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PubMed1992

An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy.

Golden retriever muscular dystrophy (GRMD) is a spontaneous, X-linked, progressively fatal disease of dogs and is also a homologue of Duchenne muscular dystrophy (DMD). Two-thirds of DMD patients carry detectable deletions in their dystrophin gene. The defect underlying the remaining one-third of DMD patients is undetermined. Analysis of the canine dystrophin gene in normal and GRMD dogs has failed to demonstrate any detectable loss of exons. Here, we have demonstrated a RNA processing error in GRMD that results from a single base change in the 3' consensus splice site of intron 6. The seventh exon is then skipped, which predicts a termination of the dystrophin reading frame within its N-terminal domain in exon 8. This is the first example of dystrophin deficiency caused by a splice-site mutation.

Amino Acid Sequence↗
PubMed1992

Fluorescence in situ hybridization establishes the order cen-DXS28(C7)-DXS67(B24)-DXS68(L1)-tel in human chromosome Xp21.3.

We report here on the order of three DNA markers, C7, B24, and L1, based on the arrangement of their fluorescently labeled hybridization sites in interphase cell nuclei. The three markers map distal to the Duchenne muscular dystrophy (DMD), glycerol kinase deficiency (GKD), and adrenal hypoplasia (AHC) loci on human chromosome Xp21.3. Their order has been a matter of controversy. In interphase chromatin, B24 maps between C7 and L1. We estimate from interphase distance that C7 and L1 are 300-500 kb apart. When the three markers are hybridized to interphase cells of Nijmegen1, a patient with DMD, GKD, and AHC, only C7 appears to be deleted, rather than both C7 and L1, as had been reported elsewhere. C7 is also the only one of the three markers deleted in several other DMD patients studied by others. The deletion results indicate that C7 is the most proximal of the three markers and allow the trio of ordered probes to be oriented on the chromosome: cen-C7(DXS28)-B24(DXS67)-L1(DXS68)-tel.

DNA Probes↗
PubMed1991

Two expressed human genes sustain slightly more DNA damage after alkylating agent treatment than an inactive gene.

Alkylating agent damage was quantified in human T-lymphocytes by calculating gene-specific lesion frequencies and repair rates. At 3 time points after exposure to methyl methanesulfonate (0, 6, and 24 h), T-lymphocyte DNA was extracted, digested with HindIII, and divided into 2 aliquots. Apurinic sites were formed in the DNA fragments of both aliquots by heat-induced liberation of the N-methylpurines. The methoxyamine-treated aliquot provided gene fragments which were refractory to alkaline hydrolysis (full-length fragments), while the fragments in the untreated aliquot were cleaved at apurinic sites by hydroxide. After Southern blotting, lesion frequencies were calculated by comparing the band intensity of the full-length fragment to its unprotected counterpart. The restriction fragments analyzed were from the constitutively active dihydrofolate reductase (dhfr) plus hypoxanthine phosphoribosyltransferase (hprt) genes and from the transcriptionally inactive Duchenne muscular dystrophy gene (dmd). In decreasing order, the fragments containing the most lesions per kb of DNA were: hprt greater than dhfr greater than dmd. T-Lymphocytes from 2 females had 30% more heat-labile N-methylpurines in the active X-linked hprt gene than in the inactive X-linked dmd gene. The lesion frequency found in the male's lone hprt allele was the highest observed. These lesion frequency differences are discussed in terms of chromatin structure. After 6 and 24 h, no significant repair rate differences were observed among the 3 genes.

Cell Survival↗
PubMed1992

Epidemiology of neuromuscular disorders in the under-20 population in Bologna Province, Italy.

A retrospective epidemiological survey of the principal neuromuscular disorders was undertaken in the population under the age of 20 yr in Bologna city and province. The incidence of Duchenne muscular dystrophy (DMD) proved to be 25.8 x 10(-5), that is, comparable with the outcome of neonatal screening studies. The incidence of spinal muscular atrophy (SMA) was very high (11.2 x 10(-5), probably the result of our greater awareness and recognition of this disorder. The prevalence of neuromuscular disorders in the 0-19 yr population is 1.5 times that in the general population; that of DMD is 28 x 10(-5) vs 6.3 x 10(-5) and that of the SMA 6.5 x 10(-5) vs 1.2 x 10(-5). Our results indicate that neuromuscular disorders, particularly DMD and SMA I and II, have a much higher prevalence in the first two decades of life than is generally thought. Awareness of the higher prevalence of neuromuscular disorders among the under-20s is essential to the adequate planning of medical services.

