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PubMed1989

Nocturnal rhythm of growth hormone in Duchenne patients: effect of different doses of mazindol and/or cyproheptadine.

Human growth hormone (hGH) inhibition may be beneficial for Duchenne muscular dystrophy (DMD) patients and slow the rate of progression of the disease. The purpose of the present investigation was 1) to assess, before any therapeutic trial, the natural growth hormone (GH) rhythm during physiological sleep in DMD patients and in normal control boys of comparable age; 2) to evaluate the effect of different doses of two potential GH inhibitors on nocturnal GH secretion in DMD patients receiving mazindol (1-4 mg), cyproheptadine (4-8 mg), or both drugs. The results from the present investigation showed 1) wide variability in nocturnal GH secretion before medication; 2) no correlation between nocturnal GH concentration and height, age, bone age, L-dopa provocative test, or Tanner staging; and 3) no consistent effect on GH release after mazindol, cyproheptadine therapy, or combined therapy.

Adolescent↗
PubMed1991

Familial occurrence of Duchenne dystrophy through paternal lines in four families.

In a survey of 454 families with patients affected with Duchenne muscular dystrophy (DMD) we have found 4 genealogies with 2 or more affected patients who were related through paternal lines. In 1 of these families, 2 affected cousins showed different DNA deletions suggesting 2 independent mutations; in the other 2, in which only the propositus could be studied DNA deletions were also detected in the dystrophin gene. In the last one, with 3 affected patients, no DNA deletions were detected but immunohistochemical study of muscle biopsies showed a negative dystrophin pattern typical of DMD. Although one of these families might have occurred by chance, the probability of finding the other 3 in our sample of families with DMD patients constitutes a rare event. It is suggested that other mechanisms, such as the presence of transposable elements in other sites of the genome, could be responsible in some families, for a greater predisposition for the occurrence of pathogenic deletions, duplications or mutations.

Child↗
PubMed1991

Apparent association of mental retardation and specific patterns of deletions screened with probes cf56a and cf23a in Duchenne muscular dystrophy.

A total of 162 Duchenne (DMD) patients and two girls with a DMD phenotype were analysed for deletions in the central region of the dystrophin gene in order to determine if there was a correlation between mental retardation (MR) and the pattern of deletion. Approximately 43% of the patients studied had deletions with two dystrophin cDNAs, cf23a and cf56a, and among 148 patients who were mentally assessed, 50% were mentally retarded. The average IQ in the group of patients with DNA deletions did not differ significantly from those patients with no detectable deletions. However, six unrelated DMD boys with MR showed an identical pattern of deletion. Our observations in the group of patients who had detected DNA deletions suggest that exon 52 of the dystrophin gene may be functionally significant in the manifestation of MR: 70% (19/27) of patients with a deletion of this exon were mentally retarded, whereas only 38% (15/39) of MR patients had deletions not involving exon 52. This difference was statistically significant.

Chromosome Deletion↗
PubMed1992

Use of dystrophin genomic and cDNA probes for solving difficulties in carrier detection and prenatal diagnosis of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) results from mutations in the X-linked gene coding for the muscular protein dystrophin. The isolation of genomic and cDNA probes for this gene has greatly facilitated the detection of DMD carriers, which previously relied mainly on measurements of serum creatine kinase (CK), and has enabled prenatal diagnosis of this disease. However, the relatively large size of the gene and the high frequency of recombination and mutation events within the dystrophin locus continue to pose difficulties in the genetic counselling and prenatal diagnosis of DMD, and render the conclusions of molecular analysis less clear cut. This communication presents examples of two such difficulties: the distinction between sporadic and inherited cases in families with a single patient and normal CK levels in all females, and the distinction between mutant and normal dystrophin alleles in families in which the patients have died. The combined use of genomic and cDNA probes allows one to make these distinctions. An additional complicating factor, gonadal mosaicism, is demonstrated.

Clinical Enzyme Tests↗
PubMed1993

Isolation of a yeast artificial chromosome contig spanning the X chromosomal translocation breakpoint in a patient with Rett syndrome.

