Cerebral cavernous malformations (CCM) are prevalent cerebrovascular lesions predisposing to chronic headaches, epilepsy, and hemorrhagic stroke. Using a combination of direct sequencing and MLPA analyses, we identified 15 novel and eight previously published CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) mutations. The mutation detection rate was >90% for familial cases and >60% for isolated cases with multiple malformations. Splice site mutations constituted almost 20% of all CCM mutations identified. One of these proved to be a de novo mutation of the most 3' acceptor splice site of the CCM1 gene resulting in retention of intron 19. A further mutation affected the 3' splice site of CCM2 intron 2 leading to cryptic splice site utilization in both CCM2 and its transcript variant lacking exon 2. With the exception of one in-frame deletion of CCM2 exon 2, which corresponds to the naturally occurring splice variant of CCM2 on the RNA level and is predicted to result in the omission of 58 amino acids (CCM2:p.P11_K68del), all mutations lead to the introduction of premature stop codons. To gain insight into the likely mechanisms underlying the only known CCM2 in-frame deletion, we analyzed the functional consequences of loss of CCM2 exon 2. The CCM2:p.P11_K68del protein could be expressed in cell culture and complexed with CCM3. However, its ability to interact with CCM1 and to form a CCM1/CCM2/CCM3 complex was lost. These data are in agreement with a loss-of-function mechanism for CCM mutations, uncover an N-terminal CCM2 domain required for CCM1 binding, and demonstrate full-length CCM2 as the essential core protein in the CCM1/CCM2/CCM3 complex.

An expert committee was formed to reach consensus on the use of Tilt Table Testing (TTT) in the diagnosis of disorders that may cause transient loss of consciousness (TLOC) and to outline when other provocative cardiovascular autonomic tests are needed. While TTT adds to history taking, it cannot be a substitute for it. An abnormal TTT result is most meaningful if the provoked event is recognised by patients or eyewitnesses as similar to spontaneous ones. The minimum requirements to perform TTT are a tilt table, a continuous beat-to-beat blood pressure monitor, at least one ECG lead, protocols for the indications stated below and trained staff. This basic equipment lends itself to perform (1) additional provocation tests, such as the active standing test carotid sinus massage and autonomic function tests; (2) additional measurements, such as video, EEG, transcranial Doppler, ☆ Consensus statement of the European Federation of Autonomic Societies (EFAS) endorsed by the American Autonomic Society (AAS) and the European Academy of Neurology (EAN). ☆☆ This article is co-published in the journals "Clinical Autonomic Research" and "Autonomic Neuroscience".

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Source of funding: None other than the author's own institution. 1 Incidence, seasonality and comorbidity in vestibular neuritis AbstractAims of the present study were: 1) to assess the incidence of vestibular neuritis (VN) in the adult population in two cities in Croatia, 2) to identify distribution of new VN cases in the different months and seasons by years, and 3) to identify comorbidities associated with VN. This is a prospective, population-based study conducted in the cities of Zagreb and Velika Gorica, Croatia in the 2011-2012 period. All diagnoses were confirmed either with caloric test or vestibular evoked myogenic potentials within 7 days of symptom onset. Following clinical parameters were collected from all patients: age, gender, side of the lesion, month and season of symptoms onset and comorbidities. We identified 79 new cases of VN (34 in 2011VN (34 in , 45 in 2012. The male to female ratio was 1.1:1. The mean age at the onset of the disease was 52.3 (range 20-86) years. The average annual incidence was 11.7 per 100,000 (95% CI 7,8 -15,6) in the 2011 period and 15.5 per 100,000 (95% CI 11,0 -20,0) in the 2012 period.For both years there was no statistically significant uneven distribution in the different months or seasons by years. The most frequent comorbidities present in VN patients were hypertension (30.4%), diabetes mellitus (8.9%), hyperlipidemia (7.5%) and hypothyreosis (6.3%). Our study has shown higher incidence of VN than previously reported. We have found no evidence of seasonality of VN and significant proportion of VN patients older than 50 years who had vascular risk factors present.