Genetic discovery for a rare disease in Newfoundland

By Sharon Gray | Sept. 13, 2012

The genetic cause of a rare disease reported only in patients originating from Newfoundland has been identified by researchers in Montreal, based on collaboration with researchers and clinicians at Memorial University’s Faculty of Medicine.

This condition, hereditary spastic ataxia, is characterized by lower-limb spasticity (or stiffness) and ataxia (lack of co-ordination), the latter leading to speech and swallowing problems, and eye movement abnormalities.

The disease is not deadly, but people start developing gait problems between 10 to 20 years of age and have to use the assistance of a cane in their 30s. In the most severe cases, people with this disease go on in their 50s to use other mobility devices such as a wheelchair.

It has been shown that hereditary spastic ataxia is transmitted from the affected parent to the child in a dominant fashion, which means there is a 50 per cent chance of the child having the mutation.


Over a decade ago, researchers and clinicians from Memorial University contacted Dr. Guy Rouleau, director of the Centre hospitalier universitaire Sainte-Justine and the Centre hospitalier de l'Université de Montréal, and professor of medicine at the Université de Montréal.

The families in Newfoundland have been recognized for a long time. Early pioneers at Memorial were Dr. William Pryse-Phillips and Dr. Elizabeth Ives. Dr. Pryse-Phillips was the neurologist responsible for many family members throughout the 1980s and 1990s and Dr. Ives was director of Medical Genetics and involved in this critical aspect of the clinical care of the families for many years. Dr. Kathy Hodgkinson assessed these families intensively during the first years of her time in Newfoundland, expanding the family trees, digitizing them, collecting the phenotypic data and the DNA for the laboratory in Montreal, a role that was taken on and expanded by Dr. Kanwal Richardson who continued to ascertain and develop our understanding of the families throughout the later 2000s, alongside Dr. Mark Stefanelli who is now the principal neurologist involved with family members and Dr. Bridget Fernandez, current director of Medical Genetics. 

Dr. Inge Meijer, a former doctoral candidate in the Rouleau Laboratory, discovered that these families were ancestrally related, and in 2002, identified the locus (DNA region) containing the mutation causing HSA.

A few years later, Cynthia Bourassa, lead author of the study, took over Meijer's project.

"I re-examined some unresolved details using newer and more advanced methods," explained Ms. Bourassa, who is a master's student in the Faculty of Medicine at the University of Montreal. She then teamed up with Dr. Nancy Merner, who after obtaining her PhD at Memorial University, moved to Montreal to further her career in genetic research.

"It is an honour to be a part of this study and impact the lives of my fellow Newfoundlanders,” said Dr. Merner. “I knew coming into the Rouleau Laboratory that the genetic factors of the hereditary spastic ataxia families had not yet been identified. In fact, I asked about them on my first day of work, shortly after which I teamed up with Cynthia and we found the gene."

The gene harbouring the mutation is VAMP1, encoding the synaptobrevin protein.

"Not only was the mutation present in all patients and absent from all population controls, but also, synaptobrevin is a key player in neurotransmitter release, which made sense at the functional level as well," said Ms. Bourassa.

In fact, the authors believe that this mutation in the VAMP1 gene may affect neurotransmission in areas of the nervous system where the synaptobrevin protein is located, causing the unique symptoms of hereditary spastic ataxia. In other words, there are not enough messengers released, so nerves cannot function optimally.

"The discovery will benefit the families affected with this extremely debilitating disorder," said Dr. Rouleau. "A genetic diagnostic test can be developed, and genetic counselling can be provided to family members who are at risk of developing the disease or having children with the condition."

Identification of the VAMP1 mutation was made in the Guy Rouleau Laboratory in collaboration with investigators from Newfoundland, Nova Scotia and Ontario. Funding was provided by the Canadian Institutes for Health Research, the Canada Research Chair, and the Jeanne-et-J.-Louis-Levesque Chair for the Genetics of Brain Diseases.



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