0000000000174685
AUTHOR
Sven Klimpe
Decreased dopamine D2/D3-receptor binding in temporal lobe epilepsy: an [18F]fallypride PET study.
Summary: Purpose: Although animal data are suggestive, evidence for an alteration of the extrastriatal dopaminergic system in human focal epilepsy is missing. Methods: To quantify D2/D3-receptor density, we studied seven patients with temporal lobe epilepsy (TLE) and nine agematched controls with positron emission tomography (PET) by using the high-affinity dopamine D2/D3-receptor ligand [ 18 F]Fallypride ([ 18 F]FP) suitable for imaging extrastriatal binding. TLE was defined by interictal and ictal video-EEG, magnetic resonance imaging (MRI), and [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)-PET and was due to hippocampal sclerosis (HS), based on histology in all patients. Primary analysis was ba…
A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42).
The most frequent causes of autosomal dominant (AD) hereditary spastic paraplegias (HSP) (ADHSP) are mutations in the SPAST gene (SPG4 locus). However, roughly 60% of patients are negative for SPAST mutations, despite their family history being compatible with AD inheritance. A mutation in the gene for an acetyl-CoA transporter (SLC33A1) has recently been reported in one Chinese family to cause ADHSP-type SPG42. In this study, we screened 220 independent SPAST mutation-negative ADHSP samples for mutations in the SLC33A1 gene by high-resolution melting curve analysis. Conspicuous samples were validated by direct sequencing. Moreover, copy number variations affecting SLC33A1 were screened by …
Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia
Background: Hereditary spastic paraplegias (HSP) are clinically and genetically highly heterogeneous. Recently, two novel genes, SPG11 ( spatacsin ) and SPG15 ( spastizin ), associated with autosomal recessive HSP, were identified. Clinically, both are characterised by complicated HSP and a rather similar phenotype consisting of early onset spastic paraplegia, cognitive deficits, thin corpus callosum (TCC), peripheral neuropathy and mild cerebellar ataxia. Objective: To compare the frequency of SPG11 and SPG15 in patients with early onset complicated HSP and to further characterise the phenotype of SPG11 and SPG15. Results: A sample of 36 index patients with early onset complicated HSP and …
SPG10 is a rare cause of spastic paraplegia in European families.
Contains fulltext : 71099.pdf (Publisher’s version ) (Closed access) BACKGROUND: SPG10 is an autosomal dominant form of hereditary spastic paraplegia (HSP), which is caused by mutations in the neural kinesin heavy chain KIF5A gene, the neuronal motor of fast anterograde axonal transport. Only four mutations have been identified to date. OBJECTIVE: To determine the frequency of SPG10 in European families with HSP and to specify the SPG10 phenotype. PATIENTS AND METHODS: 80 index patients from families with autosomal dominant HSP were investigated for SPG10 mutations by direct sequencing of the KIF5A motor domain. Additionally, the whole gene was sequenced in 20 of these families. RESULTS: Th…
Antiepileptic drug use in nursing home residents: a cross-sectional, regional study.
Summary The use of antiepileptic drugs (AED), their primary indication, comorbid conditions, and concomitant medications were collected from 565 nursing homes (NH) residents of six NH located around the city of Mainz, Germany representing 5.05% of all NH residents in the area. Data were collected from the electronic pharmacy files and by reviewing all available medical records. Average age was 82.2±2.4 years, 85.5% were women. Of 565 NH residents 28 (4.96%) received AED therapy, of which in 17 (63%) AED were prescribed for a seizure-related diagnosis. In 76.5% seizure types were unspecified and a distinction in focal and generalized epilepsy was made in only 23.5% of patients. Three patient…
Analysis of 100 HSP Exomes and Characterization of Mutations in Known Autosomal Dominant Genes (P05.166)
Objective: Comprehensive screening of all known autosomal dominant HSP genes in a large cohort of patients. Background Hereditary spastic paraplegias comprise a group of clinically and genetically heterogeneous neurodegenerative disorders that share the common clinical feature of lower limb spastic paraplegia. Ten genes causing autosomal dominant HSP are known to date, together explaining about 60% of cases. Knowledge about frequency of HSP subtypes and genotype-phenotype correlation is limited by the fact that most screenings so far are biased due to phenotypic pre-selection of the study cohort or inhomogeneous a priori genetic diagnostic testing. Design/Methods: We have screened a large c…
REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.
