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Eslicarbazepine acetate (ESL), a novel sodium channel blocker, is approved for mono and adjunctive treatment of partial epileptic seizures with or without secondary generalization. Its efficacy in primary generalized seizures has not yet been evaluated.To evaluate the efficacy and safety of ESL in primary generalized tonic-clonic seizures (PGTCS) in an observational study.The data were collected from a prospective population-based register. Effectiveness was measured as relative reduction in standardized seizure frequency (SSF), responder rate (≥ 50% reduction in SSF), and seizure freedom rate at 6 and 12 months after initiation of ESL. Safety and tolerability were evaluated using patients' diaries.Fifty-six adult patients with PGTCS were treated with ESL as adjunctive therapy. Of these, 30.4% (n = 17) had myoclonic seizures in addition to PGTCS. The retention rate after 12 months was 80.4% (n = 45). After initiating ESL therapy, reduction in SSF for PGTCS on ESL was 56.0% after 6 months and 56.9% after 12 months (p lt; 0.01), whereas myoclonic seizures did not show any significant improvement in frequency. The responder rate for PGTCS was 64.3% after 6 months and 66.1% after 12 months, and seizure freedom was achieved in 32.1% and 35.7%, respectively. Forty-three patients (73.2%) reported no side effects. Among the reported side effects of ESL therapy, headache (7.1%), dizziness (8.9%), tiredness (7.1%), nausea (5.4%), and hyponatremia (5.4%) were the most prevalent.Our data suggest that ESL may provide additional benefits in the treatment of patients with PGTCS and motivate randomized controlled trials in this indication.

Specific antiseizure medications (ASM) would improve the outcome in post-stroke epilepsy (PSE). The aim of this multicenter observational study was to compare different antiseizure monotherapies in PSE.We collected the data from 207 patients with PSE who did not change their initial antiseizure monotherapy during the period of 12 months. Efficacy was assessed by a standardized three month seizure frequency and seizure freedom. Safety was estimated by the reported side effects.The mean three month seizure frequency was 1.9 ± 3.1 on eslicarbazepine, 2.1 ± 3.2 on lacosamide, 3.4 ± 4.4 on levetiracetam, 4.3 ± 6.8 on lamotrigine, and 5.1 ± 7.3 on valproate (p 0.05 for eslicarbazepine or lacosamide in comparison with levetiracetam, lamotrigine and valproate, respectively). The lowest seizure frequency and the highest seizure freedom was observed on ASMs acting via the slow inactivation of sodium channels in comparison to other mechanisms of action (0.7 ± 0.9 vs 2.2 ± 2.4, p 0.01). Among side effects, the most frequently reported were vertigo (25%) and tiredness (15.9%). They were similar in all investigated groups of ASM. The independent factors increasing seizure frequency that were identified in multiple regression analyses were increased size of infarction, cortical involvement, hemorrhagic transformation, neurological deficits at admission and functional impairment. Administration of ASM with the mechanism of action via the slow inactivation of sodium channels was an independent factor decreasing the seizure frequency.Our data show that antiseizure medications acting via the slow inactivation of sodium channels, such as lacosamide and eslicarbazepine, are well tolerated and might be associated with better seizure control in PSE.

ObjectiveHereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort. MethodsWe recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. ResultsFamily history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent. InterpretationThis cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis. Ann Neurol 2016;79:646-658

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. With the output of high-quality reads and a mean coverage of 51-fold, we demonstrated a robust detection of variants. One 43-year-old female with sporadic complicated paraplegia showed two heterozygous nonsynonymous variants of unknown significance (VUS3; p.[R292W];[(T756I)]). Thus, AP5Z1 gene mutations are rare, at least in Europeans. Due to its low frequency, systematic genetic testing for AP5Z1 mutations is not recommended until larger studies are performed to add further evidence. Our findings demonstrate that amplicon-based deep sequencing is technically feasible and allows a compact molecular characterization of multiple HSP patients with high accuracy.

