3):634-44. Epub 2015 Dec 8.

Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Background GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1, encoding β-galactosidase. The range of severity is from type I infantile disease, lethal in early childhood, to type III adult onset, resulting in gradually progressive neurological symptoms in adulthood. The intermediate group of patients has been recently classified as having type II late infantile subtype with onset of symptoms at one to three years of age or type II juvenile subtype with symptom onset at 2-10 years. To characterize disease severity and progression, six Late infantile and nine juvenile patients were evaluated using magnetic resonance imaging (MRI), and MR spectroscopy (MRS). Since difficulties with ambulation (gross motor function) and speech (expressive language) are often the first reported symptoms in type II GM1, patients were also scored in these domains. Deterioration of expressive language and ambulation was more rapid in the late infantile patients. Fourteen MRI scans in six Late infantile patients identified progressive atrophy in the cerebrum and cerebellum. Twenty-six MRI scans in nine juvenile patients revealed greater variability in extent and progression of atrophy. Quantitative MRS demonstrated a deficit of N-acetylaspartate in both the late infantile and juvenile patients with greater in the late infantile patients. This correlates with clinical measures of ambulation and expressive language. The two subtypes of type II GM1 gangliosidosis have different clinical trajectories. MRI scoring, quantitative MRS and brain volume correlate with clinical disease progression and may serve as important minimally-invasive outcome measures for clinical trials.
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http://dx.doi.org/10.1002/ajmg.a.37468DOI Listing
March 2016

Cohort study of neurocognitive functioning and adaptive behaviour in children and adolescents with Niemann-Pick Disease type C1.

Dev Med Child Neurol 2016 Mar 19;58(3):262-9. Epub 2015 Nov 19.

Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD, USA.

Aim: To describe the neurocognitive and adaptive behavior profile of children and adolescents with Niemann-Pick Disease type C1 (NPC1), a rare genetic disease that frequently presents in childhood, with variable onset and symptom complex involving neurodegeneration.

Method: Thirty-eight participants (20 males, 18 females; mean age 8y 10mo, SD 4y 8mo, range 1-18y) with NPC1 were evaluated through a natural history protocol.

Results: NPC1 severity was in the mild to moderate range for most participants. Cognitive scores (n=32) ranged from very low to above average; about half of the participants exhibited a clinically significant advantage of Verbal IQ over Non-verbal IQ. Adaptive behavior scores (n=21) were generally in the borderline to impaired range. Longitudinal cognitive data (n=19) suggested a pattern of decreasing scores over time. However, most participants remained at the same general level of functioning throughout the study.

Interpretation: This study begins to systematically describe the neurocognitive phenotype of children and adolescents with NPC1, identifying heterogeneity and decline, aiding in understanding the natural history of the disease to plan treatment studies.
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http://dx.doi.org/10.1111/dmcn.12970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760874PMC
March 2016

Executive Function and Adaptive Behavior in Muenke Syndrome.

J Pediatr 2015 Aug 28;167(2):428-34. Epub 2015 May 28.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.

Objective: To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls.

Study Design: Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]).

Results: Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite.

Conclusion: Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings.
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http://dx.doi.org/10.1016/j.jpeds.2015.04.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516644PMC
August 2015

Intrafamilial variability in GMPPB-associated dystroglycanopathy: Broadening of the phenotype.

Neurology 2015 Apr 13;84(14):1495-7. Epub 2015 Mar 13.

From the National Institutes of Health (D.X.B.-G., S.D., E.A.W., C.G.B.), Bethesda, MD; Children's National Medical Center (D.X.B.-G.), Washington, DC; CS Mott Children's Hospital (E.N.), University of Michigan, Ann Arbor; Columbia University Medical Center (J.D.), New York, NY; Prevention Genetics (T.L.W.), Marshfield, WI; University of Iowa (S.A.M.), Iowa City; and University of Texas Southwestern Medical Center Dallas (S.T.I.), Dallas, TX. Dr. Winder is currently with Invitae Corp., San Francisco, CA.

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http://dx.doi.org/10.1212/WNL.0000000000001440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395885PMC
April 2015

Taurine trial in succinic semialdehyde dehydrogenase deficiency and elevated CNS GABA.

Neurology 2014 Mar 12;82(11):940-4. Epub 2014 Feb 12.

From the Departments of Child Neurology (P.L.P., J.S., E.S.B., J.Y.) and Biostatistics/Epidemiology (R.M., J.H.), Children's National Medical Center, Washington, DC; Clinical Epilepsy Branch (J.S., W.H.T., E.W.), NINDS, NIH, Bethesda, MD; and Clinical Pharmacology (K.M.G.), Washington State University, Spokane.

