Duchenne and Becker muscular dystrophy
-Rare cardiac disease
-Rare genetic disease
-Rare neurologic disease
Myopathy with eye involvement
-Rare eye disease
-Rare genetic disease
Qualitative or quantitative defects of dystrophin
-Rare genetic disease
Comment:
DMD is typically diagnosed at around 5 years of age (PMID:19945913). At the beginning, the proximal lower limb muscles are affected followed by the shoulder muscles, by the distal limb muscle, and ultimately by the respiratory muscles (PMID:26451113).
Dystrophin-associated muscular dystrophies range from the severe Duchenne muscular dystrophy (DMD) to the milder Becker muscular dystrophy (BMD; 300376). Mapping and molecular genetic studies indicate that both are the result of mutations in the huge gene that encodes ... Dystrophin-associated muscular dystrophies range from the severe Duchenne muscular dystrophy (DMD) to the milder Becker muscular dystrophy (BMD; 300376). Mapping and molecular genetic studies indicate that both are the result of mutations in the huge gene that encodes dystrophin, also symbolized DMD. Approximately two-thirds of the mutations in both forms are deletions of one or many exons in the dystrophin gene. Although there is no clear correlation found between the extent of the deletion and the severity of the disorder, DMD deletions usually result in frameshift. Boland et al. (1996) studied a retrospective cohort of 33 male patients born between 1953 and 1983. The mean age at DMD diagnosis was 4.6 years; wheelchair dependency had a median age of 10 years; cardiac muscle failure developed in 15% of patients with a median age of 21.5 years; smooth muscle dysfunction in the digestive or urinary tract occurred in 21% and 6% of the patients, respectively, at a median age of 15 years. In this cohort, death occurred at a median age of 17 years. The authors commented that the diagnosis of DMD is being made at an earlier age but survival has not changed.
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. ... - Symptomatic Hemizygotes 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. (1966) documented a high level of CPK (and other enzymes) in a 9-day-old infant from a family at risk. According to Dubowitz (1976), 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. (1977) demonstrated elevated CPK in fetal blood obtained by placental puncture and validated this as a method of prenatal diagnosis by demonstrating histologic changes in the skeletal muscle of the aborted fetus. Darras et al. (1987) reported experience suggesting that despite the large number of intragenic and flanking DNA polymorphisms then available, uncertainties often remain in the prenatal diagnosis of DMD. Bartlett et al. (1988) pointed out that mapping of deletions is a more reliable and an easier way to do prenatal diagnosis and carrier detection than by use of RFLPs. They suggested that once the entire gene is available for screening, most DMD boys will show deletions. Katayama et al. (1988) demonstrated the usefulness of RFLPs in prenatal diagnosis and carrier detection of DMD. In some of the examples cited, the authors made use of creatine phosphokinase levels as well. Speer et al. (1989) reviewed the status of prenatal diagnosis and carrier detection using cDNA probes. Clemens et al. (1991) took advantage of the existence of approximately 50,000-100,000 (CA)n loci in the human genome (Tautz and Renz, 1984) for carrier detection and prenatal diagnosis in DMD and BMD. (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. (1989) described the use of immunoblotting for dystrophin analysis in the diagnosis of DMD in cases in which a gene deletion cannot be identified and RFLPs are equivocal. Evans et al. (1991) used in utero fetal muscle biopsy to assess dystrophin in a male fetus with the same X chromosome as an affected sib. Evans et al. (1993) used the same procedure to evaluate a female fetus found on amniocentesis performed for advanced maternal age to be carrying a de novo X;1 translocation with a breakpoint at Xp21. 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. (1993) demonstrated that when conventional DNA analysis is not informative for the prenatal and postnatal diagnosis of DMD, myogenesis can be induced in cultured skin fibroblasts, amniocytes, or chorionic-villus cells by infecting the cells with a retrovirus vector containing MYOD (159970), a gene regulating myogenesis. Immunocytochemical analysis of dystrophin in the MYOD-converted muscle cells is an effective way of demonstrating dystrophin deficiency. Beggs and Kunkel (1990) presented a flow diagram illustrating procedures for the molecular diagnosis of DMD or BMD. 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. Thereafter, PCR testing and Southern blot analysis should be done, looking for deletion/duplication. These procedures detect about 65% of patients, and the Southern blot permits prognostication of severity by distinguishing in-frame versus frameshift mutations in over 90% of cases. 