Muscular Dystrophy, Becker Type
A number sign (#) is used with this entry because Becker muscular dystrophy (BMD), like Duchenne muscular dystrophy (DMD; 310200), is caused by mutation in the gene encoding dystrophin (DMD; 300377) on chromosome Xp21.
DescriptionThe muscular dystrophy that carries the Becker eponym is similar to Duchenne muscular dystrophy in the distribution of muscle wasting and weakness, which is mainly proximal, but the course is more benign, with age of onset around 12 years; some patients have no symptoms until much later in life. Loss of ambulation also varies from adolescence onward, with death usually in the fourth or fifth decade. In some cases, as in Duchenne muscular dystrophy, a degree of mental impairment is present (Emery, 2002).
As in DMD, about 5 to 10% of female carriers of this X-linked disorder show muscle weakness, and frequently enlarged calves--so-called manifesting heterozygotes. Such weakness is often asymmetric; it can develop in childhood or not become evident until adult life, and can be slowly progressive or remain static. Because weakness is essentially proximal, differentiation from limb-girdle muscular dystrophy is essential for genetic counseling. In both DMD and BMD, female carriers may develop dilated cardiomyopathy in the absence of apparent weakness (Grain et al., 2001).
Clinical FeaturesBush and Dubowitz (1991) described fatal rhabdomyolysis complicating general anesthesia in a child with Becker muscular dystrophy. Exertional cramping and probable myoglobinuria was described by Bushby et al. (1991) in a patient with atypical Becker muscular dystrophy (see 300377.0002). Minetti et al. (1993) described 2 unrelated 9-year-old boys with exercise-induced cramps and myoglobinuria associated with elevated serum levels of creatine kinase. DNA analysis of the dystrophin gene was uninformative in 1 patient; in the other, it revealed an in-frame deletion comprising exons 3-6. Gospe et al. (1989) and Doriguzzi et al. (1993) also described exercise intolerance and recurrent myoglobinuria as the only expression of BMD.
Piccolo et al. (1994) described a 32-year-old man in whom cardiac transplantation was performed for end-stage dilated cardiomyopathy and who showed a progressive increase in serum creatine kinase level while receiving cyclosporin and simvastatine immunosuppressive treatment. Revised family history led to a suspicion of X-linked inherited myopathy which was confirmed by muscle biopsy findings. Molecular genetic studies demonstrated a deletion spanning exons 45-47 at the DMD locus.
Fujii et al. (2009) reported what they believed is the first case of true Becker muscular dystrophy in a Japanese girl born of consanguineous parents. She presented at age 14 years with a 7-year history of exercise intolerance with myalgia, swelling of the thigh muscle, and red-brown urine consistent with myoglobinuria. Laboratory studies showed increased serum creatine kinase and myoglobin in the urine, but no cardiac abnormalities. Her clinically unaffected father had mildly increased serum creatine kinase and urinary myoglobin, and her clinically unaffected mother had no symptoms. Skeletal muscle biopsy of the proband showed mild dystrophic changes and faint staining for dystrophin, consistent with Becker muscular dystrophy. Molecular genetic analysis identified a homozygous deletion of exons 45 to 55 of the DMD gene, predicting an in-frame deletion of 593 residues. Each parent was heterozygous for the deletion. There was a remote family history of cardiac disease in several males.
Other FeaturesZatz et al. (1993) described an instructive pedigree in which 4 of 5 adult patients with BMD also had schizophrenia or related spectrum disorders. They considered 2 alternative hypotheses: the existence of a susceptibility locus for the mental illnesses at Xp21; or the possibility that these psychiatric disorders result from an abnormality in the expression of the dystrophin gene in the brain.
Bardoni et al. (1999) studied 24 BMD patients. Mental retardation, defined as a full IQ less than or equal to 75, was present in 6 of the 24 (25%). Mean FIQ level in the whole BMD group was 88.2. All patients with FIQ greater than 75 presented no deletions in the Dp140 regulatory sequences. A deletion including the Dp140 regulatory region was found in 5 of the 6 mentally retarded patients. The study provided evidence that the absence of Dp140 may determine the occurrence of cognitive impairment in BMD patients. Moizard et al. (1998) had previously highlighted the importance of Dp140 for mental retardation in patients with Duchenne muscular dystrophy, yet the absence of full-length dystrophin transcripts in BMD made it more difficult to understand the functional role of each single isoform. Close correlation between Dp140 and mental retardation in BMD indirectly threw light on the role of Dp140 in DMD as well.
