The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia

Familial dysautonomia (FD) is a rare fatal autosomal recessive disease caused by a
deficiency of the protein IKAP.1 This results in a selective developmental defect that
affects mostly afferent (sensory) neurons including those in the dorsal root ganglia and
cranial nerves.2, 3 We have shown recently that the protein deficiency impairs the
development of afferent baroreceptor pathways, leaving the sympathetic efferent neurons
reduced in number but functionally active. This results in the complete failure to detect
and buffer fluctuations in blood pressure leading to volatile hypertension. In addition to
the afferent baroreflex pathways, the deficiency of IKAP during embroyogenesis also affects
the function of the chemoreflex pathways. As a result, patients fail to increase ventilation
adequately in response to hypoxia and hypercapnia.4 As well as the impairment of the
neurological mechanisms that regulate breathing, patients with FD also have a combination of
obstructive, restrictive and probably also neuromuscular lung disease. Failure to coordinate
swallowing results in recurrent bouts of aspiration pneumonia occurring from birth.5, 6
Imaging studies show that almost all patients with FD have bronchial wall thickening,
atelectasis and almost 30% have bronchiectasis7. Pulmonary function tests show air flow
limitation and associated lung restriction with reduction in diffusion capacity12. Sudden
attacks of asthma like wheezing are common 8 and frequently associated with emotional
upset,5 a time when sympathetic outflow to the vasculature is increased heightened.3 There
is also a component of restrictive lung disease, with a very high incidence of scoliosis,
which frequently begins at an early age. Complicating matters further, many patients opt to
undergo spine fusion surgery, 9 which could potentially worsen further chest wall
compliance.10 Patients with FD also lack muscle spindles, 2 making it likely that they have
neuromuscular abnormalities arising from the absence of proprioceptive feedback from the
respiratory muscles involved in the coordination of breathing.

Severe respiratory disease is a leading cause of death in patients with FD and many are
treated empirically with inhaled bronchodilators. It is not known, however, whether these
drugs are effective at reversing increased airway resistance. Hence, there is an urgent need
to understand if the short acting beta-2-adrenergic agonist albuterol and the
anticholinergic ipratropium, are effective bronchodilators. Furthermore, because treatment
with these agents has potential cardiovascular side effects, we will also analyze their
effects on blood pressure, heart rate and cardiac output.

Inclusion Criteria:

- 1. Diagnosis of familial dysautonomia (Riley-Day syndrome, hereditary sensory and
autonomic neuropathy type III) 2. Ages 12 and older: Bronchodilators are routinely
used in young children with FD therefore they should be included in this study. The
spirometry maneuver is highly dependent on patient cooperation and effort, and FD
patients already have limitations that make the spirometry maneuver more problematic
to perform such as difficulty with mouth closure and drooling. Therefore, we believe
age 12 is a suitable age for FD patients to be included in this study, though in the
general population reliable results can be obtained from the age of 6 and sometimes
even younger.

3. Patients using Albuterol or Ipratroprium will be included in the study but will be
instructed not to take the 24 hours prior to the testing. It is a common practice in
clinical medicine to withhold the inhalation drugs prior to performing pulmonary
function tests in order to evaluate the response to bronchodilators, an integral part
of the test. Patients with an acute respiratory exacerbation will not be enrolled,
as withholding bronchodilators would not be advisable.

4. Patients who are taking medications that might affect autonomic function such as
anti-hypertensives, beta-blockers, midodrine and florinef will be included in the
study and we will record current medication regimen and the time the medication was
taken.

Exclusion Criteria:

- 1. Patients who last used inhaled anti-cholinergics or beta-2-agonists within 4-half
lives of the drug.

2. Patients with an acute respiratory illness 3. Patients who have had lobectomies. 4.
Patients using oxygen therapy throughout the day. 5. Patients who are unable to comply
with the study requirements.