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 (1990) 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. (1994) used primer extension preamplification (PEP) to increase the scope and capacity of single cell genetic diagnosis by generating sufficient template to perform multiple subsequent DNA analyses using PCR. They reported the simultaneous analysis of single cells at 5 commonly deleted dystrophin exons. In 93% of PEP reactions with single amniocytes, chorionic villus cells and blastomeres, successful results were obtained, and a blinded analysis of single lymphoblasts from affected males resulted in 93% diagnostic accuracy. 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. (1996) discussed procedures used for disclosure of the diagnosis of Duchenne muscular dystrophy to parents after newborn screening. Newborn screening for DMD was introduced into Wales in 1990. 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. - Heterozygotes Roses et al. (1977) concluded that isoenzyme 5 of lactate dehydrogenase is as sensitive an indicator of carrier status as creatine phosphokinase. Indeed, some carrier females with normal CPK were identified with LDH-5. 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 (308000) and hemophilia (306700). Hemopexin (142290) is elevated in some DMD carriers. Percy et al. (1981) found that hemopexin, used in combination with creatine kinase, improved the identification of carriers. Sato et al. (1978) presented evidence that red cell membrane as well as muscle membrane is involved. Beckmann et al. (1978) pointed out that the diagnosis of carrier females with plasma CPK is best in the neonatal or infant period. 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. (1989) suggested that an increased tendency of erythrocytes to form echinocytes (spine cells) on exposure to L-alpha-lysophosphatidylcholine could be used as a means of detecting DMD carriers. 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., 1991). 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., 1991). In a large follow-up study of 505 muscle biopsies from female myopathy patients, Hoffman et al. (1992) found that about 10% of women with hyperCKemia, myopathic pattern by muscle biopsy, and no family history of DMD could be identified as carriers of DMD when tested with the dystrophin immunofluorescence assay. 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., 1990; Richards et al., 1990). 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. (1989) found that only those myogenic colonies expressing the G6PD-A isozyme also expressed dystrophin. He suggested that somatic cell testing of dystrophin expression may be useful in genetic carrier tests in ambiguous cases. Hoogerwaard et al. (2005) examined skeletal muscle biopsies from 50 definite carriers of DMD and BMD, including 22 manifesting carriers, 5 carriers with exertion-dependent myalgia or cramps, and 23 nonmanifesting carriers. Although 42% of the biopsies showed nonspecific abnormalities, no association was found between histopathologic changes and muscle weakness, dilated cardiomyopathy, serum creatine kinase activities, dystrophin abnormalities, or age. For example, 5 carriers with cardiomyopathy had no dystrophin abnormalities, whereas 6 nonmanifesting carriers had abnormal immunohistochemical dystrophin patterns. - Intrafamilial Variability Sifringer et al. (2004) investigated the differences between the expression profiles of skeletal muscle biopsies from a very rare instance of 2 brothers with a different clinical course of DMD. 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. Sifringer et al. (2004) compared the transcriptomes in skeletal muscle in the 2 brothers to identify overexpressed transcripts that might be responsible for the milder phenotype. 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 (600505) showed a slightly higher expression. Upregulation of myosin light polypeptide 2 (MYL2; 160781), 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 most distinctive feature of Duchenne muscular dystrophy is a progressive proximal muscular dystrophy with characteristic pseudohypertrophy of the calves. The bulbar (extraocular) muscles are spared but the myocardium is affected. There is ... - Skeletal Muscle The most distinctive feature of Duchenne muscular dystrophy is a progressive proximal muscular dystrophy with characteristic pseudohypertrophy of the calves. The bulbar (extraocular) muscles are spared but the myocardium is affected. There is massive elevation of creatine kinase levels in the blood, myopathic changes by electromyography, and myofiber degeneration with fibrosis and fatty infiltration on muscle biopsy.The onset of Duchenne muscular dystrophy usually occurs before age 3 years, and the victim is chairridden by age 12 and dead by age 20. The onset of Becker muscular dystrophy is often in the 20s and 30s and survival to a relatively advanced age is frequent. Moser and Emery (1974) found that some female heterozygotes