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PubMed1987

Molecular analysis of the Duchenne muscular dystrophy region using pulsed field gel electrophoresis.

Genetic and molecular studies show that the Duchenne muscular dystrophy (DMD) locus at Xp21 is large and complex. We have analyzed this region using pulsed field gel electrophoresis (PFGE) and have determined physical distances between Xp21 probes. The sum of the sizes of the Sfil restriction fragments detected by these probes is greater than 4000 kb. The deletion endpoints in two DMD patients were detected by observing changes in these restriction fragments. In addition, the Xp21 breakpoint for the X;1 translocation in an affected female was mapped. These results demonstrate the applicability of PFGE for analysis of Xp21, and should facilitate the mapping of other translocations and deletions in this region, some of which lead to glycerol kinase deficiency and adrenal hypoplasia as well as DMD.

Chromosome Deletion↗
PubMed1995

Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy.

Nitric oxide (NO) is synthesized in skeletal muscle by neuronal-type NO synthase (nNOS), which is localized to sarcolemma of fast-twitch fibers. Synthesis of NO in active muscle opposes contractile force. We show that nNOS partitions with skeletal muscle membranes owing to association of nNOS with dystrophin, the protein mutated in Duchenne muscular dystrophy (DMD). The dystrophin complex interacts with an N-terminal domain of nNOS that contains a GLGF motif. mdx mice and humans with DMD evince a selective loss of nNOS protein and catalytic activity from muscle membranes, demonstrating a novel role for dystrophin in localizing a signaling enzyme to the myocyte sarcolemma. Aberrant regulation of nNOS may contribute to preferential degeneration of fast-twitch muscle fibers in DMD.

Amino Acid Oxidoreductases↗
PubMed1995

Infraspinatus muscle hypertrophy and wasting of axillary folds as the important signs in Duchenne muscular dystrophy.

Eighty-four patients with Duchenne muscular dystrophy (DMD) were examined clinically for hypertrophy and wasting in different muscles, parts of the muscles or muscle groups. Some muscles were examined under mild contraction to bring out any subclinical pseudohypertrophy. Findings revealed infraspinatus muscle hypertrophy to be significantly frequent (88%) and closely second to well known calf hypertrophy (94%). Infraspinatus hypertrophy was noted in 5 such DMD patients in whom calf hypertrophy was unremarkable. The wasting was consistently observed in the muscles forming anterior and posterior axillary folds. In conclusion, infraspinatus muscle hypertrophy and wasting of axillary folds are the important supportive clinical evidences during the examination of DMD patients.

Adolescent↗
PubMed1985

The pathogenesis of Duchenne muscular dystrophy: significance of experimental observations.

The pathogenesis of Duchenne muscular dystrophy (DMD) remains elusive, but as this is an inherited condition the primary manifestation of the disease is assumed to be in the regulatory control or biosynthesis of a protein. Current hypotheses attribute the pathological state of skeletal muscle in DMD to a defect in the nerve supply, or in the vasculature, or in the muscle itself. However, various tissues other than skeletal muscle are also affected; thus the current view of DMD requires reevaluation. The following possibilities should be considered: That the primary lesion is expressed in one of the major communication systems (nervous, vascular, or endocrine). That the primary lesion is expressed in a specific tissue: a) if in skeletal muscle, alterations in non-muscular tissues must be due to the release of muscle constituents into extracellular fluid; b) if in a non-muscular tissue, this might produce too much (or too little or none) of a constituent normally secreted into the extracellular fluid, or produce a "toxic" agent. That the primary lesion is expressed in a wide variety of tissues: the effect on a particular tissue will depend entirely upon the degree of requirement of the altered protein for function.

Humans↗
PubMed1987

Identifying and circumventing the defect in Duchenne muscular dystrophy: clinical and biochemical restoration after practical intervention.

Both direct and indirect experimental evidence independently confirms that inadequate muscle purine biosynthesis is the basic lesion in Duchenne muscular dystrophy (DMD), and indicates the presence of a partial defect at adenylosuccinate synthetase. Purine conservation by oral allopurinol gives only limited improvement, but continuous infusion of adenylosuccinate causes an immediate and lasting increase in physical strength, with restoration to normal of the abnormal serum enzyme elevations, creatine/creatinine metabolism, heart rate and ECG. Mass screening of male infants by a blood-spot test is proposed for early detection and treatment of all DMD cases, including the mutant one third with no family history. Prospects of the eventual disappearance of clinical DMD now appear possible.

