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 degrees 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 > or = 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). Fludrocortisone 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.