had myopathy resembling autosomal recessive limb-girdle muscular dystrophy (253600). Serum creatine kinase was particularly elevated in these patients. In most populations, the frequency of manifesting heterozygotes is about the same as that of females with limb-girdle muscular dystrophy. Soloway and Mudge (1979) remarked that patients with advanced muscular dystrophy may develop hypokalemia from insults (vomiting, diarrhea, diuretics) that would have little effect on normal persons. Reduced intracellular potassium stores are responsible for this perilous situation, which may be the mechanism of death. In an Italian boy with congenital myopathy, born to nonconsanguineous parents, Prelle et al. (1992) found absence of dystrophin in the patient's muscle by immunohistochemical methods and a deletion of the 5-prime end of the dystrophin gene. Although the patient showed severe mental retardation, there was no cerebral atrophy. Cardiomyopathy was also present. Frigeri et al. (1998) analyzed AQP4 expression in the skeletal muscle of mdx mice; immunofluorescence experiments showed a marked reduction of aquaporin-4 (AQP4; 600308) expression, suggesting a critical role in the membrane alteration of DMD. Wakayama et al. (2002) analyzed skeletal muscle samples from 6 patients with DMD and found markedly reduced AQP4 expression by immunohistochemical staining and markedly decreased levels of AQP4 mRNA as measured by RT-PCR, compared to controls. Genomic analysis of the AQP4 gene revealed no abnormalities. The authors concluded that the reduced mRNA was due to either decreased transcription or increased degradation of the message. Noguchi et al. (2003) performed cDNA microarray analysis on skeletal muscle biopsy specimens from 6 patients with DMD. There was increased expression of genes related to immune response, sarcomere, extracellular matrix proteins, and signaling or cell growth. Upregulation of these genes reflected dystrophic changes, myofiber necrosis, inflammation, and muscle regeneration. Genes related to muscle homeostasis and energy metabolism were downregulated. - Cardiac Muscle Myocardial involvement appeared in a high percentage of DMD patients by about 6 years of age; it was present in 95% of cases by the last years of life. Severe cardiomyopathy did not develop before age 21 in BMD and few patients showed any cardiac signs before age 13 (Nigro et al., 1983). Mirabella et al. (1993) noted that electrocardiographic abnormalities had been reported in 6.6 to 16.4% of DMD heterozygous females and that in one carrier female severe cardiomyopathy had been described in association with muscle weakness. They reported 2 carriers with dilated cardiomyopathy and increased serum CK but no symptoms of muscle weakness. Heart biopsies in both patients showed absence of dystrophin in many muscle fibers. - Smooth Muscle 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. (1988) studied gastric emptying in 11 patients with DMD. 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., 1992). Khurana et al. (1995) showed that dystrophin deficiency does not result in myonecrosis or pathologically elevated levels of intracellular calcium in the EOMs. 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. - Nervous System Mental retardation of mild degree is a pleiotropic effect of the Duchenne gene (Zellweger and Niedermeyer, 1965) As indicated later, the finding of dystrophin mRNA in brain may bear a relationship to the mental retardation in DMD patients. Emery et al. (1979) sought heterogeneity in DMD as one explanation for the high birth incidence. 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 11.1 years (range 3.5 to 20.3), Bresolin et al. (1994) found that 31% had a Wechsler full intelligence quotient (FIQ) lower than 75 and that only 24% had appropriate IQ levels by this index. Bushby et al. (1995) examined the hypothesis that the nature of the dystrophin mutation may influence the development of mental retardation. Previously, it had been shown that deletions removing the brain-specific promoter were compatible with normal intelligence. Bushby et al. (1995) studied 74 boys with DMD, 18% of which had a full scale IQ of below 70. 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. - Retinal Function Abnormal retinal neurotransmission as measured by electroretinography (ERG) was observed in boys with DMD by Cibis et al. (1993) and Pillers et al. (1993). 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. (1994) used long-duration stimuli to separate ON (depolarizing bipolar cell) and OFF (hyperpolarizing bipolar cell) contributions to the cone-dominated ERG to understand better how the retina functions in boys with DMD. 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. (1995) examined 16 boys with DMD/BMD of whom 10 had negative ERGs. Eight of the boys had DMD gene deletions downstream from exon 44. Normal dark adaptation thresholds were observed in all patients and there were no anomalous visual functions. Hence, negative ERG in DMD/BMD is not associated with eye disease. Normal ERGs were found in 6 boys with DMD/BMD. Jensen et al. (1995) speculated that a retinal or glial dystrophin may be truncated or absent in the boys with negative ERGs. 