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 strategy. Amplicon libraries of the CYP7B1-(SPG5) and SPG7-gene were generated followed by a pooled next-generation sequencing (NGS) approach. We identified three SPG5 and seven SPG7 patients. All had one homozygous or two heterozygous mutations. In total, 20 distinct mutations (CYP7B1,n = 4and SPG7,n = 16) including two novel CYP7B1 mutations (p.G51R and p.E211KfsX3) and eight novel SPG7 mutations (p.Leu8delinsLeuLeu, p.W29X, p.R139X, p.R247X, p.G344D, p.Leu346_Leu347ins11, p.R398X and p.R398Q) were detected by this comprehensive genetic testing. Our study illustrates how amplicon-based NGS can be used as an efficient tool to study genotypes and mutations in large patient cohorts and complex phenotypes.

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 significantly with lower PCS (r = )0.63; P < 0.0005) and MCS (r = )0.38; P < 0.0005) scores. MCS and PCS were reduced in patients with ! complicated" forms compared to ! pure" HSP and with decreasing walking ability. Conclusion: HRQoL is substantially impaired in patients with HSP and decreases with disease severity and the presence of ! complicating" symptoms. Patients are most a! ected by the physical restraints of their disease, but mental health is impaired as well. HRQoL is a valid parameter in HSP that should be considered in upcoming therapeutical trials.

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 in two different families with pure HSP. The RT-PCR analysis revealed that both spastin mutations are indeed splice-site mutations and cause skipping of exon 12. Furthermore, RT-PCR data suggested that these splice-site mutations may cause leaky splicing. By means of a quantitative allele-specific expression assay, we could confirm that both splice-site mutations cause leaky splicing, as the relative expression of the exon 12-skipped transcript was reduced (21.1 ± 3.6 compared to expected 50%). Conclusions: Our finding supports a “threshold-effect-model” for functional spastin in HSP. A higher level (78.8 ± 3.9%) of functional spastin than the expected ratio of 50% owing to leaky splicing might cause late age at onset of HSP. Remarkably, we could show that a quantitative allele-specific expression assay is a simple and effective tool to evaluate the role of most types of spastin splice-site mutations in HSP.

Objective: Hereditary spastic paraplegias (HSP) are genetically exceedingly heterogeneous. To date, 37 genetic loci for HSP have been described (SPG1-41), among them 16 loci for autosomal dominant disease. Notwithstanding, further genetic heterogeneity is to be expected in HSP, as various HSP families do not link to any of the known HSP loci. In this study, we aimed to map the disease locus in a German family segregating autosomal dominant complicated HSP. Methods: A genome-wide linkage analysis was performed using the GeneChip Mapping 10Kv2.0 Xba Array containing 10,204 SNP markers. Suggestive loci were further analyzed by mapping of microsatellite markers. Results: One locus on chromosome 12q23-24, termed SPG36, was confirmed by high density microsatellite fine mapping with a significant LOD score of 3.2. SPG36 is flanked by markers D12S318 and D12S79. Linkage to SPG36 was excluded in >20 additional autosomal dominant HSP families. Candidate genes were selected and sequenced. No disease-causing mutations were identified in the coding regions of ATXN2, HSPB8, IFT81, Myo1H, UBE3B , and VPS29 . SPG36 is complicated by a sensory and motor neuropathy; it is therefore the eighth autosomal dominant subtype of complicated HSP. Conclusion: We report mapping of a new locus for autosomal dominant hereditary spastic paraplegia (HSP) (SPG36) on chromosome 12q23-24 in a German family with autosomal dominant HSP complicated by peripheral neuropathy. ATR = Achilles tendon reflex; CMAP = compound muscle action potential; CMT = central motor time; DML = distal motor latency; FDI = fist dorsal interosseus muscle; HSP = hereditary spastic paraplegia; MNCV = motor nerve conduction velocity; PTR = patella tendon reflex; SNAP = sensory nerve action potential; SNCV = sensory nerve conduction velocity; SPRS = Spastic Paraplegia Rating Scale; TA = tibialis anterior muscle.

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 mutational hotspots to be less frequent than previously thought. Nevertheless, the assays introduced represent a valid pre-screen easily implementable in the molecular diagnosis of HSP.