InheritanceSeveral affected males in the large kindred reported by Becker (1957) had produced children and the resulting pedigree pattern was consistent with X-linked inheritance. Others have described such families. Allelism with the Duchenne type was considered possible and in the 1980s was proved by molecular genetic studies. (There is more than one form of X-linked, late-onset muscular dystrophy; Emery-Dreifuss muscular dystrophy (310300) is the other principal form. It is determined by a mutation on Xq28, which disrupts a gene encoding emerin (300384).)
MappingKingston et al. (1983, 1984) found linkage of BMD with the cloned sequence L1.28 (designated DXS7 by the seventh Human Gene Mapping Workshop in Los Angeles; D = DNA, X = X chromosome, S = segment, 7 = sequence of delineation). The interval was estimated to be about 16 cM, which is also the approximate interval between DXS7 and DMD. DXS7 is located between Xp11.0 and Xp11.3. 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. (1984) found no evidence of linkage of BMD to colorblindness; Xg also showed no linkage.
Roncuzzi et al. (1985) used 10 X-linked DNA polymorphisms (5 on Xp and 5 on Xq) to map the Becker locus in 2 pedigrees. They narrowed the position on Xp. They pointed out that by somatic cell hybridization the constitution of recombinant chromosomes and linkage phase can be determined, e.g., in cases in which the maternal grandfather is not available. They suggested that this approach may be particularly useful for rare X-linked disorders such as Lowe syndrome and Hunter syndrome, that the recombinant X chromosomes should be maintained as fibroblasts or lymphoblastoid cells in cell repositories, and that the approach is also useful in autosomal mapping. Brown et al. (1985) and Fadda et al. (1985) also assigned BMD to Xp by linkage to RFLPs.
DiagnosisGrimm (1984) commented on the problems of genetic counseling arising from the difficulties in distinguishing the milder Becker muscular dystrophy from autosomal recessive limb-girdle muscular dystrophy. A daughter of a man with the latter condition has virtually no risk of affected children, whereas half the sons of a daughter of a man with Becker muscular dystrophy are expected to be affected.
Population GeneticsIn 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%.
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.
Molecular GeneticsMonaco et al. (1988) provided an explanation for the phenotypic differences between DMD and BMD: although no fundamental difference in the size of deletions at the locus appeared to be present in the 2 forms of disease, the deletions in DMD caused frameshifts while those in BMD did not. This finding is consistent with the fact that most patients with DMD are found to have no dystrophin protein in muscle, whereas patients with BMD are found to have an abnormally short variety (or, in 1 case, an abnormally long variety) of dystrophin. Presumably the dystrophin protein that is formed in BMD is partially functional.
England et al. (1990) demonstrated that a family segregating for a very mild BMD (1 affected member was still ambulant at age 61) had a mutation that removed the central part of the dystrophin gene encompassing 5,106 bp of coding sequence, almost half the coding information. Immunologic analysis of muscle from one of the patients showed that the mutation resulted in the production of a truncated polypeptide localized correctly in the muscle cell. Immunostaining with antibody against the central part of the dystrophin molecule resulted in no staining of muscle membranes; immunostaining with antibody against the N- and C-terminal portions did yield muscle membrane staining. They concluded that the findings are meaningful in the context of gene therapy which would be facilitated by the replacement of the very large DMD gene with a more manipulatable mini-gene construct.
