Detection of carriers for duchenne muscular dystrophy. Quality control of creatine kinase assay

Summary A report by Bullock and coworkers has emphasized the need for standardization of the CK assay in carrier detection for DMD. A collaborative study, according to a well-specified design and involving two laboratories in Paris and Lyon, indicates that the reliability of this assay can be improved provided that special attention is paid to information about participating subjects, laboratory protocol, and repeated sampling. On a random sample of young women, mean and variance of 1n(CK) are 1.66 and 0.015 respectively. Within and between variance components are in a 3:4 ratio, homogeneous between populations. Additional use of a common test serum should insure good reliability of this assay among laboratories.     

Use of creatine kinase for detecting severe X-linked muscular dystrophy carriers.

Women thought to be at risk of being carriers of Duchenne muscular dystrophy were given "odds" against their having an affected child. These were calcuated from a combination of the genetic risk from the family history and an estimation of the biochemical risk from measuring the serum creatine kinase concentration. The women were told the actual risk estimate and it was put into perspective for them as a high, medium, or low risk. Of 25 women at high risk six have had children, all girls; the two in the medium-risk group have had no children; and the 46 women at low risk have had 19 boys and 25 girls. None of the boys has the disease. With detailed counselling most potential carriers of this disease reach decisions in child bearing that are in line with their degree of risk.     

Cell based therapy for duchenne muscular dystrophy

Mutations in the dystrophin gene cause an X‐linked genetic disorder: Duchenne muscular dystrophy (DMD). Stem cell therapy is an attractive method to treat DMD because a small number of cells are required to obtain a therapeutic effect. Here, we discussed about multiple types of myogenic stem cells and their possible use to treat DMD. The identification of a stem cell population providing efficient muscle regeneration is critical for the progression of cell therapy for DMD. We speculated that the most promising possibility for the treatment of DMD is a combination of different approaches, such as gene and stem cell therapy. J. Cell. Physiol. 221: 526–534, 2009. © 2009 Wiley‐Liss, Inc.     

Enhanced urinary spontaneous luminescence in duchenne muscular dystrophy

Urinary spontaneous visible luminescence is enhanced in children with Duchenne Muscular Dystrophy (DMD). This result is indicative of systemic oxidative stress in DMD patients. It is proposed that measurement of the urinary luminescence could be employed to follow the progress of the disease, as well as the response of the patients to antioxidant therapy.     

An unusual case of left ventricular aneurysm in duchenne muscular dystrophy

Various structural anomalies of the left ventricular papillary muscles have been observed in recent years. Many of these have been linked to electrocardiographic aberrations. Recently two reports have appeared where the base of the posterior papillary muscle was identified as the source of frequent premature ventricular complexes. In some of these patients these frequent premature ventricular complexes have led to left ventricular dysfunction. In this report a newly discovered structural variant of the anterior papillary muscle is described--the bifid papillary muscle. Furthermore, it is proposed that this bifid papillary muscle is the source of frequent ventricular premature complexes, presenting as bigeminy in a patient with normal left ventricular function.     

Serum creatine kinase isoenzymes in progressive muscular dystrophy

Creatine kinase isoenzymes in sera and muscle biopsies obtained from 50 controls, 72 patients with progressive muscular dystrophy (PMD), 68 patients with other neuromuscular disorders, 17 carriers of Duchenne-type PMD and 15 patients with myocardial infarction were studied. MB isoenzyme was detected in the sera of 58 patients with PMD and 56 out of 61 muscle biopsies. The MB activity varied between 4 and 400 IU/1 or 3.4--22% of total activity. The MB activity was demonstrated in a considerably smaller number of cases with polymyositis, dystrophic myotonia and Kugelberg-Welander disease. The MB isoenzyme in sera of PMD persisted for many years. It is admitted that the MB isoenzyme in the serum of patients with PMD originates chiefly from skeletal muscle.     

Myofibrillar creatine kinase in Duchenne and avian muscular dystrophy

The presence and activity of the fraction of creatine kinase (CK) which was associated with myofibrils and located in the M line of the sarcomeres was determined in normal and dystrophic avian muscle and in normal and dystrophic (Duchenne) human muscle. Myofibrils were isolated from homogenates of muscle and washed nine times so as to remove nonmyofibrillar CK. In myofibrils from dystrophic muscle the enzyme CK was localized to the M line using immunofluorescent techniques and was enzymatically active. These results suggest that in both avian and Duchenne muscular dystrophy, there is not a myofibrillar disorder of the phosphocreatine shuttle.     

