• Article abstract
• Acknowledgment
• References

• Table 1
• Table 2
• Table 3
• Figure. Age-adjusted...

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.

Myotonic dystrophy (DM), an autosomal dominant disorder, is the most common adult form of muscular dystrophy. DM results from an unstable CTG-repeat expansion in the 3' untranslated region of a myotonin kinase gene at 19q13.3. 1 The clinical picture of DM includes ptosis and weakness of the facial, jaw, and anterior neck muscles, distal weakness of the limbs progressing to proximal weakness, myotonia, and involvement of other systems such as cataracts or cardiac conduction defects. 2 The prevalence of DM ranges from 2.1 to 14.3 per 100,000 population worldwide, but has a prevalence of 189 per 100,000 population in the Saguenay-Lac-Saint-Jean (SLSJ) region (Quebec, Canada) where a common ancestor couple has been identified. 3

There is a high risk of dying from congenital DM in the neonatal period. 4 However, there is only one study on mortality in other DM phenotypes. 5 In the present study, specific causes of mortality were analyzed in a large cohort of DM patients followed for 10 years. Survival rates and relative risks of death were computed in relation to suspected mortality predictors, particularly in relation to the phenotype and the severity of the muscular involvement.

Methods. Patients. The study cohort included 367 DM patients followed at the Neuromuscular Clinic of the Complexe Hospitalier de la Sagamie (NMC) from 1984 to 1993. Given the referral system of our public health services, the DM patients followed at the NMC included almost all known DM patients living in the SLSJ area at the time of enrollment. Each patient met the diagnostic criteria for definite DM or obligate carrier. 6 During the current study, molecular confirmation of the diagnosis was obtained in 173 patients (47.1%), but all of them are related to a common ancestor couple. 3 Four patients were lost to follow-up.

Data collection. At the time of enrollment, charts were reviewed to determine the age at onset of DM symptoms, the sex of the affected parent, the DM phenotype, and the muscular weakness severity. Disease duration was defined as the delay between age at onset and time of enrollment. The DM phenotype, a categorical variable, was established according to the classification of Koch et al. 7 based on the age at onset of symptoms. Muscular weakness was determined using a simplified version of a previously published five-point muscular disability rating scale 8 based on the distal to proximal progression of the muscular involvement in DM; the muscular weakness, a categorical variable, was classified as no limb weakness, distal limb weakness, or proximal limb weakness.

Death certificates were reviewed to determine the cause of death. Deaths were coded according to the International Classification of Diseases, 9th revision. Autopsy was performed in 28 patients (37%).

Statistical analysis. Baseline characteristics in men and women were compared with the Mann-Whitney test and the [chi]² distribution. Analysis of variance was used to compare the age at death according to DM phenotype.

Mortality in DM patients was compared with mortality in the general population of the SLSJ region using the standardized mortality ratio (SMR), a ratio of observed-to-expected deaths. 9 The number of expected deaths was obtained by applying the 1987-1990 age-specific mortality rates of the SLSJ population. The latter rates were abstracted from regular publications of the Bureau de la Statistique du Québec.

Because few patients were lost to follow-up during the study, the cumulative incidence of deaths was a realistic estimation of the 10-year cumulative mortality risk. Kaplan-Meier survival curves were used to estimate the survival experience according to patient's baseline characteristics, and log-rank tests were used to test for differences in survival distributions. Cox proportional hazards models were used to take into account the simultaneous effect of age and of other predictor variables of survival identified by univariate analysis and to estimate the 10-year age-adjusted relative risks of death and confidence intervals (CIs). A p value less than 0.05 was considered significant. Statistical analyses were performed using the SPSS statistical software package. 10

Results. Baseline characteristics of the study population. The study population (n = 367) included 182 men and 185 women (table 1). The median age at enrollment was 33 years. The age at onset of disease occurred earlier in men (17 years) than it did in women (20 years) (p < 0.05). The median disease duration (12 years) was similar for men and women. Maternal transmission was identified in 44% of the 265 patients in whom the affected parent was known. Most of the patients had an early-adult (44%) or an adult (33%) phenotype of DM. Twenty-nine percent of the patients had no limb weakness, 36% had distal weakness, and 35% had proximal weakness.

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We examined six factors that may predict survival in DM patients, five of which were significant by univariate analysis: age (p < 0.0001), sex (p = 0.03), DM phenotype (p = 0.03), disease duration (p < 0.0001), and muscular weakness (p < 0.0001). The age-adjusted analysis using Cox regression models identified two significant predictors-DM phenotype (p = 0.007) and muscular weakness (p = 0.001).

