Marc De Braekeleer

Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada).

Saguenay-Lac-St-Jean is a geographically isolated region located in northeastern Quebec. Opened to the white settlement in 1838, its immigrants mainly came from Charlevoix, another isolated region of

Founder effect in familial hyperchylomicronemia among French Canadians of Quebec.

Familial hyperchylomicronemia has reached a high prevalence in the French Canadian population of eastern Quebec. The birth places of 58 carriers identified through the birth of one affected child clustered in three regions. The genealogies of these 58 individuals showed that no founder was common to all of them. Three sets of founders were found, one for each region, with little overlapping between two regions. These results strongly suggest that more than one mutation, introduced by the French migrants in the 17th century, are segregating in the French Canadian population. Perche, a region situated between Paris and Normandy, appeared to be the most likely putative center of diffusion of at least one mutation in the lipoprotein lipase gene segregating in the modern-day French Canadian population of Quebec.

Complete identification of cystic fibrosis transmembrane conductance regulator mutations in the CF population of Saguenay Lac-Saint-Jean (Quebec, Canada)

Over the past few years, we have conducted a systematic study of 230 cystic fibrosis (CF) chromosomes in the Saguenay Lac‐Saint‐Jean (SLSJ) population which has a high CF incidence (1/936 live births). We identified 11 mutations accounting for 100% of the CF chromosomes found in patients born in SLSJ. Our results indicate that denaturing gradient gel electrophoresis (DGGE) is a powerful method of identifying CF mutations. They have also considerable implications for genetic counselling and molecular characterization of doubtful patients. They make carrier screening technically feasible in this population.

Geographic distribution and genealogy of mutation 207 of the lipoprotein lipase gene in the French Canadian population of Québec

SummaryMutations in the lipoprotein lipase (LPL) gene, leading to partial or total inactivation of the enzyme, result in a hereditary clinical syndrome called familial LPL deficiency. The French Canadian population, which is primarily and historically located in the province of Québec, has the highest worldwide frequency of LPL-deficient patients. We have analyzed the prevalence, spatial distribution, and genealogy in the Québec population of a LPL gene mutation, M-207 (P207L in conventional notation), which changes the amino acid proline to leucine in position 207 of the LPL protein and inactivates the enzyme. Our results show that M-207 is the most prevalent LPL gene mutation among French Canadians and accounts for the largest proportion of LPL-deficient patients in this population. Genealogical reconstruction of French Canadian LPL-deficient patients point to 16 founders of M-207, all of whom migrated to Québec in the early seventeenth century from the north-western part of France, especially from the region of Perche. Most of the carriers of M-207 are, at present, found in the Charlevoix, Saguenay-Lac-St-Jean regions of eastern Québec. On the basis of the number of homozygote M-207 LPL-deficient patients so far identified, we estimate that there are at least 31,000 carriers of this mutation in the province of Québec. This constitutes a large pool of individuals at risk for atherosclerosis and other lipid-related diseases, since LPL deficiency is considered to be a significant contributing factor in the etiology and development of these diseases.

Prevalence, geographical distribution and genealogical investigations of mutation 188 of lipoprotein lipase gene in the French Canadian population of Québec.

Bergeron J, Normand T, Bharucha A, Ven Murthy MR, Julien P, Gagné C, Dionne C, De Braekeleer M, Brun D, Hayden MR, Lupien PJ. Prevalence, geographical distribution and genealogical investigations of mutation 188 of Hpoprotein lipase gene in the French Canadian population of Québec. Clin Genet 1992:41: 206–210.

Herpes simplex virus and human papillomavirus sites correlate with chromosomal breakpoints in human cervical carcinoma

The distribution of 1,912 breakpoints observed in a series of 148 cervical cancers was analyzed. Fifty bands were shown to be nonrandomly involved in chromosome structural rearrangements. One hundred thirty-three breaks were noted in bands known to contain a human papillomavirus integration site, and 454 breaks were noted in bands containing a herpes simplex virus breakage site. We suggest that herpes simplex viruses and, possibly, papillomaviruses play an important role in the carcinogenesis and/or development of cytogenetic abnormalities in cervical cancers.

