Address for correspondence: David Robertson, M. D., Autonomic Dysfunction Center, AA3228 Medical Center North, Vanderbilt University, Nashville, TN 37232-2195. Voice: 615-343-6499; fax: 615-343-8649.
David.robertson{at}mcmail.vanderbilt.edu
Ann. N.Y. Acad. Sci. 971: 506-514 (2002).
Norepinephrine and epinephrine are critical determinants of
minute-to-minute regulation of blood pressure. Here we review
the characterization of two syndromes associated with a genetic
abnormality in the noradrenergic pathway. In 1986, we reported
a congenital syndrome of undetectable tissue and circulating
levels of norepinephrine and epinephrine, elevated levels of
dopamine, and absence of dopamine-ß-hydroxylase (DBH).
These patients appeared with ptosis and severe orthostatic hypotension
and lacked sympathetic noradrenergic function. In two persons
with DBH deficiency, we identified seven novel polymorphisms.
Both patients are compound heterozygotes for a variant that
affects expression of DBH protein via impairment of splicing.
Patient 1 also has a missense mutation in DBH exon 2, and patient
2 carries missense mutations in exons 1 and 6. Orthostatic intolerance
is a common syndrome affecting young women, presenting with
orthostatic tachycardia and symptoms of cerebral hypoperfusion
on standing. We tested the hypothesis that abnormal norepinephrine
transporter (NET) function might contribute to its etiology.
In our proband, we found an elevated plasma norepinephrine with
standing that was disproportionate to the increase in levels
of dihydroxphenylglycol, as well as impaired norepinephrine
clearance and tyramine resistance. Studies of NET gene structure
revealed a coding mutation converting a conserved alanine residue
in transmembrane domain 9 to proline. Analysis of the protein
produced by the mutant cDNA demonstrated greater than 98% reduction
in activity relative to normal. The finding of genetic mutations
responsible for DBH deficiency and orthostatic intolerance leads
us to believe that genetic causes of other autonomic disorders
will be found, enabling us to design more effective therapeutic
interventions.
