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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. [ABSTRACT FROM AUTHOR]

Background: Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.Methods: We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.Results: All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.Conclusions: Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Working memory (WM) impairment is one of the most frequent cognitive deficits in Parkinson's disease (PD). However, it is not known how neural activity is altered and compensatory responses eventually fail during progression. We aimed to elucidate neural correlates of WM and compensatory mechanisms in PD. Eighteen cognitively normal PD patients (PD-CogNL), 16 with PD with mild cognitive impairment (PD-MCI), 11 with PD with dementia (PDD), and 17 healthy controls (HCs) were evaluated. Subjects performed an n-back task. Functional MRI data were analyzed by event-related analysis for correct responses. Brain activations were evaluated by comparing them to fixation cross or 0-back task, and correlated with n-back task performance. When compared to fixation cross, PD-CogNL patients had more activation in WM areas than HCs for both the 2- and 3-back tasks. PD-MCI and PDD patients had more activation in WM areas than HCs for the 0- and 1-back task. 2-back task performance was correlated with brain activations (vs. 0-back task) in the bilateral dorsolateral prefrontal cortex and frontal eye field (FEF) and left rostral prefrontal cortex, caudate nucleus, inferior/superior parietal lobule (IPL/SPL), and anterior insular cortex as well as anterior cingulate cortex. 3-back task performance was correlated with brain activations (vs. 0-back task) in the left FEF, right caudate nucleus, and bilateral IPL/SPL. Additional activations on top of the 0-back task, rather than fixation cross, are the neural correlates of WM. Our results suggest PD patients have two types of compensatory mechanisms: (1) Hyperactivation for different WM load tasks depending on their cognitive status. PD-CogNL have hyperactivation for moderate and heavy working memory load tasks while maintaining normal working memory performance. In contrast, PD-MCI and PDD have hyperactivation for control task and light working memory load task, leaving less neural resources to further activate for more demanding tasks and resulting in impaired working memory performance. (2) Bilateral recruitment of WM-related areas, in particular the DLPFC, FEF, IPL/SPL and caudate nucleus, to improve WM performance., (Copyright © 2022. Published by Elsevier Inc.)

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 ( P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667.

Background: Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder with defective DNA nucleotide excision repair and associated with a high frequency of skin cancer. Approximately 25% of patients develop progressive neurological degeneration. Complementation groups XP-A and XP-D are most frequently associated with neurological disorders., Design/methods: This is a retrospective review of patients with XP who were evaluated at NIH from 1986 to 2015 and had nerve conduction studies (NCS). In the complementation groups with peripheral neuropathy, further comparisons of the NCS were made with audiological, brain imaging, neuropsychological assessments that were also performed on most of the patients. Limited neuropathology of XP-A and XP-D patients were examined.., Results: The 33 patients had NCS: XP-A (9 patients), XP-C (7 patients), XP-D (10 patients), XP-E (1 patient), XP-V (4 patients), and XP-unknown (2 patients). Peripheral neuropathy based on nerve conduction studies was documented only in two complementation groups: 78% (7/9) of XP-A patients had a sensorimotor neuropathy while 50% (5/10) of XP-D patients had a sensory neuropathy only. Analysis of sural sensory nerve amplitude in both complementation groups XP-A and XP-D correlated with sensorineural hearing loss (SNHL), MRI/CT severity, and Full-scale Intelligence Quotient (IQ). Analysis of fibular motor nerve amplitude in complementation XP-A correlated with SNHL and MRI/CT severity. Limited follow-up studies showed gradual loss of NCS responses compared to an earlier and more rapid progression of the hearing loss., Conclusions: Despite similar brain imaging and audiological findings patients, XP-A and XP-D complementation groups differ in the type of neuropathy, sensorimotor versus sensory alone. A few cases suggest that sensorineural hearing loss may precede abnormal NCS in XP and therefore serve as valuable clinical indicators of XP patients that will later develop peripheral neuropathy., (© 2021. The Author(s).)

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.

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., (© 2019 International Parkinson and Movement Disorder Society.)

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., (© 2019 American Academy of Neurology.)

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.

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., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

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 2  = 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., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

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., Clinicaltrials: gov NCT01838655., Funding: Intramural program of the National Eye Institute.

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.

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., (© 2017 Wiley Periodicals, Inc.)

