Scientific research has been carried out in Canadian regions in view of studying families presenting two new forms of ataxias
By Inge Meijer,
Bursary holder 2003-2005
Summary
My interest in biology and particularly in human genetics developed while I was in high school and in my native country (Surinam), since some members of my family was afflicted with a cancer of which the origins are in some cases genetic. Afterwards, I had the privilege of continuing my studies at McGill University where in June 2000 I obtained a Bachelor’s degree in Science in molecular genetics/biology. In the course of the last year of my Bachelor’s degree, I registered for a specialized program (Honours program) which gave me the opportunity to work part-time in the laboratory of the neurogeneticist Dr. Guy A. Rouleau. The project which was assigned to me concerned the genetic characterization of familial spastic paraplegia in Quebec, a neurodegenerative disease which affects the legs of afflicted individuals.
In September 2000, I started my doctoral program in biology in Dr. Rouleau’s laboratory. I then continued the genetic work which I had already undertaken on familial spastic paraplegia and hereditary spastic ataxia. Hereditary spastic ataxia takes in a heterogeneous group of neurodegenerative diseases which are characterized by spasticity of the legs and a generalized ataxia. The principal project is directed towards the identification of a gene responsible for the disease which will also allow us to better understand its normal function in the nervous system. The nature of such a discovery would also help us to better understand the pathogenesis of ataxias and be used for the development of prenatal diagnostic tests and screening for individuals at risk.
For this study we followed three families, originally from the Avalon peninsula situated in Newfoundland, suffering form a dominant hereditary spastic ataxia. We have at our disposal DNA samples obtained from more than 60 patients. The clinical portrait of these families is quite variable. The majority of the patients were afflicted by an exaggeration of the tendinous reflexes of the lower limbs before the age of 20 years, followed by a combination of anomalies of the ocular movements, of involuntary movements of the head, of dyarthria and of dysphagia. Most of the patients experienced extreme difficulty to walk towards the age of 40 years but their life expectancy is not reduced. Existing neuropathology has allowed us to show that there is a degeneration of the tractus corticospinalis (a set of neurons which joins the cerebellar cortex (or the brain) with the motor neurons of the spinal chord) and the posterior limiting layer. Nonetheless, examinations by MRI of the brain and the spinal chord of the patients do not show anomalies. The similarity of the symptoms in these different families of Newfoundland as well as their geographical proximity, led us to formulate the hypothesis that there is only one single genetic anomaly responsible for this disease. Their distinct clinical diagnosis incited us to carry out an entire genomic screening by using only one of the families. A screening of the entire genome consists of an analysis of the genetic markers situated at regular intervals on the totality of the DNA in order to identify the chromosome which is transmitted only to the affected individuals – an analysis of the link. This genomic screening directed us towards chromosome 23p13 and more profound analyses showed that the critical region stretches on around 6 million bases and contains 48 genes. All these genes were classified according to their level of expressivity in the central nervous system and their functional pertinence as regards hereditary spastic ataxia. The analysis of each of the candidate genes in the different patients is presently in course and it will be followed until the responsible mutation is identified. One point to bring up is the fact that the three Newfoundland families share an identical part of chromosome 12, which supports our hypothesis that the disease is caused by a common mutation. We are also continuing our collection of samples from families afflicted with dominant hereditary spastic ataxia. We have recently identified a fourth family from Nova Scotia. This family shares the critical region already established in the individuals from Newfoundland and this genetic similarity suggests that there are ancestral relationships between the 4 families. After the identification of the mutation, we foresee studying the function of the gene involved by using cellular culture systems and model organisms (fruit fly, striped fish, etc.) with the goal of finding the physiopathological mechanism which brings about the disease.
I would like to thank McGill Universityand the Research Institute of CUSM and CAFA (2003-2005) for their financial support and for their interest in our research work concerning spastic ataxia during all this period. We also thank the families who participated in this project. Many thanks to Mrs. E. Meijer and Dr. P. Dion for translating this document.
My publications :
- Grewal KK. Stefanelli MG IA, Hand CK, Rouleau GA, Ives EJ, A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy. Am J Med Genet A. 2004 Dec 155, 13 (3) : 249-54
- Meijer IA, Hand CK, Grewal KK. Stefanelli MG Ives EJ Rouleau GA. A locus for autosomal dominant hereditary spastic ataxia, SAX 1, maps to chomosome 12p13. Am J Hum Genet 2002 Mar, 70(3). 763-9