Mutations in SEPT9 cause hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy affecting the brachial plexus. HNA is triggered by environmental factors such as infection or parturition. We report three mutations in the gene septin 9 (SEPT9) in six families with HNA linked to chromosome 17q25. HNA is the first monogenetic disease caused by mutations in a gene of the septin family. Septins are implicated in formation of the cytoskeleton, cell division and tumorigenesis.

Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene.

Autosomal-dominant striatal degeneration (ADSD) is an autosomal-dominant movement disorder affecting the striatal part of the basal ganglia. ADSD is characterized by bradykinesia, dysarthria, and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. Using genetic linkage analysis, we have mapped the causative genetic defect to a 3.25 megabase candidate region on chromosome 5q13.3-q14.1. A maximum LOD score of 4.1 (Theta = 0) was obtained at marker D5S1962. Here we show that ADSD is caused by a complex frameshift mutation (c.94G>C+c.95delT) in the phosphodiesterase 8B (PDE8B) gene, which results in a loss of enzymatic phosphodiesterase activity. We found that PDE8B is highly expressed in the brain, especially in the putamen, which is affected by ADSD. PDE8B degrades cyclic AMP, a second messenger implied in dopamine signaling. Dopamine is one of the main neurotransmitters involved in movement control and is deficient in Parkinson disease. We believe that the functional analysis of PDE8B will help to further elucidate the pathomechanism of ADSD as well as contribute to a better understanding of movement disorders.

Treatment of status epilepticus in a large community hospital.

BACKGROUND: Status epilepticus (SE) is a neurological emergency usually requiring immediate medical treatment. Due to the lack of adequate studies, treatment guidelines and their application vary between countries and institutions. We intended to analyze current treatment of SE in a German community hospital. METHODS: We retrospectively identified patients from a large community hospital in northern Germany who had been diagnosed with SE between August 2008 and December 2010. Their charts were reviewed regarding sociodemographic variables, treatment and outcome. RESULTS: We studied the first SE episode in 172 patients with a median age of 69 years (range 18-90 years). The etiology was acute symptomatic in 30 patients, progressive symptomatic in 22 patients and remote symptomatic in 120 patients. Presentation was generalized convulsive in 60 patients, non-convulsive in 72 patients and simple motor/aura in 40 patients. Median latency from onset to treatment start was 0.75 h (range 0.2-336 h). Initial treatment had a success rate (SR) of 40%. Second line treatment had a success rate of 54%. In patients whose seizures were refractory to the first two drugs, success rates were between 31% and 55%, with only a minority of the patients receiving established drugs such as phenytoin or barbiturates. Multivariate analysis revealed non-convulsive semiology as the only factor significantly associated with refractoriness. SE could be terminated in 95% of the patients and in-hospital mortality was 10%. Benzodiazepines and phenytoin had the most severe side effects. CONCLUSIONS: Status epilepticus can be terminated successfully and with low in-hospital mortality in the vast majority of the patients treated in a large community hospital. The success rate of each treatment step is between 30% and 55% regardless of the substances used.

Oncostatin M induces growth arrest by inhibition of Skp2, Cks1, and cyclin A expression and induced p21 expression.

Oncostatin M has been characterized as a potent growth inhibitor for various tumor cells. Oncostatin M-treated glioblastoma cells cease proliferation and instigate astrocytal differentiation. The oncostatin M-induced cell cycle arrest in G(1) phase is characterized by increased level of the cyclin-dependent kinase (CDK) inhibitory proteins p21(Cip1/Waf1/Sdi1) and p27(Kip1). Induction of p21 protein corresponds to increased mRNA level, whereas p27 accumulates due to increased stability of the protein. Interestingly, stabilization of p27(Kip1) occurs even in S phase, showing that p27 stabilization is a direct consequence of oncostatin M signaling and not a result of the cell cycle arrest. Degradation of p27 in late G(1) and S phase is initiated by the ubiquitin ligase complex SCF-Skp2/Cks1. Oncostatin M inhibits expression of two components of this E3 ligase complex (Skp2 and Cks1). Although combined overexpression of Skp2 and Cks1 rescues p27 degradation in S phase, it can not override p27 accumulation in G(1) phase and cell cycle arrest by oncostatin M. In addition to increasing Cdk inhibitor level, oncostatin M also impairs cyclin A expression. Cyclin A mRNA and protein level decline shortly after oncostatin M addition. The accumulation of two CDK inhibitor proteins and the repression of cyclin A expression may explain the broad and potent antiproliferative effect of the cytokine.