Adolescent↗
PubMed1992

A deletion including the brain promoter of the Duchenne muscular dystrophy gene is not associated with mental retardation.

A total of 161 unrelated Duchenne (DMD) and Becker muscular dystrophy (BMD) patients were screened for deletions in the brain promoter region of the dystrophin gene. Southern blot analysis using a probe for the brain promoter detected a deletion in this region in only one of the DMD families, in a patient with normal intelligence. This deletion also included the promoter of the muscle-type dystrophin and the exons encoding the actin-binding and part of the spectrin-like domains. Our data suggest that deletions in the brain promoter region are rare in DMD and are compatible with normal intelligence.

Adult↗
PubMed1993

Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy.

We have analysed the results of clinical assessment, X-inactivation status, deletion screening and dystrophin analysis in eight manifesting carriers of Duchenne and Becker muscular dystrophy (DMD and BMD). Only two had a prior family history of X-linked muscle disease, all had normal karyotypes and none were twins. Presentation varied from 2 to 25 yr and progression varied from a DMD-like severity to a very mild BMD-like course. In one girl the initial symptoms were restricted to learning difficulties. Where methods for assessing X-inactivation were informative, three patients showed an abnormal pattern. However, in one patient, the obligate carrier daughter of a BMD patient who had presented at the age of 2 yr, X-inactivation appeared normal in lymphocytes and muscle. While dystrophin analysis seems to be reliable in identifying manifesting carriers of DMD and BMD, the relationship between X-inactivation status, dystrophin analysis and phenotype is not simple.

Adolescent↗
PubMedDate not supplied

Morphometric analysis of mdx diaphragm muscle fibres. Comparison with hindlimb muscles.

Histological, histochemical and morphometric characteristics of diaphragm muscles from mdx and control mice were compared with those of hindlimb muscles [extensor digitorum longus (EDL), tibialis anterior (TA) and soleus (SA) muscles]. In contrast to mdx limb muscles, regeneration after muscle necrosis does not restore diaphragm muscle structure. In mdx mice at 270 days of age, 70-80% of fibres in hindlimb muscles had central nuclei, compared with only 35% in diaphragm muscle. At 270 days of age, mdx diaphragm muscle was characterized by perimysial and endomysial fibrosis; this latter feature was absent from mdx hindlimb muscles. Fibre diameter remained smaller than the control in mdx diaphragm muscle. We suggest that the similarity in muscle pathology between the diaphragms of mdx mice and in patients suffering from Duchenne muscular dystrophy (DMD) makes these an appropriate model for DMD, since respiratory failure is the leading cause of death in DMD patients.

Aging↗
PubMedDate not supplied

The role of the dystrophin-glycoprotein complex in the molecular pathogenesis of muscular dystrophies.

The dystrophin-glycoprotein complex is considered to be a major trans-sarcolemmal structure which provides a linkage between the subsarcolemmal actin cytoskeleton and the extracellular matrix component laminin. Recently, deficiency of the dystrophin-associated proteins has been shown to play an important role in the molecular pathogenesis of several forms of muscular dystrophy. These include Duchenne muscular dystrophy (DMD), symptomatic DMD carriers, Becker muscular dystrophy and severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype prevalent in North Africa. In Fukuyama-type congenital muscular dystrophy (FCMD), the finding of abnormal expression of the dystrophin-associated proteins may provide a clue to its molecular pathogenesis. These recent findings indicate that the linkage between the subsarcolemmal cytoskeleton and extracellular matrix via the dystrophin-glycoprotein complex is critical for maintaining the integrity of muscle cell function.

Child↗
PubMed1995

Phospholipase A2 activity in dystrophinopathies.