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.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G 4 C 2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G 4 C 2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72 -associated ALS (c9ALS). Therapeutics that target G 4 C 2 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 G 4 C 2 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 C9ORF72 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 G 4 C 2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G 4 C 2 RNA and downstream G 4 C 2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G 4 C 2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention., (Copyright © 2017, American Association for the Advancement of Science.)

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.

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., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

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., (© 2015 Wiley Periodicals, Inc.)

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.

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.

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., (Copyright © 2013 Movement Disorder Society.)

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.

Objective: The goal of the work described here was to evaluate relationships among resection volume, seizure outcome, and cognitive morbidity after temporal lobectomy for intractable epilepsy., Methods: Thirty patients with mesial temporal sclerosis were evaluated pre- and postoperatively with the Wechsler Adult Intelligence Scale III, Wechsler Memory Scale III, and three-dimensional coronal spoiled gradient recall acquisition MRI. Preoperative whole-brain volumes were calculated with Statistical Parametric Mapping. Resection volume was calculated by manual tracing. Systat was used for statistical analysis., Results: All resections included the temporal tip, at least 1cm of the superior temporal gyrus, and 3 to 5cm of the middle and inferior temporal gyri. Left were significantly smaller than right temporal resections. Seizure-free patients had significantly larger resections. Immediate verbal memory was significantly worse after left temporal lobectomy. Surgical outcome and resection volume did not affect postoperative neuropsychological results., Conclusions: Dominant temporal lobe resections are associated with immediate verbal memory deficits. Larger resection volume was associated with improved seizure control but not worse cognitive outcome.

Two unrelated xeroderma pigmentosum (XP) patients, with and without neurological abnormalities, respectively, had identical defects in the XPC DNA nucleotide excision repair (NER) gene. Patient XP21BE, a 27-year-old woman, had developmental delay and early onset of sensorineural hearing loss. In contrast, patient XP329BE, a 13-year-old boy, had a normal neurological examination. Both patients had marked lentiginous hyperpigmentation and multiple skin cancers at an early age. Their cultured fibroblasts showed similar hypersensitivity to killing by UV and reduced repair of DNA photoproducts. Cells from both patients had a homozygous c.2T>G mutation in the XPC gene which changed the ATG initiation codon to arginine (AGG). Both had low levels of XPC message and no detectable XPC protein on Western blotting. There was no functional XPC activity in both as revealed by the failure of localization of XPC and other NER proteins at the sites of UV-induced DNA damage in a sensitive in vivo immunofluorescence assay. XPC cDNA containing the initiation codon mutation was functionally inactive in a post-UV host cell reactivation (HCR) assay. Microsatellite markers flanking the XPC gene showed only a small region of identity ( approximately 30kBP), indicating that the patients were not closely related. Thus, the initiation codon mutation resulted in DNA repair deficiency in cells from both patients and greatly increased cancer susceptibility. The neurological abnormalities in patient XP21BE may be related to close consanguinity and simultaneous inheritance of other recessive genes or other gene modifying effects rather than the influence of XPC gene itself.

Purpose: Hypothalamic hamartomas (HHs) have been associated with uncontrolled seizures, and aggressive therapy including surgery is often recommended. However, some patients, particularly those with other findings associated with Pallister-Hall syndrome (PHS), have a more benign course., Methods: Thirty-seven of 40 PHS patients and 16 of 16 patients with isolated HH had a lesion confirmed on magnetic resonance imaging (MRI). Records for all patients were reviewed for the following information: presence of seizures, age at seizure onset, seizure type, seizure frequency, number of antiepileptic medications (AEDs) at the time of evaluation, past AEDs, MRI characteristics of the HH, presence of endocrine dysfunction, and presence of developmental and behavioral problems., Results: All isolated HH patients had a history of seizures, compared with 13 of 40 PHS patients (all PHS patients with seizures had hamartomas). In isolated HH, seizures started earlier in life, occurred more frequently, and were harder to control than those in patients with PHS. Isolated HH patients were more likely to have behavioral and developmental problems than were PHS patients. The T2 signal of the hamartoma was isointense to gray matter in the majority of PHS patients, but showed a significant increase in all but one patient with isolated HH., Conclusions: Patients with isolated HH have a distinct clinical phenotype, showing more severe seizures and neurologic dysfunction, HH showing increased T2 signal, and are more likely to have precocious puberty. In contrast, PHS patients usually have well-controlled seizures and other endocrine disturbances than precocious puberty. Patients with HH with or without seizures should be evaluated carefully for other clinical manifestations of PHS, particularly before surgery is considered.

