Muscular dystrophies represent a group of more than 30 molecular and clinical heterogeneous genetic disorders, which cause progressive degeneration of the skeletal muscle fibers. Their main feature is severe muscle weakness that predominantly affects limb, axial and facial muscles to a variable degree.

The severity of the disease, age of onset and rate of progression vary significantly in the different forms of muscular dystrophies. The primary cause of various disease forms can be pinpointed to the particular mutation in genes encoding a myriad of proteins – including extracellular matrix proteins, membrane-associated proteins, nuclear proteins and cytoplasmic proteases.

Pattern of inheritance

The genetic cause of muscular dystrophy is passed from one or both parents to an offspring by a specific pattern that varies depending on the type of muscular dystrophy. Three primary types of inheritance are known: X-linked recessive, autosomal dominant and autosomal recessive. It must be noted that mutations can always develop “de novo”; therefore lack of family history does not rule out the possibility of muscular dystrophies.

In the process of reproduction, male and female gametes (sperm and eggs) contribute one sex chromosome each. A set of sex chromosomes in males is XY, while females have XX sex chromosomes; hence the male can contribute the X or Y chromosome, whereas females contribute one of their X chromosomes. A male infant is a result of males contributing their Y chromosome, and female infant is a result of X chromosome contribution.

Duchenne and Becker muscular dystrophy (as well as some types of Emery-Dreifuss muscular dystrophy) arise as a result of mutations on one of the X chromosomes carried by the female parent. The aforementioned muscular dystrophies affect 50 percent of male infants, while daughter of a carrier has a 50 percent chance of becoming a carrier (and occasionally mild symptoms). Such inheritance pattern is called X-linked recessive inheritance.

Myotonic dystrophies, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, some types of congenital muscular dystrophies and some types of limb-girdle muscular dystrophy can develop if either of the parent's chromosomes carries the defect, which is subsequently passed to the infant. This type, known as autosomal dominant inheritance, can affect both sexes and the severity of the disease can vary greatly.

A majority of congenital muscular dystrophy types, a rare form of Emery-Dreifuss muscular dystrophy, as well as some types of limb-girdle muscular dystrophy arise when both parents pass on the faulty gene, so both copies of the gene in question are abnormal. Although parents do not exhibit any symptoms, each of their offspring (regardless of sex) will have a 25 percent chance of developing the disease. This is called autosomal recessive inheritance.

Main mechanisms leading to muscular dystrophy

The exact mechanisms of muscle weakness in muscular dystrophy eluded scientists for a long time, but it became clear that the molecular causes responsible for performance hindrances in these diseases involve both functional and structural modifications of the acto-myosin interactions.

It has been demonstrated that most muscular dystrophies share some common pathologic features, such as altered homeostasis of calcium ions, an increase of profibrotic cytokines, proteolytic enzyme activation, infiltration of muscle tissue by inflammatory cells of the immune system, metabolic and mitochondrial alterations, defective autophagy and intracellular accumulation of reactive oxygen species. All of the above can contribute to muscle wasting.

At the early stage of the disease, reduced protein content in myofibriles (basic rod-like units of a muscle) can arise in apparently uninjured tissues, as a result of an imbalance between protein synthesis and their breakdown. That is followed by consecutive rounds of muscle degeneration and regeneration, leading to fibrosis and fatty replacement of muscle tissue. That forms the basis of the pathological findings in muscular dystrophies.