Claude Prévost

A 10-year study of mortality in a cohort of patients with myotonic dystrophy

Objective: To determine the age and causes of death as well as the predictors of survival in patients with myotonic dystrophy (DM). Methods: In a longitudinal study, a cohort of 367 patients with definite DM was followed for 10 years. Results: During the 10-year period, 75 of the 367 DM patients (20%) died. The mean age at death (53.2 years, range 24 to 81) was similar for men and women. Among these 75 patients, 32 (43%) died of a respiratory problem, 15 (20%) of cardiovascular disease, 8 (11%) of a neoplasia, and 8 (11%) died suddenly. The ratio of observed to expected deaths was significantly increased to 56.6 (95% confidence interval [CI] 38.7 to 78.0) for respiratory diseases, 4.9 (95% CI 2.7 to 7.7) for cardiovascular diseases, and 2.5 (95% CI 1.1 to 4.6) for neoplasms. The mean age at death was 44.7 years for the childhood phenotype of DM, 47.8 years for the early-adult, 55.4 years for the adult, and 63.5 years for the mild phenotype (F = 4.8, p = 0.005). The age-adjusted risk of dying was 3.9 (95% CI 1.3 to 11.0) times greater for a patient with a distal weakness and 5.6 (95% CI 2.2 to 14.4) times greater for a patient with proximal weakness as compared with a person without limb weakness. Conclusions: Life expectancy is greatly reduced in DM patients, particularly in those with early onset of the disease and proximal muscular involvement. The high mortality reflects an increase in death rates from respiratory diseases, cardiovascular diseases, neoplasms, and sudden deaths presumably from cardiac arrhythmias.

The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum

Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+–Cl− transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuals with ACCPN. Four distinct protein-truncating mutations were found: two in the French Canadian population and two in non–French Canadian families. The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional. Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system.

Myotonic dystrophy Clinical assessment of muscular disability in an isolated population with presumed homogeneous mutation

We evaluated the muscular disability of 295 patients affected by the adult form of myotonic dystrophy (DM) and living in the Saguenay-Lac-Saint-Jean region (Quebec, Canada). The patients are known to have a common ancestral couple, and a homogeneous DM mutation is presumed. Using a five-point muscular disability rating scale (MDRS), we confirmed, in each age group, the wide expressivity of the muscular involvement usually observed in DM. Based on the duration of the disease and the MDRS, we also found a great variation in the rate of disease progression. There were no significant relationships between the rate of disease progression and the sex of the patient, the sex of the affected parent, or the age at onset of the disease. Furthermore, there was an absence of association between the age at onset and the sex of the patient or the sex of the affected parent. The variable severity of the muscular involvement, and the absence of relationship between age at onset and rate of disease progression, suggest a multiallelic influence at the DM locus or at other loci.

Clinical characteristics of myotonic dystrophy type 1 patients with small CTG expansions

The authors report a genotype-phenotype correlation study in 102 patients with myotonic dystrophy type 1 carrying small CTG repeat expansions. Most patients carrying 50 to 99 CTG repeats were asymptomatic, except for cataracts. Myotonia, weakness, excessive daytime sleepiness, and myotonic discharges at EMG were significantly more present in the patients with 100 to 200 CTG repeats. These findings highlight different outcomes related to the expansion size, even among small CTG expansions.

Neuropathie sensitivo-motrice héréditaire avec ou sans agénésie du corps calleux : étude radiologique et clinique de 64 cas

: In 1971, Andermann and Andermann described an autosomal recessive syndrome found within the Charlevoix and the Saguenay populations (Quebec, Canada) characterized by agenesis of the corpus callosum (ACC) associated with motor and sensory neuropathy, mental retardation and dysmorphic features. A study of CT in 64 patients demonstrated a total ACC in 37 cases (57.8%), partial ACC in 6 cases (9.4%) and the presence of the corpus callosum in 21 cases (32.8%). The latter was confirmed by MRI in 3 cases. CT of patients without ACC revealed a high frequency of developmental or degenerative midline anomalies, particularly interhemispheric fissure enlargement and posterior fossa atrophy. The clinical presentation and the natural course of the neuropathy, the intellectual impairment and the behavioural manifestations are identical amongst individuals with or without ACC. Individuals with or without ACC are found within the same family and often within the same sibship. These observations support the hypothesis of a single genetic syndrome in which the constant manifestation is the motor and sensory neuropathy.

The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada

Mutations at the hexosaminidase A (HEXA) gene which cause Tay-Sachs disease (TSD) have elevated frequency in the Ashkenazi Jewish and French-Canadian populations. We report a novel TSD allele in the French-Canadian population associated with the infantile form of the disease. The mutation, a G→A transition at the +1 position of intron 7, abolishes the donor splice site. Cultured human fibroblasts from a compound heterozygote for this transition (and for a deletion mutation) produce no detectable HEXA mRNA. The intron 7+1 mutation occurs in the base adjacent to the site of the adult-onset TSD mutation (G805A). In both mutations a restriction site for the endonuclease EcoRII is abolished. Unambiguous diagnosis, therefore, requires allele-specific oligonucleotide hybridization to distinguish between these two mutant alleles. The intron 7+1 mutation has been detected in three unrelated families. Obligate heterozygotes for the intron 7+1 mutation were born in the Saguenay-Lac-St-Jean region of Quebec. The most recent ancestors common to obligate carriers of this mutation were from the Charlevoix region of the province of Quebec. This mutation thus has a different geographic centre of diffusion and is probably less common than the exon 1 deletion TSD mutation in French Canadians. Neither mutation has been detected in France, the ancestral homeland of French Canada.