Objective: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease., Study Design: Patients with type 3 Gaucher's disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years., Results: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients had asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration., Conclusions: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher's disease. Most treated patients do not deteriorate neurologically. Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease.

The authors compared stretch-evoked somatosensory evoked potentials (SEP) of 18 type 3 Gaucher disease (GD3) patients (two with progressive myoclonus epilepsy [PME]) with 22 age-matched normal controls and six patients with type 1 (nonneuronopathic) Gaucher disease (GD1). The mean P1-N2 SEP amplitude in GD3 patients was significantly larger than the SEP in controls and in GD1 patients, and there was a significant negative correlation between SEP amplitude and the IQ of GD3 patients. The authors conclude that abnormal cortical inhibition is a unifying feature of GD3 patients and correlates with the degree of cognitive deficit.

Objective: An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DMS-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI)., Method: From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine., Results: Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, chi 2 = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed., Conclusions: These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine.

Objective: To examine the validity of diagnostic criteria for a subgroup of children with atypical psychosis (n = 19), designated here as "multidimensionally impaired." These children are characterized by poor attention and impulse control, psychotic symptoms, and poor affective control., Method: Children and adolescents (n = 19) meeting our criteria for multidimensionally impaired syndrome with onset of psychotic symptoms at or before age 12 years were identified from a total of 150 in-person screenings for very early-onset schizophrenia between 1990 and 1996. We compared the premorbid adjustment, family history, follow-up status, and laboratory measures for a subgroup of these children with those of (1) a rigorously defined group of 29 children with DSM-III-R schizophrenia and (2) 19 children with attention-deficit hyperactivity disorder., Results: Patients with multidimensionally impaired syndrome and patients with very early-onset schizophrenia shared a similar pattern of early transient autistic features, postpsychotic cognitive decline, and an elevated risk of schizophrenic-spectrum disorders among their first-degree relatives. This pattern was not seen in the attention-deficit hyperactivity disorder group. In contrast to very early-onset schizophrenia, the multidimensionally impaired group had significantly poorer scores on the Freedom From Distractibility factor on the WISC-R, a less deviant pattern of autonomic reactivity, and no progression to schizophrenia., Conclusions: The findings support the distinction of the multidimensionally impaired cases as separate from those with other psychiatric disorders, and there is somewhat greater evidence to suggest that this disorder belongs in the schizophrenia spectrum.

Objective: To determine the genetic and clinical features of resistance to thyroid hormone in a study from a single institution., Design: Prospective, controlled study., Setting: National Institutes of Health., Patients: 104 patients with resistance to thyroid hormone from 42 kindreds and 114 unaffected relatives sharing the patients' environmental and genetic backgrounds., Measurements: Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor beta (TR beta) gene (exons 9 and 10). Assessment of tissue-specific compensation for resistance., Results: Inheritance was autosomal dominant in 22 families, sporadic in 14 families, and unknown in 6 families. We found mutations in 25 kindreds (64 patients); 16 mutations were in exon 9 and 9 were in exon 10 of the TR beta gene. In persons with resistance to thyroid hormone, we measured the increased incidence of goiter (65%), attention-deficit hyperactivity disorder (60%), IQ less than 85 (38%), speech impediment (35%), and short stature (18%). We also described new clinical features, such as frequent ear, nose, and throat infections (56%); low weight-for-height in children (32%); hearing loss (21%); and cardiac abnormalities (18%). Genotype, age, whether the mother had resistance to thyroid hormone, and sex influenced the phenotype. Tissue resistance varied from kindred to kindred and involved, in decreasing order, the pituitary gland, the brain, the bone, the liver, and the heart., Conclusions: This study underscores the incidence of classic features of resistance to thyroid hormone, describes new clinical characteristics of this condition for the first time, and stresses the heterogeneity of the phenotype.

Background: Most flaps used in periocular reconstruction are random pattern flaps., Objective: To discuss the principles of periocular flaps as they relate to oculoplastic surgery, with an emphasis on reconstruction of the eyelids and ocular adnexa., Methods: The advantages, disadvantages, and techniques of reconstruction are reviewed., Conclusion: The ability to conceptualize and utilize flaps in periocular surgery enormously extends the surgeon's capabilities to produce optimal results for the patient.