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[Use of the direct capping technic in lymphocytes for the detection of women carrying the Duchenne type muscular dystrophy].

Duchenne muscular dystrophy (DMD) is a progressive X-linked recessive condition. The detection of female carriers is important for genetic counseling but no precise method is available in our country. Based on the demonstration by other authors of an impaired lymphocyte "capping" in DMD patients and carriers, we evaluated the usefulness of this method in the detection of DMD carriers. Nineteen control subjects, 9 obligate carriers, 6 DMD patients, and 10 probable carriers, were studied. The analysis of variability intra and interobserver of the results of "capping" showed variation coefficients of 17% and 19%, respectively. The comparison of groups (F test) showed no difference between controls, obligate carriers and DMD patients. When a diagnostic value of 30 was chosen, we obtained 78% specificity and 40% sensitivity. It was concluded that, under the conditions of this study, we were unable to demonstrate a diminished lymphocyte "capping" in DMD patients and carriers as compared with normal subjects.

Adult↗
PubMed1993

[Palliative treatment of myopathies. Contribution of surgical treatments].

The knowledge acquired over the last few years on Duchenne's muscular dystrophy (DMD) serves as the basis for management of all types of myopathy. After reviewing the current classification of muscle dystrophies and the principles of orthopedic management of these conditions, a historical perspective of surgical procedures used in DMD is presented. The various modes of discovery of myopathy are described. Deformities of the limbs and spine related to DMD are reviewed and their outcome is detailed. In DMD patients, the surgical procedures described allowed to delay loss of the ability to walk by 1 year 7 months to 3 years 8 months according to the severity of the condition, and provided significant improvements in quality of life. Surgical stabilization of the scoliosis ensured preservation of comfortable sitting in every case, as well as preservation of autonomous upper limb motion, with a low rate of complications. Surgical indications in DMD are well-established and serve as the basis for making surgical decisions in the other myopathies, except during early infancy. The principles and orientations of treatment of the other myopathies are defined, in the light of the variability of lesions and of the rate of muscle function loss. In these non-DMD myopathies, medical and surgical treatments are of as yet unquantifiable benefit but provide a substantial improvement in quality of life.

Adolescent↗
PubMed1994

Specific T cell receptor gene rearrangements at the site of muscle degeneration in Duchenne muscular dystrophy.

Mononuclear cells infiltrate degenerating muscles of Duchenne muscular dystrophy (DMD) patients. Using a quantitative PCR, we first characterized the T cells infiltrating muscle biopsies from six DMD patients. High levels of TCR V beta 2 transcripts were observed in DMD muscle tissue. TCR V beta 2 transcripts from seven DMD patients and five controls were sequenced, and the VDJ junctional region analyzed in 166 clones. One specific amino acid motif, RVSG, was found in the third complementary determining region (CDR3) of TCR V beta 2 chains in samples from five DMD patients, but not in controls. A specific immune reaction at the site of tissue degeneration may play an important role in the pathogenesis of DMD.

Amino Acid Sequence↗
PubMed1993

The effects of dystrophin gene mutations on the ERG in mice and humans.

PURPOSE: The authors' earlier findings of a negative electroretinogram (ERG) in a boy with Duchenne muscular dystrophy (DMD) led them to investigate dystrophin gene deletions and ERGs in five boys with DMD. The authors wanted to determined whether there were similar ERG findings in an animal model for DMD, the mdx mouse. METHODS: Ganzfeld ERGs were recorded in five boys with DMD after a complete ophthalmic examination. The dystrophin gene was analyzed by Southern blot hybridization. ERGs were recorded in anesthetized mdx and control mice with a modified Grass photostimulator (Grass Instrument Company, Quincy, MA). RESULTS: Ophthalmic examinations in all five boys had normal findings, yet an abnormal negative ERG was recorded for each subject. The subjects' gene deletions were variable, ranging from large deletions to no detectable deletions. The ERGs of the mdx mice were normal and did not differ significantly from those of the control mice. CONCLUSIONS: The authors believe the unique ERG recorded for the human subjects is a manifestation of DMD associated with defects at the dystrophin gene locus and represents a new clinical entity. The ERG of the mdx mouse may be spared for several reasons, including milder effects of the mouse gene defect, differences in muscle and retinal gene product, or species differences in the biochemical role of dystrophin. The ERG shows promise of becoming a noninvasive diagnostic tool for DMD and its milder allelic forms.

