The Muscular Dystrophies Victor Dubowitz Department Ofpaediatrics and Neonatal Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK
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Postgrad Med J: first published as 10.1136/pgmj.68.801.500 on 1 July 1992. Downloaded from Postgrad Med J (1992) 68, 500- 506 © The Fellowship of Postgraduate Medicine, 1992 The muscular dystrophies Victor Dubowitz Department ofPaediatrics and Neonatal Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK Introduction In 1879 William Gowers, the eminent British The main breakthrough has been in Duchenne neurologist, painted a remarkably lucid word pic- and Becker muscular dystrophy, or the Xp2l ture of Duchenne muscular dystrophy in his series dystrophies as some would now have us call them. of lectures on pseudohypertrophic muscular The location of the gene for the X-linked paralysis, published in the Lancet.' This disease, he Emery-Dreifuss muscular dystrophy on the long said, is one of the most interesting, and at the same arm of the X chromosome at Xq28 was discovered time most sad, of all those with which we have to a few years back3 but there has as yet been no deal; interesting because ofits peculiar features and further progress in its resolution. The locus for the mysterious nature; sad on account of our dominantly inherited facioscapulohumeral dyst- powerlessness to influence its course. rophy on the long arm of chromosome 4 has only Almost exactly a century later Duchenne dys- recently been found4 and other dystrophies such as trophy found itself at the centre of one of the most the autosomal recessive congenital dystrophy and exciting breakthroughs in the modern science of limb girdle dystrophy will undoubtedly follow suit molecular genetics. It was the first genetic disorder once sufficient collaborative clinical and laboratory in which a previously unknown biochemical abnor- effort is concentrated on them. copyright. mality was resolved by the process of reversed genetics, with initial location, isolation and cloning of the gene and then identifying the protein it The Duchenne dystrophy story encodes. Moreover, we now seem to be on the verge of treating the disease by one or other of the Locating the gene potential routes of gene therapy. This would cer- tainly have delighted Gowers. At the same time The discovery of the gene locus for Duchenne molecular genetics has generated a most complex dystrophy at Xp2l came, almost simultaneously, http://pmj.bmj.com/ and almost totally incomprehensible newjargon of from three sources. Through the application of the its own, which must surely have turned Gowers in new techniques of molecular genetics it became his grave. possible to isolate DNA sequences from cloned The muscular dystrophies, a term first coined by fragments derived from the human X chromosome Erb in 1891, are a group of genetically determined and to determine their exact location. Duchenne disorders characterized by degeneration of skeletal dystrophy was the first disease to be localized in this muscle and no associated structural abnormality in way by linkage with these restriction fragment on September 30, 2021 by guest. Protected the central or peripheral nervous system. They have length polymorphisms (RFLPs).5 Secondly, a been subdivided into various clinical types on the number of documented females with Duchenne basis of the clinical distribution and severity of dystrophy associated with an X:autosomal trans- muscle weakness, and the mode ofinheritance. The location all had the breakpoint on the X rate of progression of the disease is also variable chromosome at this locus. Thirdly, a number of and some, such as congenital muscular dystrophy, cases of Duchenne dystrophy with associated X- may remain relatively static or even show func- linked disorders, such as chronic granulomatous tional improvement over time. Some of the animal disease, retinitis pigmentosa and McLeod's synd- models of the dystrophies may be devoid of any rome were found to have a cytogenetically visible clinical weakness as may some of the milder deletion at the same site.6 Linkage studies in cases variants of, for example, Becker dystrophy, which of Becker dystrophy pointed to the same locus, can present solely with cramps on exercise.1'2 confirming that the two conditions are allelic and due to abnormalities in the same gene. This fits in with the clinical observation that Becker dystrophy has a similar clinical pattern to Duchenne apart Correspondence: Professor V. Dubowitz, M.D., Ph.D., from its later onset and milder course and that there F.R.C.P., D.C.H. is an overlap of cases between the two.' Postgrad Med J: first published as 10.1136/pgmj.68.801.500 on 1 July 1992. Downloaded from THE MUSCULAR DYSTROPHIES 501 The clinical phenotype of cDNA probes covering the whole dystrophin gene. This enables one (in a blood sample) to detect Although it can be argued that all cases ofmuscular exon deletions within the gene, which occur in dystrophy associated with the Xp2l gene form a about 50-60% of