Effects of Universal Mobile Telecommunications System (UMTS) electromagnetic fields on the blood-brain barrier in vitro.

The extensive use of mobile phone communication has raised public concerns about adverse health effects of radiofrequency (RF) electromagnetic fields (EMFs) in recent years. A central issue in this discussion is the question whether EMFs enhance the permeability of the blood-brain barrier (BBB). Here we report an investigation on the influence of a generic UMTS (Universal Mobile Telecommunications System) signal on barrier tightness, transport processes and the morphology of porcine brain microvascular endothelial cell cultures (PBEC) serving as an in vitro model of the BBB. An exposure device with integrated online monitoring system was developed for simultaneous exposure and measuring of transendothelial electrical resistance (TEER) to determine the tightness of the BBB. PBEC were exposed continuously for up to 84 h at an average electric-field strength of 3.4-34 V/m (maximum 1.8 W/kg) ensuring athermal conditions. We did not find any evidence of RF-field-induced disturbance of the function of the BBB. After and during exposure, the tightness of the BBB quantified by 14C-sucrose and serum albumin permeation as well as by TEER remained unchanged compared to sham-exposed cultures. Permeation of transporter substrates at the BBB as well as the localization and integrity of the tight-junction proteins occludin and ZO1 were not affected either.

Norepinephrine transporter (NET) promoter and 5'-UTR polymorphisms: association analysis in panic disorder.

Several biochemical and pharmacological studies suggest that the catecholaminergic system involving the norepinephrine transporter (NET) is relevant for the pathogenesis of panic disorder. Three single nucleotide polymorphisms in the promoter or untranslated 5' region of the NET gene were investigated by means of RFLP analysis in a sample of 115 German patients with panic disorder and 115 matched controls. Statistical analysis failed to show association with the overall diagnosis of panic disorder. In the subgroup of patients with panic disorder without agoraphobia, however, two polymorphisms were found to be associated with the disease (G/C (rs2397771): p < 0.05; T/C (rs2242446): p < 0.01). While our data do not support a major function of the NET gene in the development of panic disorder, it may play a role in the subgroup of panic disorder without agoraphobia.

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder.

IMPORTANCE: Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target. OBJECTIVE: To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab-seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose). MAIN OUTCOMES AND MEASURES: Annualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects. RESULTS: Patients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) (P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) (P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers (P = .02) and pain levels (P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each. CONCLUSIONS AND RELEVANCE: Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.

Elastin polymorphism haplotype and intracranial aneurysms are not associated in Central Europe.

BACKGROUND AND PURPOSE: The occurrence of intracranial aneurysms and of aneurysmal subarachnoid hemorrhage are influenced by genetic factors. Recent genomic studies in Japan have defined 3 chromosomal loci and 1 haplotype of elastin polymorphisms as important risk factors, both for affected sib pairs and sporadic patients. METHODS: We have genotyped 2 single nucleotide polymorphisms in the elastin gene and evaluated their allelic association with intracranial aneurysm in a Central European sample of 30 familial and 175 sporadic patients and 235 population controls. RESULTS: We found no allelic association between this elastin polymorphism haplotype and intracranial aneurysm. CONCLUSIONS: Our data probably reflect increased genetic heterogeneity of intracranial aneurysm in Europe compared with Japan.

Clinical features and molecular genetics of hereditary peripheral neuropathies.