Animals↗
PubMed1995

[Respiratory failure: respiratory disorder during sleep in patients with myotonic dystrophy].

Myotonic dystrophy (MyD) patients have been reported to show severe nocturnal desaturation related to sleep respiratory disorders. However, the reason of respiratory failure in MyD has remained unclear. In this study, ten patients with MyD underwent overnight polysomnography to evaluate the mechanisms which would cause respiratory failure, compared with Duchenne muscular dystrophy (DMD) patients in these three views: 1) sleep-related nocturnal desaturation, 2) histopathological evaluation of respiratory muscles, and 3) abnormalities of respiratory center. Nocturnal desaturation was more prominent in MyD rather than DMD. Apnea-hypopnea index (AHI) was higher in MyD than DMD. Type of respiratory disorder during sleep was mainly central apnea-hypopnea pattern, including Cheyne-Stokes respiration. In histopathological findings, central core change in respiratory muscle related to respiratory muscle fatigue was found less frequently in MyD than DMD. In respiratory center function, MyD showed hyporesponse to both alveolar hypercapnic and hypoxic stimulation. However, DMD showed normal response to both stimulations. We concluded that respiratory failure in patients with MyD would be attributed to respiratory center disorder rather than respiratory muscle weakness, which is the main cause of respiratory failure in patients with DMD.

Humans↗
PubMed2026

Duchenne muscular dystrophy: from gene to gene-ius therapies.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional dystrophin, leading to progressive muscle degeneration, loss of ambulation, respiratory failure, cardiomyopathy, and premature mortality. Despite advances in multidisciplinary supportive care, DMD remains an incurable disease associated with substantial physical, psychosocial, and economic burdens. The monogenic nature of DMD and its well-defined molecular pathogenesis have made it a prime target for the development of precision therapies aimed at restoring dystrophin expression or modifying disease progression. This review provides an overview of the genetic and molecular mechanisms underlying DMD, summarizes its clinical manifestations and natural history, and discusses current standards of care. It further examines recent advances in disease-modifying therapeutic strategies, including exon-skipping antisense oligonucleotides, nonsense mutation readthrough agents, adeno-associated virus (AAV)-mediated micro-dystrophin gene replacement, and emerging genome-editing technologies such as CRISPR/Cas9. The review also highlights the limitations of existing treatments, including mutation specificity, variable efficacy, immune-related challenges, and uncertainties regarding long-term durability and safety. Finally, it considers future directions in therapeutic development, emphasizing the need for combination approaches, improved delivery systems, and next-generation gene-editing platforms to achieve more effective and lasting clinical outcomes. Collectively, these advances represent a paradigm shift in DMD management and offer renewed hope for improving survival and quality of life for affected individuals.

Humans↗
PubMed2005

Intermittent prednisone therapy in Duchenne muscular dystrophy: a randomized controlled trial.

BACKGROUND: Prednisone treatment is used to prolong ambulation in patients with Duchenne muscular dystrophy (DMD). However, since severe adverse effects often accompany prednisone treatment, it is debatable whether the benefits of prednisone treatment outweigh its adverse effects. OBJECTIVES: To study the effects of prednisone on muscle function and to determine the extent of steroid-related adverse effects and their influence on the quality of life of ambulant patients with DMD. DESIGN: A randomized, placebo-controlled, crossover trial with 6 months of treatment: prednisone or placebo (0.75 mg/kg daily) during the first 10 days of each month. After a washout period of 2 months, patients received the other regimen for an additional 6 months. SETTING: University hospital and rehabilitation center in the Netherlands. PATIENTS: Seventeen ambulant patients with DMD aged 5 to 8 years. MAIN OUTCOME MEASURE: Change in muscle function assessed by timed functional testing: running 9 m, climbing 4 standard-sized stairs, and rising from the floor to a standing position. RESULTS: The increase in time needed to run 9 m (P = .005) and to climb 4 standard-sized stairs (P = .02) was significantly lower during the prednisone period. CONCLUSIONS: Prednisone slowed deterioration of muscle function and muscle force in ambulant patients with DMD. Although adverse effects were present, patient quality of life was not affected. Therefore, short-term prednisone treatment can be recommended to preserve motor functions in ambulant patients with DMD.