Objectives: The objective of this open-label study was primarily to assess the effect of taurine on adaptive behavior and secondarily to collect safety and tolerability data in patients with succinic semialdehyde dehydrogenase deficiency.

Methods: In the current study, subjects were titrated weekly from a starting dose of 50 mg/kg/d to a target 200 mg/kg/d, and assessed for safety, tolerability, and adaptive functioning using age-normalized Adaptive Behavior Assessment Scales.

Results: Eighteen patients (8 males/10 females, aged 0.5-28 years, mean 12 years) were recruited. Three subjects withdrew because of perceived lack of efficacy. One serious adverse event occurred (hospitalization for hypersomnia) on 16 g/d (200 mg/kg/d), leading to a dose-lowering paradigm with a maximum dose of 10 g/d. Results did not show clinically meaningful improvement in the adaptive domains after taurine therapy. Pre- and posttherapy adaptive scores also demonstrated no statistically significant difference (p > 0.18).

Conclusions: Adaptive behavior did not improve significantly with taurine intervention. Further therapeutic clinical trials including an on-off paradigm using biomarkers are planned.

Classification Of Evidence: This study provides Class IV evidence that for patients with succinic semialdehyde dehydrogenase deficiency, taurine does not significantly improve adaptive behavior. The study is rated Class IV because of the absence of a control group.
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http://dx.doi.org/10.1212/WNL.0000000000000210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3963004PMC
March 2014

Cognitive, sensory, and psychosocial characteristics in patients with Bardet-Biedl syndrome.

Am J Med Genet A 2013 Dec 5;161A(12):2964-71. Epub 2013 Nov 5.

Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Forty-two patients with a clinical diagnosis of Bardet-Biedl syndrome ages 2-61 years were given a neuropsychological test battery to evaluate cognitive, sensory, and behavioral functioning. These tests included the Wechsler scales of intelligence, Rey Auditory Verbal Learning Test, Boston Naming Test, D-KEFS Verbal Fluency Test, D-KEFS Color-Word Interference Test, D-KEFS Sorting Test, Wide Range Achievement Test: Math and Reading Subtests, Purdue Pegboard, The University of Pennsylvania Smell Identification Test, Social Communication Questionnaire, Social Responsiveness Scale, and Behavior Assessment System for Children, Second Edition, Parent Rating Scale. On the age appropriate Wechsler scale, the mean Verbal Comprehension was 81 (n = 36), Working Memory was 81 (n = 36), Perceptual Reasoning was 78 (n = 24) and Full Scale IQ was 75 (n = 26). Memory for a word list (Rey Auditory Verbal Learning Test) was in the average range with a mean of 89 (n = 19). Fine motor speed was slow on the Purdue with mean scores 3-4 standard deviations below norms. All subjects were microsmic on the University of Pennsylvania Smell Identification Test. Of these 42 patients, only 6 were able to complete all auditory and visual tests; 52% were unable to complete the visual tests due to impaired vision. A wide range of behavioral issues were endorsed on questionnaires given to parents. Most had social skill deficits but no pattern of either externalizing or internalizing problems. We identify a characteristic neuro-behavioral profile in our cohort comprised of reduced IQ, impaired fine-motor function, and decreased olfaction.
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http://dx.doi.org/10.1002/ajmg.a.36245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419571PMC
December 2013

Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis.

Dement Geriatr Cogn Dis Extra 2013 16;3(1):233-50. Epub 2013 Aug 16.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md., USA.

Introduction: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes.

Methods: The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model.

Results: More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores.

Conclusion: The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.
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http://dx.doi.org/10.1159/000353456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776403PMC
September 2013

Response inhibition in motor conversion disorder.

Mov Disord 2013 May 2;28(5):612-8. Epub 2013 Apr 2.

Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.

Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P < .001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.25435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096145PMC
May 2013

Auditory analysis of xeroderma pigmentosum 1971-2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration.

Brain 2013 Jan;136(Pt 1):194-208

Dermatology Branch, National Cancer Institute, Bethesda, MD 20892, USA.

To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum-type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average ≥10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system.
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http://dx.doi.org/10.1093/brain/aws317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562077PMC
January 2013

The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow.

Brain 2012 Aug;135(Pt 8):2440-8

Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI Intramural Research Program, National Institutes of Health,Bethesda, MD 20892, USA.

