■ Abstract Familial dysautonomia (FD) patients frequently experience debilitating orthostatic hypotension. Since physical countermaneuvers can increase blood pressure (BP) in other groups of patients with orthostatic hypotension, we evaluated the effectiveness of countermaneuvers in FD patients.In 17 FD patients (26.4 ± 12.4 years, eight female), we monitored heart rate (HR), blood pressure (BP), cardiac output (CO), total peripheral resistance (TPR) and calf volume while supine, during standing and during application of four countermaneuvers: bending forward, squatting, leg crossing, and abdominal compression using an inflatable belt. Countermaneuvers were initiated after standing up, when systolic BP had fallen by 40 mmHg or diastolic BP by 30 mmHg or presyncope had occurred.During active standing, blood pressure and TPR decreased, calf volume increased but CO remained stable. Mean BP increased significantly during bending forward (by 20.0 (17-28.5) mmHg; P = 0.005) (median (25 th -75 th quartile)), squatting (by 50.8 (33.5-56) mmHg; P = 0.002), and abdominal compression (by 5.8 (-1-34.7) mmHg; P = 0.04) -but not during leg-crossing. Squatting and abdominal compression also induced a significant increase in CO (by 18.1 (-1.3-47.9) % during squatting (P = 0.02) and by 7.6 (0.4-19.6) % during abdominal compression (P = 0.014)). HR did not change significantly during the countermaneuvers. TPR increased significantly only during squatting (by 37.2 (11.8-48.2) %; P = 0.01). However, orthopedic problems or ataxia prevented several patients from performing some of the countermaneuvers. Additionally, many patients required assistance with the maneuvers.Squatting, bending forward and abdominal compression can improve orthostatic BP in FD patients, which is achieved mainly by an increased cardiac output. Squatting has the greatest effect on orthostatic blood pressure in FD patients. Suitability and effectiveness of a specific countermaneuver depends on the orthopedic or neurological complications of each FD patient and must be individually tested before a therapeutic recommendation can be given.■ Key words physical maneuvers · familial dysautonomia · syncope · autonomic failure · impedance cardiography 1 Published in "Journal of Neurology 253(1): 65-72, 2006" which should be cited to refer to this work.

This report extends previous investigations of endogenous catecholamine levels in patients with orthostatic hypotension due to familial dysautonomia (FD), to define better the neurochemical phenotype and elucidate possible pathophysiological mechanisms. Ten FD patients (age 26.1 +/- 2.6 (SEM) years) and eight control subjects (age 29.5 +/- 3.7 years) were studied. Heart rate, blood pressure and venous blood samples were obtained while supine and after 5 min in the upright position. Plasma levels of dihydroxyphenylalanine (DOPA), noradrenaline (NA), adrenaline (A), dopamine (DA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) were measured. When supine, the FD group had greater NA and DOPA levels, and lower DHPG levels. Plasma NA did not increase with erect posture in FD patients. Individual FD mean blood pressures were correlated positively with plasma NA levels when supine and with plasma DA and DOPAC when upright. In FD, DOPA:DHPG ratios were above the range found in normal subjects or that reported in patients with acquired forms of dysautonomia regardless of posture, whereas DOPAC:DHPG ratios remained normal. Thus FD patients have a characteristic neurochemical pattern which probably reflects either decreased vesicular storage of catecholamines or limited oxidative deamination despite normal or increased tyrosine hydroxylation.

Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits.

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Cardiovascular abnormalities are prominent in the genetic disorder, familial dysautonomia (FD). To determine if autonomic dysfunction involves cardiac, as well as peripheral vascular integrity, noninvasive tests were performed in 10 FD patients and 8 healthy control subjects while supine and at 90° tilt. Simultaneous blood pressure (BP) and heart rate (HR) and QTc were obtained, while performing signal-averaged electrocardiography (SAECG) and heart rate variability (HRV). FD subjects were tested on 2 separate days, before and 1 h after oral fludrocortisone or midodrine; controls were tested once without medication. With tilt, all FD subjects decreased mean BP > 24 mm Hg by 5 min. On SAECG, 70% of supine FD subjects had a prolonged tQRS; only 2 FD subjects shortened tQRS with tilt. The QTc interval was prolonged ( > 440 ms) in 2 supine FD subjects; with tilt, the QTc prolonged in a third. Frequency domain analysis of HRV revealed that mid (MF) and high frequency band areas were significantly decreased when supine, but not when upright. On time domain analysis, the pNN50 was significantly decreased in FD subjects (8.9 ± 1.7 vs. 17.7 ± 3.6%, p < 0.01). Fiudrocortisone lowered supine BP and HR and increased supine MF area. Midodrine raised supine and erect BP, lowered erect HR, and shortened erect QTc. Although all FD subjects have abnormal orthostatic BP and HR responses, cardiac tone, as assessed by electrocardiographic and HRV responses, varies. Prolongation of the tQRS appears to be a sensitive but not specific indicator of autonomic dysfunction. QTc prolongation may indicate more extensive sympathetic dysfunction. HRV data suggest some FD patients have abnormalities in parasympathetic, as well as sympathetic, cardiac tone.

Familial dysautonomia (FD) is a genetic disease associated with a high incidence of sudden death. If fatal bradyarrhythmia is an etiological factor then the incidence of sudden death should decrease after pacemaker placement. Retrospective review of 596 registered FD patients revealed that 22 FD patients (3.7%) had pacemakers placed between December 1984 and June 2003. Clinical and electrocardiographic indications for placement and demographic data were assessed for 20 of the 22 patients (10 males, 10 females, ages 4 to 48 years). Two patients were excluded because of insufficient data. Prior to pacemaker placement, presenting symptoms were syncope and cardiac arrest, 16/20 (80%) and 6/20 (30 %), respectively. Asystole was the most frequent electrocardiographic finding and was documented in 17/20 patients (85 %). Other electrocardiographic abnormalities included bradycardia, AV block, prolonged QTc and prolonged JTc. The average duration of pacemaker utilization was 5.7 years (range 5 months to 14.5 years). Complications included infection (1 patient) and wire migration (2 patients). In the one patient with infection, the pacemaker was permanently removed. This patient then experienced multiple syncopal episodes and death. There were 7 other deaths. Three deaths occurred suddenly without preceding events, and 4 patients had non-cardiac causes of death. None of these 7 deceased patients had recurrence of syncope after pacemaker placement. In the 12 surviving patients, 6 had recurrence of syncope but none had cardiac arrest. Pacemaker placement may protect FD patients from fatal bradyarrhythmia and may decrease the incidence of syncope. However, data are limited and prospective analysis is needed.

Nausea and dysautonomic crises severely limit function and quality of life for a large number of individuals with familial dysautonomia. We treated a small cohort of 15 patients with familial dysautonomia who suffered frequent dysautonomic crises with pregabalin. Nausea and overt crises markedly decreased in 13 (87%) of these patients and the overall assessments of benefit were extremely favorable, suggesting that pregabalin may be a potentially useful therapeutic agent for this disorder.

The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IkappaB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IkappaB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.