Mortality in Myotonic Dystrophy
abstract & commentary
Source: Die-Smulders CEM, et al. Age and causes of death in adult onset myotonic dystrophy. Brain 1998;121: 1557-1563.
Among 328 patients with myotonic dystrophy (MD) collected from 1950 onward and followed by two generations of neurologists in Southern Limburg, Netherlands, 180 were characterized as adult onset, between the ages of 10-50 years, of which 83 (47 men and 36 women) died by January 1997. Survival was calculated using the Kaplan-Meier method and was compared to survival tables for the Dutch population. Causes of death, known for 70, were divided into disease and non disease-related categories, and they were compared to expected frequencies for the general Dutch population.
Most patients (63%) died between the ages of 50-65 years, at a mean age of 54 years, 52 years for men, and 56 years for women (difference not statistically significant), with a median (50%) survival of 59 and 60 years for men and women, respectively. Survival to 45 years was slightly, but significantly, lower in the MD group than would be expected for the normal population, and survival to 65 years was a strikingly low 18% compared with an expected survival of 78%. Pneumonia (31%), arrhythmias (29%), fractures (7%), and postoperative complications (6%) were responsible for 73% of deaths (disease-related), whereas 27% died of non-disease related causes (malignancy in 10%, and other causes, including motor vehicle accidents, myocardial infarctions, stroke, and tuberculosis in 17%). Curiously, the frequency of malignancy among the MD patients was lower (10%) than in the general population (37%). Among 13 patients who underwent molecular analysis for the expanded CTG repeat on the long arm of chromosome 19, a weakly positive correlation was found between repeat length and younger age of death (P = 0.08).
Commentary
The myotonic dystrophy (MD) CTG repeat expansion on chromosome 19q13.3 is sandwiched between two genes, one encoding myotonic dystrophy protein kinase (DMPK), and the other myotonic dystrophy associated homeodomain protein (DMAHP). Although CTG repeat length appears to explain disease severity (Kinoshita M, et al. Muscle Nerve 1998;Suppl 7:S187), as well as the phenomena of anticipation and variable expressivity, it does not explain the preferential involvement of distal more than proximal muscles. Analysis of CTG repeat length revealed no differences between proximal (vastus lateralis) vs. more severely affected distal (tibialis anterior) muscles among four affected patients (Ansved T, et al. Muscle Nerve 1998;Suppl 7:S186). Preliminary evidence suggests that DMAHP, however, may play a significant role in MD pathogenesis (Winchester C, et al. ibid:S45).
Also presently unexplained is the alveolar hypoventilation seen in DM. Among eight MD patients diagnosed on clinical, electrodiagnostic, and muscle biopsy studies, as well as by molecular analysis of family members in five, quantitative immunohistochemical analysis of the autonomic respiratory center in the medullary reticular formation was performed post-mortem. Significant loss of tyrosine hydroxylase immunoreactive neurons was evident in the dorsal central, ventral central, and subtrigeminal medullary nuclei of three MD patients with a history of alveolar hypoventilation, but not in the five MD cases without such history, nor in 10 age-matched controls, both latter groups showing comparable neuronal density (Ono S, et al. Neurology 1998;51:1121-1124). Catecholaminergic neuronal dropout may play a central role in the respiratory insufficiency of DM patients.
Therapy for MD remains symptomatic but recent trials suggest that potential treatment may soon be available. Reviewing 19 studies, including 17 published reports, one paper in press involving an open trial using DHEA (an anabolic steroid), and one submitted-for-publication report, anabolic agents including insulin growth factor 1 (IGF-1), DHEA, and troglitazone, a drug used to overcome insulin resistance, appear to increase muscle mass and strength (Moxley RT, et al. ibid:S45). Full reports of these results should be forthcoming in the near future.
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