Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals.

BIOCHEMISTRY IN ANAESTHESIA Modern Trends In Anaesthesia. II. Aspects of Hydrogen lon Regulation and Biochemistry in Anaesthesia. Edited by Prankis T. Evans, M.B., B.S., F.R.C.S., F.F.A. R.C.S., and T. Cecil Gray, M.D., FF.A. R.C.S., Hon.F.F.A. R.A.C.S. (Pp. 219+vii; illustrated. 60s.) London: Butterworths. 1962. In this stimulating book a group of experts have written on hydrogen-ion regulation and biochemistry in anaesthesia. This vast subject has been divided rather artificially and only certain aspects of biochemistry have been covered, and the divisions are more related to clinical practice than basic physiology and biochemistry. TIhe sections have been written by specialists in each field; the material they contain is beyond criticism, and there is valuable practical advice. Some chapters are well written, though others are not so easy to read. All are packed with information, and, what is equally valuable, they provide a source of further information for the inquiring mind, for the references and bibliographies are excellent. It is a pleasure to have complicated electrophysics presented in a readable way (\" Measurement of pH and Pco l\"); \"The Cholinesterases\" is an embracing account of difficult physiological and biochemical problems. Throughout the book there is a wealth of valuable material, indeed so much so that at times too much appears to have been attempted within the space available, as in \" Effects of Hypercapnia.\" These are minor criticisms of a good book, or perhaps it would be wiser to call it a collection of papers on chosen subjects, for there is understandably a lack of cohesion among the various chapters, and even some slight overlapping, which renders the whole less valuable than its several parts. No one can read these papers without interest and profit (and occasionally amusement) and they should fulfil the editor's hope that they will stimulate further interest in basic science. The book is well presented; the printing and paper are good, but the price will not encourage widespread use of the book among the younger members of our specialty. G. E. H. ENDEPBY.

Blood Groups in Man.

Duchenne muscular dystrophy (DMD) is the most common sex linked lethal disease in man (one case in about 4000 male live births). The patients are wheelchair bound around the age of 8-10 years and usually die before the age of 20 years. The mutation rate, estimated by different methods and from different population studies, is in the order of 7 X 10(-5), which is higher than for any other X-linked genetic disease. Moreover, unlike other X linked diseases such as hemophilia A or Lesh-Nyhan's disease, there seems to be no sex difference for the mutation rates in DMD. Several observations of DMD in girls bearing X-autosomal translocations and linkage studies on two X chromosomal DNA restriction fragment length polymorphisms indicate that the DMD locus is situated on the short arm of the X chromosome, between Xp11 and Xp22. It may be of considerable length, and perhaps consisting of actively coding and non-active intervening DNA sequences. Thus unequal crossing over during meiosis in females could theoretically account for a considerable proportion of new mutations. However, there is no structurally or functionally abnormal protein known that might represent the primary gene product, nor has any pathogenetic mechanism leading to the observed biochemical and histological alterations been elucidated. Among the numerous pathogenetic concepts the hypothesis of a structural or/and functional defect of the muscular plasma membrane is still the most attractive. It would explain both the excess of muscular constituents found in serum of patients and carriers, such as creatine kinase (CK), as well as the excessive calcium uptake by dystrophic muscle fibres, which, prior to necrosis, could lead to hypercontraction, rupture of myofilaments in adjacent sarcomeres and by excessive Ca uptake to mitochondrial damage causing crucial energy loss. The results of studies on structural and functional membrane abnormalities in cells other than muscle tissue, e.g., erythrocytes, lymphocytes and cultured fibroblasts, indicate that the DMD mutation is probably demonstrable in these tissues. However, most of the findings are still difficult to reproduce or even controversial. DMD is an incurable disease; therefore most effort, in research as well as in practical medicine, is concentrated upon its prevention.(ABSTRACT TRUNCATED AT 400 WORDS)

Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention.

Duchenne muscular dystrophy (DMD) is one of the most common and serious human X-linked disorders. It occurs at a frequency of up to 1 in 5,000 newborn males in most populations studied, with about one-third of all cases due to new mutations1. The primary biochemical defect remains unknown, and no proven prenatal diagnostic test exists, although raised serum creatine kinase levels act as a somewhat equivocal guide to carrier females2. Previous studies have shown no measurable genetic linkage of the DMD locus with any X-chromosome marker3,4. Therefore, if a cloned sequence of the X chromosome could be used to define the locus, and to provide a closely linked set of markers, it would be of considerable importance in the prediction and prevention of DMD, as well as a step towards identifying the basic biochemical defect causing the disease. We present here evidence of an X-chromosome sequence, defined by its restriction enzyme polymorphism, that is loosely linked to DMD, at a distance of approximately 10 centimorgans, as determined by studies on nine informative families. The polymorphism occurs in 29% of women in a control London population and in 22% of carriers for DMD. The linkage data support cytogenetic evidence that DMD is on the short arm of the X chromosome. The object of this letter is to encourage others to make use of our probe, which seems to be linked to the DMD locus.

Linkage relationship of a cloned DNA sequence on the short arm of the X chromosome to Duchenne muscular dystrophy

Duchenne and Becker muscular dystrophies are collectively termed dystrophinopathy. Dystrophinopathy and severe childhood autosomal recessive muscular dystrophy (SCARMD) are clinically very similar and had not been distinguished in the early 20th century. SCARMD was first classified separately from dystrophinopathy due to differences in the mode of inheritance. Studies performed several years ago clarified some immunohistochemical and genetic characteristics of SCARMD, but many remained to be clarified. In 1994, the sarcoglycan complex was discovered among dystrophin-associated proteins. Subsequently, on the basis of our immunohistochemical findings which indicated that all components of the sarcoglycan complex are absent in SCARMD muscles, and the previous genetic findings, we proposed that a mutation of any one of the sarcoglycan genes leads to SCARMD. This hypothesis explained and predicted various characteristics of SCARMD at the molecular level, most of which have been verified by subsequent discoveries in our own as well as various other laboratories. SCARMD is now called sarcoglycanopathy, which is caused by a defect of any one of four different sarcoglycan genes, and thus far mutations in sarcoglycan genes have been documented in the SCARMD patients. In this review, the evolution of the concept of sarcoglycanopathy separate from that of dystrophinopathy is explained by comparing studies on these diseases.

From dystrophinopathy to sarcoglycanopathy: Evolution of a concept of muscular dystrophy

A female with Duchenne muscular dystrophy who was a carrier of a balanced translocation t(X;6)(p21;q21) is reported. Four other previously described (X;A) translocations associated with DMD share with the present case a breakpoint at Xp21. The extremely low probability of five independent (X;A) translocations having a breakpoint at Xp21 points to a non-rand association of this site with the DMD phenotype. A DMD locus at Xp21 could be damaged by the translocation, giving rise to Duchenne muscular dystrophy. Alternatively, a pre-existing DMD gene could weaken the chromosome, favouring breaks at Xp21.

https://jmg.bmj.com/content/jmedgenet/18/6/442.full.pdf

A M Vianna-Morgante

Papers

Translocation (X;6) in a female with Duchenne muscular dystrophy: implications for the localisation of the DMD locus.