The broad range of muscular disorders has greatly expanded in the last decades thanks to advances in the field of genetics. Although there are acquired causes of muscle disease (immunologic, toxic, endocrine-metabolic), genetic causes account for 80% of cases, with more than 200 known genes so far.
As a whole, they are considered rare diseases, with an overall prevalence of 1/3 500 live births. The increase in survival and the discovery of new therapeutic targets have contributed to the growing importance of this group of pathologies. It is worth noting that, although they are chronic and usually progressive degenerative diseases, over 50% have their onset in childhood.
We use the term “structural” for those forms of muscle disease that primarily affect the structure of muscle fibers and lead to alterations in their function.
To better assess this group of disorders, two main categories were considered based on the age of onset of symptoms:
- Congenital structural genetic muscle disorders (present from birth)
- Child- and adult-onset structural genetic muscle disorders
The group of congenital structural genetic muscle disorders includes all genes related to congenital myopathy and congenital muscular dystrophy.
Congenital myopathies comprise a group of disorders characterized by non-dystrophic morphological abnormalities on muscular biopsy. An approximate prevalence of 3.5-5/10 000 live births has been estimated (Sharma et al., 2009). Most of these diseases manifest at birth or shortly thereafter with hypotonia, delay in motor development, and static or non-progressive weakness. Although these symptoms may be present since birth, diagnosis is often not reached until well into childhood or even in adulthood, since many of these signs may go unnoticed.
On the other hand, congenital muscular dystrophies, despite showing symptoms from birth, usually have a more severe and progressive development and are characterized by the presence of muscular dystrophy on biopsy.
The group of child- and adult-onset structural genetic muscle disorders encompasses the rest of muscular dystrophies: a group of inherited diseases that affect skeletal muscle, characterized by a progressive degeneration of muscle fibers determining loss of strength. This heterogeneous group of diseases has been a subject of clinical and molecular studies for decades, leading to increasingly complex classifications based on genotype-phenotype correlation attempts.
So far, one of the most useful classifications for the clinical practice is still the prevailing weakness pattern, which allows identifying phenotypes to guide genetic studies. We have relied on this classification to guide clinical decision making aimed at selecting the most suitable panel for molecular diagnosis:
- Dystrophinopathies (DMD)
- Limb-girdle muscular dystrophies (both at the pelvic and shoulder level)
- Emery-Dreifuss muscular dystrophy (characterized by a scapulohumeral-peroneal distribution and early contractures, associated with heart disease)
- Distal myopathies (with a pattern of weakness predominantly involving distal muscles)
- Oculopharyngeal muscular dystrophy*
- Facioscapulohumeral muscular dystrophy**
With the exception of oculopharyngeal muscular dystrophy*, whose main pathogenic mechanism is a triplet repeat expansion in the PABPN1 gene (analyzed in our laboratory on specific request), and facioscapulohumeral muscular dystrophy**, whose main pathogenic mechanism is the contraction of a repetitive region in the DUX4 gene (detected by a technique not performed in our laboratory), there are specific panels for the study of the remaining pathologies. We have developed an additional panel for the study of myofibrillar myopathies, selected for their characteristic findings on muscle biopsy.