Rett syndrome is a neurodevelopmental disorder observed exclusively in females. A de novo X;3 translocation was detected in a patient (TH) with Rett syndrome. The X chromosomal breakpoint maps to Xp21.3 between the distal end of the Duchenne muscular dystrophy (DMD) gene and the DXS28 (C7) locus. To determine if this translocation caused the Rett syndrome in this patient, our efforts focused on mapping and cloning of the X chromosomal breakpoint in this patient. Toward these goals, we generated a set of radiation-reduced hybrid cell lines for the short arm of the X chromosome to use as a source for region-specific markers. Using Alu-PCR, 13 new DNA markers were isolated from a radiation-reduced hybrid, which retained both DMD and DXS28. These markers were localized within Xp21 using DNA from males with various interstitial deletions in this region. Two new markers, K23-2p and K23b-1, were found to be closer flanking markers to the X chromosomal breakpoint than DMD and DXS28. Long range restriction mapping using K23-2p and K23b-1 determined that the maximum distance between them was 800 kb. Several of the new markers were developed into sequence tagged-sites and were used to isolate yeast artificial chromosome (YAC) clones. A total of 22 YAC clones was isolated and characterized; these YACs were then developed into 3 large contigs in the Xp21.3 region. This effort resulted in the cloning of the region containing the X chromosomal translocation breakpoint of the Rett syndrome patient in a 170-kb YAC clone.

Animals↗
PubMed1995

Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family.

A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. "Idiopathic" hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggest that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of the maternal DMD gene and of a paternal gene, causing hyperCKemia.

Base Sequence↗
PubMed2001

Comparative analysis of PCR-deletion detection and immunohistochemistry in Brazilian Duchenne and Becker muscular dystrophy patients.

We studied 48 patients with dystrophinopathies (29 Duchenne muscular dystrophy (DMD), 13 Becker muscular dystrophy (BMD), four possible carriers, one female with DMD, and one intermediate form, using polymerase chain reaction (PCR) analysis of muscle tissue for 20 exons and compared them with immunohistochemistry studies for dystrophin. Of these, 42 (87.5%) showed at least one intragenic deletion. Most of them (47.45%) involved exons 2 to 20. All BMD patients presented deletions on the dystrophin gene. The 29 patients with DMD showed abnormal dystrophin in immunohistochemistry studies, some with total absence (17/29), others with residual (3/29), and the remaining with scattered positive fiber (9/29). The majority of the 13 patients with BMD had abnormal immunohistochemistry studies with diffuse reduction in the majority of muscle fibers (10/13), a few with patch discontinuation in the sarcolemma (2/13), and one normal (1/13). The immunohistochemistry exam for dystrophin is still the gold-standard method for DMD/BMD diagnosis. An ethnic difference, the analysis of several exons, the sample size, and the use of muscle tissue could explain this high frequency of deletions in the dystrophin gene found in our cases.

Brazil↗
PubMed1980

Serum creatine kinase BB and MM concentrations determined by radioimmunoassay in neuromuscular disorders.

We measured the MM and BB isoenzymes of serum creatine kinase (CK) by radioimmunoassay in 89 patients with neuromuscular disorders and 44 definite or possible carriers of Duchenne muscular dystrophy (DMD). The CK-MM isoenzyme was closely associated with total CK enzymatic activity. CK-BB was not as closely correlated with total CK but was usually increased in the inflammatory myopathies and DMD and normal in myasthenia gravis, Guillain-Barré syndrome, and amyotrophic lateral sclerosis as well as in neuropathies in which CK is usually normal. In myopathies, CK-BB may be useful for assessing the level of disease activity or the regenerative component. More study is necessary to assess the role of CK-BB in detection of DMD carriers.

Child↗
PubMed1997

Duchenne muscular dystrophy and the neuromuscular junction: the utrophin link.

Although the precise function of utrophin at the postsynaptic membrane of the neuromuscular junction still remains unclear, despite recent genetic 'knockout' experiments, a separate study in a transgenic mouse model system for Duchenne muscular dystrophy (DMD) has nonetheless shown that overexpression of utrophin into extrasynaptic regions of muscle fibers can functionally compensate for the lack of dystrophin and alleviate the muscle pathology. In this context, the next step is to identify the mechanisms presiding over expression of utrophin at the neuromuscular synapse in attempts to induce its expression throughout DMD muscle fibers. In fact, additional studies have shown that an important DNA element contained with the utrophin promoter may confer synapse-specific expression to the utrophin gene. Identification of the events culminating in the transactivation of the utrophin gene within synaptic myonuclei should provide important cues for the development of an effective therapeutic strategy for DMD.

Animals↗
PubMed1989

Elevated plasma levels of haptoglobin in Duchenne muscular dystrophy:electrophoretic variants in patients with a severe form of the disease.

Analysis of plasma proteins of Duchenne muscular dystrophy (DMD) patients and normal age-matched boys using two dimensional gel electrophoresis and densitometry indicated a three-fold increase in the average haptoglobin level in DMD plasma. Two electrophoretic variants of haptoglobin in which the alpha 2 chain had more basic or more acidic spots were found in DMD patients with a rapidly progressing form of the disease. The basic variant was present in relatively low amount. Possible reasons for the elevated haptoglobin levels are discussed.

