What kind of trait is duchenne muscular dystrophy

Noting that in DMD functional impairment of smooth muscle in the gastrointestinal tract can cause acute gastric dilatation and intestinal pseudoobstruction that may be fatal, Barohn et al. Strikingly delayed gastric emptying times were observed. Enigmatically, the extraocular muscles EOMs remain clinically unaffected during the course of Duchenne muscular dystrophy Kaminski et al.

Khurana et al. They reported in vitro experiments demonstrating that extraocular muscles are inherently more resistant to necrosis caused by pharmacologically elevated intracellular calcium levels when compared with pectoral musculature. They suggested that the EOMs are spared in DMD because of their intrinsic ability to maintain calcium homeostasis better than other striated muscle groups. This suggested further that modulating levels of intracellular calcium in muscle may be of potential therapeutic use in DMD.

Mental retardation of mild degree is a pleiotropic effect of the Duchenne gene Zellweger and Niedermeyer, As indicated later, the finding of dystrophin mRNA in brain may bear a relationship to the mental retardation in DMD patients. Emery et al. Affected boys were categorized according to whether they had severe mental handicap or not. Those with severe mental defect had later age of onset and confinement to wheelchair, less marked fall in creatine kinase with age, and a greater urinary excretion of certain amino acids.

In 50 DMD patients with a mean age of Bushby et al. Previously, it had been shown that deletions removing the brain-specific promoter were compatible with normal intelligence. The authors found no significant IQ difference between the patients with promoter deletions and those without, nor did they find a relationship between the length of the deletion and full scale IQ. They found, however, that boys with distal deletions were more likely to be mentally retarded than were those with proximal deletions.

Electroretinography is a recording of summed electrical signal produced by the retina when stimulated with a flash of light. The dark-adapted ERGs, recorded under scotopic testing conditions, have shown normal a-waves a response of negative polarity generated by the photoreceptors but reduced amplitude rod-isolated b-waves a response of positive polarity originating primarily from the ON-bipolar cells in DMD patients.

This type of ERG abnormality with profound b-wave suppression is commonly associated with night blindness; however, there have been no reports of night blindness or any other visual abnormality in boys with DMD, and dark-adaptometry studies have been normal. Fitzgerald et al.

In the ERGs of 11 DMD boys, they found abnormal signal transmission at the level of the photoreceptor and ON-bipolar cell in both the rod and cone generated responses. Jensen et al. Eight of the boys had DMD gene deletions downstream from exon Normal dark adaptation thresholds were observed in all patients and there were no anomalous visual functions.

The ophthalmic features of DMD include normal ERG a-wave with reduced b-wave, normal visual acuity, and normal retinal morphology. Immunocytochemistry revealed strong AQP4 water channel expression in Muller cells in mouse retina and in fibrous astrocytes in optic nerve.

Li et al. Significantly reduced ERG b-wave potentials were recorded in month-old null mice with smaller changes in 1-month-old mice. Morphologic analysis of retina by light and electron microscopy showed no differences in retinal ultrastructure. That retinal function was mildly impaired in Aqp4-null mice suggested a role for Aqp4 in Muller cell fluid balance. The authors suggested that AQP4 expression in supportive cells in the nervous system facilitated neural signal transduction in nearby electrically excitable cells.

Costa et al. Patients were divided into 2 groups according to the region of deletion in the dystrophin gene: 12 patients had deletion upstream of exon 30, and 32 downstream of exon No color defect was found in the patients with a deletion upstream of exon A negative correlation between the color thresholds and age was found for the controls and patients with DMD, suggesting a nonprogressive color defect. Nine of the patients had developed DCM during the follow-up period.

These carriers were on average older, were more symptomatic, and more often had hypertension, exertional dyspnea, and chest pain compared to mutation carriers without DCM. The findings suggested that female carriers of a mutation can develop progressive cardiac abnormalities and should undergo routine cardiac evaluation, preferably by echocardiology.

Mercier et al. Five had a Duchenne-like phenotype with loss of ambulation before age 15 years, 13 had a Becker-like phenotype with muscle weakness but persistence of ambulation after age 15 years, and 8 had exercise intolerance.