Phospholipase A2 activity in human muscle with or without dystrophin abnormality was studied. The results showed an increased phospholipase A2 activity in Duchenne muscular dystrophy (DMD) patients (1160 +/- 160, P < 0.01) compared to controls (< 200 U mg-1). DMD fetal muscle showed normal levels, but levels then increased dramatically postnatally. Highest levels were found at 5 yr of age (10 times normal) and then declined to 1.5-2 times normal by age 10. Steroid treatment did not change the phospholipase A2 levels significantly. In patients with abnormal dystrophin, i.e. Becker muscular dystrophy, phospholipase A2 activity was increased in the age group 3-15 (920 +/- 230 U mg-1, P < 0.01), while older patients (17-49) showed a non-significant (220 +/- 60 U mg-1) increase. The lack of phospholipase A2 activation in fetuses with DMD, indicates that activation is not a direct consequence of dystrophin deficiency. Phospholipase A2 activity has been shown to be connected to the formation of several inflammatory mediators such as prostaglandins, leukotriens, platelet activating factor and lysophospholipids. Phospholipase A2 activation may therefore play an important role in the development of inflammation and necrosis, with subsequent fibrosis and massive loss of muscle function, which develops in Duchenne and Becker muscular dystrophy.

Adolescent↗
PubMed1996

Cardiac and respiratory involvement in advanced stage Duchenne muscular dystrophy.

This study aimed to describe myocardial involvement, respiratory impairment and pulmonary blood flow abnormalities in advanced-stage Duchenne muscular dystrophy (DMD). Twenty-one wheelchair-bound patients, aged from 10 to 24 yr, underwent electrocardiographic and echocardiographic examination, conventional spirometry, diurnal arterial blood gas analysis, and nocturnal polysomnography (SaO2 monitoring). Diagnosis was confirmed by neurological examination, dystrophin analysis at protein and DNA level. Patients were classified into two groups: group A normoxemic (14 cases) and group B with nocturnal hypoxemia (seven cases). Group A was further split into two subgroups, one without, and one with, left ventricular dilation (A1 = nine patients, end diastolic volume (EDV) = 51 ml m-2, ejection fraction (EF) = 56 per cent; A2 = five patients, EDV = 112 ml m-2, EF = 32 per cent; P < 0.05). Left ventricular regional wall motion abnormalities were found in 55, 40, and 43 per cent of groups A1, A2, and B patients respectively. Analysis of pulsed Doppler pulmonary data highlighted a significant reduction in corrected time to peak velocity in group B patients, when compared with control, A1, and A2 groups respectively. In group A, we observed a direct correlation between ejection fraction and corrected time-to-peak velocity. Two patterns of cardiac involvement may be recognized in advanced-stage DMD: left ventricular wall motion abnormalities and dilated cardiomyopathy. Doppler data which could suggest pulmonary hypertension may be observed in patients with dilated cardiomyopathy, and in patients with nocturnal hypoxemia. Therefore, in the management of advanced-stage DMD, a careful diagnosis of the heart-lung relationship should be performed, and both conventional treatment of heart failure and ventilatory therapy are necessary to improve the quality of life and survival in these patients.

Adolescent↗
PubMed2004

Evidence of early impairments in both right and left ventricular inotropic reserves in children with Duchenne's muscular dystrophy.

In Duchenne's muscular dystrophy (DMD), cardiac function deteriorates with time and heart failure is one of the major causes of death. The aim of the study was to determine if a decrease in the ventricular inotropic reserves could be an early sign of cardiac dysfunction in these children. Nineteen children with DMD (aged 9 to 18 years, mean age 13.6 +/- 2.4) underwent equilibrium radionuclide angiography at rest and during an inotropic stimulation with low-dose dobutamine perfusion (7.5 to 15 microg. kg(-1). min(-1)). In all patients, this investigation was short (<30 minutes), successful, and uncomplicated. At rest, left ventricular (LV) ejection fraction (EF) was normal (>0.50) in 79% of patients, and right ventricular (RV) EF was normal (>0.45) in 95%. There was a trend toward a decrease with age for rest LVEF (p = 0.051) but not for rest RVEF (p = 0.8). By contrast, marked declines with age could be documented for the increases (Delta) in LVEF and RVEF during dobutamine perfusion (p = 0.002 for DeltaLVEF and p = 0.015 for DeltaRVEF). Thus, by multivariate analysis, the sole best indicator of decline in cardiac function with age was LVEF determined with dobutamine. In children with DMD, low-dose dobutamine radionuclide angiography gives evidence of an early decline with age of the inotropic reserves of both ventricles.

Adolescent↗
PubMed2006

Non-viral gene therapy for Duchenne muscular dystrophy: progress and challenges.

