A survey of manifesting carriers of Duchenne and Becker muscular dystrophy in Wales

Manifesting carriers of Duchenne and Becker muscular dystrophy are uncommon but well described. Such patients are of particular importance with regard to the differential diagnosis from autosomal recessive limb-girdle muscular dystrophy. All mothers of affected males known to the Genetic Register of Muscular Dystrophy Families in Wales were contacted, and 167 out of a possible 190 were examined. It was estimated from pedigree and creatine kinase analysis that 119 out of the 167 were carriers of the Duchenne/Becker gene. Three manifesting carriers were identified, giving the proportion affected as 3/119 = 2.5%. We estimate the prevalence of manifesting carriers to be 1 in 100,000 of the female population, a figure comparable to the prevalence of autosomal recessive limb-girdle muscular dystrophy. During the period of the survey, several other women with similar clinical findings but without an appropriate family history were seen. We strongly suspect that some of these are also manifesting carriers of the Duchenne/Becker gene.     

Childhood onset of left ventricular dysfunction in a female manifesting carrier of muscular dystrophy

Duchenne muscular dystrophy and Becker muscular dystrophy are X-linked disorders that result from a mutation in the dystrophin gene that reduces the production or effectiveness of the protein dystrophin. These disorders are clinically characterized by progressive muscle degeneration. Manifesting female carriers are generally not identified as such until after puberty, when symptoms such as muscle weakness may arise. This clinical report describes a female manifesting carrier who started to show deterioration of left ventricular systolic function, but no marked skeletal muscle weakness, at the age of 10 years. The patient's cardiac function improved significantly after dual drug therapy with an ACE inhibitor (enalapril) and a beta-blocker (carvedilol). Our case adds to the existing evidence that left ventricular myocardial dysfunction may occur during childhood in female carriers of dystrophinopathies.     

Relatively low proportion of dystrophin gene deletions in Israeli Duchenne and Becker muscular dystrophy patients

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55–65%). Seventy-eight percent of the deletions were confined to exons 44–52, half of these to exons 44–45, and the remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. © 1994 Wiley-Liss, Inc.     

Duchenne muscular dystrophy and myotonic dystrophy in the same patient

We report on the first patient identified with myotonic dystrophy and Duchenne muscular dystrophy (DMD). The family of the propositus had a strong history of myotonic dystrophy, and there was an intrafamilial pathological expansion of the responsible CTG repeat between the mildly affected mother (160 repeats; normal 27 repeats) and her more severely affected son (650 repeats), and his sister (650 repeats). The propositus was an isolated case of Duchenne muscular dystrophy with marked dystrophin deficiency in muscle biopsy. The patient was still ambulatory post age 16. Myotonic dystrophy could interfere to some extent with the progression of Duchenne dystrophy. However, other interpretations are possible. Twelve percent of dystrophin revertant fibers as observed by immunohistochemistry could be sufficient to ameliorate typical DMD clinical severity, or the patient may present a somatic mosaic. The pathophysiological interactions of these two unlinked disorders are discussed at the clinical and histopathological levels. © 1995 Wiley-Liss, Inc.     

Emery-Dreifuss syndrome: Genetic and clinical varieties

Two familial and 2 sporadic cases of Emery-Dreifuss syndrome are reported. One family presented a rare autosomal dominant variant of Emery-Dreifuss muscular dystrophy, another with X-linked recessive inheritance showed unusual intrafamilial variability. One of sporadic cases closely resembled rigid spine syndrome, the other was clinically intermediate between Emery-Dreifuss muscular dystrophy and rigid spine syndrome, showing that they are not distinct disorders. © 1994 Wiley-Liss, Inc.     