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 muscles. Stimulus-response (S-R) curves were constructed by plotting the MEP size and CSP duration against stimulus intensities. The absolute duration of CSP and the size MEPs correlated significantly and to a similar extent with stimulus intensity (r = 0.60 and 0.53, respectively). The slope of the MEP-S-R was steeper compared with CSP-S-R, particularly at low stimulation intensities. CSP duration saturated earlier and CSP-S-Rs were shifted upwards at a given stimulus intensity compared with MEP-S-Rs. The findings suggest that recruitment of inhibition and excitation within the sensorimotor cortex correlate. However, inhibitory effects are recruited at lower intensities and saturate earlier than excitation.

Background: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurodegenerative disease. The most frequent cause of autosomal dominant HSP is mutation of SPAST ( SPG4 locus), but additional pedigrees remain mutation negative by conventional screening despite linkage to SPG4 . Objective: To determine the frequency of genomic copy number aberrations of SPAST in autosomal dominant HSP. Methods: We developed and validated a multiplex ligation-dependent probe amplification assay targeting SPAST and SPG3A , another gene frequently involved in autosomal dominant HSP. In a multicenter study we subsequently investigated 65 index patients with autosomal dominant HSP, all of whom had previously been screened negative for SPAST mutations. Independent secondary samples, additional family members, and cDNA were analyzed to confirm positive findings. Results: Aberrant MLPA profiles were identified in 12 cases (18%). They exclusively affect SPAST , represent deletions, segregate with the disease, and are largely pedigree specific. Internal SPAST deletions entail expression of correspondingly shortened transcripts, which vary in stability. Age at onset in SPAST deletion carriers does not differ from that associated with other SPAST mutations. Conclusions: Partial SPAST deletions, but not SPAST amplifications and SPG3A copy number aberrations, represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency.

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 a family history compatible with autosomal recessive inheritance was collected and screened for mutations in SPG11 and SPG15. Overall frequency of SPG11 was 14% (5/36) but was considerably higher in patients with TCC (42%). One patient with mental retardation and thinning of the corpus callosum was compound heterozygous for two novel SPG15 mutations. Additionally, several new polymorphisms and sequence variants of unknown significance have been identified in the SPG15 gene. Conclusions: TCC seems to be the best phenotypic predictor for SPG11 as well as SPG15. No clinical features could discriminate between SPG11 and SPG15. Therefore, priority of genetic testing should be driven by mutation frequency that appears to be substantially higher in SPG11 than in SPG15.

Hereditary spastic paraplegias (HSP) are a heterogeneous group of neurological disorders. Insidiously progressive spastic weakness of the lower extremities is the common criterion in all forms described. Clinically, HSP is differentiated into pure (uncomplicated) and complex (complicated) forms. While pure HSP is predominantly characterized by signs and symptoms of pyramidal tract dysfunction, additional neurological and non-neurological symptoms occur in complicated forms. Autosomal dominant, autosomal recessive, and X-linked modes of inheritance have been described and at least 48 subtypes, termed SPG1-48, have been genetically defined. Although in autosomal dominant HSP families 50–60% of etiologies can be established by genetic testing, genotype predictions based on the phenotype are limited. In order to realize high-throughput genotyping for dominant HSP, we designed a resequencing microarray for six autosomal dominant genes on the Affymetrix CustomSEQ array platform. For validation purposes, 10 previously Sanger sequenced patients with autosomal dominant HSP and 40 positive controls with known mutations in ATL1, SPAST, NIPA1, KIF5A, and BSCL2 (32 base exchanges, eight small indels) were resequenced on this array. DNA samples of 45 additional patients with AD spastic paraplegia were included in the study. With two different sequencing analysis software modules (GSEQ, SeqC), all missense/nonsense mutations in the positive controls were identified while indels had a detection rate of only 50%. In total, 244 common synonymous single-nucleotide polymorphisms (SNPs) annotated in dbSNP (build 132) corresponding to 22 distinct sequence variations were found in the 53 analyzed patients. Among the 22 different sequence variations (SPAST n = 15, ATL1 n = 3, KIF5A n = 2, HSPD1 n = 1, BSCL2 n = 1, NIPA1 n = 0), 12 were rare variants that have not been previously described and whose clinical significance is unknown. In SPAST-negative cases, a genetic diagnosis could be established in 11% by resequencing. Resequencing microarray technology can therefore efficiently be used to study genotypes and mutations in large patient cohorts.