Hereditary peripheral neuropathies are the most common monogenetically inherited diseases of the nervous system. The prevalence of the Hereditary Motor and Sensory Neuropathy Type 1A (HMSN 1A or Charcot-Marie-Tooth Neuropathy 1A, CMT1A) alone is estimated to be as high as 1/5000. In 1991, a duplication on chromosome 17p11.2 was identified as the causative genetic defect of CMT1A. Since then causative mutations in 17 genes have been identified. This review summarises the clinical and molecular genetic features of primary inherited neuropathies. It is aimed primarily at clinicians and geneticists. Therefore less emphasis is placed on the pathology and the (often unknown) underlying biological disease mechanisms.

Neurological manifestations of the oculodentodigital dysplasia syndrome.

Oculodentodigital dysplasia (ODDD) (MIM 164200) is a rare autosomal dominant inherited disorder affecting the development of the face, eyes, limbs and dentition. Neurological complications are thought to be occasional manifestations of the disorder. This report illustrates the neurological manifestations by a pedigree of two ODDD patients with spastic paraparesis, cerebral white matter hyperintensity and basal ganglia hypointensity. A systematic review of the English, French, German and Italian literature on ODDD is also provided to summarize the neurological manifestations of the disorder. 243 previously described ODDD cases presented a spectrum of neurological manifestation including spasticity (25), subcortical white matter lesions (9) and basal ganglia changes (6) on MRI. Additional findings consisted of gaze palsy and squinting (28), bladder and bowel disturbances (21), visual loss (20) and blindness (4), hearing loss (15), ataxia (11), nystagmus (9), muscle weakness (5) and paresthesias (3). Neurological manifestations, including spasticity associated with MRI changes, are an underrecognized feature in the ODDD phenotype. A clinical guide to the neurological manifestations of ODDD may assist in the assessment of patients with this condition.

Late onset postpartum eclampsia: a rare and difficult diagnosis.

Late postpartum eclampsia without the classical pre-eclamptic signs oedema, proteinuria and hypertension is a rarely noticed complication of pregnancy. In three patients eclampsia started no earlier than 6, 8 and 11 days postpartum. Seizures were preceded by headache, vomiting, visual disturbance or impaired level of consciousness. One patient suffered a series of seizures making neurointensive care necessary. In another patient the clinical course was complicated by an additional Guillain-Barré syndrome. Aside from the typical parieto-occipital lesions brain MRI showed cerebellar hyperintensities on T2 weighted sequences as well as abnormalities on diffusion weighted images in one patient. In all patients neurological deficits and MRI findings were reversible.

Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections.

Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account known factors influencing plasma homocysteine levels. Ninety-five patients with past sCAD were compared with 95 age- and sex-matched healthy individuals. Homocysteine, vitamin B6, B12, folate, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), cystathionine beta-synthase (CBS 844ins68bp) and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 G1958A) were assessed and any associations were analysed using multivariate statistics. The occurrence of sCAD was associated with elevated homocysteine levels with an odds ratio of 1.327 per 20 % percentile. Homocysteine levels were influenced by gender, smoking status, occurrence of hypertension, vitamin B12 and folate levels, and by the MTHFR TT genotype. MTHFR, CBS 844ins68bp, and MTHFD1 G1958A genotype were not independently associated with the occurrence of sCAD. These data suggest that elevated homocysteine is associated with the occurrence of sCAD. The MTHFR C677T polymorphism is associated with the homocysteine level.

Cervical artery dissection--clinical features, risk factors, therapy and outcome in 126 patients.

The highly variable clinical course of cervical artery dissections still poses a major challenge to the treating physician. This study was conducted (1) to describe the differences in clinical and angiographic presentation of patients with carotid and vertebral artery dissections (CAD, VAD), (2) to define the circumstances that are related to bilateral arterial dissections, and (3) to determine factors that predict a poor outcome. Retrospectively and by standardised interview, we studied 126 patients with cervical artery dissections. Preceding traumata, vascular risk factors, presenting local and ischemic symptoms, and patient-outcome were evaluated. Patients with CAD presented more often with a partial Horner's syndrome and had a higher prevalence of fibromuscular dysplasia than patients with VAD. Patients with VAD complained more often of neck pain, more frequently reported a preceding chiropractic manipulation and had a higher incidence of bilateral dissections than patients with CAD. Bilateral VAD was significantly related to a preceding chiropractic manipulation. Multivariate analysis showed that the variables stroke and arterial occlusion were the only independent factors associated with a poor outcome. This study emphasises the potential dangers of chiropractic manipulation of the cervical spine. Probably owing to the systematic use of forceful neck-rotation to both sides, this treatment was significantly associated with bilateral VAD. Patients with dissection-related cervical artery occlusion had a significantly increased risk of suffering a disabling stroke.