Duchenne肌营养不良的基因治疗研究进展

Duchenne肌营养不良（DMD）为X连锁常见的神经肌肉遗传病之一，由于骨骼肌肌膜上的抗肌萎缩蛋白完全或部分缺失引起。不幸的是，从发现这种疾病以来已经历经大约150年，但是还是不可治愈。然而，20年前DMD基因的发现却大大地改变了这种疾病的发展状况。最近，基因治疗的研究取得了较大的进展。本文就DMD的基因治疗的进展加以综述。     

DMD基因内微卫星标记对女性携带者的诊断意义

目的对1临床诊断为Duchenne肌营养不良家系中两名女性个体进行连锁分析,以确定她们是否为Duchenne肌营养不良致病基因携带者。方法抽取家系成员外周血并提取基因组DNA,选取3个DMD基因内微卫星标记作引物进行PCR扩增,扩增产物经ABI PRISM377测序仪电泳后进行连锁分析。结果在我们所研究的Duchenne肌营养不良家系中,一女性个体为Duchenne肌营养不良致病基因携带者,而另一女性个体为正常基因型。结论基因内标记可以排除染色体交换,运用DMD基因内微卫星标记可以成功诊断Duchenne肌营养不良家系中女性个体是否为致病基因携带者。     

Canine X-linked muscular dystrophy as an animal model of Duchenne muscular dystrophy: A review

Canine X-linked muscular dystrophy is a spontaneously occurring, progressive, degenerative myopathy of dogs that is clinically and pathologically similar to Duchenne muscular dystrophy in man. The molecular basis for the disease has been shown to be a lack of dystrophin, the protein product of the Duchenne muscular dystrophy gene. Breeding colonies of dystrophic dogs have been established. This report reviews the findings of genetic, clinical, pathologic, molecular biologic, and immunocytochemical studies of the canine model, and compares the features of the canine disease to those of Duchenne dystrophy in man.     

Entropy won't get the better of me

We observed a decreased proportion of capped lymphocytes using polyvalent immunoglobulin and concanavalin-A as ligands in limb-girdle muscular dystrophy patients, obligate carriers, and individuals who are at-risk for being limb-girdle muscular dystrophy carriers. Using the proportion of capped cells as a parameter, we found there was overlap between the carrier and control range. However, we were able to estimate the risk of being a carrier in the Amish who have an increased prevalence of the limb-girdle muscular dystrophy gene.     

Fukuyama-type congenital muscular dystrophy (FCMD) and oc-dystroglycanopathy

ABSTRACT  Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), and muscle-eye-brain (MEB) disease are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. Through positional cloning, we identified the gene for FCMD and MEB, which encodes the fukutin protein and the protein 0-linked mannose pi, 2-N-acetylglucosaminy ltransferase (POMGnTl), respectively. Recent studies have revealed that posttranslational modification of oc-dystro-glycan is associated with these congenital muscular dystrophies with brain malformations. In this review Fukuyama-type congenital muscular dystrophy (FCMD), other CMDs with brain malformations, and their relation with a-dystroglycan are discussed.     

Identification of lamin A/C ( LMNA) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B

Mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders: autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B; MIM 159001); dilated cardiomyopathy type 1A (CMD1A; MIM 115200); and familial partial lipodystrophy (FPLD; MIM 151660). Recently, we have studied two Korean patients with atrioventricular conduction defects. They had variable extents of muscular dystrophy; one patient was diagnosed with EDMD2 and the other with LGMD1B. We performed a mutation analysis of the LMNA gene by direct sequencing and found two different missense mutations: R249Q and R377L, in the EDMD2 and LGMD1B patient, respectively. The R249Q mutation is located within the central rod domain of the LMNA gene, and has been described in at least five unrelated sporadic EDMD2 patients. On the other hand, the R377L mutation, also located within the rod domain, is a novel mutation, although a histidine substitution instead of leucine (R377H) has been reported previously in an LGMD1B patient. To our knowledge, this is the first report of LMNA gene mutations in Korean patients with EDMD2 and LGMD1B. Received: November 19, 2001 / Accepted: February 8, 2002     

