Survival in Duchenne muscular dystrophy

Objective:

To determine the survival in a population of German patients with Duchenne muscular dystrophy.

Patients and methods:

Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected.

Results:

67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 % to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years.

Conclusion and clinical relevance:

our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients.Key words: duchenne muscular dystrophy, survival, ventilation     

The Canadian experience with long-term deflazacort treatment in Duchenne muscular dystrophy

Deflazacort is the most commonly prescribed corticosteroid for the treatment of Duchenne muscular dystrophy in Canada. We review the long-term experience with deflazacort treatment at two centers in Canada; Montreal and Toronto. Deflazacort has benefitted both cohorts by prolonged ambulation, preserved cardiac and respiratory function, less scoliosis and improved survival. Common side effects in both cohorts include weight gain, decreased height and cataract formation. The Canadian experience supports the use of deflazacort in treating boys with Duchenne muscular dystrophy.     

Dermatomyositis developing in a Duchenne muscular dystrophy carrier

SIR, Duchenne muscular dystrophy (DMD) is the commonest musculardystrophy and its clinical manifestations are well recognized.Less commonly female carriers can become symptomatic, with symptomsranging from mild generalized weakness to inability to walk.Manifesting carriage of DMD is a rare but important cause ofproximal muscle weakness in females, but other diagnoses needto be excluded. A 42-yr-old lady presented with a lifelong history of fluctuatingproximal muscle weakness, fevers, clumsiness and falls. Herbrother had died at 19 yr     

Hypoxemia during sleep in Duchenne muscular dystrophy

Overnight polysomnography after acclimatization was performed on 14 patients with Duchenne muscular dystrophy (mean age, 18.3 yr; mean VC, 1.24 L). Despite their lack of sleep-related symptoms and normal daytime blood gas tensions, periods of hypopnea and/or apnea (H/A) were observed in all patients (mean frequency 9.6/h; range, 3.7 to 17.0; mean duration 23.1; range of means, 16 to 36 s). In 9 patients, between 0.5 and 12.3 oxygen desaturations of greater than 5% occurred per hour, with falls from a mean SaO2 baseline of 95.4 +/- 0.6% (SEM) to a mean nadir of 74.2 +/- 3.9% (range, 58 to 90). This desaturating group (n = 9) showed longer and more frequent H/A than did the 5 nondesaturators; the proportion of REM sleep occupied by H/A was 37.7 +/- 3.8% in the desaturating group compared with only 15.1 +/- 5.1% in the remainder (p less than 0.01). The severity of sleep-disordered breathing could not be reliably predicted from daytime pulmonary function test results, and only maximal static expiratory pressure appeared significantly lower in the desaturating group. Hypopneas were associated with reduced chest wall movement in all subjects, and with chest wall paradox in one; continued submental "inspiratory" EMG activity throughout "central" apneas in 2 subjects suggested that these episodes were not truly central in origin. Sleep hypoxemia is imputed in the progression of several chronic respiratory diseases, and its prevention in Duchenne and related neuromuscular diseases may influence morbidity and mortality.     

Drug screening in a zebrafish model of Duchenne muscular dystrophy

Two known zebrafish dystrophin mutants, sapje and sapje-like (sap(c/100)), represent excellent small-animal models of human muscular dystrophy. Using these dystrophin-null zebrafish, we have screened the Prestwick chemical library for small molecules that modulate the muscle phenotype in these fish. With a quick and easy birefringence assay, we have identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish without restoration of dystrophin expression. Three of seven candidate chemicals restored normal birefringence and increased survival of dystrophin-null fish. One chemical, aminophylline, which is known to be a nonselective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and up-regulate the cAMP-dependent PKA pathway in treated dystrophin-deficient fish. Moreover, other PDE inhibitors also reduced the percentage of affected sapje fish. The identification of compounds, especially PDE inhibitors, that moderate the muscle phenotype in these dystrophin-null zebrafish validates the screening protocol described here and may lead to candidate molecules to be used as therapeutic interventions in human muscular dystrophy.     

Non-compaction on autopsy in Duchenne muscular dystrophy

Left ventricular hypertrabeculation (LVHT)/non-compaction is frequently associated with neuromuscular disorders. Recently, LVHT has been detected in a 28-year patient with Duchenne muscular dystrophy. Here, the patho-anatomic findings of this patient are presented, which showed LVHT located within in the apex and the anterior and lateral wall, being the most demanded segments during systole. The septum and the left ventricular outflow tract were not involved. The patho-anatomic specimen also showed aberrant bands and false tendons, a frequent finding in hearts with LVHT. The patho-anatomic findings were in line with those of LVHT patients with or without neuromuscular disorders.     

Cardiomyopathy in Duchenne muscular dystrophy: pathogenesis and therapeutics

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by the absence of dystrophin, a sarcolemmal protein which links the cytoskeleton to the extracellular matrix by interacting with a large number of proteins. Heart failure is a classic complication of this disease. The authors review the pathogenesis and therapeutics of cardiac involvement in DMD.     