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. (2002) compared ERGs and retinal morphology in wildtype mice and transgenic knockout mice with no Aqp4. Significantly reduced ERG b-wave potentials were recorded in 10-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. (2007) evaluated color vision in 44 patients with Duchenne muscular dystrophy using 4 different color tests. 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 30. Of the patients with DMD, 47% (21/44) had a red-green color vision defect. Of the patients with deletion downstream of exon 30, 66% had a red-green color defect. No color defect was found in the patients with a deletion upstream of exon 30. A negative correlation between the color thresholds and age was found for the controls and patients with DMD, suggesting a nonprogressive color defect. The percentage (66%) of patients with red-green defect was significantly higher than the expected value (less than 10%) for the normal male population (P less than 0.001). Costa et al. (2007) suggested that the findings might be partially explained by a retinal impairment related to dystrophin isoform Dp260. - Carrier Females In a 9-year follow-up of study of 99 Dutch female carriers of DMD or BMD mutations, Schade van Westrum et al. (2011) found that 11 carriers (10%) (10 DMD and 1 BMD) fulfilled the criteria for dilated cardiomyopathy (DCM). 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. (2013) reviewed the features of 26 female carriers of pathogenic mutations in the DMD gene who were referred for symptoms related to the disorder before 17 years of age. 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. Initial symptoms included significant muscle weakness (88%), mostly affecting the lower limbs, or exercise intolerance (27%). Cardiac dysfunction was present in 19%, and cognitive impairment in 27%. Cognitive impairment was associated with mutations in the distal part of the gene. Muscle biopsy showed dystrophic changes in 83% and mosaic immunostaining for dystrophin in 81%. The X-chromosome inactivation pattern was biased in 62% of cases. Mercier et al. (2013) concluded that carrier females may have significant symptoms of the disorder.
Tuffery-Giraud et al. (2009) described a French database for mutations in the DMD gene that includes 2,411 entries consisting of 2,084 independent mutation events identified in 2,046 male patients and 38 expressing females. This corresponds to an estimated ... Tuffery-Giraud et al. (2009) described a French database for mutations in the DMD gene that includes 2,411 entries consisting of 2,084 independent mutation events identified in 2,046 male patients and 38 expressing females. This corresponds to an estimated frequency of 39 per million with a genetic diagnosis of a 'dystrophinopathy' in France. Mutations in the database include 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. About 24% of the mutations are de novo events. The true frequency of BMD in France was found to be almost half (43%) that of DMD. Among 624 index cases evaluated for DMD mutations, Oshima et al. (2009) reported that a genomic rearrangement was detected in 238 (38.1%) samples. Deletions were detected in 188 (79.0%), and included 31 cases with single-exon deletions and 157 cases with multi-exonic deletions. Most of the deletions fell between exons 45 and 52 and between exons 8 and 13 of the gene. Duplications were detected in 44 (18.5%) cases, of which 12 involved single exons and 32 multiple exons. Complex rearrangements were detected in 6 (2.5%) cases. The remaining 386 cases showed normal results. Oshima et al. (2009) selected 15 unique rearrangement, of which none shared a common breakpoint, and used array CGH and MLPA analyses to evaluate the mechanism rearrangements. 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. Analysis of 3 complex intragenic DMD gene rearrangements identified several features that could result in genomic instability, including breakpoints that aligned with repetitive sequences, an inversion/deletion involving a stem-loop structure, replication-dependent fork stalling and template switching (FoSTeS), and duplications causing secondary deletions. - Modifier Genes Pegoraro et al. (2011) examined 106 DMD patients for variations in 29 genes selected as candidate modifiers of disease severity. Skeletal muscle mRNA profiling identified the G allele of dbSNP rs28357094 in the promoter of the SPP1 gene (166490), which encodes osteopontin, as having a significant effect on both disease progression and response to glucocorticoids. In an autosomal dominant model, carriers of the G allele (35% of subjects) had more rapid progression and 12 to 19% less grip strength. The association was validated in a second cohort of 156 patients.