Frequency of the IVS12+5G→A splice mutation of the fumarylacetoacetate hydrolase gene in carriers of hereditary tyrosinaemia in the French Canadian population of Saguenay-Lac-St-Jean

Hereditary tyrosinaemia type I (HTI), an autosomal recessive inborn error of metabolism, is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase. The highest incidence of HTI is observed in the Saguenay‐Lac‐St‐Jean region (SLSJ) (Québec, Canada), where 1 out of 22 individuals is thought to be a carrier. A splice mutation (IVS12+5G|adA) has recently been identified in this particular region. Here, we have determined the frequency of this mutation in a population of obligate carriers from the SLSJ region by allele‐specific oligonucleotide hybridization and a method using a restriction enzyme digestion. Over 95 per cent of the HTI carriers were found to have the IVS12+5G|adA splice mutation. Screening for this mutation based on the two methods reported here is thus a reliable and rapid way of detecting carriers of hereditary tyrosinaemia type I in that region at high risk.

Psychosocial impact of predictive testing for myotonic dystrophy type 1

In the Saguenay‐Lac‐Saint‐Jean region (Quebec, Canada), a predictive DNA‐testing program for myotonic dystrophy type 1 (DM1) has been available as a clinical service since 1988. From 1 to 12 years (median, 5 years) after receiving predictive testing, a total of 308 participants (44 carriers and 264 non‐carriers) answered a questionnaire to determine the psychosocial impact of this genetic testing. The main reasons for wanting to be tested were to learn if children are at risk for DM1 or for reproductive decision making (75%) and to relieve the uncertainty for themselves (17%). The majority of participants (96.1%) remembered correctly their test result. At the time of the survey, the perception of the general well‐being, the psychological distress (Psychiatric Symptom Index), and the self‐esteem (Rosenberg Self‐Esteem Scale) were similar in carriers, in non‐carriers, and in the reference (Quebec) population. When participants indicated a change in different aspects of their lives following predictive testing, it was perceived as a change for the better by non‐carriers and as a change for the worse by carriers. Nevertheless, for a majority of carriers and of non‐carriers, the test result did not bring changes in their lives. All respondents believed that predictive testing should be available for the at‐risk population and the vast majority of carrier and of non‐carriers would recommend the use of predictive testing to their family members. Predictive testing for individuals at‐risk of DM1 can be offered safely within a well‐organized clinical and genetic counseling program that includes careful pre‐test counseling, pre‐test clinical assessment, post‐test psychological support, and follow‐up for those identified as carriers.

Epidemiological surveillance of myotonic dystrophy type 1: A 25-year population-based study

This epidemiological study investigates the evolution of the prevalence and the phenotypes in a large cohort of myotonic dystrophy type 1 (DM1) patients living in the Saguenay-Lac-Saint-Jean (SLSJ) region (Quebec, Canada) over a 25-year period (1985-2010). In 1985, 406 patients with DM1 were known. From 1985 to 2010, 352 new DM1 patients were diagnosed and 321 patients died. During this period, we observed a significant ageing of the DM1 population, from a median age of 34.5years to 49.0years. The proportion of patients with an adult phenotype decreased significantly from 78% to 53% while the proportion of patients with a mild phenotype increased from 6% to 26%. Reasons for the ageing of the DM1 population and the changes in the distribution of DM1 phenotypes include the progressive lowering of total fertility rates over the last decades, a reduction of births at risk as a result of genetic counselling and prenatal diagnosis, and an increase in the number of mildly affected patients often recognised at an older age by predictive testing and molecular analysis. Although the DM1 prevalence remains very high in 2010 (158/100,000) in the SLSJ region, we observe a trend toward a decline in point prevalence rates over the last 10years.

Epidemiological study of ruptured intracranial aneurysms in the Saguenay-Lac-Saint-Jean region (Quebec, Canada)

BACKGROUND Using a population-based register of the Saguenay-Lac-Saint-Jean region (Quebec, Canada), the genealogical reconstruction of 533 individuals with intracranial aneurysm (IA) showed a familial aggregation (the presence of aneurysm in two or more first- to third-degree relatives) for 159 (29.8%) of them; this proportion is much higher than reported elsewhere. OBJECTIVE As part of an ongoing project to assess a genetic predisposition to intracranial aneurysms in the Saguenay-Lac-Saint-Jean population, the objective of the present study was to determine whether age-specific rates of reputed cerebral aneurysms were higher than in other populations. DESIGN A retrospective study of cases of proven ruptured IAs which were hospitalized during the 1973 to 1992 period was conducted. Age-adjusted rates were computed and compared to those reported in the Helsinki population. RESULTS We identified 412 cases of ruptured aneurysms. The age-adjusted incidence rate was 7.2/100,000/year (6.2 for men, 8.1 for women), which is similar to the incidence rates reported in other studies. Although the mean age at time of rupture was younger (46.6 years +/- 13.8) than usually reported, no increase in age-specific incidence rates was detected. CONCLUSIONS The results of this epidemiological study neither support nor reject the hypothesis of a genetic predisposition to intracranial aneurysms in the Saguenay-Lac-Saint-Jean population.