Cognitive impairment was associated with mutations in the distal part of the gene. Blau et al. This was based on the observation that the number of viable myoblasts obtained per gram DMD muscle tissue was greatly reduced and those that grew in culture had a decreased proliferative capacity and aberrant morphology.

The hypothesis was tested by determining whether the myoblast defect was X-linked. Webster et al. In a total of 1, muscle clones, although the proportion of defective clones was increased, the cellular defect did not consistently segregate with a single G6PD phenotype in the myoblast clones from any individual. The hypothesis that the DMD gene is expressed in skeletal myoblasts and limits proliferation, was further tested by Hurko et al.

Both cloned and mass cultures were grown until senescence and the G6PD phenotype was scored. Myoblasts expressing the 2 different alleles at the G6PD locus did not differ in proliferative capacity, suggesting that expression of the Duchenne gene does not result in a decrease in proliferative capacity of the myoblasts. Thus, the hypothesis of Blau et al. Baricordi et al. This was taken to mean that the capping impairment is an intrinsic cellular defect in DMD and not a phenomenon secondary to progression or activity of the disease.

Further, it may indicate that there is a generalized membrane disorder in this condition. Haslett et al. They identified genes that differed significantly in expression levels between unaffected and DMD muscle. Many of the differentially expressed genes reflected changes in histologic pathology; e. Significantly more genes were overexpressed than were underexpressed in dystrophic muscle, with dystrophin underexpressed, whereas other genes encoding muscle structure and regeneration processes were overexpressed, reflecting the regenerative nature of the disease.

Straub et al. In muscle biopsy samples from 13 of 16 DMD patients, Kleopa et al. In disease tissue, utrophin was present along the whole circumference of the sarcolemma, whereas it was present only along vessels and nerve endings in controls. Expression of utrophin in disease tissue showed a positive correlation with age at wheelchair-dependency in DMD, suggesting that utrophin expression has an ameliorating effect on the severity of DMD.

In Duchenne patients, Labarque et al. Decreased expression of these isoforms was associated with increased Gs see, e. Functional studies showed that DMD platelets had slower aggregation in response to collagen with extensive shape changes and reduced platelet adhesion under flow conditions. Platelet membrane receptors were normal. The decreased collagen activation was shown to result from both Gs activation and cytoskeletal disruption.

Overall, the findings suggested that DMD platelets have a disorganized cytoskeleton due to dysfunctional dystrophin Dp71, and also manifest Gs hyperactivity with reduced platelet collagen reactivity, which may result in increased bleeding during surgery.

The Haldane rule Haldane, predicts that one-third of cases of a genetic lethal X-linked recessive will be the consequence of new mutation. Haldane further suggested that the mutation rate for Duchenne muscular dystrophy might be higher in males. Such would result in a lower proportion of cases being new mutants. Caskey et al. Ionasescu et al. Bucher et al. They found that only 9 When only the mothers of isolated cases were studied, They felt that a higher male than female mutation rate was the cause of the discrepancy.

In a study of probands who constituted two-thirds of the known cases in Japan, Yasuda and Kondo could not demonstrate an effect of maternal grandfather's age at birth of the proband's mother.

They pointed out that the data relevant to a maternal grandfather age effect in hemophilia A are conflicting, just as the data for DMD are inconsistent with those of Bucher et al. Examining the frequency of affected boys among the next-born male sibs of 37 initially 'sporadic' cases of DMD, Lane et al.

The estimated proportion of new mutant cases in the combined clinic population of families was 0. They proposed that the absence of affected males in earlier generations in families of isolated cases may be explained in part by a high ratio of male to female stillbirths and infant deaths which in this study was more than 3 times that in the general population.

Note that there is at least one other 'Haldane's rule' Haldane, : 'When in the F1 offspring of two different animal races one sex is absent, rare, or sterile, that sex is the heterozygous, heterogametic or XY sex. Danieli and Barbujani concluded that the proportion of sporadic cases was 0.

In a segregation analysis of 1, DMD families, Barbujani et al. They mentioned the previously discussed possible explanations for the finding, such as sex differences in mutation rate, and added a new one, namely, the occurrence of multiple DMD cases in the same sibship as a consequence of mutational mosaicism of the maternal germ cells, a phenomenon documented in a number of instances. As might perhaps have been anticipated, a report appeared concerning a man with DMD who had fathered 2 children, a normal son and a carrier daughter Thompson, Therefore, barring gonadal mosaicism, it is unlikely that the maternal aunts and their daughters are carriers of the DMD gene.

