Skeletal myopathies are a group of diseases characterized by progressive muscle atrophy and weakness, generally due to a degeneration of skeletal, smooth, and cardiac muscles. Some of the most representative diseases in this group are Duchenne and Becker muscular dystrophies (DMD/BMD), which follow an X-linked transmission pattern; limb-girdle muscular dystrophies, of which both autosomal dominant (Emery-Dreifuss muscular dystrophy and LMNA mutations) and recessive forms (some types of Charcot-Marie-Tooth disease) have been described.
- Clinically diagnosed subjects [physical examination findings, electromyography or anatomopathological alterations in skeletal muscle (muscle histology), with or without cardiac affectation.]
- Familial study: A search for a mutation previously identified in a proband (relatives of patients diagnosed with skeletal myopathy in which a mutation associated with the disease has been previously identified).
One of the most widely known pathologies is Duchenne muscular dystrophy (DMD), with an X-linked recessive inheritance pattern (DMD gene, Xp21.2). This disease affects mainly men, with an incidence of 1 in 3,000 male live births, since carrier women are usually asymptomatic. A low percentage of these women express mild to moderate forms of the disease.
Subjects affected with DMD are characterized by progressive symmetrical muscular weakness, proximal before distal. Symptoms begin in childhood, pseudohypertrophy of calf muscles and positive Gowers’ sign may present themselves during this period. The mean age at which the ability to walk is lost is 13 years. Patients usually develop dilated cardiomyopathy after the age of 18. Diagnosis is based on signs and symptoms, familial history, laboratory tests (serum creatine-kinase levels 100-200 times higher than normal) and muscle biopsy (shows signs of dystrophy and total absence of dystrophin), and it is usually easier in males, since the laboratory tests and biopsy may not be conclusive in women. Therefore, differential diagnosis includes Becker muscular dystrophy and limb-girdle muscular dystrophies. The genetic study of the DMD gene allows identifying deletions (50%-60%, with techniques such as MLPA, CGH array and other techniques that allow identifying CNVs), duplications (10%, with techniques such as MLPA, CGH array and other techniques that allow identifying CNVs), and other mutations (20%-35% through NGS).
- Becker muscular dystrophy (BMD): It is the mildest form of dystrophinopathies and often manifests itself through a dilated cardiomyopathy, which may be disproportionate in relation to the magnitude of skeletal muscle involvement. The onset of disease occurs later than in the case of DMD. Diagnosis is based on the signs and symptoms, familial history, laboratory tests and muscle biopsy. The genetic study of the DMD gene allows identifying deletions (60%), duplications (10%-20%,), and other mutations (10%-20%).
- Limb-girdle muscular dystrophy: They are a heterogeneous group of rare genetic muscle diseases with an autosomal dominant or recessive inheritance pattern. The prevalence of these pathologies is about 5 individuals per one million inhabitants, and the most common forms are often the dominant forms. In this pathology, the first sign is usually pelvic muscle weakness. Diagnosis is usually difficult to specify, since the signs, symptoms and familial history usually overlap among these pathologies, and laboratory tests and muscle biopsy are often not specific. Therefore, the genetic testing and its correlation facilitate the differential diagnosis among these muscular dystrophies. An example of this is the lamin A/C (LMNA) gene. Mutations identified in this gene have been detected in different diseases: autosomal dominant limb-girdle muscular dystrophy type 1B (autosomal dominant LGMD1B), Emery-Dreifuss muscular dystrophy (autosomal dominant), one form of familial dilated cardiomyopathy, some inherited forms of familial lipodystrophy, and a form of Charcot-Marie-Tooth disease (autosomal recessive).
Autosomal dominant limb-girdle muscular dystrophies (LGMD): LGMD1A (MYOT gene), LGMD1B (LMNA gene), LGMD1C (CAV3 gene), LGMD1D (DES gene) and LGMD1E.
Autosomal recessive limb-girdle muscular dystrophies (LGMD): LGMD2A (CAPN3 gene), LGMD2B, LGMD2D (SGCA gene), LGMD2E (SGCB gene), LGMD2F (SGCD gene), LGMD2G (TCAP gene), LGMD2I (FKRP gene), LGMD2J (TTN gene) and United Kingdom and German populations.
The probability of identifying a mutation related to the disease depends on the presentation and findings suggesting a genetic inheritance pattern.
Skeletal Myopathy Panel
It is indicated as a first approach upon clinical suspicion of myopathy of genetic origin, particularly when the phenotype is compatible with any of the described pathologies, generally manifested through progressive muscle weakness. This panel does not include all genes related to inherited cardiomyopathies, which are usually present from birth or childhood and are generally not progressive
ACTA1, AGK, AGL, BAG3, CAPN3, CAV3, COQ2, CRYAB, DES, DMD, EMD, FHL1, FKRP, FKTN, FLNC, GAA, HRAS, KCNE3, KCNJ2, LAMA2, LAMP2, LDB3, LMNA, MURC, MYH7, MYL2, MYL3, MYOT, PHKA1, PRKAG2, SGCA, SGCB, SGCD, SLC22A5, SLC25A4, SURF1, TAZ, TCAP, TNNI3, TTN, BSCL2*, CACNA1C*, DLD*, DOLK*, PMM2*, TMEM43*.
Notes on Genes:
Priority Genes: These genes include >70% of the mutations that have been previously associated with the development of skeletal myopathy and/or their testing is recommended by the guidelines. Secondary genes: Other genes related to the disease. *Candidate genes: With no evidence, but likely to be related to the phenotype.