Adenosine Monophosphate↗
PubMedDate not supplied

Muscle CT scans in preclinical cases of Duchenne and Becker muscular dystrophy.

Skeletal muscle CT scans were performed in patients with Duchenne (DMD) as well as Becker muscular dystrophy (BMD) in the preclinical or early clinical stage, at the levels of the 3rd lumbar vertebra, the mid thigh, and the maximum circumference of the calf. Only slight intramuscular low density areas and muscular atrophy were ascertained on gross visual inspection from the age of 3 years onward in DMD. However, the mean CT numbers calculated for individual muscles clearly decreased with increasing age in all muscles except anterior and posterior tibialis, which indicated them to be well preserved. Comparison of the rates of decrease in the CT numbers revealed that a rapid change in the paravertebral group commenced in the muscles on the lateral side, while among the adductors of the thigh, gracilis tended to be comparatively well preserved; this is the pattern of muscle involvement characteristic of symptomatic patients. In BMD, the atrophic change was extremely slight, and the CT numbers of the muscles were higher than the corresponding values for DMD in the same age group. CT numbers represent more objective indices for the assessment of muscular lesions as compared with gross visual inspection of skeletal muscle CT scans at the preclinical stage.

Adolescent↗
PubMedDate not supplied

A carrier of Duchenne muscular dystrophy with dilated cardiomyopathy but no skeletal muscle symptom.

A 29-year-old female developed dilated cardiomyopathy at 20 years of age but with no muscle symptoms. Her 2-year-old son with Duchenne muscular dystrophy (DMD)_had no demonstrable deletion in the dystrophin gene, but all fibers except for 5% 'revertant' fibers in a muscle biopsy specimen had no dystrophin. Both skeletal and cardiac muscle biopsy specimens from the mother showed a mosaic distribution of dystrophin-positive and -negative fibers, and so she was diagnosed as being a manifesting carrier of DMD. We conclude that, when one encounters a female patient with idiopathic cardiomyopathy with a high serum creatine kinase level, the suspicion of her being a manifesting DMD carrier should be ruled out.

Adult↗
PubMedDate not supplied

Molecular deletion patterns in Turkish Duchenne and Becker muscular dystrophy patients.

The dystrophin gene deletion patterns of Duchenne/Becker dystrophy were investigated in 57 DMD, 7 BMD and 1 DMD-BMD intermediate muscular dystrophy patients. Deletions, analyzed by multiplex amplification of selected exons, were observed in 58% (38 cases) of the patients. It was found that exon 48 was the most frequently affected, while exon 44 was the least frequently affected. The number of deleted exons was variable, but single exon deletions were more frequent (41%) than larger deletions in our population and the great majority of deletions began distal to exon 44. The application of PCR to deletion analysis in D/BMD was found to be very useful in delineating the extent of the deletion in most of the cases (82%). It was seen that the frequency of deletion breakpoints in distal part of the dystrophin gene (exons 42-52) was detected in 64% of our cases. In our group, the frequency of deletion breakpoints in the same area of the dystrophin gene was between that of the French and the Finnish patients. The distribution of deletion breakpoints within the dystrophin gene of the Turkish population seems to have some differences from other populations. Deletion breakpoints were found to be clustered mainly in three separate regions covering introns 44, 45 and 50 within the central region of the dystrophin gene. Intron 44 was mostly 5' breakpoints but it was found not to be involved as 3' breakpoints. The correlation between phenotype and type of deletion agreed with the reading frame theory except for one DMD case.

Adolescent↗
PubMedDate not supplied

Duchenne/Becker muscular dystrophy: from molecular diagnosis to gene therapy.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked muscular dystrophies. The recent isolation of the defective gene in DMD/BMD and the identification of its protein product, dystrophin, have revolutionized our ability to diagnose DMD/BMD and promoted speculation regarding the application of gene therapy. The purpose of this review is to present progress made in this area of research, with particular reference to dystrophin Kobe, which is caused by exon skipping during splicing due to the presence of an intra-exon deletion. On the basis of result of molecular analysis of dystrophin Kobe we propose a novel way of gene therapy for DMD, in which antisense oligonucleotides transform DMD into BMD phenotype by inducing exon skipping.

Genetic Therapy↗
PubMed1994

A molecular survey of Israeli Duchenne and Becker muscular dystrophy patients.