Contains fulltext : 71291.pdf (Publisher’s version ) (Closed access) Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploins…
Evaluating the effect of spastin splice mutations by quantitative allele-specific expression assay
Background: Mutations in the SPG4/SPAST gene are the most common cause for hereditary spastic paraplegia (HSP). The splice-site mutations make a significant contribution to HSP and account for 17.4% of all types of mutations and 30.8% of point mutations in the SPAST gene. However, only few studies with limited molecular approach were conducted to investigate and decipher the role of SPAST splice-site mutations in HSP. Methods: A reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and quantitative allele-specific expression assay were performed. Results: We have characterized the consequence of two novel splice-site mutations (c.1493 + 1G>A and c.1414−1G>A) in the SPAST gene…
Disease severity affects quality of life of hereditary spastic paraplegia patients
Background and purpose: Hereditary spastic paraplegia (HSP) causes progressive gait disturbance because of degeneration of the corticospinal tract. To assess its impact on Health-Related Quality of Life (HRQoL), we analyzed the correlation of HRQoL with disease severity and clinical symptoms in HSP. Methods: HRQoL was assessed by the Short-Form 36 (SF-36) Mental and Physical Component summary scores (MCS and PCS) in 143 German patients with HSP. Disease severity was assessed by the Spastic Paraplegia Rating Scale (SPRS) and landmarks of walking ability. Patients with ! pure" or ! complicated" HSP were compared. Results: Higher SPRS scores indicating higher disease severity correlated signif…
Does the Recruitment of Excitation and Inhibition in the Motor Cortex Differ?
The level of excitability within the motor cortex can be described as a balance between excitation and inhibition, but it is unknown how well both processes correlate. To address this question, the authors measured motor cortical excitability and inhibition in healthy human subjects, comparing the recruitment of motor evoked potentials (MEPs) and the duration of the cortical silent period (CSP) after transcranial magnetic stimulation (TMS). Single-pulse "focal" TMS was applied at intensities varying between 90% and 200% of motor thresholds to the right motor cortex of 15 healthy volunteers. The peak-to peak size of MEP responses and the duration of the CSP were measured in small hand muscle…
AP5Z1/SPG4 8 frequency in autosomal recessive and sporadic spastic paraplegia
Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. …
Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder defined clinically by progressive lower limb spasticity and weakness. HSP is a genetically highly heterogeneous condition with at least 46 gene loci identified so far, involving X-linked, autosomal recessive (AR) and autosomal dominant inheritance. For correct diagnosis, molecular testing is essential because clinical parameters by themselves are not reliable to differentiate HSP forms. The purpose of this study was to establish amplicon-based high-throughput genotyping for AR-HSP. A sample of 187 index cases with apparently sporadic or recessive spastic paraplegia were analyzed by applying an array-based amplification stra…
Sex differences in early carotid atherosclerosis (from the community-based Gutenberg-Heart Study).
The objectives of this study were to describe gender differences in intima-media thickness (IMT) in a community-based population study and to define normal IMT values for healthy men and women. In total, 4,814 participants (aged 35 to 74 years; 2,433 men, 2,381 women) from the Gutenberg-Heart Study (GHS) were included. IMT was measured at both common carotid arteries using an edge detection system. Median IMT was 0.62 mm (25th percentile 0.55, 75th percentile 0.70) in women and 0.65 mm (25th percentile 0.57, 75th percentile 0.75) in men and was significantly associated with age (p0.0001). On multivariate analysis, advanced age, smoking, and arterial hypertension were positively associated w…
Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots.
Item does not contain fulltext Mutations in NIPA1 cause hereditary spastic paraplegia type 6 (SPG6 HSP). Sequencing of the whole gene has revealed alterations of either of two nucleotides in eight of nine SPG6 HSP families reported to date. By analysing CpG methylation, we provide a mechanistic explanation for a mutational hotspot to underlie frequent alteration of one of these nucleotides. We also developed PCR RFLP assays to detect recurrent NIPA1 changes and screened 101 independent HSP patients, including 45 index patients of autosomal dominant HSP families. Our negative finding in this cohort for which several other causes of HSP had been excluded suggests NIPA1 alterations at mutation…
The safety and efficacy of add-on levetiracetam in elderly patients with focal epilepsy: A one-year observational study
Abstract Purpose The long-term safety and efficacy of levetiracetam (LEV) was evaluated as add-on therapy in focal epilepsy patients ( n =491) aged at least 65 years who failed at least one monotherapy. Methods Patients ( n =491) with focal epilepsy treated with at least one antiepileptic drug in monotherapy with insufficient seizure control were included in this prospective open-label study. The recommended LEV dose range was 1000–3000mgperday. Follow-up visits were done approximately after 3, 6 and 12 months. Safety and efficacy was analysed based on all patients who received LEV (safety population, n =491) and all patients who were seen at all visits and completed the trial (per protocol…