SPG10 is a rare cause of spastic paraplegia in European families

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

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

Sonographische Analyse der Larynxelevation bei neurogener Dysphagie

Ziel unserer Studie war die Analyse der vertikalen Larynxexkursion beim Schluckvorgang mittels Ultraschalluntersuchung bei Gesunden und bei Patienten mit neurogener Dysphagie. Dazu wird ein 7,5 MHz Linearschallkopf von der Seite longitudinal über dem Larynx plaziert und die Kontur des Zungenbeins und Schildknorpels dargestellt. Der Abstand zwischen Hyoid und Oberrand des Schildknorpels wird während der Larynxelevation mittels Videoaufzeichnung analysiert. Die mittlere Distanz wird in Ruhe und beim Schlucken (5 ml Wasser) ausgemessen und anschließend die relative Verkürzung der Distanz beim Schlucken berechnet. Normwerte wurden bei 42 Probanden (57 ±19 Jahre) ermittelt. Bei 18 Patienten (63 ±8 Jahre) lagen der neurogenen Dysphagie folgende Diagnosen zugrunde: zerebrale Ischämien: n=5, Amyotrophe Lateralsklerose (ALS): n=3, Multiple Sklerose (MS): n=3, M. Parkinson: n=2, Multisystematrophie: n=2, Myasthenia gravis: n=1, Chorea Huntington: n=1, Myositis: n=1. Bei Gesunden ergab sich in Ruhe eine mittlere Distanz von 220 (± 30)mm und eine kürzeste Distanz von 85 (±11)mm während des Schluckens. Dies entsprach einer prozentualen Verkürzung um 61% (±3) unter physiologischen Bedingungen. Bei neurogener Dysphagie betrug die relative Larynxelevation lediglich 42% (±10) [p < 0,0001]. Absolut betrug die mittlere Distanz in Ruhe 185 (±45)mm und die kürzeste Distanz 105 (±18)mm während des Schluckvorganges. In unserer Pilotstudie konnten wir bei Patienten mit neurogener Dysphagie unterschiedlicher Ätiologie eine gegenüber Gesunden signifikant verminderte Larxnxelevation nachweisen. Vorteile einer Ultraschalluntersuchung des Schluckvorganges sind die nichtinvasive Quantifizierung der Larynxelevation und die Wiederholbarkeit der Untersuchung

Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24.

Contains fulltext : 80386.pdf (publisher's version ) (Closed access)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

Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots.

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