Child, Preschool↗
PubMedDate not supplied

Improved antisense oligonucleotide induced exon skipping in the mdx mouse model of muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by dystrophin gene mutations that preclude synthesis of a functional protein. One potential treatment of the disorder has utilised antisense oligoribonucleotides (AOs) to induce removal of disease-associated exons during pre-mRNA processing. Induced in-frame mRNA transcripts encode a shorter but functional dystrophin. We have investigated and improved the design of AOs capable of removing exon 23, and thus the disease-causing nonsense mutation, from mRNA in the mdx mouse model of DMD. METHODS: H-2K(b)-tsA58 mdx cultures were transfected with complexes of Lipofectin and AOs. Exon skipping was detected by RT-PCR and subsequent protein production was demonstrated by Western blotting. AOs were delivered at a range of doses in order to compare relative efficiencies. RESULTS: We describe effective and reproducible exon 23 skipping with several AOs, including one as small as 17 nucleotides. Furthermore, the location of a sensitive exon 23 target site has been refined, whilst minimum effective doses have been estimated in vitro. These doses are significantly lower than previously reported and were associated with the synthesis of dystrophin protein in vitro. CONCLUSIONS: These results demonstrate the increasing feasibility of an AO-based therapy for treatment of DMD. By refining AO design we have been able to reduce the size and the effective dose of the AOs and have dramatically improved the efficiency of the technique.

Animals↗
PubMed2004

Effects of exercise and steroid on skeletal muscle apoptosis in the mdx mouse.

Reports concerning the influence of exercise loading and steroid administration on dystrophinopathy are inconsistent. To investigate the effect of muscle exercise in Duchenne muscular dystrophy (DMD), 15 control and 15 mdx mice, an animal model of DMD, were divided into free-living (n = 6), exercise (n = 6), and immobilization (n = 3) groups. Free-living and exercise groups were further divided into steroid-treated and sham-treated groups to evaluate the effect of steroid administration. We measured apoptotic changes by in situ DNA nick-end labeling (TUNEL), DNA fragmentation assay, and Western blotting for Bcl-2 and BAX. Apoptosis was most prominent in the sham-treated exercise group, and it was significantly reduced in the steroid-treated exercise group. The steroid-treated free-living group showed a higher rate of apoptotic change than the sham-treated free-living group. Apoptosis was minimized in the free-living condition, whereas exercise loading and immobilization caused apoptotic change in this muscular dystrophy animal model. Steroid administration induced apoptosis in muscle of free-living mice, but alleviated the apoptotic damage caused by exercise loading in mdx mice. These findings suggest that steroid administration may be effective in preventing a postexercise deterioration of skeletal muscle in animal models of DMD.

Animals↗
PubMed2004

Localization and early time course of TGF-beta 1 mRNA expression in dystrophic muscle.

Fibrosis is a common pathological feature observed in muscle from patients with Duchenne muscular dystrophy (DMD). In the dystrophic (mdx) mouse model of DMD, the diaphragm is more severely affected than other skeletal muscles. The level of transforming growth factor-beta1 (TGF-beta1), an inflammatory cytokine, is significantly elevated in mdx diaphragm. However, little is known about the onset of TGF-beta1 messenger ribonucleic acid (mRNA) expression, or which cells express the mRNA. In this study, we characterized the location and time course of expression of TGF-beta1 mRNA in diaphragm from mdx mice. TGF-beta1 mRNA was significantly elevated in mdx diaphragm at 6 and 9 but not 12 weeks of age, and these changes corresponded with changes in type I collagen mRNA and hydroxyproline concentration. Mononucleated cells localized to areas of fiber necrosis highly expressed the TGF-beta1 transcript in mdx diaphragm. Neutralization of TGF-beta1 by decorin administration resulted in a 40% reduction in the level of diaphragm muscle type I collagen mRNA. These findings support a role for TGF-beta1 during the early stages of fibrogenesis in dystrophic diaphragm muscle. Therapeutic interventions aimed at neutralizing this cytokine may be beneficial in slowing the development of fibrosis in DMD.

Animals↗
PubMed2006

Utrophin is a calpain substrate in muscle cells.

