The term Congenital Myopathies (CM) refers to a heterogeneous group of inherited disorders generally presenting with precocious onset and variable clinical course. The CM clinical spectrum ranges from severe forms presenting with congenital hypotonia, delayed motor milestones, feeding difficulties, muscle weakness, facial muscle involvement, and ophtalmoplegia (including progressive scoliosis chronic respiratory failure and, in many cases, early mortality), to milder forms characterized by slowly progressive weakness or asymptomatic presentations. They are generally classified in different subtypes according to their histopathological appearance revealed on diagnostic muscle biopsy. These CM, which show structural changes in the muscle fibers, can be divided into these most common histologic types:
1. Core Myopathies are characterized by the histopathological finding of areas lacking histochemical oxidative and glycolytic enzymatic activity. These “cores” present with myofibrillar structure disorganization and without mitochondria and are referred to as either central cores or minicores. Myopathies with cores are most commonly associated with autosomal dominant mutations in the RYR1 gene, which encodes the skeletal muscle ryanodine receptor. Multiminicores are associated with autosomal recessive mutations in RYR1 or SEPN1 gene, that encodes selenoprotein N1, a member of the selenocysteine-containing protein family, which may play a role in intracellular calcium homeostasis and protection against redox-related cellular damage.
2. Nemaline Myopathies are characterized by typical rod-like accumulations of Z-disk-derived material in the muscle cells. Rods typically are found in the sarcoplasm but may also be intranuclear. Rod formation has been associated with mutations in proteins that belong to the sarcomere thin filaments. The most common mutations are autosomal recessively inherited and involve the nebulin (NEB) gene, or dominanty inherited affecting the α-actin (ACTA1) and tropomyosin 3 (TPM3) gene. Other defects have been disclosed within tropomyosin 2 (TPM2), troponin T1 (TNNT1), cofilin (CLF2) and, most recently, KBTBD13 and KLHL40.
3. Centronuclear Myopathies (CNM) are characterized by excessive centralized nuclei within myofibers on muscle biopsy. X-linked CNM or myotubular myopathy is caused by recessive mutations in the MTM1 gene coding for myotubularin, a member of phosphoinositide phosphatase protein family. Some individuals with dominant CNM harbor mutations in the DNM2 gene, encoding the dynamin-2 protein, a large GTPase involved in the interaction with actin. A rare form of CNM is associated with recessive mutations in the BIN1 gene encoding the protein amphiphysin 2, which binds to DNM2 during clathrin-mediated endocytosis.
4. Myofibrillar myopathies (myopathy with desmin accumulation) are characterized by intermediate filaments aggregation of desmin or other proteins inside the muscle fibers. There are two main forms due to mutations in DES (desmin) and CRYAB (-B-crystallin) genes, but other uncommon forms are linked to mutations in MYOT (myotilin), ZASP (zaspin) and FLNC (filamin C).