Decreased total nitric oxide production in patients with duchenne muscular dystrophy

Plasma nitric oxide (NO) levels in Duchenne muscular dystrophy (DMD) patients were significantly lower than those observed in both healthy controls and in patients with other neuromuscular disorders. The correlation between NO level and ejection fraction was significant (r=–0.384, p=0.0391) in the DMD group. Disruption of NO systems may contribute to the development of muscular dystrophy and have implications for therapeutic strategies.     

Molecular genetic analysis of 67 patients with duchenne/becker muscular dystrophy

Summary A total of 56 Duchenne muscular dystrophy (DMD) patients and 11 Becker muscular dystrophy (BMD) patients was analyzed by extended multiplex amplification of the DMD/BMD gene; deletions were found in 60% of these patients. The data obtained were used to test the frameshift hypothesis and to compare the distribution of familial versus isolated cases. A significant correlation was found between deletions and isolated cases. Additional experiments were performed in order to determine the deletion breakpoints more precisely. These data are a prerequisite for carrier analysis in the respective families by detection or exclusion of aberrant cDNA fragments derived from ectopic lymphocyte RNA. This diagnostic technique is illustrated by 5 examples.     

Lung function monitoring in patients with duchenne muscular dystrophy on steroid therapy

ABSTRACT: BACKGROUND: Duchenne muscular dystrophy (DMD) is a sex-linked inherited muscle disease characterized by a progressive loss in muscle strength and respiratory muscle involvement. After 12 years of age, lung function declines at a rate of 6% to 10.7% per year in patients with DMD. Steroid therapy has been proposed to delay the loss of motor function and also the respiratory involvement. OBJECTIVE: In this uncontrolled, prospective study, the objectives were to assess the pulmonary function of patients with DMD on steroid therapy and to evaluate the influence of chronological age, age at onset of therapy, and walking ability (ambulant or non-ambulant) on lung volumes. METHOD: In 21 patients with DMD aged between seven and 16 years, the forced vital capacity (FVC) and the forced expiratory volume in one second (FEV1) were evaluated at three different times during a period of two years. RESULTS: We observed in this period of evaluation the maintenance of the FVC and the FEV1 in this group of patients independently of chronological age, age at onset of steroid therapy, and walking capacity. CONCLUSION: The steroid therapy has the potential to stabilize or delay the loss of lung function in DMD patients even if they are non-ambulant or older than 10 years, and in those in whom the medication was started after 7 years of age.     

The use of discriminant analysis of serum creatine kinase levels for detection of heterozygote carriers of Duchenne muscular dystrophy

The possibility of using discriminant analysis of creatine kinase levels for detection of Duchenne muscular dystrophy heterozygote carrier was studied. Application of combined genealogical and biochemical information enhanced detection of heterozygotes. It is proposed to apply this method for medical and genetic counselling.     

DNA-diagnosis of carriers of the Duchenne muscular dystrophy gene

Duchenne muscular dystrophy carrier detection has been performed by using probes XJ1.1 (intragenic probe) and probe 754 for a girl. The carrier probability was estimated by means of a computer program GenRisk combining pedigree and DNA-probe data and turned out to be 95%.     

Dystrophin analysis in duchenne muscular dystrophy: use in fetal diagnosis and in genetic counseling.

In this report we describe the use of dystrophin analysis both in the diagnosis of Duchenne muscular dystrophy (DMD) in an aborted fetus and in genetic counseling. Our consultand's initial carrier risk, as based on family history and creatine kinase determinations, was calculated as 0.6%. DNA analysis of her family (and fetus) modified this risk to 8.5%. Skeletal muscle of the 23-wk male abortus was found to be histologically indistinguishable from that of age-matched controls. However, immunoblot testing for dystrophin indicated that the fetus had indeed inherited dystrophin deficiency. The carrier risk of the consultand was thus elevated to 100%. Dystrophin assays should be employed whenever the diagnosis of fetal DMD is equivocal (e.g., cases in which a gene deletion cannot be identified). Assay results are crucial for genetic counseling for subsequent pregnancies and for studies of the early pathogenesis of muscular dystrophy.