Dopamine-*-hydroxylase deficiency and cognitive function

In recent years, cognitive neuroscientists have become increasingly interested
in understanding the role in cognition of the locus coeruleus-norepinephrine
neuromodulatory system (i.e., the noradrenergic system). One way of
investigating the noradrenergic system in humans is by examining cognitive
abilities in patients with abnormal noradrenergic function. A particularly
interesting group in this regard are patients with dopamine-*-hydroxylase (D*H)
deficiency. This is a rare genetic syndrome that is characterized by a complete
lack of norepinephrine, due to the congenital absence of the enzyme D*H. This
enzyme is responsible for the conversion of dopamine into norepinephrine and in
view of the total absence of this enzyme, patients with this syndrome are
unable to synthesize any norepinephrine from dopamine. In this study, we will
test some of these patients on a battery of cognitive tasks that have been
proposed to depend on normal noradrenergic function. In addition, EEG and MRI
data will be collected. The patients will be tested ON and OFF medication, on
separate occasions. The results will be highly informative about cognitive
function in D*H deficiency, and, more in general, about the role of the
noradrenergic system in cognition.

The main objective is to understand the role of the noradrenergic system in
human cognition by testing specific hypotheses about task performance in D*H
patients. A secondary objective is to understand whether and how cognitive
function is compromised in D*H deficiency.

The study uses a quasi-experimental design. Patients will be tested ON and OFF
medication, on separate occasions. A matched healthy control group will also be
tested twice, in order to establish normal performance scores, and practice
effects across the two test sessions.

Risk of non-invasive measurements: The risks associated with the cognitive
tasks and EEG recording procedures are negligible. There are also no known
risks associated with MRI. This is a noninvasive technique involving no
catheterizations or introduction of exogenous tracers. Some people become
claustrophobic while inside the magnet and in these cases the study will be
terminated immediately at the subject's request. The only absolute
contraindications to MRI studies are the presence of intracranial or
intraocular metal, or a pacemaker. Relative contraindications include pregnancy
and claustrophobia. Subjects who may be pregnant, who may have metallic foreign
bodies in the eyes or head, or who have cardiac pacemakers will be excluded
because of potential contraindications of MRI in such subjects.
Burden of invasive measurements: The only invasive procedure will be
venapuncture. This has the usual risk of discomfort upon insertion of the
needle and of hematoma.
Risk of stopping medication: stopping L-DOPS will cause levels of
norepinephrine to fall to non-measurable low values. A gradual recurrence of
orthostatic symptoms (fatigue and vertigo) will follow, In our experience this
develops only slowly. Patients recognize these symptoms well, given that they
have lived into adulthood without effective treatment. With proper
instructions, probably self-evident for these patients, orthostasis will not be
dangerous or detrimental in any way.