The History of Muscular Dystrophy

What is muscular dystrophy?

Muscular dystrophy is an inherited disorder, which is often characterized by a progressive type of muscular degeneration and weakness. There are several types of muscular dystrophy, wherein each type eventually leads to an increased disability, strength loss, and potential deformities. It greatly affects the muscles and causes skeletal and muscular degeneration. 

There have been remarkable changes taking place in the field of myology, which is the study of the muscular system. Current knowledge of these neuromuscular disorders has emerged from the developments of enzyme histochemistry and histopathology. Later on, laboratory techniques have been involved such as electron microscopy and immunocytochemistry, which have paved the way for the pathophysiology of myopathies to be better understood, especially at the cellular level. They have not only made the diagnosis easy to understand, but they have also improved the accuracy level of the diagnosis. 

History of Muscular Dystrophy

Beginning

In the second half of the 19th century, most neuromuscular diseases were basically diagnosed and treated by many American and European doctors. The disorder called as pseudohypertrophic muscular dystrophy was earlier recognized. In 1836, the most commonly known disorder called Duchenne muscular dystrophy (DMD) was initially reported by Gaetano Conte. In 1861, Guillaume-Benjamin-Amand Duchenne, a French neurologist, wrote regarding a muscular dystrophy case. After seven years, he provided a comprehensive report of 13 individuals with muscular dystrophy. One of the most commonly known forms, as well as the most severe form of muscular dystrophy, called Duchenne muscular dystrophy, was named after him. 

During the 19th and 20th centuries, there were some efforts carried out to differentiate the primary from the secondary myopathies. At around this time, doctors have realized that the root cause of the disorder can be primarily due to the muscle itself causing an issue or it can be atrophy, which may be secondary. Moreover, when it comes to the origin, it can be neurogenic. In the 70s and 80s, the neurogenic theory of Duchenne muscular dystrophy made it more complicated. However, over the past few decades, DNA analysis has provided a clear distinction between individuals.

However, there were some efforts given in the investigation of the lesions, which were microscopically done. In this early period, knowledge about the condition remained relatively static even though new clinical entities were recognized. During the era of 19th and 20th centuries, there were a lot of fruitless attempts, which were carried out to explain the origins as well as the pathogenesis of dystrophies. However, none of them succeeded.

Myopathology Era

In the year 1962, when Pearson, Adams and Denny-Brown published their investigations together, the stagnation era finally came to an end. They published their investigation about the skeletal muscle reaction to injury. This was published in their seminal monograph called Diseases of Muscle. Their work significantly provided further clinical knowledge, especially deep insights into muscular disorders through the descriptions of the involved underlying pathological processes.

Their work unified the fragmented clinical landscape into the field of neurology. One of the other important contemporary work, which was oriented toward the general form of biology instead of the clinical application, was based on the work carried out by Geoffrey Bourne in The Structure and Function of Muscle.

The available biological information on the muscles at that time was brought in combination by this monograph and various streams of veterinary science as well as zoology. For this reason, substantial progress was achieved in myopathology in the second half of the 20th century. In the past, it was often believed that muscle regeneration was nonexistent or quite limited until in 1962 when the natural ability of mammalian skeletal muscles to completely regenerate was discovered. 

It was believed from all various experiments that the conclusions that were being drawn were based on the surgical form of injuries. The downside was mostly a surgical form of injury that could lead to tearing of the sarcolemma and the endomysium. The muscles regenerate and the framework tends to remain intact in genetic muscle disorders or toxic metabolic diseases. 

With this model, experimental studies using the Setonix brachyurus or quokka from Rottnest Island established cyclical necrosis or regeneration, which involves exhaustion, muscle fiber outfall, and end-stage muscle lesion, as the cause of the progression of weakness when it comes to human muscular dystrophy. 

The principle of pathogenesis is quite similar in all progressive primary muscle disorders when there is necrosis, whether they are genetically determined or damaged as a result of autoimmune or toxic metabolic factors. Hence, there are principles that have been laid out that govern muscle reaction to injury. There was real hope in the discovery wherein the muscles said to possess the power to completely regenerate. This lead to the fact that muscular dystrophy can have a certain potential cure. There was a great amount of enthusiasm with this possibility worldwide. It resulted in the increase in research activity, which was further enhanced by international meetings or conferences. 

Clinician Era

After World War II, the clinician phase also showed improvement. It began with a publication in the year 1954 by Nattrass and Walton, wherein they had provided the classification of muscular dystrophies. This remained very much popular until the era of molecular genetics. The classification was published based on the genetic factors as well as clinical factors such as the sex association with DMD, limb-girdle muscular dystrophy or LGMD, myotonic and facioscapulohumeral forms. Changes in the multi-author book were carried out by John Walton in the year 1971. These changes brought together with it the current knowledge of the Disorders of the Voluntary Muscles, which ran various editions. 

Due to such changes, the clinical appreciation of the distinct entities started to grow in precision as well as in numbers. At the same time, there were also investigations carried out in the pattern of inheritance. Hence, in this way, due to the work carried out by Alan Emery and Peter Becker, the genetics of the neuromuscular form of diseases started to become way better compared to the previous knowledge.

The clinician era was illustrated by the thorough accuracy of all clinical workups of patients. This was then supported by significant laboratory assistance, which was provided by the serum creatine kinase. More diseases were clearly identified with the combination of electrophysiology and muscle biopsy. Also, there was an improvement in diagnostic accuracy.

In 1986, a particular gene on the X chromosome was identified by MDA-supported researchers. It was observed that a flaw in this gene would lead to DMD. In 1987, the protein associated with this gene was also identified and it was called dystrophin.

Thus, it was later concluded that due to the lack of this protein, muscles would become fragile and easily damaged. DMD has an X-linked recessive inheritance pattern. A child can be affected when the gene is passed from the mother to an unborn child. The mother is regarded as the carrier in such cases. 

A DMD carrier is the one who has a normal dystrophin gene on one X chromosome and one abnormal dystrophin gene on the other X chromosome. No signs and symptoms may be shown by the majority of carriers, but few may do. Symptoms may vary from mild skeletal muscle weakness to cardiac involvement. 

Golden Era of Molecular Genetics

The age of DNA technology came after many years of unproductive dalliance with myoblast transfer therapy although there were some great advances made in decades after World War II. However, the application of molecular genetic technology to this field was yet to come. The pedigree of families was already documented by the clinicians, so the gene for several inherited neuromuscular disorders became possible to locate overnight.

In the field of cure, the discovery of dystrophin gave great hopes. At the Australian Neuromuscular Research Institute, workshops were held in the year 1992 with a great kind of optimism expressed. A normal gene was introduced into the dystrophic muscle cell beginning from the viral vectors. However, there was a lot of disappointment in spite of the vigorous and imaginative efforts used to introduce the gene. Valuable clinical benefits of DNA analysis, on the other hand, were unexpectedly received by many.

The technique of alternate splicing exon skipping is another promising genetic therapeutic approach. This technique was pioneered by Sue Fletcher and Steve Wilton from the ANRI. Recently, this skipping method has shown to be refined and also improved using the morpholinos, thereby replacing the antisense oligonucleotides.

There was a lot of excitement surrounding this new discovery, which was later followed by conducting human trials in Europe. The pioneering trial is currently being supported by the MRC, which is based in the UK. It is used as a methodology in boys suffering from DMD.