Duchenne muscular dystrophy (DMD) is one of the most common lethal, hereditary diseases of childhood. Since the identification of the genetic basis of this disorder, there has been the hope that a cure would be developed in the form of gene therapy. This has yet to be realized, but many different gene therapy approaches have seen dramatic advances in recent years. Although viral-mediated gene therapy has been at the forefront of the field, several non-viral gene therapy approaches have been applied to animal and cellular models of DMD. These include plasmid-mediated gene delivery, antisense-mediated exon skipping, and oligonucleotide-mediated gene editing. In the past several years, non-viral gene therapy has moved from the laboratory to the clinic. Advances in vector design, formulation, and delivery are likely to lead to even more rapid advances in the coming decade. Given the relative simplicity, safety, and cost-effectiveness of these methodologies, non-viral gene therapy continues to have great promise for future gene therapy approaches to the treatment of DMD.

Animals↗
PubMed2004

Coagulation system activated in Duchenne muscular dystrophy patients with cardiac dysfunction.

We investigated basic abnormalities of coagulation and fibrinolysis in Duchenne muscular dystrophy (DMD) patients with cardiac dysfunction. Forty seven patients with DMD, aged 13-37 years old, were enrolled. Based on left ventricular ejection fraction (LVEF) results determined by echocardiography, patients were divided into 3 groups: LVEF less than 30% (markedly depressed group), LVEF between 30 and 50% (slightly depressed), and LVEF greater than 50% (normal). We measured serum levels of total fibrin and fibrinogen degradation products (FDP), as well as plasma fibrinogen, thrombin-antithrombin complex (TAT), prothrombin fragment (F1+2), and D-dimer. The levels of TAT and F1+2 in the markedly depressed group were significantly elevated compared with the other groups, whereas FDP, fibrinogen, and D-dimer levels did not differ among the groups. We concluded that activated coagulation is associated with cardiac dysfunction in patients with DMD.

Adolescent↗
PubMed2005

Intraperitoneal administration of phosphorothioate antisense oligodeoxynucleotide against splicing enhancer sequence induced exon skipping in dystrophin mRNA expressed in mdx skeletal muscle.

Antisense oligodeoxynucleotide against the splicing enhancer sequence (SES) in exon 19 of the dystrophin gene have been shown to induce exon 19 skipping and promote the expression of internally deleted dystrophin by correcting the translational reading frame in the cultured Duchenne muscular dystrophy (DMD) myocytes with the deletion of exon 20. Transfection of the antisense oligodeoxynucleotide, therefore, has been proposed as a promising means for therapeutic modification of dystrophin mRNA of DMD, a fatal disorder caused by defects in the dystrophin gene. A systemic delivery method targeting the large number of diseased muscles remains to be established for clinical application of antisense oligodeoxynucleotide. In this study, we investigated capability of oligodeoxynucleotide transfer into the skeletal muscles of mdx mouse, a mouse model of DMD. Thirty-one mer phosphorothioate oligodeoxynucleotide complementary to the SES of dystrophin exon 19 was intraperitoneally administered to mdx mice without any carrier. Histochemical study disclosed that fluorescence-labeled oligodeoxynucleotide appeared in the nuclei of femoral skeletal muscle cell at the second day after injection of 20 mg/kg BW oligodeoxynucleotide, and still visible at 14th day. Reverse transcription (RT)-PCR analysis of dystrophin transcript in these cells disclosed that a proportion of it showed skipping of exon 19 from second to seventh day after injection. These results showed that the intraperitoneally administered oligodeoxynucleotide could be transfected to nucleus of mdx skeletal muscle without any carrier and was able to induce exon skipping in vivo.

Animals↗
PubMed2006

Altered expression, intracellular distribution and activity of lymphocyte calpain II in Duchenne muscular dystrophy.

BACKGROUND: Calpain II is an calcium-dependent cysteine protease involved in essential regulatory or processing functions of the cell, mediated by physiological concentrations of Ca(2+). However, in an environment of abnormal intracellular calcium as in Duchenne muscular dystrophy (DMD), calpain is suggested to cause membrane alterations. METHODS: Twelve individuals with dystrophin gene deletion and an equal number of age and sex matched controls were chosen for the study. The expression pattern of calpain II (both at RNA and protein levels), its cellular location upon activation and its activity in lymphocytes were specifically assessed to know if our earlier report of increased calpain activity in DMD lymphocytes is a result of de novo synthesis or is due to basic defect in calcium handling. RESULTS: We found a significant increase in the expression, alteration in calpain II distribution and increased activity of this enzyme. CONCLUSION: Membrane abnormalities and altered signaling pathways observed in DMD lymphocytes may be due to increased association of calpain II onto membrane and cytosol.