Duchenne (DMD) and Becker (BMD) muscular dystrophy are allelic X-linked recessive diseases caused by a mutation in the dystrophin gene located on the short arm of chromosome X (Xp21). The dystrophin gene is the largest gene known in humans, extending over 2300 kb and containing more than 70 exons coding for a 420 KD protein comprising 3685 amino acids. The gene is highly unstable, with a high percentage of deletions and rearrangements. A third of dystrophin mutations are new mutations. The frequency of DMD is 1:3500 liveborn males, and that of BMD 1:10000. These dystrophies are severe, progressive, and lethal. BMD/DMD patients and 2/3 of female carriers have high levels of creatine phosphokinase (CK). During the past 5 years, 169 families with patients affected by progressive muscular dystrophy were examined and counselled. We were able to exclude the diagnosis of DMD/BMD in 49 families on the basis of clinical symptoms and signs, normal dystrophin on biopsy (11 families) and/or the absence of linkage to chromosome X by analysis of RFLP derived haplotypes. Molecular analysis was performed on 111 DMD/BMD families (five BMD and 106 DMD) with 81 available probands. This study resulted in the establishment in Israel of an integrated diagnostic protocol for DMD/BMD, employing genetic, biochemical and molecular techniques. Molecular analysis provided most of the families with new and essential information.

DNA, Complementary↗
PubMedDate not supplied

Malignant hyperthermia susceptibility in X-linked muscle dystrophies.

To evaluate malignant hyperthermia (MH) susceptibility in X-linked muscular dystrophies, halothane and caffeine contracture tests were performed on muscle fiber bundles from five patients with Duchenne muscular dystrophy (DMD) and two patients with Becker muscular dystrophy (BMD). Two DMD patients and one BMD patient had positive contracture tests. Since a positive contracture test is currently the best indicator of anesthetic susceptibility in the MH population, and episodes of MH in dystrophic patients have been reported, patients with DMD and BMD may be at risk for developing similar anesthetic complications. Awareness of this potential anesthetic risk is of importance because orthopedic interventions are increasingly more common in these patients.

Adolescent↗
PubMedDate not supplied

Rehabilitation of communication impairment in dystonia musculorum deformans.

Augmentative and alternative communication (AAC) aids were used in three young, intellectually normal patients with dystonia musculorum deformans (DMD) who had severe speech and writing impediments. These aids included speech therapy, communication boards, and voice synthesizers for verbal communication and typewriters, memowriters, and computer software and printers for written communication. At times customized accessing was needed which required specific adaptive modifications. Implementation of the AAC aids system was determined effective for DMD patients in view of the intellect-sparing nature of the disorder. Improvement was hampered by the progressive nature of the disease and by the emotional stress of accepting the long-term use of AAC. Correct and early diagnosis of communication impediments are crucial for the appropriate AAC aids prescription and implementation. An AAC protocol is suggested to meet the special communication needs of DMD patients.

Adolescent↗
PubMedDate not supplied

Prediction of dystrophin phenotype by DNA analysis in Duchenne/Becker muscular dystrophy.

Allele-specific molecular diagnosis of Duchenne and Becker muscular dystrophies (DMD and BMD) has been largely dependent upon muscle biopsy for dystrophin protein assay. We performed lymphocyte DNA mutation analysis by polymerase chain reaction on 14 boys presenting with a clinical picture compatible with DMD or BMD. DNA analysis revealed that 12 of 14 boys had a deletion of the dystrophin gene, thus establishing the diagnosis of DMD/BMD. Furthermore, genotypes for 9 of 12 deletion patients permitted prediction of the specific allelic disorder (i.e., DMD or BMD). Subsequent dystrophin testing confirmed all of the DNA-based diagnoses. We propose that DNA mutation analysis be included in the initial evaluation of patients suspected of having DMD/BMD, thus potentially eliminating the need for muscle biopsy in the majority of patients.

Biopsy↗
PubMed1988

Molecular and genetic mapping of the mouse mdx locus.

mdx is an X-linked muscular dystrophy mutant of the mouse and a putative homolog of the human X-linked muscular dystrophy locus--Duchenne muscular dystrophy (DMD). Utilizing a C57BL/10/Mus Spretus interspecific cross in which the mdx mutation was segregating, we have constructed a detailed genetic map around the mdx locus on the mouse X chromosome. We were unable to detect recombinants between mdx and exonic probes derived from the human DMD gene. These genetic data support the contention from biochemical studies (E.P. Hoffman, R. H. Brown, and L. M. Kunkel, 1987, Cell 51: 919-928) that DMD and mdx are homologous genes.