BACKGROUND Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach. METHODS Within a 1-year recruitment period, patients suspected of having acute (symptom onset RESULTS The study included 205 patients (39 ICH, 163 ischemic stroke, 3 stroke mimic). GFAP concentrations were increased in patients with ICH compared with patients with ischemic stroke [median (interquartile range) 1.91 μg/L (0.41–17.66) vs 0.08 μg/L (0.02–0.14), P < 0.001]. Diagnostic accuracy of GFAP for differentiating ICH from ischemic stroke and stroke mimic was high [area under the curve 0.915 (95% CI 0.847–0.982), P < 0.001]. A GFAP cutoff of 0.29 μg/L provided diagnostic sensitivity of 84.2% and diagnostic specificity of 96.3% for differentiating ICH from ischemic stroke and stroke mimic. CONCLUSIONS Plasma GFAP analysis performed within 4.5 h of symptom onset can differentiate ICH and ischemic stroke. Studies are needed to evaluate a GFAP point-of-care system that may help optimize the prehospital triage and management of patients with symptoms of acute stroke.

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 with higher IMT in men and women. A subgroup of 1,025 subjects without cardiovascular risk factors or previous cardiovascular disease was analyzed to define normal IMT values. Nomograms were calculated according to age and gender. For each age group, IMT95th percentile was defined as abnormal. In this subgroup, gender differences in IMT became nonsignificant at older ages. At the age of 35 years, IMT was 0.71 mm in men and 0.61 mm in women at the 95th percentile. In comparison, at the age of 74 years, IMT at the 95th percentile was 0.90 mm in men and 0.89 mm in women. In conclusion, men had higher carotid IMT than women, but predictors of early carotid atherosclerosis were similar across genders. In young subjects without cardiovascular risk factors, normal values for IMT were lower in women compared with men. In contrast, in older subjects, gender differences in IMT became nonsignificant.

Intracortical disinhibitory mechanisms play a crucial role in epilepsy. Therefore, the recruitment of motor cortical excitability was evaluated to distinct between focal and generalized epileptic syndromes. Twenty-five untreated patients with epilepsy and 20 controls were enrolled. Classification into focal (FE, n=10) or idiopathic generalized (IGE, n=15) epilepsy was based on seizure semiology, EEG and MRI. The recruitment of motor cortical inhibition and facilitation was measured by varying the stimulus intensity (SI) of the first conditioning stimulus in a paired-pulse transcranial magnetic stimulation (TMS) paradigm producing stimulus-response (S-R) curves of intracortical excitability. S-R curves were then compared with other commonly used TMS measures of cortical excitability [cortical silent period (CSP) and motor threshold (MT)]. In patients with IGE, inhibition occurred only at higher conditioning SIs compared to patients with focal epilepsy and controls. Recruitment of inhibition was unchanged in patients with focal epilepsy compared to controls. Recruitment of facilitation (ICF), CSP duration and MT, were not different between patients with FE or IGE or between patients and controls. These results suggest that the recruitment for motor cortical inhibition in patients with IGE is less effective. This may reflect a disturbed access to or an increased threshold of inhibitory neurons within the motor cortex. Impaired recruitment of inhibition might be a helpful parameter to access cortical excitability in newly diagnosed patients with generalized or focal epilepsy.

Hereditary spastic paraplegia (HSP) is a neurodegenerative condition defined clinically by lower limb spasticity and weakness. Homozygous mutations in CYP7B1 have been identified in several consanguineous families that represented HSP type 5 (SPG5), one of the many genetic forms of the disease. We used direct sequencing and multiplex ligation-dependent probe amplification to screen for CYP7B1 alterations in apparently sporadic HSP patients (n = 12) as well as index patients from non-consanguineous families with recessive (n = 8) and dominant (n = 8) transmission of HSP. One sporadic patient showing HSP as well as optic atrophy carried a homozygous nonsense mutation. Compound heterozygosity was observed in a recessive family with a clinically pure phenotype. A heterozygous missense change segregated in a small dominant family. We also found a significant association of a known coding polymorphism with cerebellar signs complicating a primary HSP phenotype. Our findings suggest CYP7B1 alterations to represent a rather frequent cause of HSP that should be considered in patients with various clinical presentations.