Genetic epidemiology of cystic fibrosis in Saguenay-Lac-St-Jean (Quebec, Canada)

Cystic fibrosis (CF) is an autosomal recessive disorder with a prevalence at birth estimated at 1/2000–1/2500 livebirths in Caucasian populations. Some 127 CF individuals are known in Saguenay‐Lac‐St‐Jean (SLSJ), a geographically isolated region of Quebec. The prevalence at birth was estimated at 1/902 live borns, and the carrier rate was estimated at 1/15 inhabitants in the SLSJ region. The mean inbreeding coefficient was only slightly elevated in the CF group compared with three control groups, and was due to remote consanguinity. The mean kinship coefficient was 2.4 times higher in the CF group than in the control groups. In SLSJ region, the places of origin of the CF individuals and their parents did not show a clustered nonuniform distribution. Endogamy was not higher in the CF group than in control groups.

Stroke-like episodes in autosomal recessive cytochrome oxidase deficiency.

Stroke‐like episodes, defined as periods of acute localized neurological dysfunction during which brain imagery suggests cerebral ischemia but vascular anatomy is normal, occurred in 3 patients with autosomal recessive Saguenay‐Lac St‐Jean (SLSJ) cytochrome oxidase (COX) deficiency. The patients developed focal neurological deterioration and frontal hypodensities on cerebral computerized tomography (CT). Arteriography, performed in 1 patient during an acute episode, showed normal vascular anatomy. Nevertheless, capillary shunting was evident both in regions that appeared abnormal on the initial cerebral CT study and in regions that appeared normal but subsequently developed Leigh disease. Stroke‐like episodes did not exacerbate systemic acidosis, and acidotic decompensations occurred independently of stroke‐like episodes. In conclusion, stroke‐like episodes occur in autosomal recessively inherited congenital lactic acidoses as well as in those caused by mitochondrial DNA mutations. In some cases, acute localized neurovascular changes occur in regions that subsequently develop Leigh disease. Ann Neurol 1999;45:389–392

Fertility in myotonic dystrophy in Saguenay-Lac-St-Jean: a historical perspective.

Myotonic dystrophy (MD) is an autosomal dominant disorder that has a high prevalence in Saguenay‐Lac‐St‐Jean. A case‐control study, based on a population register, of 373 MD patients who married in this region between 1855 and 1971 was conducted to determine whether their fertility was affected by the disorder. Six demographic parameters, that is the number of children, the age at marriage, the ages at the time of birth of the first and the last child, the interval between the marriage and the birth of the first child, and the interval between consecutive births, were analyzed. The mean number of children born to MD and control individuals was not different (P>0.05). However, MD males had more children than MD females although they have started delaying their marriage since 1921. Fertility fell significantly in both the MD and control groups during the period of observation. This change reflects the decline in fertility of French Canadians in general during this period, but mainly after 1940.

CORRELATION OF SWEAT CHLORIDE CONCENTRATION WITH GENOTYPES IN CYSTIC FIBROSIS PATIENTS IN SAGUENAY LAC-SAINT-JEAN, QUEBEC, CANADA

OBJECTIVESnSaguenay Lac-Saint-Jean, a geographically isolated region of northeastern Quebec has a high incidence of cystic fibrosis (CF) and three mutations only account for 94% of the CF chromosomes. The objective of the present study was to determine whether different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene had different effects upon the sweat chloride concentration.nnnDESIGN AND METHODSnThe sweat chloride concentration of 114 patients was measured by quantitative pilocarpine iontophoresis.nnnRESULTSnCF patients carrying the A455E mutation, usually associated with pancreatic sufficiency, had lower sweat chloride concentrations than those carrying mutations associated with pancreatic insufficiency (delta F508 and 621 + 1G-->T).nnnCONCLUSIONSnOur results confirm that mutations resulting in a reduction of the chloride current at the apical membrane of epithelial cells induce lower sweat chloride values. However, there are differences in the chloride current between genotypes, even if they are composed of mutations apparently having the same functional effect.