Miciak et al. They demonstrated that the molecular defect was different in each and speculated about instability of the DMD gene and possible involvement of transposons. They referred to similar observations by Zatz et al. Vitiello et al. In 3 cases in which dystrophin of normal size was expressed at low levels, the DNA sequence of the promoter region showed no abnormality. A possible example of gonadal mosaicism for the DMD locus was discussed by Wood and McGillivray , who described a family in which a female ancestor of an individual with Duchenne muscular dystrophy seemed to have transmitted 3 distinct types of X chromosome to her offspring, as indicated by RFLP analysis.

The authors postulated that in this individual the mutation arose as a postzygotic deletion, resulting in germinal mosaicism. Witkowski suggested another explanation for those cases in which gonadal mosaicism has been suspected: such a female may represent a chimera that has originated from 2 fertilized eggs, one carrying the mutation.

This, of course, has quite different implications regarding the risk that a maternal aunt of the proband is a carrier. Melis et al. Immunohistochemical analysis of muscle dystrophin and haplotype analysis of the DMD locus demonstrated that the X chromosome carrying the DMD gene was transmitted from the healthy maternal grandfather to his 3 daughters, including the proband's mother.

The definition of carrier status in 2 possible carriers permitted accurate genetic counseling and the prevention of the birth of an affected boy. Witkowski presented the pedigree of a family with a balanced autosomal translocation in 3 generations: a son of a carrier exhibited lymphocytes with a normal karyotype as well as lymphocytes with the balanced translocation.

She also cited the 47,XXX karyotype as a possible alternative explanation to germline mosaicism; there are known sibships in which boys have received 3 different haplotypes on the X chromosome from the mother. Unexpectedly, Passos-Bueno et al. Yoshioka observed unusually severely affected heterozygous females and suggested that factor s other than lyonization may be involved.

One of the women was the product of a consanguineous mating, suggesting modification of expression by homozygosity at an autosomal locus. Burn et al. Hybridization of fibroblasts from each twin with RAG-mouse cell line deficient in HPRT showed that in the affected twin it was the mother's X chromosome that was predominantly the active one, whereas in the normal twin it was the father's.

In female monozygotic twins discordant for muscular dystrophy, Richards et al. Uniparental disomy and chromosome abnormality were excluded, but on the basis of methylation differences of the paternal and maternal X chromosomes, Richards et al. Lupski et al. One was a manifesting heterozygote, whereas the other was normal.

Unlike the study of Richards et al. They suggested that the result was consistent with the model of twinning and X-inactivation proposed by Nance in that these twins probably represented asymmetric splitting of the inner cell mass ICM : the affected twin probably arose when a small proportion of the ICM split off after lyonization had occurred.

In this situation, the original ICM could have given rise to the normal twin with random lyonization, while the newly split cells would experience catch-up growth and lead to the affected twin. Many DMD patients have rare staining dystrophin-positive fibers. Indeed, the dystrophin-positive fibers have been referred to as 'revertants. Klein et al. These results indicated that positively stained fibers were not the result of somatic mosaicism in deletion patients. Thanh et al. They showed that 15 revertant fibers in a DMD patient with a frameshift deletion of exon 45 had correction of the frameshift by the additional deletion of exon 44 or perhaps exon 46 in some fibers from the dystrophin mRNA, but not by larger deletions.

The results were consistent with somatic mutations in revertant-fiber nuclei, which result in removal of additional exons from dystrophin mRNA. These data did not clearly distinguish between additional somatic deletions and somatic effects on dystrophin mRNA splicing, however, and both mechanisms may be operating. Pena et al. Her sister was clinically normal but had an affected son. Eleven affected males in 3 generations and 7 separate sibships of the kindred were known.

An undetected monozygotic twinning event was proposed by Glass et al. They concluded that females heterozygous for BMD have less likelihood of showing manifestations of muscular dystrophy than do females heterozygous for DMD.