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: Three novel KIF5A mutations were detected in German families, including one missense mutation (c.759G>T, p.K253N), one in frame deletion (c.768_770delCAA, p.N256del) and one splice site mutation (c.217G>A). Onset of gait disturbance varied from infancy to 30 years of age. All patients presented clinically with pure HSP, but a subclinical sensory-motor neuropathy was detected by neurophysiology studies. CONCLUSIONS: SPG10 accounts for approximately 3% of European autosomal dominant HSP families. All mutations affect the motor domain of kinesin and thus most likely impair axonal transport. Clinically, SPG10 is characterised by spastic paraplegia with mostly subclinical peripheral neuropathy.

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 haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.

Fragestellung: Spastische Spinalparalysen (SP) sind eine genetisch heterogene Gruppe von Erkrankungen, denen eine progrediente spastische Gangstorung auf dem Boden einer Pyramidenbahndegeneration gemeinsam ist. Aktuell sind 31 Gene oder Loci fur diese Erkrankung bekannt, darunter 13 loci fur autosomal dominante Erkrankungsformen. Methoden: Wir fuhrten eine Genom-weite Kopplungsanalyse an einer grosen, sich uber drei Generationen erstreckenden Familie durch. 10.000 SNPs wurden mittels Microarray in insgesamt 14 Familienangehorigen (7 Betroffene) genotypisiert. Zusatzliche Mikrosatellitenmarker wurden fur alle in Frage kommenden Loci (NPL score >1,5) genotypisiert. Mittels Fine-Mapping und Haplotyp-Rekonstruktion wurden die Grenzen des neuen SP-Locus definiert. Uber 25 autosomal dominante Familien wurden auf Kopplung zu dem neuen Locus untersucht und Kandidaten-Gene sequenziert. Ergebnisse: Die Genom-weite Kopplungsanalyse erbrachte vier genomische Regionen mit NPL-Scores uber 1,5. Genotypisierung zusatzlicher Mikrosatellitenmarker bestatigte die Kopplung zu einer Region auf Chromosome 12q23–24 mit einem maximalen multipoint LOD-Score von 2,4. Haplotyp-Rekonstruktion definierte D12S318 und D12S1023 als Grenzen des neuen Locus, der somit eine Region von etwa 12MB umfasst. Keine weiteren Familien mit Kopplung zu 12q23–24 konnten identifiziert werden. Sequenzierung von CKAP4 und IQCD, deren Genprodukte eine Homologie zu dem neuronalen Motorprotein KIF5A, mutiert bei der SPG10, aufweisen, erbrachte keine Variationen der codierenden Sequenz in betroffenen Familienmitgliedern. Die betroffenen Familienmitglieder zeigten sensible Defizite (Oberflachensensibilitat, Temperaturdiskrimination, Vibrations-Sinn) und distale Muskelatrophie der unteren Extremitaten zusatzlich zu den Symptomen einer reinen spastischen Spinalparalyse. Das mittlere Erkrankungsalter lag bei 23,5 Jahren. Schlussfolgerungen: Wir beschreiben einen neuen Locus fur autosomal dominante spastische Spinalparalyse mit sensiblen Defiziten und distal betonten Muskelatrophien der unteren Extremitaten auf Chromosom 12q23–24.