Anti-Inflammatory Agents↗
PubMed1998

Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy?

Molecular study and neuropsychological analysis were performed concurrently on 49 patients with Duchenne muscular dystrophy (DMD) in order to find a molecular explanation for the cognitive impairment observed in most DMD patients. Complete analysis of the dystrophin gene was performed to define the localization of deletions and duplications in relation to the different DMD promoters. Qualitative analysis of the Dp71 transcript and testing for the specific first exon of Dp140 were also carried out. Neuropsychological analysis assessed verbal and visuospatial intelligence, verbal memory, and reading skills. Comparison of molecular and psychometric findings demonstrated that deletions and duplications that were localized in the distal part of the gene seemed to be preferentially associated with cognitive impairment. Two altered Dp71 transcripts and two deleted Dp140 DNA sequences were found in four patients with severe cerebral dysfunction. These findings suggest that some sequences located in the distal part of the gene and, in particular, some DMD isoforms expressed in the brain may be related to the cognitive impairment associated with DMD.

Adolescent↗
PubMed1999

Defective growth in vitro of Duchenne Muscular Dystrophy myoblasts: the molecular and biochemical basis.

As the molecular basis of Duchenne Muscular Dystrophy (DMD) was being discovered, increasing focus was placed on the mechanisms of progressive failure of myoregeneration. In this study, we propose a pathogenesis model for DMD, where an autocrine growth factor release of TGF-beta1-from necrotic myofibers-could contribute to the increasing loss of muscle regeneration. In fact, we report evidence that DMD myoblasts reduce their proliferation rate, in time and later cultures; in connection with this, we observed TGF-beta1 increase in conditioned media of DMD myoblasts, able to control the myoblast growth by reducing fusion and differentiation of DMD satellite cells.

Cell Differentiation↗
PubMed1988

A grandpaternally derived de novo deletion within Xp21 initially presenting in carrier females diagnosed as Kugelberg-Welander syndrome.

We report on two sisters with a history of muscle weakness and an electromyogram (EMG) diagnosis of Kugelberg-Welander syndrome (KWS) or juvenile spinal muscular atrophy. A half-brother to these women was diagnosed to have Duchenne muscular dystrophy (DMD). Using molecular probes, we identified a deletion within Xp21 in this isolated case of DMD. Sequences detected by pXJ1.1 are deleted, while fragments detected by pERT87 are intact. Both of these probes are derived from the DMD locus. We have shown that the affected sisters share with their half-brother DNA markers that are linked to the DMD gene and inherited from their maternal grandfather. Dosage analysis of Southern blots show monosomy for pXJ1.1, which has allowed us to determine carrier status within this family and to show that the half-sisters are manifesting DMD carriers.

Chromosome Deletion↗
PubMed1988

Fine mapping of glycerol kinase deficiency and congenital adrenal hypoplasia within Xp21 on the short arm of the human X chromosome.

We have studied patients with Duchenne muscular dystrophy (DMD), DMD together with glycerol kinase (GK) deficiency, or DMD together with both GK deficiency and congenital adrenal hypoplasia (AHC). Analysis of deletions in these patients allows the mapping of these mutations in Xp21. The following order is proposed: Xpter - L1 - AHC - GK - DMD - Xcen. One of the boys with DMD, GK, and AHC is shown by pulsed-field-gel electrophoresis to have a deletion which has a proximal endpoint at least 500 kb distal from the pERT87 (DXS164) locus.

Acid Phosphatase↗
PubMed1989

Dystrophin immunocytochemistry in muscle culture: detection of a carrier of Duchenne muscular dystrophy.

