Genetic breakthrough for rare disease
DNA find could help B12 deficiency

Rosenblatt and Lerner-Ellis published an article
dedicated to Tirone in Nature Genetics.
Photos: CLAUDIO CALLIGARIS
http://www.mcgill.ca/reporter/38/08/rosenblatt/

James Martin

For McGill human genetics chair David Rosenblatt, the identification of the gene
responsible for a devastating disease is more than a medical breakthrough two
decades in the making - it's a lasting memorial to PhD student Jamie Tirone, who
died in May 2004.

Tirone worked in Rosenblatt's lab, analysing the DNA of patients with the cblC
type of combined homocystinuria and methylmalonic aciduria, an inherited disease
that impairs the body's ability to handle vitamin B12. Jordan Lerner-Ellis, a
friend and co-student, continued Tirone's project, ultimately identifying the
gene now known as MMACHC.

Vitamin B12, found exclusively in animal products, is crucial for synthesizing
red blood cells and maintaining the nervous system. It also keeps homocysteine
levels in check, reducing the risk of heart disease, stroke, and dementia.
Patients with cblC typically face anemia, developmental delay, visual impairment
and a high risk for seizures.

The disease usually becomes apparent during the first few months of life,
although adolescent or adult onset does occur. One-third of babies with early
onset symptoms of the disease die within the first year. The identification of
MMACHC allows doctors to diagnose the disease much earlier than previously
possible - usually within a week of birth. Earlier diagnosis dramatically
increases the survival rate.

"We're also able to assess, at the molecular level, whether family members are
carriers," says Rosenblatt. "This is important to know because if you're not a
carrier, even if someone in your family has the disease, you have no risk of
passing the disease to your children." There are also applications for
pre-natal, and pre-in vitro implant, diagnosis.

Worldwide, there are approximately 350 people living with the disease. Current
treatment involves twice-weekly injections of high vitamin B12 doses for life.
"The results are not superb," admits. Rosenblatt. "I'm not the type to overhype
things and we don't expect any improvements in the short term, but identifying
the MMACHC gene will hopefully lead to more effective treatments."

Working with the laboratory of James Coulton, Department of Microbiology and
Immunology, Rosenblatt's team used computer modelling to demonstrate the
similarity between the protein encoded by the MMACHC gene and a protein involved
in bacterial vitamin B12 metabolism. The information will contribute to
understanding how all humans use the vitamin.

"Diagnosis, risk assessment and treatment are obviously important for patients
and their families," says Rosenblatt, "but we're also learning how normal people
handle vitamin B12 - and knowing how vitamins work is of great general
importance.

"Vitamin B12 deficiency in adults is usually due to faulty absorption or
inadequate diet - for example, a strict vegan diet. In addition, vitamin B12
deficiency is more common in the elderly. The study of the rare diseases of
vitamin B12 metabolism teaches us a great deal about the mechanism whereby
vitamin B12 deficiency causes disease. Knowledge about how the vitamin works may
allow us to recognize earlier signs of deficiency in the general population."

Rosenblatt says the researchers relied greatly on the expertise of colleagues in
the Department of Human Genetics and the McGill University Genome Quebec
Innovation Centre. He credits the project's success to "the superb collaborative
environment at McGill."

"At a memorial service held for Jamie," he recalls, "Father Robert Clark
expressed the hope that someone else in the laboratory would take over the
project that was so important to Jamie. Jordan took up the challenge and with
hard work succeeded in finding the MMACHC gene."