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OBJECTIVES: Cardiac involvement has been reported in carriers of dystrophin mutations giving rise to Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). The progress of these abnormalities during long-term follow-up is unknown. We describe the long-term follow-up of dilated cardiomyopathy (DCM) in DMD/BMD carriers. METHODS: A long-term follow-up study was performed among Dutch DMD/BMD carriers first analyzed in 1995. A cardiac history was taken, and all carriers were assigned a functional score to assess skeletal muscle involvement. Electrocardiography and M-mode and 2-D echocardiography were performed. DCM was defined as an enlarged left ventricle with a global left ventricle dysfunction or fractional shortening less than 28%. Slow vital capacity of the lung was measured by a hand-held spirometer. RESULTS: Ninety-nine carriers were monitored with a median follow-up of 9 years (range 7.0-10.6 years). Eleven carriers with DCM (10 DMD, 1 BMD) were identified. Nine of them developed DCM in the follow-up period. One of the patients with DCM reported in the 1995 study died of cardiac failure at age 57 years. DCM was more frequently found in carriers who were functionally symptomatic. CONCLUSION: Cardiac abnormalities in DMD/BMD carriers are progressive, as in patients with DMD/BMD.

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A 34-year-old pregnant patient, admitted with severe pre-eclampsia and the 'haemolysis, elevated liver enzymes, low platelets' (HELLP) syndrome at 31 weeks gestational age, was treated with magnesium sulphate for imminent eclampsia. The further management was aimed at prolonging gestation. During treatment, a delirium developed with myoclonus. As the foetal condition deteriorated, caesarean section was performed. Afterwards, the delirium proved to have been due to hypocalcaemia. After appropriate treatment the patient recovered. In pre-eclampsia, the calcium metabolism is disturbed. Hypermagnesaemia inhibits parathyroid hormone secretion and can therefore cause hypocalcaemia. In rare cases, this may cause a delirium, which is unusual in pre-eclampsia. If the clinical (neurological) picture in a pregnant woman with severe pre-eclampsia, who is receiving treatment with magnesium sulphate, is not fully understood, hypocalcaemia should be considered.

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Duchenne and Becker muscular dystrophy are caused by a mutation in the dystrophin gene, located on the short arm of the X chromosome. Three so called dystrophinopathy patients, a women aged 54 and two men aged 23 and 21 years, suffered from a severe dilated cardiomyopathy. Such a cardiomyopathy can develop in both carriers and patients. In addition, it is often more important for prognosis than muscle weakness. For these two reasons it is important to screen both groups for (early) cardiological abnormalities. If these are present, regular follow-up is necessary to start timely therapy. When cardiological investigations yield normal results, it is advised to screen carriers with a five-year interval. Dystrophinopathy patients should be checked every year, because the cardiomyopathy sometimes develops and deteriorates over a short period of time. Patients with dilated cardiomyopathy and with a positive family history for dilated cardiomyopathy, muscle weakness or high serum creatine kinase activity should be screened for a mutation in the dystrophin gene.

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A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1) to estimate the frequency of electrocardiographic (ECG) and echocardiographic abnormalities; (2) to establish the proportion of carriers with dilated cardiomyopathy and (3) to assess possible associations between dilated cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers, aged 18-60 years, were traced through the files of the central register kept at the department of Human Genetics in Leiden. Investigations included full medical history, physical examination, ECG and two-dimensional and M-mode echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%, BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%, BMD 16%). Only 38% had a completely normal investigation of the heart. We found no association between genotype and cardiac manifestations. Our study underlines that cardiac involvement is part of the dystrophinopathies. Carriers should be told about the increased risk of this complication when asking genetic advice. It also implicates that a complete cardiological evaluation should be performed at least once in all carriers. If left ventricle dilatation or dilated cardiomyopathy is present a yearly follow up is needed, in order to start timely therapy.

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BACKGROUND: Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of definite carriers to estimate the proportion and to assess the clinical profile of carriers with symptoms. We also assessed a possible correlation between genotype and phenotype. METHODS: Carriers of DMD and BMD, aged 18-60 years, were traced through the files of the central register kept at the Department of Human Genetics in Leiden, Netherlands. For each carrier who agreed to participate a medical history was taken, and muscle-strength assessment by hand-held dynamometry and manual muscle testing and cardiological assessment were done. FINDINGS: 129 carriers of muscular dystrophy (85 DMD, 44 BMD) participated in the study. In 90 women from 52 (70%) families, 37 different mutations were found. 28 (22%) women had symptoms. 22 (17%) had muscle weakness, varying from mild to moderately severe. Muscle weakness was found in carriers of DMD and BMD, but dilated cardiomyopathy was found only in seven (8%) carriers of DMD, of whom one had concomitant muscle weakness. There was an unexpectedly high proportion of left-ventricle dilation (18%). No genotype-phenotype correlation was found. INTERPRETATION: Clinical manifestation of muscle weakness, dilated cardiomyopathy, or both can be found in about a fifth of carriers of DMD and BMD. If left-ventricle dilation is taken into account, the proportion of carriers with symptoms is even higher, amounting to 40%.

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We evaluated the course of cardiac involvement in 27 previously reported patients with Becker muscular dystrophy (BMD) originating from nine kindreds. Since almost all affected individuals of each kindred were included, intrafamilial variability could be studied. We also attempted to identify associations between cardiac involvement, functional ability and mutations at DNA level. The mean follow-up period was 12.5 years. The number of patients with electrocardiographic abnormalities progressed from 44% to 71%. Dilated cardiomyopathy (DCM) with or without congestive heart failure was now present in 33% as compared with 15% in the previous study. In addition, 22% developed borderline echocardiographic abnormalities. Six patients (22%) became symptomatic and four patients died of congestive heart failure. In all families cardiac abnormalities were found. There was no association between DCM and mutation type. Despite equal functional motor ability, there was a considerable intrafamilial variation in cardiac involvement, even in brother pairs. We conclude that cardiac abnormalities are the rule and not the exception in BMD and are progressive over time. Left ventricular dilatation may begin at any moment in the course of BMD and the rate of progression is unpredictable. A substantial proportion of patients will develop an incapacitating and life-threatening DCM.

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The clinical features and disease course of six patients from a family with autosomal dominant inheritance of presenile dementia and a hypokinetic syndrome are described. In the past, these patients have carried diagnoses of Pick's disease, Huntington's disease, Parkinson-dementia, and one patient was described as suffering from a 'peculiar type of presenile dementia' in a case report. In the two cases examined, the most distinctive neuropathological features were extensive globular deposits of periodic acid-Schiff plus diastase (PAS)-positive material, having tinctural properties of amyloid only to a limited degree, in the cerebellum and cerebral cortex. These globules stained positively with antibodies against prion protein. Southern blot of MspI-digested genomic DNA showed an abnormal band of approximately 950 bp in all three patients from which material was available. Direct sequencing of the abnormal allele revealed an insert consisting of eight extra 24-nucleotide repeats in the patients, which was absent in a healthy first degree relative who was considered well beyond the age of onset of symptoms in this family. The nucleotide sequence of the abnormal insert of 192 bp was different from that of a previously described insert of equal length. Adding to previous descriptions of mutations in the prion protein gene, this report emphasizes the clinical, neuropathological and genetic heterogeneity of inherited prion disease.

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