Abbadi et al. Results in lymphocytes and skin fibroblast cell lines suggested a partial mirror inactivation with the normal X chromosome preferentially active in the unaffected twin, and the maternally deleted X chromosome preferentially active in the affected twin. Pegoraro et al. All 13 had skewed X-inactivation patterns in peripheral blood DNA. Of the 9 isolated cases informative in their assay, 8 showed inheritance of the dystrophin gene mutation from the paternal germline.

Only a single case showed maternal inheritance. Thus they suggested that there is some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation.

Chelly et al. The one X chromosome in the girl was normal by high resolution banding, but DNA analysis by Southern blotting and hybridization with 7 cloned probes mapping in the Xp21 region showed a deletion of 3 of the probes. In this case, the paternal chromosome was lost and the maternal X chromosome suffered a deletion mutation in the Xp Suthers et al. The mild expression may be due to the fact that he was heterozygous for the muscular dystrophy mutation.

The nephews indeed may have had Duchenne muscular dystrophy. Among 35 children produced by 34 deliveries in 13 women who were mothers of males attending a muscular dystrophy clinic, Geifman-Holtzman et al. Of the 6 infants with breech presentation, 2 were males affected with DMD, 1 was a female heterozygote, 1 was a male who died perinatally, and the carrier status of the other 2 females was unknown.

Thus, the authors concluded that maternal rather than fetal muscle weakness was the significant factor in determining fetal position at term. They suggested that subtle changes in uterine or pelvic girdle muscle tone may contribute to a higher rate of fetal breech presentation in carriers of the DMD gene.

Yoshioka et al. Reported genetic mechanisms for female DMD include 1 a skewed pattern of X-chromosome inactivation in female carriers of a DMD mutation Azofeifa et al. Katayama et al. Although the child was phenotypically female, the karyotype showed 46,XY, and she was found to have a mutation in the AR gene causing androgen insensitivity syndrome AIS; The unaffected mother was found to be heterozygous for the AR mutation, but did not have the DMD mutation, indicating it was de novo in the proband.

Rajakulendran et al. MRI showed muscle atrophy and fatty replacement on the affected side, and histologic studies showed decreased dystrophin staining.

Both had increased serum creatine kinase. The older woman had areflexia of the affected side, no family history of muscular dystrophy, and showed skewed ratio of X inactivation in lymphocytes. The younger woman had an affected son and showed normal X inactivation in lymphocytes.

Greenstein et al. The mother was thought not to be a carrier. Possibly the break at Xp21 caused a null mutation; the normal X chromosome was inactivated. Verellen et al. Canki et al. The mother was thought to be heterozygous. Zneimer et al. The twins carried a deletion of approximately kb within the dystrophin gene on one X chromosome.

A unique DNA fragment generated from an exon within the deletion was hybridized in situ to metaphase chromosomes of both twins, a probe that would presumably hybridize only to the normal X chromosome and not to the X chromosome carrying the deletion. The chromosomes were identified by reverse-banding R-banding and by the addition of 5-bromodeoxyuridine in culture to distinguish early and late replicating X chromosomes, corresponding to active and inactive X chromosomes, respectively.

The experiment showed predominant inactivation of the normal X chromosome in the twin with DMD. With an improved method of high resolution R-banding, Werner and Spiegler showed deletion of Xp His healthy mother was heterozygous for the deletion, which was subject to random X inactivation in lymphocytes.

Saito-Ohara et al. His mother carried this inversion on one allele. The patient's condition was originally misdiagnosed as cerebral palsy. Because the DMD gene is located at Xp The molecular-cytogenetic characterization of both breakpoints revealed 3 genetic events that probably had disastrous influence on neuromuscular and cognitive development: deletion of part of the DMD gene at Xp Tran et al.

The first exon of KUCG1 was spliced to a dislocated part of the dystrophin gene, producing a chimeric dystrophin transcript. Brain MRI in the patient was normal. However, sequencing of the KUCG1 gene in 10 additional Japanese families with X-linked mental retardation did not identify any mutations.

Duchenne muscular dystrophy is not linked to colorblindness or G6PD Emery et al. No linkage with Xg has been found; total lod scores were Lindenbaum et al. A number of females with X-autosome translocations with the breakpoint in the Xp21 band have shown Duchenne muscular dystrophy. One interpretation is that the gene locus is in that region and that the locus on the normal X is inactivated.