DM phenotype. The mean age at death increased significantly with the age at onset of the disease and was 44.7 years for the childhood phenotype, 47.8 years for the early-adult phenotype, 55.4 years for the adult phenotype, and 63.5 years for the mild phenotype (F = 4.8, p = 0.005). No death was recorded among the 18 patients with the congenital form of DM; all these patients, except one, were less than age 21 years at enrollment. The ratio of observed-to-expected deaths was significantly increased for all these DM phenotypes except the mild one (table 3). DM phenotype was also significantly associated with survival (log-rank test, p = 0.003) (figure). Using the Cox regression model adjusted for age, the relative risk of death during the 10-year period was 4.4 (95% CI 1.7 to 11.1) times higher for the adult, 4.7 (95% CI 1.7 to 12.6) times higher for the early-adult, and 12.8 (95% CI 3.1 to 53.5) times higher for the childhood phenotype of DM than it was for the mild phenotype.

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Discussion. In the present study, the mortality in DM was 7.3 times higher than it was in an age-matched reference population. The mean age at death (53 years) was similar to that reported by Klein, 11 Grimm, 12 and deDie-Smulders 5 (51 to 54 years), but higher than that reported by Thomasen 13 and Bell 14 (44 years). Reardon et al. 4 showed, using life table analysis, that congenital DM patients have a 25% probability of dying before the age of 18 months and only a 50% chance to survive until the mid-30s. Our data confirmed Harper's 2 suggestion that the age at death is related to the age at onset of DM symptoms. Indeed, we found that age-adjusted survival was much lower in the childhood phenotype than it was in each of the adult phenotypes.

The high mortality due to pneumonia and acute respiratory failure in DM patients is not surprising, especially in those with proximal muscular weakness. These patients had a higher prevalence of chronic hypercapnic respiratory failure 15 and perioperative pulmonary complications (PPC). 16,17 In the present series, we found two deaths from PPC. Respiratory muscle weakness develops in parallel with the progression of limb weakness and is usually severe when proximal limb weakness supervenes. The weakness of mastication and swallowing muscles is usually superimposed on respiratory muscle weakness and leads to an increased frequency of aspiration and pneumonia. Indeed, the death certificates mentioned aspiration pneumonia in five patients. Besides the progressive disability of respiratory muscles that decreases the inspiratory capacity, abnormal central ventilatory control mechanisms contribute to the increased risk of alveolar hypoventilation in DM. 18-20

The excess in cardiovascular mortality may result from several factors. Alterations in left ventricular function are common in DM, and their severity is proportional to the clinical severity of muscle symptoms. 21 Although the prevalence of ischemic heart disease has not been reported to be increased in the DM population, 22 Moorjani et al. 23 reported a significant linkage disequilibrium between the APOE-[small element of]4 allele and DM among French Canadian families from the northeastern part of Quebec. Individuals with the APOE-[small element of]4 allele have a higher risk of myocardial infarction and coronary heart disease than those with the APOE-[small element of]3 allele. 24 However, because plasma concentrations of LDL cholesterol are lower in DM patients than in controls, 23 another mechanism than the APOE disequilibrium must be sought to explain the excess cardiovascular mortality in this population. Conversely, disturbances in cardiac conduction, a frequent finding in adults with DM, may compromise survival to cardiovascular ischemic events. 21,25 The risk of pulmonary embolism might be increased in DM patients with proximal limb weakness and compromised ambulation.

The occurrence of sudden death is well recognized in DM, but the true incidence of this problem is unknown. 26 Many patients have first-degree heart block and are particularly at risk for subsequent development of complete heart block and sudden death. Melacini 27 found that, even in asymptomatic DM patients, a conduction system deficit may be present; cardiac death (sudden death, left ventricular failure) may occur in approximately 12% of these patients. A higher rate of sudden death was found by Hiromasa et al. 28 (30%) and Nguyen et al. 22 (33%). As many as 20% of the patients died of cardiac dysrythmia in the series of congenital DM patients reported by Reardon. 4 The EKG remains a useful tool for the evaluation and follow-up of DM patients. 26,29,30 At the NMC, most of the DM patients were assessed with an EKG on a 1-year or 2-year basis. During the follow-up period, 13 of the 367 DM patients (3.5%) needed a pacemaker because of complete heart block; one died suddenly despite a functioning pacemaker and probably of ventricular fibrillation. The cumulative incidence of sudden death was 2.2% for the 10-year period in this unselected cohort for cardiac symptoms or disease; a higher figure may have been expected if no regular cardiac assessment had been done.

There was no convincing evidence of a general tendency to neoplasia in DM. 2 However, in the present study, cancer was slightly increased in the DM population, but no particular type of neoplasia was identified. Despite numerous case reports associating DM with several types of benign and malignant tumors, 31-33 only the prevalence of multiple pilomatricomas has been established to be higher in DM patients than in the general population. 34 Unstable DNA sequences, like the CTG-trinucleotide repeats found in DM, may cause alteration of tumor suppressor gene expression, alteration in coding features of proteins, or change in bystander oncogene expression such as that occurs with DNA methylation. 35 Our data may support the hypothesis that tumor suppression is impaired in DM.

Acknowledgment
The authors are indebted to Mrs. Carmen Bouchard and Mr. Marc Fiset from the Régie régionale de la santé et des services sociaux du Saguenay-Lac-Saint-Jean for providing data on Quebec life tables.

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