all Duchenne as well as Becker continuous clinical spectrum of a single disease, it cases. This has considerably increased the diagnos- would be helpful to have some degree of interna- tic potential in carrier detection and antenatal tional consensus on the definition of the different diagnosis (with chorionic villus biopsy in early grades of severity of Xp21 disease, in order to at pregnancy), and also the accurate diagnosis of least be able to compare data from one laboratory isolated cases particularly of Becker dystrophy with those from another. It is of course also which may have been misdiagnosed as spinal important from the point ofview ofthe patient and muscular atrophy on the misinterpretation of his family to be able to give some form ofprognosis atrophic fibres in the muscle biopsy, or as and appropriate supportive therapy. autosomal limb girdle dystrophy. It has also helped The vast majority of boys with Duchenne mus- to confirm the diagnosis of Becker dystrophy in cular dystrophy lose the ability to walk cases presenting with cramps on exercise, a com- independently by the age of 12 years. If one defines mon and well-recognized presenting symptom.' Becker dystrophy as maintaining independent Some ofthese cases have no detectable weakness or ambulation beyond the 16th birthday, this clearly disability but have a grossly elevated creatine separates the two phenotypes and also recognizes kinase and a dystrophic muscle biopsy. cases of intermediate severity which bridge the gap Contrary to early speculations, neither the size of between the two and lose ambulation between 13 the deletion nor the location-bears any consistent and 16 years. One can then dispense with ill-defined relation to the severity ofthe clinical condition. In a terms such as 'outliers' or 'mild Duchenne' or review of 218 of our patients with Duchenne, 'severe Becker'. There is of course considerable Becker or intermediate phenotypes, 124 had dele- variability within the Becker group with some cases tions with the cDNA probes.' Seventy-four remaining ambulant and practically free of separate deletions were found,with 55 being unique disability into late adult life and others having to one patient and the remaining 19 occurring in at copyright. considerable disability already in their late teens. least two unrelated patients. Some deletions such as Similarly within the Duchenne group some cases of exons 33-34 and 33-35 occurred only with may already be unable to walk by 6 or 7 years of Becker patients and of exons 3-7 in four patients age. with intermediate severity and one Becker. We also found no correlation of associated mental retarda- tion with any selective deletions. Isolating, cloning and characterizing the gene In order to explain the varying clinical severity, Monaco et al." postulated that in Duchenne http://pmj.bmj.com/ The isolation of the gene was achieved by Kunkel dystrophy the deletion, irrespective of size, leads to and his colleagues by an ingenious approach of a frame shift of the triplet codons for amino acids preparing a library ofcloned sequences correspond- resulting in a severely truncated non-functional ing to the DNA deleted in a patient with Duchenne protein, whereas in Becker dystrophy the dystrophy, chronic granulomatous disease, nucleotides remain in frame, and can produce a retinitis pigmentosa and McLeod's syndrome and a functional protein, although reduced in size. Over visible deletion in the Xp2l region.7 This was 90% of cases with deletions conform to this on September 30, 2021 by guest. Protected followed within a comparatively short period of hypothesis. There have, however, been some excep- time by the complete cloning of the gene,8 and the tions. Thus Malhotra et al.'2 demonstrated a 3-7 discovery of the protein product of the gene, which exon deletion, with disruption of the translational they named dystrophin.9 The gene is a gigantic size, frame, in six Becker, five intermediate and two encompassing over 2,000 kilobases (2 million base Duchenne cases, and postulated mechanisms that pairs), with over 60 exons spanning the gene. might compensate for the effects of the frame shift Dystrophin is a correspondingly large protein of in the milder cases. over 400 kilodalton in size, but with very low abundance, comprising only about 0.002% oftotal Dystrophin in muscle biopsies striated muscle protein. In their initial biochemical studies of dystrophin in relation to Duchenne and Becker muscular dyst- Clinical applications rophies and other neuromuscular disorders, Hoffman et al.'3 concluded that dystrophin was Gene deletions absent in severe Duchenne dystrophy, was present Kunkel's group have produced, and made but of abnormal molecular size in mild Becker available to genetic laboratories worldwide, a series muscular dystrophy, and was present in normal Postgrad Med J: first published as 10.1136/pgmj.68.801.500 on 1 July 1992. Downloaded from 502 V. DUBOWITZ amounts and size in other forms of muscular In addition to the original Hoffman antibodies, dystrophy.