Placing nasogastric tubes and intracranial pressure.

Recently, a new method for placing nasogastric tubes (NGT) in dysphagic patients was proposed, which uses the swallowing reflex and was therefore called 'reflex placement.' The authors describe the use of this method in a patient with a large left sided striatocapsular hemorrhage, in whom decompressive craniotomy had been performed previously. Whereas the conventional approach of placing NGT led to a massive increase of intracranial pressure (ICP) and to a decline in cerebral perfusion pressure (CPP), the new method allowed a swift placement with only minor changes of ICP and CPP. The strict avoidance of intermittent peaks of ICP constitutes a basic principle of care in patients with space occupying brain lesions. We therefore suggest that, despite the admittedly larger effort, the reflex placement of NGTs should be used in such circumstances.

Use of oxcarbazepine for treatment of refractory status epilepticus.

PURPOSE: Oxcarbazepine (OXC) is an effective anticonvulsant used for treatment of partial and secondarily generalized seizures. However, there is almost no data regarding its effectiveness and tolerability when used for treatment of status epilepticus (SE). METHODS: We retrospectively identified all patients who received OXC for treatment of SE in our hospital between July 2008 and December 2010 in our hospital and analyzed all available data. RESULTS: We identified 13 patients (median age 79 years) who were treated with OXC for refractory SE after failure of first- and second-line therapy in our institution. In the majority of patients, etiology was remote symptomatic (10/13), and semiology was nonconvulsive (10/13). OXC was initiated as third or later agent in almost all patients after median latency of 81 h with a median maximum daily dose of 1800 mg. OXC was the last drug before SE cessation in 8/13 patients. Relevant hyponatriemia <125 mmol/l was seen in 3 patients. CONCLUSION: OXC may be an effective alternative in refractory SE, but patients need to be monitored closely for hyponatriemia. PRACTICE IMPLICATIONS: OXC could be used for refractory SE under close electrolyte monitoring when standard agents fail or are unsuitable.

The glu298asp polymorphism in the nitric oxide synthase 3 gene is associated with the risk of ischemic stroke in two large independent case-control studies.

The search for genes involved in the pathogenesis of stroke has been highlighted as a field of needs. We followed the concept, that stroke represents a complex genetic disorder, and analyzed the contribution of 106 informative single nucleotide polymorphisms (SNPs) from 63 candidate genes for cardiovascular diseases for the risk of stroke. We conducted two independent case-control studies in two different German regions and recruited a total of 1,901 hospitalized stroke cases and 1,747 regional population controls. The smaller of both studies was used as the replication study. Multiplex PCR in combination with allele-specific hybridization was used for genotype determination. Descriptive statistics, permutations and multivariable logistic regression were used in the analyses. After permutation testing 5 SNPs, located in the nitric oxide synthase 3, the alpha 2 integrin, the interleukin 13, the selectin P and the chemokine receptor 2 genes, had a significant allele difference between cases and controls in the larger study. For one of these SNPs, the glu298asp polymorphism in the nitric oxide synthase 3 gene, an association with ischemic stroke was replicated in the second study and also in a combined analysis of both studies. This association was independent of age, gender, hypertension, diabetes and hypercholesterolemia in both studies. Using large sample sizes and a replication study approach, we found evidence for a role of a polymorphism in the nitric oxide synthase 3 gene in stroke onset.

Genetic association of Huntington's disease and restless legs syndrome? A family report.

We report on a family with comorbidity of Huntington's disease (HD) and idiopathic restless legs syndrome (RLS). All family members investigated and affected by RLS are also affected by HD, but not vice versa. The association of HD and RLS is discussed with respect to dopaminergic dysfunction.