免疫荧光检测抗肌萎缩蛋白诊断肌营养不良症的临床应用

目的 采用免疫荧光技术对Duchenne型肌营养不良症（Duchenne muscular dystrophy,DMD),Becker型肌营养不良症（Becker muscular dystrophy,BMD)，面肩肱型肌营养不良症（facioscapulohumeral muscular dystrophy,FSHD)以及神经性肌萎缩患者骨骼肌细胞膜的dystrophin蛋白进行检测，为临床诊断、分类肌营养不良症提供简便的实验方法。方法 对47例患者选择3种dystrophin 的鼠抗单克隆抗体、羊抗和兔抗多克隆抗体，分别进行免疫荧光技术检测。结果 16例DMD患者均为阴性染色；11例BMD患者为弱阳性染色；10例FSHD和10例神经性肌萎缩患者均为阳性染色。结论 检测肌营养不良症患者骨骼肌膜dystrophin蛋白，有助于肌营养不良症的临床诊断和分型。     

A rare form of limb girdle muscular dystrophy (type 2E) seen in an Iranian family detected by autozygosity mapping

Sarcoglycanopathies (SGPs) constitute a subgroup of autosomal recessive limb girdle muscular dystrophies (LGMDs) which are caused by mutations in sarcoglycan (SGs) genes. SG proteins form a core complex consisting of α, β, γ and δ sarcoglycans which are encoded by SGCA, SGCB, SGCG and SGCD genes, respectively. Genetic defect, in any of these SG proteins, results in instability of the whole complex. This effect can be helpful in interpreting muscle biopsy results. Autozygosity mapping is a gene mapping approach which can be applied in large consanguineous families for tracking the defective gene in most autosomal recessive disorders. In the present study, we used autozygosity mapping, to find the gene responsible for muscular dystrophy. Proband was a 10-year-old boy referred to our center for ruling out DMD (Duchenne muscular dystrophy). According to the pedigree and clinical reports, we assessed him for SGPs. Haplotyping, using the four short tandem repeat (STR) markers for each of the SG genes, showed that the phenotype may segregate with SGCB gene; and observing two crossing overs which occurred within the gene suggested that the mutation might be in the first two exons of SGCB gene. Mutation analysis showed a 26?bp duplication (10?bp before the initiation codon till 13?bp after the ATG start codon). This will cause a frameshift in protein synthesis.     

In memoriam. Dr. Peter Browen, 1932–1988

We have characterized deletions of the dystrophin gene in patients suffering from relatively mild muscular dystrophy. Our data show that most of the Becker muscular dystrophy (BMD) patients have intragenic deletions which leave the protein reading frame in phase. Remarkably, large deletions of the region corresponding to the central triple helical repeats in the protein can result in an exceptionally mild phenotype. Three brothers suffering from BMD, glycerol kinase deficiency, and adrenal hypoplasia possess a deletion at the 3′ end of the gene. They also display developmental delay. Thus the 3′ processing of the gene must be necessary for the correct function of the dystrophin molecule.     

外显子跳跃治疗Duchenne型肌营养不良症的研究进展

Duchenne型肌营养不良症是一种致死性肌肉疾病,抗肌萎缩蛋白基因缺陷是导致本病的原因,目前本病尚无特效的疗法.反义寡核苷酸(antisense oligonucleotides,AOs)诱导的外显子跳跃作为一种新的治疗手段具有良好的应用前景.本文主要从外显子跳跃治疗的原理、基础研究及临床研究进行综述.     

CD4+ cells,macrophages, MHC-I and C5b-9 involve the pathogenesis of dysferlinopathy

Objective: Dysferlin is a sarcolemmal protein that plays an important role in membrane repair by regulating vesicle fusion with the sarcolemma. Mutations in the dysferlin gene (DYSF) lead to multiple clinical phenotypes, including Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD 2B), and distal myopathy with anterior tibial onset (DMAT). Patients with dysferlinopathy also show muscle inflammation, which often leads to a misdiagnosis as inflammatory myopathy. In this study, we examined and analyzed the dyferlinopathy-associated immunological features. Methods: Comparative immunohistochemical analysis of inflammatory cell infiltration, and muscle expression of MHC-I and C5b-9 was performed using muscle biopsy samples from 14 patients with dysferlinopathy, 7 patients with polymyositis, and 8 patients with either Duchenne muscular dystrophy or Becker muscular dystrophy (DMD/BMD). Results: Immunohistochemical analysis revealed positive staining for immune response-related CD4⁺ cells, macrophages, MHC-I and C5b-9 in dysferlinopathy, which is in a different mode of polymyositis and DMD/BMD. Conclusion: These results demonstrated the involvement of immune factors in the pathogenesis of dysferlinopathy.     