Calpains are Ca2+ -dependent cytosolic cysteine proteases that participate in the pathology of Duchenne muscular dystrophy (DMD). Utrophin is a functional homolog of dystrophin that partially compensates for dystrophin deficiency in myofibers of mdx mice. In this study, we investigated the susceptibility of utrophin to cleavage by calpain in vitro and in muscle cells. We found that utrophin is a direct in vitro substrate of purified calpain I and II. Cleavage of utrophin by calpain I or II generates specific degradation products that are also found in cultured control and DMD myotubes under conditions with elevated intracellular Ca2+ levels. In addition, we showed that activation of cellular calpains by Ca2+ ionophore treatment reduces utrophin protein levels in muscle cells and that calpain inhibition prevents this Ca2+ -induced reduction in utrophin levels. These observations suggest that, beside its known effect on general muscle protein degradation, calpain contributes to DMD pathology by specifically degrading the compensatory protein utrophin.

Animals↗
PubMed2006

Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule.

The severe Duchenne and milder Becker muscular dystrophy are both caused by mutations in the DMD gene. This gene codes for dystrophin, a protein important for maintaining the stability of muscle-fiber membranes. In 1988, Monaco and colleagues postulated an explanation for the phenotypic difference between Duchenne and Becker patients in the reading-frame rule: In Duchenne patients, mutations induce a shift in the reading frame leading to prematurely truncated, dysfunctional dystrophins. In Becker patients, in-frame mutations allow the synthesis of internally deleted, but largely functional dystrophins. Currently, over 4700 mutations have been reported in the Leiden DMD mutation database, of which 91% are in agreement with this rule. In this study we provide an update of the mutational variability in the DMD gene, particularly focusing on genotype-phenotype correlations and mutations that appear to be exceptions to the reading-frame rule.

Databases, Genetic↗
PubMed2007

Reliable surrogate outcome measures in multicenter clinical trials of Duchenne muscular dystrophy.

We studied the reliability of a series of endpoints in an evaluation of subjects with Duchenne muscular dystrophy (DMD). The endpoints included quantitative muscle tests (QMTs), timed function tests, forced vital capacity (FVC), and manual muscle tests (MMT). Thirty-one ambulatory subjects with DMD (mean age 8.9 years; range 5-16 years) were evaluated at eight sites by 15 newly trained evaluators as a test of interrater reliability of outcome measures. Both total QMT score [intraclass correlation coefficient (ICC) 0.96] and individual QMT assessments (ICC 0.85-0.96) were highly reliable. Forced vital capacity and all timed function tests were also highly reliable (ICC 0.97-0.99). MMT was the least reliable assessment method (ICC 0.61). These data suggest that primary surrogate outcome measures in large multicenter clinical trials in DMD should use QMT, FVC, or time function tests to obtain maximum power and greatest sensitivity.

Adolescent↗
PubMedDate not supplied

Element analysis of skeletal muscle in Duchenne muscular dystrophy using x-ray fluorescence spectrometry.

Concentrations of calcium, iron, copper, and zinc were simultaneously measured by x-ray fluorescence spectrometry in muscle biopsies from 11 normal subjects, 13 patients with Duchenne muscular dystrophy (DMD), and 3 DMD carriers. Calcium and copper levels were significantly elevated in patients with DMD compared to controls, and one presumptive carrier also showed an elevated calcium concentration. Comparisons with morphological data for the same samples showed a significant positive correlation between calcium concentration and the percentage area of type 2 fibers in controls, but no other correlations were found to be significant. These results illustrate the value of x-ray fluorescence spectrometry and provide further evidence for the involvement of calcium in dystrophic processes.

Adolescent↗
PubMedDate not supplied

Respiratory function in the muscular dystrophies.

The purpose of this investigation was to compare the respiratory function of patients with different clinical types of muscular dystrophy (MD). A total of 190 patients representing facioscapulohumeral MD (n = 20), limb-girdle MD (n = 50), Becker MD (n = 20), Duchenne MD (n = 90), and the "intermediate" type of MD (n = 10) were studied using simple spirometric respiratory function tests. The respiratory modifications observed in the 3 adult forms indicate that pulmonary function was almost normal. Respiratory function in Duchenne muscular dystrophy (DMD) was always characterized by a restrictive syndrome which severely impaired pulmonary function. The vital capacity (VC) underwent ascending, plateau, and descending phases during the course of the disease. The VC at the plateau stage may be used as an estimate of life span. The most interesting finding was the high degree of variability in the restrictive syndrome associated with DMD. In the DMD group 30% presented a severe restrictive respiratory syndrome associated with a life span of less than 20 years (Type 1), 40% had a serious restrictive syndrome and variable mortality (Type 2), and the remaining 30% had a moderate restrictive respiratory syndrome (Type 3).

Adolescent↗