Sequence of cardiac changes in Duchenne muscular dystrophy

Boys with Duchenne muscular dystrophy (DMD) rarely have clinical evidence of myocardial dysfunction during life. Nevertheless, congestive heart failure is a frequent terminal event and autopsy invariably shows dystrophic myocardial involvement. Little is known regarding the progression of heart functional abnormalities in boys with DMD from birth to death. Therefore we have examined the hearts of 18 DMD boys aged 4 to 15 years with the following non-invasive methods: cardiovascular physical examination, electrocardiography, chest x-ray, serum enzymes, and echocardiography. Control subjects were 25 normal boys matched to their DMD counterparts by age and by body surface area. The dystrophic patients were divided into early (N = 9) and late (N = 9) DMD according to manual muscle testing of skeletal muscles. In early DMD, six of 23 cardiac indices differed from control boys; in the late stage, an additional five indices became abnormal. Early DMD was characterized by these abnormalities: tachycardia, large ECG R/S ratio in V1, augmented q wave voltages in Leads I, II, and V5 of the ECG, diminished contractile excursion of the left venticular posterior wall (LVPW) and interventricular septum, and decreased rate of relaxation of the LVPW. In late DMD additional cardiac abnormalities appeared: enlarged heart volume by x-ray, reduced cardiac ejection fraction, diminished change in left ventricular diameter from diastole to systole, reduced maximal systolic endocardial velocity, and decreased rate of circumferential fiber shortening as detected in the echocardiogram. Most of the cardiac abnormalities were revealed only by echocardiography, which is thus shown to be a sensitive method for monitoring the progression of cardiac dystrophy during the life span of the DMD child.     

Cardiac involvement in a female carrier of Duchenne muscular dystrophy

A 42 year-old female carrier of Duchenne muscular dystrophy (DMD) was referred with suspected subacute myocarditis and non-sustained ventricular tachycardia. Echochardiography and cardiac catheterization revealed severely reduced left ventricular function (LVF). Coronary artery disease was excluded. Cardiac magnetic resonance imaging showed transmural, intramural and subepicardial late gadolinium enhancement. Myocardial biopsy excluded viral infection and showed severe myopathic changes with abnormal expression of dystrophin and utrophin. Moleculargenetic analysis of the DMD gene revealed frameshift duplication of exon 2. The patient received conventional heart failure therapy, implantable cardioverter/defibrillator-implantation and prednisolone to attenuate cardiac degradation. 6 months later she had improved clinically though LVF was still severely reduced.     

进行性肌营养不良症基因诊断及家系分析

目的　在假肥大型进行性肌营养不良症家系中进行基因诊断与遗传咨询。方法　用多重聚合酶链反应方法扩增dystrophin基因 9对外显子 ,检测有无外显子缺失 ,用聚合酶链反应方法扩增位于dystrophin基因内含子及 5′、3′端的短串联重复顺序 ,所得产物进行等位片段长度多态性连锁分析。结果　在 2个肌营养不良家系中检测到外显子及重复顺序片段缺失 ,在 1个家系中仅发现重复顺序片段缺失 ,在 1例散发家系中未发现缺失。通过分析均得到正常染色体、致病染色体与有再发风险的染色体单体型。结论　多重聚合酶链反应与短串联重复顺序多态性分析方法 ,可在Duchenne型和Becker型肌营养不良家系进行基因诊断、携带者检测及遗传咨询。     

The heart in Duchenne muscular dystrophy: a non-invasive longitudinal study.

Sixteen boys with Duchenne muscular dystrophy (DMD) underwent serial investigations of echocardiographic left ventricular dimensions, systolic time intervals (STI), ECG and vectorcardiography (VCG). Spirometry with measurement of vital capacity and forced expiratory volume was also performed, as well as tests of muscle function. ECG was abnormal with high right precordial R-amplitudes even in the youngest patients. In contrast, VCG QRS area progressively diminished with age. STI and echocardiographic contractility indices decreased with increasing age. There was no clinically useful relationship between the various non-invasive variables on the one hand and results from skeletal muscle tests or lung function tests on the other, or between the different cardiac investigation methods. It is concluded that several non-invasive tests are needed during follow-up studies of Duchenne patients to evaluate the effects of treatment or assess prognosis.     

A female carrier of Duchenne muscular dystrophy complicated with cardiomyopathy

A 45-year-old female carrier of Duchenne muscular dystrophy (DMD) complicated with cardiomyopathy is described. She had no symptoms of muscle weakness or heart failure. Her chest X-ray film revealed marked cardiomegaly. Echocardiogram showed marked enlargement and severe hypokinesis of the left ventricle. In myocardial scintigraphic images, perfusion defects of the myocardium were revealed. Dystrophin immunostaining of myocardial biopsy specimens showed a mosaic pattern of dystrophin-negative and -positive fibers. Cardiomyopathy is sometimes the only clinical symptom in female carriers of DMD. They are thought to be in a high risk group for developing heart failure.     

Row-a-boat phenomenon: respiratory compensation in advanced Duchenne muscular dystrophy

BACKGROUND: "Row-a-boat" phenomenon (RBP) is a spontaneous upper-body movement in patients with advanced Duchenne muscular dystrophy (DMD), when sitting upright supported by a belt around the body in a wheelchair. However, the role of RBP has not been clarified. OBJECTIVES: To support the hypothesis that RBP is an abnormal pattern of respiration to compensate for the atrophied respiratory muscles in advanced DMD. PATIENTS AND METHODS: Age, degree of ventilator dependency, and blood gas and spirometry values of 12 patients with spontaneous RBP were compared to those of 8 patients without RBP. All patients were men, and all exhibited a comparable level of motor function (unable to ambulate). Spirometry was undertaken with an ambulatory pneumotachograph in six patients with RBP in two conditions: sitting with RBP and sitting without RBP. In the latter condition, because a patient's shoulders, neck, and head were manually restricted, RBP was prevented. RESULTS: We found that the patients with RBP were older (mean, 25.98 years vs 19.84 years), more dependent on mechanical ventilation (13.96 h/d vs 4.31 h/d), and had lower FVC and percentage of FVC (511.3 mL vs 762.5 mL and 13.37% vs 20.11%, respectively) than those without RBP. We also found that the frequency of RBP was identical with tidal breathing, and FVC was increased by 50.8% by simply allowing RBP. CONCLUSION: We conclude that RBP is a respiratory movement to compensate for the atrophied respiratory muscles in advanced DMD.