Genetic breakthrough for rare disease

DNA find could help B12 deficiency

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."