Animals↗
PubMed1989

Analysis of molecular deletions with cDNA probes in patients with Duchenne and Becker muscular dystrophies.

In the course of a systematic survey of DMD and BMD patients with intronic probes and with cDNA probes covering three-fourths of the coding sequence, 45 molecular deletions within the DMD gene were investigated. Forty-two percent of the breakpoints were located in the intronic sequence containing probe P20, whereas the other deletions were widespread around the more proximal part of the gene. Most of the BMD deletions were in the P20 region. Pulsed field gel electrophoresis was used to determine the size of some deletions and allowed us to estimate the physical distance between the intronic probes JBir and P20. The reading frame was checked in 11 cases with proximal deletions and found to be disrupted in 6 of 7 DMD patients, in 1 intermediate case, and, unexpectedly, in 3 BMD patients.

Adolescent↗
PubMed1990

Chromosomal localization of ZFX--a human gene that escapes X inactivation--and its murine homologs.

The ZFY gene, found in the sex-determining region of the human Y chromosome, encodes a zinc-finger protein that may be the pivotal sex-determining signal. A closely related gene, ZFX, is found on the human X chromosome, and it may also function in sex determination. ZFX is one of a few genes on the human X chromosome that are known to escape X inactivation. We report the localization of ZFX, by meiotic linkage analysis and physical mapping, distal to POLA but proximal to DXS41 (p99-6), near the boundary of bands Xp21.3 and Xp22.1. (Our results suggest the following order of loci in Xp21-p22: cen-DMD-[GK,AHC]-DXS67 (pB24)-POLA-ZFX-[DXS41 (p99-6), DXS274 (CRI-L1391)]-DXS43 (pD2)-pter.) These findings contradict the model that escape from X inactivation is limited to genes near the short-arm telomere (i.e., in Xp22.3). Instead, escape from X inactivation is likely a property of several noncontiguous segments of the X chromosome. Curiously, in mouse, the homologous Zfx gene maps to X chromosome band D, near the center from which an X-inactivating signal is thought to spread. As judged by comparative mapping, it appears that an X-chromosomal segment that spans the ZFX and DMD genes has remained grossly intact during the divergence of mouse and human from a common ancestor. Conservation of this chromosomal segment may extent to marsupials, where homologs of the ZFX and DMD genes have been observed in proximity, but on an autosome. While autosomal homologs of ZFX have not been observed in other placental mammals, a locus derived from a processed Zfx transcript is found on mouse chromosome 10 band B3 or B4.

Animals↗
PubMed1991

Physical mapping at a potential X-linked retinitis pigmentosa locus (RP3) by pulsed-field gel electrophoresis.

A genetic locus (RP3) for X-linked retinitis pigmentosa (XLRP) has been assigned to Xp21 by genetic linkage studies and has been supported by two Xp21 male deletion patients with XLRP. RP3 appears to be the most centromeric of several positioned loci, including chronic granulomatous disease (CGD), McLeod phenotype (XK), and Duchenne muscular dystrophy (DMD). In one patient, BB, the X-chromosome deletion includes RP3 and extends to within the DMD locus. Using a DMD cDNA, the centromeric endpoint of this patient was cloned and used as a starting point for chromosome walking along a normal X chromosome. A single-copy probe, XH1.4, positioned near the centromeric junction but deleted in BB, was used along with a CGD cDNA probe to establish a refined long-range physical map. Both probes recognized a common SfiI fragment of 205 kb. As the CGD gene covers approximately 30-60 kb, the RP3 locus has been restricted to approximately 150-170 kb. A CpG island, potentially marking a new gene, was identified within the SfiI fragment at a position approximately 35 kb from the deletion endpoint in BB.

Centromere↗
PubMed1992

A transposon-like element in the deletion-prone region of the dystrophin gene.

The central portion of the dystrophin gene locus is a preferential site for deletions causing progressive muscular dystrophy of the Duchenne type (DMD). The nucleotide sequence of a deletion junction fragment from a DMD patient was determined, revealing that the proximal breakpoint of the deletion in intron 43 fell within the sequence of a transposon-like element. This segment, belonging to the THE-1 family of human transposable elements, is normally present in a complete form in intron 43 of the dystrophin gene. The deletion mutation was maternally transmitted and eliminated two-thirds of the THE-1 element. Analysis of DNA from additional DMD patients revealed a second deletion with the proximal breakpoint mapping within the same THE-1 element.

Base Sequence↗