In a 12-year prospective study in the Campania region of southern Italy, Nigro et al. (1983) found an incidence of DMD of 21.7 per 100,000 male live births and of BMD of 3.2 per 100,000. The latter might ... In a 12-year prospective study in the Campania region of southern Italy, Nigro et al. (1983) found an incidence of DMD of 21.7 per 100,000 male live births and of BMD of 3.2 per 100,000. The latter might be underestimated because of lesser severity but surely not to an extent to explain an incidence one-seventh of that of DMD. Of the DMD patients, 38.5% were familial; of the BMD cases, 50%. Williams et al. (1983) analyzed 244 Toronto pedigrees of DMD. The incidence of DMD in Ontario was estimated to be 292 per million male births. The proportion of sporadic cases was one-third, demonstrating equal mutation rates in males and females. A multifactorial component (H = 0.379) contributing to familial resemblance for CPK measurements was found. They illustrated use in genetic counseling of a computer program COUNSEL, which takes the multifactorial component in CPK into account. Mostacciuolo et al. (1987) presented population data on the incidence and prevalence of the Becker and Duchenne forms of muscular dystrophy and estimated mutation rates for each. Muller and Grimm (1986) pointed out that by using X chromosomal RFLPs to establish DNA haplotypes in 3-generation DMD families, one can calculate the ratio of mutation rates in males and females from the proportion of DMD patients who have inherited their maternal grandfather's X-chromosome. In the Netherlands, van Essen et al. (1992) estimated the prevalence rate of DMD at birth to be 1:4,215 male live births. The prevalence rate in the male population on January 1, 1983 was estimated to be 1:18,496. An extensive tabulation of previous data was provided. Roddie and Bundey (1992) observed that in the West Midlands region of Britain, DMD is twice as common as expected in Asiatic Indians and less common than expected in Pakistanis. Although the numbers were small, they could not be explained by bias of ascertainment and were considered to be real. They suggested that a possible mechanism for the high frequency of DMD in Indians is the presence of repetitive elements in the wildtype gene that predispose to mutations. Shomrat et al. (1994) suggested that in Israeli patients with either Duchenne or Becker muscular dystrophy, deletions in the DMD gene constitute a much smaller proportion of cases than is found in European and North American populations. The figures were 37% in Israelis as compared to 55 to 65% in the other populations. They pointed to reports suggesting that the proportion of deletions among mutant dystrophin alleles is lower also in some Asian populations such as Japanese and Chinese than it is in Western countries. They found no correlation between the size of the deletion and the severity of the disease. All of the deletions causing frameshift resulted in the DMD phenotype. Onengut et al. (2000) compared patterns of DMD gene deletions in 4 populations: Turks, Europeans, North Indians, and Indians from all over India. Statistical tests revealed differences in the proportions of small deletions. In contrast, the distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in the 4 populations were not significantly different. The variations strongly suggested that sequence differences exist in the introns, and that the differences are in agreement with genetic distances among populations. The similarities suggested that some intronic sequences have been conserved and that those will trigger recurrent deletions.