The fundamental cause of all forms of muscular dystrophy lies in mutations within genes that are crucial for the proper structure and function of muscles . These genetic alterations can disrupt the production of essential muscle proteins, leading to the progressive muscle weakness and degeneration that characterize these disorders . Muscular dystrophies can be inherited in several distinct patterns, each influencing the likelihood of the condition being passed on to future generations.
A. X-linked Inheritance
In X-linked inheritance, the mutated gene responsible for the muscular dystrophy is located on the X chromosome . Males, who possess one X and one Y chromosome, will be affected if they inherit an X chromosome carrying the mutated gene . Females, with two X chromosomes, typically need to inherit the mutated gene on both X chromosomes to be affected by an X-linked recessive disorder; however, if they inherit one mutated X chromosome, they become carriers . Carrier females usually do not show significant symptoms because their other X chromosome carries a normal copy of the gene, which can compensate for the mutated one, although some carriers may experience milder symptoms . Duchenne and Becker muscular dystrophies are the most well-known examples of X-linked recessive muscular dystrophies . A female carrier of an X-linked recessive MD has a 50% chance of passing the mutated gene to each of her children. If a son inherits the mutated X chromosome, he will develop the disease. If a daughter inherits the mutated X chromosome, she will also be a carrier .
B. Autosomal Dominant Inheritance
Autosomal dominant inheritance occurs when only one copy of the mutated gene, inherited from either parent, is sufficient to cause the disorder . If an individual has an autosomal dominant form of muscular dystrophy, each of their children has a 50% chance of inheriting the mutated gene and developing the condition . Examples of muscular dystrophies that follow this inheritance pattern include Myotonic Dystrophy, Facioscapulohumeral MD, Oculopharyngeal MD, as well as some forms of Limb-Girdle MD and Distal Myopathies .
C. Autosomal Recessive Inheritance
In autosomal recessive inheritance, an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the muscular dystrophy . The parents, who each carry one copy of the mutated gene and one normal copy, are typically unaffected carriers . For each pregnancy, there is a 25% chance that the child will inherit two copies of the mutated gene and be affected, a 50% chance that the child will inherit one mutated copy and be a carrier, and a 25% chance that the child will inherit two normal copies and be unaffected . Some forms of Limb-Girdle MD, Congenital MD, and certain Distal Myopathies are inherited in an autosomal recessive manner .
D. Spontaneous Mutations
In some instances, a genetic mutation that causes muscular dystrophy can occur spontaneously in an individual without any prior family history of the condition . This is known as a de novo or spontaneous mutation. While the exact reason for these new mutations is not always clear, they can lead to the development of muscular dystrophy in individuals whose parents do not carry the mutated gene . These spontaneous mutations can then potentially be passed on to future generations.
Several specific gene mutations have been identified as the underlying cause of different types of muscular dystrophy. For example, mutations in the DMD gene, located on the X chromosome, lead to Duchenne and Becker muscular dystrophies . This gene provides instructions for making dystrophin, a protein essential for the stability and protection of muscle fibers . In DMD, the mutation typically results in the absence of functional dystrophin, while in BMD, some dystrophin is produced but is often abnormal . Myotonic dystrophy is caused by an expansion of a CTG trinucleotide repeat in the DMPK gene . Facioscapulohumeral MD is often associated with a deletion of a 3.3 kb repeat on chromosome 4, specifically in the D4Z4 region . Certain forms of Congenital MD are caused by mutations in the gene encoding merosin, a protein found in the muscle membrane . Emery-Dreifuss MD can result from mutations in the EMD gene, which codes for the protein emerin, or in the LMNA gene, which codes for lamin A/C . Limb-Girdle MD is genetically heterogeneous, with mutations in numerous genes, including those encoding sarcoglycans, calpain, dystroglycan, and dysferlin . Similarly, Distal Myopathies are caused by a variety of genetic defects affecting genes such as titin, dysferlin, and GNE . These diverse genetic abnormalities all ultimately disrupt the production or function of proteins critical for maintaining healthy muscle tissue, leading to the characteristic progressive muscle weakness observed in muscular dystrophy.