Norman et al. (1990) found deletions of the dystrophin gene in 41 (71%) of 58 separate BMD families. In 34 (83%) of these families, the deletion started in the same intron near the center of the gene. Nordenskjold et al. (1990) described 2 brothers with identical inherited deletions of a single exon in the middle of the DMD gene. One brother had Becker muscular dystrophy, diagnosed at age 11, whereas the older brother was normal at age 18. It appears that some additional factor precipitated the expression of the disease in the younger brother. In the family reported by England et al. (1990), the BMD phenotype was associated with the largest intragenic deletion, encompassing 46% of the gene, reported to that time. Passos-Bueno et al. (1994) reported a yet larger deletion, involving exons 13 to 48 in a 37-year-old BMD patient with a mild phenotype. This deletion corresponded to 50% of the coding region. The observation had important implications for gene therapy based on minigenes, since it confirmed that deletions of up to 66% of the rod domain are compatible with a mild phenotype.
In hopes of shedding light on the molecular basis for the extreme variability seen among patients with BMD, Beggs et al. (1991) correlated DNA and protein data on 68 patients with detectable but abnormal dystrophin. They found evidence for differences in clinical presentation depending on whether in-frame deletions removed the amino terminus, the proximal portion of the rod domain, or the distal region. However, they also showed that patients with similar in-frame deletions and even similar protein levels may have significantly different clinical presentations, suggesting that epigenetic and environmental factors play a significant role in determining the severity of a patient's disease. In 86% of BMD patients with dystrophin of altered size, deletions or duplications were found and the observed sizes of dystrophin fitted well with predictions based on DNA data. Deletions within the amino-terminal domain I tended to result in low levels of dystrophin and a more severe phenotype. The phenotypes of patients with deletions or duplications in the central rod domain were more variable. This region could be divided into 3 portions based on differences in clinical presentations. Deletions around exons 45 to 53 were most common and generally caused typical BMD. Deletions or duplications in the proximal portions of this domain tended to cause severe cramps and myalgia. Loss of the middle of this region caused a very mild phenotype; the single such patient found had elevated serum creatine phosphokinase levels as his only manifestation.
Matsumura et al. (1994) studied patients with Becker muscular dystrophy and very large deletions that remove most of the dystrophin rod domain. These patients had slightly reduced DAGs and DAPs. In 2 patients whose deletion extended into the NH2-terminal domain, immunostaining for DAG and DAP was reduced further and the boys had a more severe phenotype. Arikawa-Hirasawa et al. (1995) found an extremely short dystrophin resulting from a large deletion in a boy with severe muscular dystrophy. The entire actin-binding site at the N terminus was missing, although the protein was predicted to have a putative binding site for the dystrophin-associated glycoprotein and still could associate with the sarcolemmal membrane.
In a 12-year-old boy with asymptomatic dystrophinopathy who had persistently high serum creatine kinase levels and a characteristic myogenic pattern on electromyography, Yagi et al. (2003) observed a 132-bp insertion between exons 2 and 3 of the DMD gene in both lymphocyte and muscle mRNA. Sequencing the regions flanking the insertion revealed a point mutation in intron 2 (300377.0083) that creates an AG dinucleotide consensus sequence for a splicing acceptor site, predicted to produce a novel exon structure that is then incorporated into dystrophin mRNA. Yagi et al. (2003) stated that the creation of a splice acceptor site by a single nucleotide change leading to an extra exon structure is a novel molecular mechanism in human disease.
Approximately 80% of Becker patients have deletions in the dystrophin gene, most of which correspond to an exact multiple of codons so that some partially functional dystrophin of altered sequence is produced. Tuffery-Giraud et al. (2005) reported 5 splice site mutations in the DMD gene in 5 patients with Becker muscular dystrophy. In 2 cases, the milder phenotype was due to exon skipping leading to an in-frame deletion. In 2 other cases, intronic mutations resulted in complex splicing changes, but with some residual normal transcripts. The last case resulted in a truncated transcript missing only part of the C terminus of the protein, suggesting that this region is not critical for dystrophin function. Tuffery-Giraud et al. (2005) noted that the characterization of DMD mRNA changes may aid in therapeutic strategies involving the induction of exon-skipping events in order to restore the reading frame (see Goyenvalle et al., 2004).
Tuffery-Giraud et al. (2009) described a French database of 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.
HistoryA review of reports of Becker muscular dystrophy was given by Zellweger and Hanson (1967), who also reported a family with many affected males.