The muscular dystrophies represent disorders of progressive muscular degeneration and weakness. As a group they exhibit clinical heterogeneity that reflects diverse molecular mechanisms responsible for them, and range from congenital to adulthood onset. All are genetic, but different types reflect different genes that are implicated in the pathogenesis. Recent advances in the field resulted with improved methods of diagnosis and the development of novel therapeutic approaches.
The word dystrophy has its roots in two ancient Greek words: “dys” which means abnormal or faulty, and “trophe” which means food or nourishment. The reason for such designation was a thought that there was a defect in the nourishment of the muscle, in the same way that a person who does not eat the correct food will not grow adequately.
Skeletal muscle represents a highly specialized organ system which in humans evolved for locomotion and energy metabolism. The functional unit of the skeletal muscle is myofiber, which can be defined as a multinucleated tubular structure created by the fusion of multiple mononucleated muscle cells or myoblasts.
Various structural and regulatory proteins are required in order to maintain the proper function and integrity of the muscle. Hence mutations of the genes involved in synthesis and regulation of those proteins can be responsible for the disruption of the muscle tissue. Such progressive muscle tissue damage can result in weakness and sometimes even loss of muscle bulk or replacement of normal muscle structure by scar tissue or fat.
In certain forms of muscular dystrophy, functional loss of proteins that are part of dystrophin complex can weaken the plasma membrane of the muscle cells to the extent where even the normal exercise tears the membrane. That results in the influx of extracellular ions (such as sodium and calcium) which destroy sarcoplasmic function; hence the affected muscle tissue loses contractile cells.
The extracellular matrix of the muscle can be viewed as a meshwork of collagen, glycoproteins and proteoglycans, and provides an attachment and signaling scaffold for myofibers. Mutations in several genes encoding the structural components of this matrix are responsible for congenital muscular dystrophies. Loss of integrin-mediated linkage between cytoskeleton and the extracellular matrix is another important step in the development of muscular dystrophy.
A careful family history and the physical examination still represent a pivotal step in establishing a correct diagnosis, although a myriad of different laboratory test are employed in order to confirm the suspicion. Genetic testing often represents an important approach not only for diagnosing muscular dystrophies, but also to detect potential carriers.
The most important tools to address potential differential diagnostic issues are the determination of creatine kinase (CK) levels in order to see if there is a persistent increase of CK in plasma samples, magnetic resonance imaging (MRI) of the brain, nerve conduction velocity studies with repetitive stimulation to recognize abnormalities of neuromuscular transmission, muscle biopsy, as well as specific metabolic or genetic testing.
The diagnosis of congenital muscular dystrophies requires the expertise in multiple specialties (such as neurology, pathology, neuroradiology, and genetics) available in only a few centers worldwide with sufficient experience to recognize a plethora of different subtypes. In addition, ECG and pulmonary function test are often indispensable in the postoperative care of dystrophic patients.
The advent of molecular diagnosis is essential for genetic and prenatal counseling, phenotype-genotype correlations, as well as for adequate management and prognosis for muscle dystrophies. Early identification of causative mutations will enable clinicians to take proactive measures to halt or even reverse muscle degeneration.