Myopathology in congenital myopathies

Abstract

Congenital myopathies are clinically and genetically a heterogeneous group of early onset neuromuscular disorders, characterized by hypotonia and muscle weakness. Clinical severity and age of onset are variable. Many patients are severely affected at birth while others have a milder, moderately progressive or nonprogressive phenotype. Respiratory weakness is a major clinical aspect that requires regular monitoring. Causative mutations in several genes have been identified that are inherited in a dominant, recessive or X-linked manner, or arise de novo. Muscle biopsies show characteristic pathological features such as nemaline rods/bodies, cores, central nuclei or caps. Small type 1 fibres expressing slow myosin are a common feature and may sometimes be the only abnormality. Small cores (minicores) devoid of mitochondria and areas showing variable myofibrillar disruption occur in several neuromuscular disorders including several forms of congenital myopathy. Muscle biopsies can also show more than one structural defect. There is considerable clinical, pathological and genetic overlap with mutations in one gene resulting in more than one pathological feature, and the same pathological feature being associated with defects in more than one gene. Increasing application of whole exome sequencing is broadening the clinical and pathological spectra in congenital myopathies, but pathology still has a role in clarifying the pathogenicity of gene variants as well as directing molecular analysis.

Untangling the complexity of limb‐girdle muscular dystrophies

“…34,[137][138][139][140][141] Mutations in DES, DNAJB6, LMNA, MYOT, PLEC, and TTN give rise to MFMs of various clinical phenotypes and to LGMD without myofibrillar pathology on muscle biopsy (see Table 2). Mutations in genes encoding for other Z-disk-related proteins, such as ACTA1, FHL1, and NEB, in addition to MFM, can also cause congenital myopathies with different histopathologic features, 142,143 whereas mutations in FHL1 and LMNA can also underlie an EDMD phenotype. 66 Mutations in PLEC, another Z-disk-interacting protein, may lead to LGMD2 without skin lesions (LGMD2Q) or epidermolysis bullosa simplex with associated congenital myasthenic syndrome, muscular dystrophy, or pyloric atresia.…”

Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1‐related nemaline myopathy (NEM3)

“…44 Muscle biopsies normally show numerous rods, but other pathological features have also been described. 45 Data on in vivo muscle function in NEM3 are scarce. Magnetic resonance imaging of muscles of 4 NEM3 patients showed that both lower and upper leg muscles (including the vastus lateralis muscle, from which the majority of the studied biopsies were obtained) had diffuse abnormalities, including fatty replacement of muscle tissue and smaller muscle cross-sectional area.…”

Nemaline rod myopathy treated with L-tyrosine to relieve symptoms in a neonate

“…Nemaline rods are not specific to nemaline myopathy, can be seen in normal myotendinous junction, extraocular muscles and aging muscle and as a minor occurrence in several other myopathies. 10 Infantile onset myopathy was excluded as our patient did not have dilated cardiomyopathy or arthrogryposis, adult onset myopathy was excluded according to the age group. For, HIV rod myopathy, the mother was negative for HIV serology.…”