To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.

Orthostatic (postural) hypotension (OH) is a common, yet under diagnosed disorder. It may contribute to disability and even death. It can be the initial sign, and lead to incapacitating symptoms in primary and secondary autonomic disorders. These range from visual disturbances and dizziness to loss of consciousness (syncope) after postural change. Evidence based guidelines for the diagnostic workup and the therapeutic management (non-pharmacological and pharmacological) are provided based on the EFNS guidance regulations. The final literature research was performed in March 2005. For diagnosis of OH, a structured history taking and measurement of blood pressure (BP) and heart rate in supine and upright position are necessary. OH is defined as fall in systolic BP below 20 mmHg and diastolic BP below 10 mmHg of baseline within 3 min in upright position. Passive head-up tilt testing is recommended if the active standing test is negative, especially if the history is suggestive of OH, or in patients with motor impairment. The management initially consists of education, advice and training on various factors that influence blood pressure. Increased water and salt ingestion effectively improves OH. Physical measures include leg crossing, squatting, elastic abdominal binders and stockings, and careful exercise. Fludrocortisone is a valuable starter drug. Second line drugs include sympathomimetics, such as midodrine, ephedrine, or dihydroxyphenylserine. Supine hypertension has to be considered.

PurposePatients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure.MethodsAs a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension.ResultsIn patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management.ConclusionsThe establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.

The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation.

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".