A rating scale for the functional assessment of patients with familial dysautonomia (Riley Day syndrome).

OBJECTIVE: To develop a reliable rating scale to assess functional capacity in children with familial dysautonomia, evaluate changes over time, and determine whether severity within a particular functional category at a young age affected survival. STUDY DESIGN: Ten functional categories were retrospectively assessed in 123 patients with familial dysautonomia at age 7 years ± 6 months. Each of the 10 Functional Severity Scale categories (motor development, cognitive ability, psychological status, expressive speech, balance, oral coordination, frequency of dysautonomic crisis, respiratory, cardiovascular, and nutritional status) were scored from 1 (worst or severely affected) to 5 (best or no impairment). Changes over time were analyzed further in 22 of the 123 patients who were also available at ages 17 and 27 years. RESULTS: Severely impaired cardiovascular function and high frequency of dysautonomic crisis negatively affected survival (P < .005 and P < .001, respectively). In the 22 individuals followed up to age 27 years, psychological status significantly worsened (P = .01), and expressive speech improved (P = .045). From age 17 to 27 years, balance worsened markedly (P = .048). CONCLUSION: The Functional Severity Scale is a reliable tool to measure functional capacity in patients with familial dysautonomia. The scale may prove useful in providing prognosis and as a complementary endpoint in clinical trials.

Neuroimaging supports central pathology in familial dysautonomia.

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.

Pregabalin: a new approach to treatment of the dysautonomic crisis.

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.

IKBKAP mRNA in peripheral blood leukocytes: a molecular marker of gene expression and splicing in familial dysautonomia.

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.

Effect of physical countermaneuvers on orthostatic hypotension in familial dysautonomia.

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 40mmHg or diastolic BP by 30mmHg 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.

Fludrocortisone in patients with familial dysautonomia--assessing effect on clinical parameters and gene expression.

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.

Pacemakers in patients with familial dysautonomia--a review of experience with 20 patients.

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.