Merosin-deficient muscular dystrophy: pathogenesis, clinical manifestations and therapeutic strategies

Merosin-deficient muscular dystrophy is the most common form of congenital muscular dystrophies (CMD), characterized by genetic heterogeneity and a severe course in most cases. CMD pathogenesis is associated with a partial or complete absence of laminin α2 chains in the basal membrane of muscle fiber caused by a mutation in the LAMA2 gene. The clinical manifestations of LAMA2-associated muscular dystrophy vary from severe CMD (CMD 1A) with an early onset to a relatively mild course with a late onset and phenotype of limb-girdle muscular dystrophy. CMD type 1A is characterized by a delay in motor development from the first months of the life (while the vast majority of children do not master the ability to walk independently), facial muscles weakness, ptosis, ophthalmoplegia, spine rigidity, early occurrence of contractures in the shoulder, elbow, hip and knee joints, restrictive respiratory disorders, nutritional problems, such as disorders of swallowing and chewing, gastroesophageal reflux, low body weight; some children suffer from mental retardation and epilepsy.

The limb-girdle forms are accompanied by a late onset and less pronounced motor disorders; the involvement of the musculoskeletal system, as in the congenital form, is manifested by the rigidity of the spine and contractures in the joints, especially ulnar and ankle; pseudo-hypertrophies of the quadriceps and calf muscles; cardiomyopathy is often observed; respiratory failure is absent.

Based on the multisystemic nature of the disease, all patients require long-term interdisciplinary monitoring and management. There are given recommendations of the International Consensus on standards of treatment for patients with CMD, describing in detail the scope and procedure for providing them with the necessary care. Knowledge of the characteristic clinical course and pathogenesis of LAMA2-associate muscle dystrophies becomes especially relevant in the context of actively developing specific methods of their therapy. Currently, there are being investigated several therapeutic strategies for restoring and / or maintaining the structure of the basement membrane in merosin-deficient muscular dystrophy: the use of linker proteins, the initiation of polymerization of laminin α2, the genome removal technology CRISPR/Cas9, the inhibition of apoptosis.

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