Personalised medicine using genomics shows patients can stop taking
3 February 2013
Genetic analysis of two children with an adrenal disease has
shown that they did not need to take one of the drugs they had been
taking for many years, saving costs and reducing potential side effects.
Using genome-wide analysis, investigators at the Sainte-Justine
University Hospital Research Center and the University of Montreal
have potentially eliminated a lifetime drug prescription that two
children with a previously unknown type of adrenal insufficiency had
been receiving for 14 years.
Over a lifespan, the adjustment in treatment represents an
approximate saving of $10,000 in drug and test costs per patient.
Moreover, the less invasive treatment regime can potentially reduce
the lifetime risk of hypertension in the patients.
“This is a real case of personalized medicine made possible today
through the use of novel techniques in genomics,” said Dr Mark
Samuels, lead author of a paper published on the subject in January
2013 in the Journal of Clinical Endocrinology and Metabolism. Dr.
Johnny Deladoëy was the senior author of the article.
Fourteen years ago both children were diagnosed with adrenal
insufficiency, a condition that occurs when the adrenal glands do
not secrete enough hormones to control sugar and mineral levels in
the blood. After having sequenced the part of the genome that codes
for genes in one patient, the investigators identified mutations in
POMC, the gene behind the disorder. They then showed that the
disorder in the second patient was also caused by a similar mutation
in the gene POMC.
Identifying the causal gene allowed them to conclude that the
only thing missing in the patients was the production of cortisol,
the hormone that regulates blood sugar. They thus advised the
patients to continue cortisol treatment, but that fludrocortisone
treatment was unlikely to be necessary. So far, fludrocortisone has
been stopped in one patient without any adverse effects, while the
condition of the second patient is still being evaluated.
In addition to reducing the risks of hypertension induced by
fludrocortisone and allowing the patients and their family to feel
more confident about the origin of the disease, the investigators’
discovery made it possible to reduce by as much as $10,000 the
health costs for patients with this type of adrenal insufficiency.
Over a 70-year lifespan, this is what the fludrocortisone treatment
and the blood tests required in the patients treated with it adds up
The physicians did not modify the treatment earlier in the
children’s lives due to lack of a clear molecular diagnosis hence an
imperfect understanding of the disease. Not only could withholding
one of the replacement hormones have potentially led to a fatal
outcome, but also analyzing the whole genome that led to the
diagnosis would have been unthinkable just a few years ago.
“Due to the astronomical costs associated previously with
analyzing the whole genome, certain genes had to be targeted that
were potentially responsible for the disorder and only these genes
were analyzed in spite of the risk of not finding the right gene,”
explains Dr. Samuels, a researcher in human genetics. Today, lower
genome analysis costs make an analysis of the whole genome
Surprise from genetic analysis
The two children in the study were hospitalized at the ages of 4
months or 4 years respectively, for hypoglycemia and associated
convulsions. A diagnosis of adrenal insufficiency was made and the
two children were saved by administering replacement hormones. Their
ACTH (the pituitary hormone that controls the adrenal gland) blood
concentrations were very high, which seemed to implicate the adrenal
The adrenal gland produces two vital hormones: cortisol to
regulate glycemia and aldosterone to control minerals. When in
doubt, in the event of adrenal insufficiency, both hormone types (cortisol
and fludrocortisone, an aldosterone analogue) are prescribed.
Nevertheless, fludrocortisone treatment can lead to side effects
such as hypertension.
Hoping to better target patient treatment, the investigators went
about tracking down the exact cause of adrenal insufficiency. They
proceeded to analyze part of the genome that codes for genes in one
patient’s DNA (whole-genome sequencing being still too expensive for
the time being).
To their great surprise, the analysis indicated the presence of
two mutations in POMC, the gene that codes for ACTH, in the patient.
Direct sequencing of the POMC gene in DNA from the second patient
confirmed the occurrence of one of the mutations in that child as
The researchers then collaborated with Dr. Michel Bouvier
(University of Montreal) and Dr. Nicole Gallo-Payet (University of
Sherbrooke) to validate the discovery by performing in vitro
tests on cells using two synthetic ACTHs produced for the
experiment: one normal and the other carrying the mutation observed
in both children. These studies showed that, while high levels were
detected in the blood, the mutant ACTH was inactive. Due to
technical limitations, the standard diagnostic test that detects
ACTH was unable to distinguish between the normal and the mutated
form found in the patients.
“The genome analysis allowed us to incriminate the POMC gene.
Since the gene was not suspect according to the blood tests, we
would have missed the cause of the disease without this new
technique,” concludes Dr. Deladoëy, a physician and researcher in
endocrinology and diabetology.
This case of personalized medicine made possible through novel
genomic techniques is just the tip of the iceberg. In the near
future, investigators hope to succeed in refining the treatment of
many patients using these techniques.
1. Samuels ME et al. Bioinactive ACTH Causing
Glucocorticoid Deficiency. JCEM jc.2012-3199;
About the study
The study was conducted as part of the Canadian Pediatric Genetic
Disorders Sequencing Consortium (FORGE Canada), which is funded by
the Canadian Institutes of Health Research (CIHR), Genome Canada,
Génome Québec, Genome British Columbia and the Ontario Genomics
Institute (OGI-049), with the participation of the McGill University
and Genome Quebec Centre for Innovation.