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MUHC and McGill scientists identify gene for debilitating vitamin B12 disease

December 01, 2005

Scientists at the MUHC and McGill University have identified a gene responsible for a disease that impairs the body's ability to handle vitamin B12 and that may contribute to heart disease, stroke and dementia. The details of the CIHR and March of Dimes funded research are published in this week's issue of Nature Genetics. The research, which began more than 20 years ago, will allow doctors to perform earlier diagnosis, assess 'carriers' of the disease-Combined Methylmalonic aciduria (MMA) and Homocystinuria-and open the door to new and improved treatments for this debilitating disease.

"Although this disease sometimes starts in adolescence or adulthood, we usually diagnose this rare inability to process vitamin B12 in the first few months of life," says Dr. David Rosenblatt, Chairman of Human Genetics at McGill, Director of Medical Genetics in Medicine at the MUHC, Chief of Medical Genetics at the Jewish General Hospital and lead researcher of the new study. "Babies may have breathing, feeding, visual and developmental difficulties, older patients may develop sudden neurological disease."

Vitamin B12, which is found in all animal products-including dairy, eggs, meat, poultry, and fish-but not in plants, is vital for synthesis of red blood cells and maintenance of the nervous system. Vitamin B12 also helps control homocysteine levels in the human body. Homocysteine control is important because in excess this compound can increase the risk of heart disease, stroke, and dementia.

17 year-old Michael-a typical MMA and Homocystinuria patient-was diagnosed at 6-months of age, and has battled numerous medical challenges as a result of his condition. Michael is developmentally delayed, visually impaired and does not talk; he has suffered seizures since he was three years old, had a stroke by the age of seven and has since developed rheumatoid arthritis and scoliosis. Michael's diagnosis, which led the way to treatment involving injections of vitamin B12, was conducted at Dr. Rosenblatt's laboratory at the MUHC-one of only two centres in the world that perform these tests.

After more than 20-years of data collection, Dr. Rosenblatt, his student Jordan Lerner-Ellis and their team have now unlocked some of the secrets of this rare but debilitating condition. "Using over 200 patient samples, representing the majority of the world's 350 known cases, we have identified the responsible gene, called MMACHC," says Dr. Rosenblatt. "In collaboration with the laboratory of Dr. James Coulton, Department of Microbiology and Immunology at McGill, we used computer modelling to demonstrate the similarity between the protein encoded by the MMACHC gene and a protein involved in bacterial vitamin B12 metabolism." This new link between bacterial and mammalian species may help us better understand how humans use vitamin B12. Ultimately these discoveries have enabled us to develop early diagnosis and carrier assessment tests for the disease-something that was not previously possible.

"This discovery offers earlier diagnosis and treatment options for genetic diseases such as Methylmalonic aciduria and Homocystinuria. This represents a step toward improving the lives of those afflicted with such rare and devastating genetic diseases," says Dr. Roderick McInnes, Scientific Director of CIHR's Institute of Genetics. This breakthrough represents hope for Michael and his family, and many others that have been touched by this disease. "Michael is a very loving and caring child, who has had to overcome many challenges," says his mother Karen. "We are overjoyed that this research may one day give courageous children like Michael a fighting chance at a better quality of life."

McGill University