Calpain↗
PubMed2005

Splicing intervention for Duchenne muscular dystrophy.

The manipulation of pre-mRNA to alter gene transcript splicing patterns offers considerable potential for many genetic disorders. In particular, the targeted removal of one or more exons from a gene transcript can skip over, or compensate for, disease-causing mutations. Duchenne muscular dystrophy (DMD), the most common and severe form of muscular dystrophy, is one such disorder that could benefit from this strategy. Splicing modulation can convert a DMD phenotype into the less severe allelic Becker-like phenotype. Recent studies using antisense oligonucleotide-targeted exon skipping to induce near normal dystrophin in vivo in animal models, and in vitro in DMD cell lines, highlight the promise of this approach. On the basis of these successes, human clinical trials could be realized in the near future.

Animals↗
PubMed2006

Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease due to a mutation in the dystrophin gene and the consequential protein deficiency in muscle. How the lack of the sarcolemmal protein dystrophin gives rise to the final disease status is still not clear. Several evidences suggest a role of nuclear factor kappa-B (NF-kappaB), a pleiotropic transcription factor, in muscle degeneration and regeneration in DMD patients and mdx mice. We investigated the effects of NF-kappaB blocking by pyrrolidine dithiocarbamate (PDTC), a well-known NF-kappaB inhibitor, on dystrophic process in mdx mice. Five-week-old mdx and wild-type mice received three times a week for 5 weeks either PDTC (50 mg/kg) or its vehicle. PDTC treatment: (i) increased forelimb strength (+20%; P < 0.05) and strength normalized to weight (+24%; P < 0.05) and a decreased fatigue percentage (-61%; P < 0.05) in mdx mice, (ii) blunted the augmented NF-kappaB nuclear binding activity and the enhanced TNF-alpha expression in dystrophic muscles (P < 0.01), (iii) at a quantitative morphological evaluation of extensor digitorum longus (EDL) and biceps muscles, increased area with normal fibers (P < 0.05, in EDL), reduced muscle necrosis (P < 0.05 in biceps; P < 0.01 in EDL), and enhanced muscle regeneration (P < 0.01, in biceps). Our data support the hypothesis that NF-kappaB contributes to the perpetuation of the dystrophic damage and show that its blockade produces beneficial effects on functional, biochemical, and morphological parameters in mdx mice. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.

Animals↗
PubMed2005

Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy.

OBJECTIVES: The aim of this research was to examine the effects of perindopril on cardiac function in patients with Duchenne muscular dystrophy (DMD). BACKGROUND: Duchenne muscular dystrophy, an inherited X-linked disease, is characterized by progressive muscle weakness and myocardial involvement. METHODS: In phase I, 57 children with DMD and a left ventricular ejection fraction (LVEF) >55% (mean 65.0 +/- 5.4%), 9.5 to 13 years of age (mean 10.7 +/- 1.2 years), were enrolled in a three-year multicenter, randomized, double-blind trial of perindopril, 2 to 4 mg/day (group 1), versus placebo (group 2). In phase II, all patients received open-label perindopril for 24 more months; LVEF was measured at 0, 36, and 60 months. RESULTS: Phase I was completed by 56 (27 in group 1 and 29 in group 2) and phase II by 51 patients (24 in group 1 and 27 in group 2). There was no difference in baseline characteristics between the treatment groups. At the end of phase I, mean LVEF was 60.7 +/- 7.6% in group 1 versus 64.4 +/- 9.8% in group 2, and was <45% in a single patient in each group (p = NS). At 60 months, LVEF was 58.6 +/- 8.1% in group 1 versus 56.0 +/- 15.5% in group 2 (p = NS). A single patient had an LVEF <45% in group 1 versus eight patients in group 2 (p = 0.02). CONCLUSIONS: Early treatment with perindopril delayed the onset and progression of prominent left ventricle dysfunction in children with DMD.

Adolescent↗