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, H(2)(15)O positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA-associated parkinsonism.
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http://dx.doi.org/10.1093/brain/aws174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407426PMC
August 2012

Neurocognitive phenotype of isolated methylmalonic acidemia.

Pediatrics 2012 Jun 21;129(6):e1541-51. Epub 2012 May 21.

National Institute of Mental Health, National Institutes of Health, Building 49 Room 4A18 Bethesda, MD 20892-4472, USA.

Objective: Methylmalonic acidemia (MMA) is a metabolic disorder with a poorly defined long-term neurocognitive phenotype. We studied the neuropsychological outcomes of patients and examined clinical covariates that influenced cognition.

Methods: A diverse cohort with mut, cblA, or cblB subtypes of isolated MMA (N = 43), ages 2 to 32 years, were evaluated at a single center over a 6-year period. The influence of clinical, laboratory, and metabolic parameters on neuropsychological testing results was determined.

Results: Early-onset mut patients (n = 21) manifested the most severe neurocognitive impairments, with a mean ± SD full-scale IQ (FSIQ) of 71.1 ± 14.75. Late-onset mut patients (n = 6) had a mean FSIQ of 88.5 ± 27.62. cblA (n = 7), cblB (n = 6), and mut patients diagnosed prenatally or by newborn screening (n = 3) obtained mean FSIQs in the average range (100.7 ± 10.95, 96.6 ± 10.92, and 106.7 ± 6.66, respectively). Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ (P = .001 and P = .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not. FSIQ remained stable over longitudinal testing (n = 10). Decreased scores on processing speed, compared with all other intellectual domains, emerged as a specific neurocognitive manifestation.

Conclusions: The neurocognitive outcomes seen in isolated MMA are highly variable. An earlier age of disease onset, the presence of hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairment. In all patient subtypes, selective deficits in processing speed were present.
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http://dx.doi.org/10.1542/peds.2011-1715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362903PMC
June 2012

Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes.

Arthritis Rheum 2012 Jul;64(7):2375-86

Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.

Objective: Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID.

Methods: We conducted a cohort study of 26 NOMID patients ages 0.80-42.17 years who were followed up at the NIH and treated with anakinra 1-5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated.

Results: Sustained improvements in diary scores, parent's/patient's and physician's global scores of disease activity, parent's/patient's pain scores, and inflammatory markers were observed (all P<0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P=0.0026 and P=0.0076, respectively), albumin levels, and opening pressures (P=0.0012 and P<0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication.

Conclusion: These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.
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http://dx.doi.org/10.1002/art.34409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474541PMC
July 2012

Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy.

Epilepsia 2012 Jan 2;53(1):129-33. Epub 2011 Nov 2.

Clinical Epilepsy Section, NINDS NIH, Bethesda, Maryland 20892, USA.

Purpose: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study.

Methods: We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video-electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1).

Key Findings: Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory.

Significance: Our study suggests that reduced left hippocampal 5HT1A-receptor binding may play a role in memory impairment in patients with TLE.
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http://dx.doi.org/10.1111/j.1528-1167.2011.03309.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253243PMC
January 2012

The saccadic and neurological deficits in type 3 Gaucher disease.

PLoS One 2011 20;6(7):e22410. Epub 2011 Jul 20.

Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

Unlabelled: Our objective was to characterize the saccadic eye movements in patients with type 3 Gaucher disease (chronic neuronopathic) in relationship to neurological and neurophysiological abnormalities. For approximately 4 years, we prospectively followed a cohort of 15 patients with Gaucher type 3, ages 8-28 years, by measuring saccadic eye movements using the scleral search coil method. We found that patients with type 3 Gaucher disease had a significantly higher regression slope of duration vs amplitude and peak duration vs amplitude compared to healthy controls for both horizontal and vertical saccades. Saccadic latency was significantly increased for horizontal saccades only. Downward saccades were more affected than upward saccades. Saccade abnormalities increased over time in some patients reflecting the slowly progressive nature of the disease. Phase plane plots showed individually characteristic patterns of abnormal saccade trajectories. Oculo-manual dexterity scores on the Purdue Pegboard test were low in virtually all patients, even in those with normal cognitive function. Vertical saccade peak duration vs amplitude slope significantly correlated with IQ and with the performance on the Purdue Pegboard but not with the brainstem and somatosensory evoked potentials. We conclude that, in patients with Gaucher disease type 3, saccadic eye movements and oculo-manual dexterity are representative neurological functions for longitudinal studies and can probably be used as endpoints for therapeutic clinical trials.

Trial Registration: ClinicalTrials.gov NCT00001289.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022410PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140522PMC
December 2011