Dystrophin is the gene product which is affected in Duchenne muscular dystrophy (DMD). We studied differentiating clonal muscle cultures derived from normal muscle and from the mother of a DMD patient by immunocytochemistry, using anti-dystrophin antibody. While clonal cultures derived from normal muscle expressed dystrophin in all myotubes, two populations of myogenic cells could be demonstrated in muscle from this possible DMD carrier; in 13 clones the myotubes expressed dystrophin and in 7 clones dystrophin was undetectable. No DNA deletion, duplication or rearrangement was detected by Southern blot analysis of DNA from this family using cDNA probes. Thus, immunocytochemical analysis of clonal muscle cultures may be a useful method to determine whether mothers of DMD patients are carriers of the DMD mutation, especially in the absence of demonstrable gene defects.

Adult↗
PubMed1993

Mental retardation locus in Xp21 chromosome microdeletion.

Xp21 microdeletion syndrome is associated with variable size Xp21 deletions that usually include the glycerol kinase locus. The clinical phenotypes we studied in this chromosome region include: Xpter - Aland Island eye disease (AIED) -adrenal hypoplasia (AH) -glycerol kinase (GKD) -Duchenne muscular dystrophy (DMD) -retinitis pigmentosa (RP) -ornithine transcarbamylase (OTC) -centromere. In a compilation of 18 individuals in 14 families with the AH, GKD, and DMD loci deleted, 17 were male and all were developmentally delayed. In contrast, we report mentally retarded female carriers in two Xp21 deletion syndrome families with DMD, GKD, and AH in affected males. In the first family with normal karyotypes, a submicroscopic deletion was associated with DMD in the retarded male and with retardation in carrier females. In the second family an X chromosome with a cytogenetically deleted Xp21 distal to the OTC and RP genes segregated in the affected male and retarded female carriers. DNA analysis at the DMD locus verified the cytogenetic findings. This report of mental retardation in otherwise asymptomatic female carriers of Xp21 deletion classifies one form of mental retardation in females.

Adrenal Glands↗
PubMed1995

Deficiency of brain synaptic dystrophin in human Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by a defect in dystrophin, a high molecular weight protein that is located predominantly in muscle, but which has been detected in brain. Brain dystrophin has been localized to the synapse, in the postsynaptic density (PSD), and is absent in the mdx mouse, an animal model of human DMD. To define the potential pathogenic role of dystrophin deficiency in cognitive impairment, we examined the protein in human DMD brain. The 427-kd dystrophin was absent in the PSD from DMD brain, but was normally expressed in the brain from an age-matched control subject. Our findings indicate that dystrophin is deficient in human DMD cortical synapses and provide a potential pathogenic mechanism for cognitive impairment.

Brain Chemistry↗
PubMed1995

Phenotype of dystrophinopathy in old mdx mice.

BACKGROUND: Mdx mutant mice, like patients with Duchenne Muscular Dystrophy (DMD), lack dystrophin, a subsarcolemmal protein, that results in myofiber necrosis. However young mdx mice, in contrast to DMD children, exhibit a successful muscle regeneration and not an extensive fibrosis. METHODS: Old mdx mice were monitored clinically up to their spontaneous death, and most of their organs were studied histologically to look for differences with those of the wild C57BL/10 mice strain. RESULTS: In old mdx mice (at least 20 months of age), we report clinical and pathological features of muscular dystrophy, i.e., progressive motor weakness and loss of myofibers replaced by extensive connective tissue, similar to the phenotype of dystrophinopathy observed in DMD patients. Various degrees of dystrophic involvement were observed in cardiac, respiratory, postural, and hindlimb skeletal mdx muscles and also in smooth muscles of the digestive and urinary tracts. No gross histological abnormalities were found in other tissue than muscular tissue. CONCLUSIONS: Late in life, mdx mice develop a muscular dystrophy close to DMD dystrophinopathy. We suggest that the study of the effects of ageing in mdx mice would give clues to better understand the pathophysiology of DMD.

Aging↗
PubMed2000

Chemoprevention of lung cancer by lycopene.