Klinisches Leitsymptom der spastischen Spinalparalysen (SP) ist eine progrediente spastische Gangstorung auf dem Boden einer Pyramidenbahndegeneration. Die Erkrankung ist typischerweise auf die unteren Extremitaten beschrankt. Sensible Defizite und periphere Neuropathie konnen als komplizierende Zusatzsymptome auftreten. Ziel der Studie ist die Typisierung sensibler Defizite, Bestimmung der Frequenz peripherer Neuropathien und Charakterisierung der Pyramidenbahnstorung bei der SP. 97 Patienten mit SP wurden klinisch und elektrophysiologisch untersucht. Kriterium fur die Diagnose sensibler Defizite waren Beeintrachtigungen von Vibrationsempfinden, Lagesinn, Temperatur- oder Spitz-Stumpf-Diskrimination. Eine periphere Neuropathie wurde klinisch bei Auftreten von Muskelatrophien oder abgeschwachten Muskeleigenreflexen angenommen. Die elektrophysiologische Charakterisierung beinhaltete motorisch evozierte Potentiale (MEP) in F-Wellen-Technik, die motorische Neurographie von N. tibialis und N. ulnaris sowie die sensible Neurographie von N. suralis und N. radialis. Klinische Zeichen einer sensiblen Beteiligung wurden in 59% der Patienten, klinische Zeichen einer peripheren Neuropathie in 34% der Patienten beobachtet. In 21% der Patienten war elektrophysiologisch eine subklinische Affektion des peripheren Nervensystems zu sichern. Bei allen Patienten bestanden klinische Zeichen einer Pyramidenbahnstorung zu den Beinen. Pathologische MEPs zum M. abductor hallucis fanden sich jedoch lediglich bei 76% der Patienten. Eine ausgedehnte Verlangerung der zentralmotorischen Latenz (>20ms), vereinbar mit einem vorwiegend demyelinisierenden Schadigungsmuster, fand sich in 48% der Patienten. MEPs zu den Armen waren in 34% der Patienten auffallig. Schlussfolgerungen: 1) Die haufige subklinische Beteiligung des peripheren Nervensystems bei der SP stellt die Frage, ob diese Patienten als reine oder komplizierte Form der SP klassifiziert werden sollen. 2) Die weitere genetische Charakterisierung unserer Kohorte wird die Definition Genotyp-spezifischer elektrophysiologischer Schadigungsmuster von zentralen und peripheren, motorischen und sensiblen Bahnen ermoglichen. 3) Beteiligung der oberen Extremitaten bei Patienten mit Erkrankungen des ersten Motoneurons fuhrt haufig zur Diagnose einer primaren Lateralsklerose. Dieses Kriterium scheint, angesichts pathologischer MEPs zu den Armen bei einem Drittel unserer Patienten, davon 60% mit positiver Familienanamnese, nicht ausreichend zu sein.

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 based on regions of interest (ROIs) defined on individual MRIs. For each patient, binding potential (BP) was calculated by using the simplified reference tissue model, and the epileptogenic was compared with the unaffected hemisphere in each ROI. To confirm the results, an additional voxel-based group analysis was performed by using statistical parametric mapping. Results: Compared with controls, [ 18 F]FP BP was significantly decreased in the epileptogenic temporal lobe in all patients. On ROI analysis, this reduction was evident in areas surrounding the seizure-onset zone at the pole (‐34.2%) and lateral aspects (‐32.9%) of the temporal lobe. Although the hippocampus [ 18 F]FDG uptake (‐8.1%) and hippocampal MR volume (‐35.1%) were significantly reduced, no significant decrease of [ 18 F]FP BP was found. Reduction of [ 18 F]FP BP did not correlate with hippocampal atrophy. Conclusions: D2/D3-receptor binding is reduced at the pole and in lateral aspects of the epileptogenic temporal lobe in patients with mesial TLE and HS. This area might correspond to “the irritative zone,” indicating that D2/D3 receptors might play a specific role in the pathophysiology of mesial TLE.

Objective: To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure disease severity and progression. Methods: A 13-item scale was designed to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory. Two independent patient cohorts were evaluated in a two-step validation procedure. Results: Application of SPRS requires less than 15 minutes and does not require any special equipment, so it is suitable for an outpatient setting. Interrater agreement of SPRS was high (intraclass correlation coefficient = 0.99). Reliability was further supported by high internal consistency (Cronbach α = 0.91). SPRS values were almost normally distributed without apparent floor or ceiling effect. Construct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative Ataxia Rating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity). Conclusion: The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity.

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 patients never had epileptic seizures and in four residents the reason for AED use was unclear. AEDs most frequently prescribed were carbamazepine (37.1%), valproic acid (25.9%), and phenytoin (14.8%). Five patients received benzodiazepines (18.5%), newer generation AED were used in only four (14.8%) cases. Residents on average took n =5.6±3.3 other drugs. Opportunities exist for health care professionals to improve the medical management of nursing facility residents receiving AEDs.