Murray et al. Spowart et al. Wieacker et al. At least 2 crossovers were found among 9 meioses in an informative family, suggesting that RC8 and STS may be about 25 cM apart. Worton et al. Thus, ribosomal RNA gene probes can be used to identify a junction fragment from the translocation site and to clone segments of the X at or near the DMD locus.

Kingston et al. DXS7 is located between Xp Thus, these 2 forms of X-linked muscular dystrophy appeared to be allelic, a possibility also supported by the finding of both severe and mild disease Duchenne and Becker, if you will in females with X-autosome translocations. Contrary to reports of others, Kingston et al.

Francke et al. A very subtle interstitial deletion of part of Xp21 was demonstrated as the presumed basis of this 'contiguous gene syndrome. At least 4 possible explanations of the discrepancy were proposed by Francke et al. One suggestion was that the deletion contained a single defect affecting perhaps a cell membrane component with the several disorders following thereon.

Mulley et al. No recombinants were observed. Grimm et al. Tuffery-Giraud et al. This corresponds to an estimated frequency of 39 per million with a genetic diagnosis of a 'dystrophinopathy' in France. Mutations in the database include 1, large deletions, large duplications, and small rearrangements, of which Among index cases evaluated for DMD mutations, Oshima et al. Deletions were detected in Most of the deletions fell between exons 45 and 52 and between exons 8 and 13 of the gene.

Duplications were detected in 44 Complex rearrangements were detected in 6 2. The remaining cases showed normal results. Oshima et al. Fourteen of the deletions had microhomology and small insertions at the breakpoints, consistent with a mechanism of nonhomologous end joining NHEJ after DNA damage and repair. Skeletal muscle mRNA profiling identified the G allele of rs in the promoter of the SPP1 gene , which encodes osteopontin, as having a significant effect on both disease progression and response to glucocorticoids.

The association was validated in a second cohort of patients. Clinical diagnosis of males affected with DMD is straightforward. Gait difficulty beginning at age three, progressive myopathic weakness with pseudohypertrophy of calves and massive elevations of serum levels of creatine kinase permit diagnosis.

Electromyography and muscle biopsy are confirmatory. Inflammatory changes seen in biopsies taken early in the course of the disorder can erroneously suggest a diagnosis of polymyositis if careful note is not made of the histologic hallmarks of dystrophy.

Heyck et al. According to Dubowitz , elevation in cord blood in a proven case had not been documented. Furthermore, many perinatal factors seem to cause elevation of CPK. Mahoney et al. Darras et al. Bartlett et al. They suggested that once the entire gene is available for screening, most DMD boys will show deletions.

In some of the examples cited, the authors made use of creatine phosphokinase levels as well. Speer et al. Clemens et al. CA n loci are a subclass of all short tandem repeat STR sequences.

Because they are frequently polymorphic, so-called pSTR, they are useful for linkage purposes and are readily studied by PCR. Bieber et al. Evans et al. In utero muscle biopsy at 20 weeks of gestation showed normal dystrophin, and serum creatine kinase was normal at the time of birth of the infant.

Situations in which testing of dystrophin by fetal muscle biopsy may be indicated were reviewed. Sancho et al. Immunocytochemical analysis of dystrophin in the MYOD-converted muscle cells is an effective way of demonstrating dystrophin deficiency.

For males with consistent clinical features, CPK levels, and muscle biopsy, they suggested that Western blot testing for dystrophin be done first. If this is normal, the patient should be studied for other neuromuscular diseases. If dystrophin is of reduced or increased size, with or without reduction in the amount of dystrophin, BMD should be suspected. If dystrophin is absent, DMD should be suspected. If no deletion or duplication is found, it is then necessary to resort to RFLP-based linkage studies, which unfortunately are laborious and time consuming.

Once the diagnosis has been made, the information can be used for carrier detection and prenatal diagnosis. In females who are having symptoms of muscular dystrophy, immunohistochemistry for dystrophin in muscle showing a patchy loss of dystrophin can be used, and when abnormality is found, the same procedures of PCR, Southern blot, and linkage studies can be pursued. If the immunohistochemistry is normal, the female can be studied for other neuromuscular diseases.