An investigation was conducted to assess the chemopreventive potential of lycopene (LP), a naturally occurring hydrocarbon carotenoid found in tomatoes and their products, administered during the post-initiation stage in a multiorgan carcinogenesis model. One hundred eighteen B6C3F1 mice of both sexes were subjected to combined treatment with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU) and 1,2-dimethylhydrazine (DMH) from day 11 after birth to week 9 (DMD treatment) (groups 1 and 2) or given their vehicles (group 3). Then group 1 received LP (25 or 50 ppm in drinking water) for 21 weeks from weeks 11 to 32. Group 2 served as a carcinogen alone control and group 3 was given only LP (25 or 50 ppm). The incidences and multiplicities of lung adenomas plus carcinomas combined in male mice in group 1 receiving LP 50 ppm were significantly decreased as compared to the DMD alone or DMD and LP 25 ppm group values (75.0 vs 18.8%, P < 0.02; 0.94+/-0.17 v.s 0.25+/-0.14, P < 0.001). While hepatocellular carcinomas were lacking in the DMD and LP groups, two cases were found in the DMD alone group (not statistically significant). The values for aberrant crypt foci (ACF) and tumors in the colon and kidney did not show any significant variation among the carcinogen-treated subgroups. The results of this study provide evidence that the tomato carotenoid, lycopene, may have potential as a chemopreventive agent against carcinogenesis in the male lung.

1,2-Dimethylhydrazine↗
PubMed1993

Abnormal signal-averaged electrocardiogram in patients with Duchenne muscular dystrophy: comparison of time and frequency domain analyses from the signal-averaged electrocardiogram.

The clinical significance of an abnormal signal-averaged electrocardiogram (SA-ECG) in time- and frequency-domain analyses was assessed in patients with Duchenne muscular dystrophy (DMD). Twenty-four DMD patients and 20 age-matched healthy volunteers were studied. The SA-ECG was recorded by time-domain signal processing using the vector-magnitude method and frequency-domain signal processing using the fast-Fourier transform. Abnormal SA-ECGs were based on comparison with controls and eight abnormal SA-ECGs were detected among 24 DMD patients, seven by frequency-domain analysis and four by time-domain analysis. The end-diastolic left ventricular volume was larger in the patients with abnormal SA-ECG than in those with normal SA-ECG (136 +/- 32 ml vs. 77 +/- 43 ml, p < 0.01). Compared with patients with normal SA-ECGs, the DMD patients with abnormal SA-ECGs had a lower left ventricular (LV) ejection fraction (54 +/- 6 vs. 61 +/- 8%, p < 0.05), as an index of LV contractility, and less LV posterior wall velocity (46 +/- 9 mm/min vs. 62 +/- 16 mm/min, p < 0.01), as an index of LV relaxation. The sensitivity and specificity of frequency-domain analysis for predicting malignant ventricular arrhythmias was 60 and 85%, respectively, compared with 30 and 92%, respectively, for time-domain analysis. The combination of time- and frequency-domain analyses can facilitate identification of DMD patients with ventricular tachyarrhythmias associated with depression of cardiac performance.

Adolescent↗
PubMed1995

Protein truncation test: analysis of two novel point mutations at the carboxy-terminus of the human dystrophin gene associated with mental retardation.

Approximately one-third of the mutations responsible for Duchenne muscular dytrophy (DMD) do not involve gross rearrangements of the dystrophin gene. Methods for intensive mutation screening have recently been applied to this immense gene, which resulted in the identification of a number of point mutations in DMD patients, mostly translation-terminating mutations. A number of data raised the possibility that the C-terminal region of dystrophin might be involved in some cases of mental retardation associated with DMD. Using single-strand conformation analysis of products amplified by polymerase chain reaction (PCR-SSCA) to screen the terminal domains of the dystrophin gene (exons 60-79) of 20 unrelated patients with DMD or BMD, we detected two novel point mutations in two mentally retarded DMD patients: a 1-bp deletion in exon 70 (10334delC) and a 5' splice donor site alteration in intron 69 (10294 + 1G-->T). Both mutations should result in a premature translation termination of dystrophin. The possible effects on the reading frame were analyzed by the study of reverse transcripts amplified from peripheral blood lymphocytes mRNA and by the protein truncation test.

Base Sequence↗