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.