Abnormality is indicative of the manifesting carrier state. Beggs and Kunkel provided useful illustrative case histories as well as a hypothetical case in which a newborn male was found to have elevated CPK on a screening program but normal physical examination and negative family history.

If Western blotting revealed absence of detectable dystrophin in the muscle and the PCR analysis detected a deletion which was confirmed by Southern blotting, his mother might carry the deletion or be normal. Even if normal, prenatal diagnosis could be offered her because of the significant probability that she was a germline mosaic.

The usefulness of such screening programs for diagnosing DMD at a stage when diagnosis can be useful to the parents in the planning of other pregnancies is worthy of consideration. Kristjansson et al. They reported the simultaneous analysis of single cells at 5 commonly deleted dystrophin exons. They suggested that transfer of unaffected male embryos and improved diagnostic reliability is achieved with the ability to perform replicate multilocus analyses from the same blastomere.

Parsons et al. Newborn screening for DMD was introduced into Wales in While screening in the newborn period for DMD was still under evaluation, preliminary evidence indicated that the excessive trauma anticipated in making such a disclosure presymptomatically could be avoided by implementing a strict protocol of disclosure and support. Parental choice should be facilitated at every stage from screen to diagnosis, and parents should be provided with maximum unbiased information on which to base their decisions.

The family should not experience delay in getting the results with the additional stress this may cause. Meetings with the primary health care team and with the pediatrician facilitated ongoing support for the family.

Roses et al. By combining the 2 enzyme determinations and screening pedigrees extensively, they found that 28 of 30 mothers were probably heterozygotes. This high proportion of carriers is consistent with a higher mutation rate in males than in females, a conclusion suggested also by data on Lesch-Nyhan syndrome and hemophilia Hemopexin is elevated in some DMD carriers. Percy et al. Sato et al. Beckmann et al. They suggested screening of all infants.

Although analysis of DNA with probes complementary to the dystrophin gene clarifies the diagnosis in at least two-thirds of isolated adult male patients, this approach in female patients is frustrated by the obfuscation of molecular deletion by heterozygosity, when gene dosage alone is not sufficiently reliable. Pulsed field gel electrophoresis may allow detection of abnormal-sized fragments of the dystrophin gene in these patients, and analysis of the dystrophin protein itself may be helpful.

Tangorra et al. With increased utilization of dystrophin protein analysis of muscle biopsies for molecular diagnosis, many female myopathy patients with no previous family history of any neuromuscular disease have been found to have a mosaic dystrophin immunostaining pattern on muscle biopsy Minetti et al.

These patients generally were diagnosed as having limb-girdle muscular dystrophy with presumed autosomal recessive inheritance before reclassification, by dystrophin testing, as female dystrophinopathy patients Arikawa et al. In a large follow-up study of muscle biopsies from female myopathy patients, Hoffman et al.

It was assumed that such female dystrophinopathy patients were heterozygous carriers who showed preferential inactivation of the X chromosome harboring the normal dystrophin gene. Such was shown to be the case, for example, in 2 sets of discordant monozygotic twins Bonilla et al. However, mosaic staining patterns have only been detected in heterozygote females with elevated levels of creatine kinase in the blood.

Diagnosis of asymptomatic women without deletions or elevated creatine kinase remains a problem. In a study of clonal myogenic cell cultures from a potential heterozygote for DMD who also was heterozygous for G6PD isozymes, Hurko et al. He suggested that somatic cell testing of dystrophin expression may be useful in genetic carrier tests in ambiguous cases. Hoogerwaard et al.

For example, 5 carriers with cardiomyopathy had no dystrophin abnormalities, whereas 6 nonmanifesting carriers had abnormal immunohistochemical dystrophin patterns. Sifringer et al. Comparison of important parameters in the development of the 2 brothers made clear that the older brother was far more affected by muscle weakness than the younger.

The younger brother was able to sit 9 months earlier and to walk 22 months earlier than the older one. The older brother was wheelchair-bound at the age of 9 years, whereas the younger one was not expected to become wheelchair dependent at the same age. Furthermore, the older boy was mentally retarded.