PGD for dystrophin gene deletions using fluorescence in situ hybridization

Duchenne muscular dystrophy and Becker muscular dystrophy (DMD and BMD) are caused by mutations in the dystrophin gene (Xp21). In two-thirds of DMD/BMD cases, the mutation is a large deletion of one or several exons. We have established PGD for DMD/BMD using interphase fluorescence in situ hybridization (FISH) analysis on single nuclei from blastomeres for the detection of deletions of specific exons in the dystrophin gene. We performed PGD for two carrier females; one had a deletion of exons 45-50 (DMD), and the other had a deletion of exons 45-48 (BMD). An exon 45-specific probe was used in combination with probes for the X and Y centromeres. Using this straightforward approach, we can distinguish affected and unaffected male embryos as well as carrier female and normal female embryos. Three cycles were performed for each patient, which resulted in a pregnancy and the birth of a healthy girl. To the best of our knowledge, this approach for PGD has not been previously reported. The use of interphase FISH is an attractive alternative to sexing or PCR-based mutation detection for PGD patients with known deletions of the dystrophin gene.     

肌营养不良征的肌电图分析

目的：探讨肌营养不良肌患的神经电生理改变。方法：对16例肌营养不良患进行常规肌电图(EMG)、神经电图(ENOG)检测，EMG检测四肢近端肌肉及腓肠肌等，观察静息状态时自发电位，测定运动单位电位(MUP)的时限、波幅、大力收缩时的募集相。测定运动、感觉神经的传导速度(MCV、SCV)及动作电位的末端潜伏期(ML)诱发电位波幅。结果：本组资料显示所检肌时限异常率占82％，波幅降低率占72％，大力收缩早募集占60％。结论：肌电图检测可以对肌营养不良和脊肌萎缩症提供很好的诊断和鉴别诊断依据。     

Usefulness of a CACA repeat polymorphism in genotype assignments in Duchenne/Becker muscular dystrophy

RFLP analysis in Duchenne/Becker muscular dystrophy (D/BMD) has been limited by the lack of informative marker loci at the 3′ end of the dystrophin gene. Recently a CACA repeat polymorphism was described in the 3′ untranslated end of the dystrophin gene which we have found helpful in genotype assignments of D/BMD families when an RFLP approach is required. The CACA repeat marker has 2 common alleles (1 and 2) that are easily visualized by a nonradioactive PCR method followed by polyacrylamide gel electrophoresis. We present 2 families which demonstrate the use of this polymorphism. Since 35–50% of females are heterozygous, this locus is a useful marker in RFLP analysis of D/BMD families. © Wiley-Liss, Inc.     

Intragenic deletions in 164 boys with Duchenne muscular dystrophy (DMD) studied with dystrophin cDNA

DNA from 164 unrelated Duchenne muscular dystrophy patients was screened with cDNA probes from the dystrophin gene. Molecular deletions were demonstrated in 82 (50%) subjects. Sixty-two deletions (76%) were detected using cDNA probes Cf56a (cDNA 8) and Cf56b (cDNA 6-7) which map to the centre of the gene, while 22 deletions (27%) mapped to the 5' end of the gene. In three subjects, the deletion extended from the 5' end to the centre of the gene. One deletion was identified by probe 47-4 (cDNA 5b-7) alone. In six of the deletions, junction fragments of altered size were observed. Using the three cDNA probes, RW2kb, Cf56a (cDNA 8) and Cf56b (cDNA 6-7), 99% of the deletions were detected. This will have implications for prenatal diagnosis in deletion families. Unlike Becker muscular dystrophy, where the deletions are more homogeneous, the deletions in the present study were heterogeneous both in size and position. No correlation between intelligence and either site or extent of deletion was found.