Cardiac sympathetic activity in 22q11 deletion syndrome.

The cathecholamines dopamine and noradrenaline share a common precursor in the
form of tyrosine. The conversion of tyrosine to dopamine/noradrenaline can be
decreased by the administration of alpha methylparatyrosine (AMPT), a
reversible tyrosine hydroxylase inhibitor. Administration of AMPT results in
lower concentrations of catecholamines in blood and urine. A deletion in
chromosome 22q11is frequently observed. This 22q11 deletion syndrome (22q11DS)
is characterised by a variable clinical phenotype with congenital heart, facial
abnormalities and behaviour problems. The gene responsible for the enzyme
catechol-O-methyl-transferase (COMT) lies in this deletion. COMT is one of
several enzymes that degrade catecholamines. Subjects with 22q11DS have only
one COMT gene and this may cause a disturbed degradation of catecholamines
compared with controls. After administration of AMPT dopamine metabolism is
more decreased in subjects with 22q11DS compared with healthy subjects. As COMT
is also involved in the degradation of noradrenaline it can be assumed that the
concentration of noradrenaline will decrease after admnistration of AMPT in
subjects with 22q11DS. This is important because there is a clear association
between a raised concentration of noradrenaline and heart arrhythmias. There
are several case reports suggesting that in people with 22q11DS there is a
relation between arrhythmias and an increased concentration of noradrenaline. A
recent publication describes a higher occurrence of sudden dead in a larger
cohort of patients with 22q11DS compared to controls. However, there is the
knowledge on cardiac sympathetic activity in these subjects is limited. Cardiac
sympathetic activity can be non-invasively visualised with
123I-meta-iodobenzylguanidine (123I-MIBG) scintigraphy. In this study we assume
that increased serum concentration noradrenaline will result in increased
cardiac sympathetic activity. It is expect that by depletion of cathecholamines
with AMPT the concentration of noradrenaline will decrease resulting in a
normalised sympathetic activity. The importance of this research lies in the
relation between raised cardiac sympathetic activity and possible fatal
arrhythmias. To what extent a raised cardiac sympathetic activity in 22q11DS is
associated with an increased risk on (fatal) arrhythmia is unknown.

The objective of this study is to investigate cardiac sympathetic ativity in
subjects with 22q11DS and the effect of catecholamine depletion.

Catecholamine depletion will be achieved by administration of the reversible
tyrosine hydroxylase inhibitor *-methylparatyrosine (AMPT). All subjects will
be given both AMPT and a placebo on two separte days. All subjects are blinded
for administration of AMPT/placebo. Before receiving any tablets, blood
examples will be collected and questionaires will be taken. After the
administration of the last tablet a second blood exemple will be collected and
questionaires will be taken again. The 123I-MIBG scans will be preformed 15
minutes and 4 hours after the last administration of AMPT/placebo.

- Possible side effects of AMPT are fatigue, rigidity (extrapyramidale
symptoms), restlessness and dysphoria. All side effects are reversibel.
- The amount of radiation that the subjects of our study are exposed to is
within the international limits. However, within the same year, subjects, as
participants to any other study, can not be exposed to additional radiation.
- To our knowledge no side effects have been reported of the administered MIBG.