Though deletions or point mutations in the DMD gene were not detected, negative immunofluorescence in both brothers supported the diagnosis of dystrophinopathy and suggested compensating mechanisms for the younger less affected brother. Six genes were found to be overexpressed 3 to 20 times in the less affected patient compared with the more severely affected boy; casein kinase 1 showed a slightly higher expression.

Upregulation of myosin light polypeptide 2 MYL2; , one of the most sensitive markers of muscle fiber regeneration, was found with the milder phenotype. The purpose of these studies was to identify modifiers that might be exploited therapeutically in Duchenne muscular dystrophy.

The management of DMD is largely symptomatic: providing assisting devices for walking, prevention of scoliosis, and respiratory toilet. Goertzen et al. In a kindred with 9 previous cases of DMD, Zatz et al. Following up on this observation Zatz and Betti, , Zatz et al. The other twin received a placebo. After 1 year, the 'code was broken' and the placebo-treated twin was found to be much worse than his mazindol-treated brother in whom the 'condition was practically arrested.

From a 6-month trial study, Mendell et al. The mechanism of the improvement was not known and it was not clear whether prolonged treatment with corticosteroids is warranted despite their side effects.

Studies had shown a correlative relationship between calpain activity in dystrophic muscle and muscle necrosis, but had not tested whether calpain activation precedes cell death or is a consequence of it. Spencer and Mellgren hypothesized that calpains may play an active role in necrotic processes in dystrophic muscle, and that inhibition of calpains might provide a therapeutic option for treatment of DMD. Malik et al. In contrast, this treatment had no effect on 8 boys with frameshift mutations.

The average muscle scale in these patients did not decrease over the study period, and some patients even had a slight increase in forced vital capacity, suggesting a clinical benefit. Only 1 patient developed a T-cell immune response to a novel epitope. The results of the study indicated that long-term dosing of gentamicin over 6 months could be safely achieved, and supported the concept that gentamicin can induce a read-through of stop codons in DMD.

Donor myoblasts injected into muscles of patients with DMD could theoretically fuse with host muscle fibers, thus contributing their nuclei which could potentially replace deficient gene products. Mendell et al. Although in 1 patient Van Deutekom et al.

Aartsma-Rus et al. The protein was detectable 16 hours posttransfection, increased to significant levels at the membrane within 2 days, and was maintained for at least a week.

Its proper function was further suggested by the restored membrane expression of 4 associated proteins from the dystrophin-glycoprotein complex. Harper et al. Studies in transgenic mdx mice, a model for DMD, revealed that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins.

Muscles expressing the smallest dystrophins were fully protected against damage caused by muscle activity and were not morphologically different from normal muscle.

Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice resulted in a striking reversal of histopathologic features of the disease. To address the need for a drug capable of suppressing premature termination, Welch et al. PTC is a PTC activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2 to 8 weeks of drug exposure.

PTC was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC for premature termination codons, its well-characterized activity profile, oral bioavailability, and pharmacologic properties indicated that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Clinical trials had been initiated for the treatment of both cystic fibrosis and DMD at the time of the report. This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes.

In males who have only one X chromosome , one altered copy of the gene in each cell is sufficient to cause the condition. In females who have two X chromosomes , a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females.

A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. In many cases, an affected male inherits the mutation from his mother, who carries one altered copy of the DMD gene. The remainder of cases probably result from new mutations in the gene in affected males and are not inherited. In X-linked recessive inheritance, a female with one mutated copy of the gene in each cell is called a carrier. She can pass on the altered gene but usually does not experience signs and symptoms of the disorder.

Occasionally, however, females who carry a DMD gene mutation may have muscle weakness and cramping. These symptoms are typically milder than the severe muscle weakness and atrophy seen in affected males.

Females who carry a DMD gene mutation also have an increased risk of developing heart abnormalities including cardiomyopathy.

Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. Duchenne and Becker muscular dystrophy.

From Genetics Home Reference. Description Muscular dystrophies are a group of genetic conditions characterized by progressive muscle weakness and wasting atrophy. Frequency Duchenne and Becker muscular dystrophies together affect 1 in 3, to 5, newborn males worldwide. Inheritance This condition is inherited in an X-linked recessive pattern.

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