Expanding the histopathological spectrum of CFL2‐related myopathies

Abstract

Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2 knockout mouse model.

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

“…It is possible that the postsynaptic deterioration may also be progressive in human NM patients, and that accumulations may not be as obvious as the rods seen emanating from the sarcomere because they do not include Z-disc proteins often examined in patient samples. Even using TEM, we found disorganized actin filaments in the postsynaptic region of DmCFL KD muscle which is reminiscent of the cytoplasmic actin disorganization shown in the biopsy from one CFL2 NM patient (Fattori et al, 2018). We find that actin-binding protein Tmod is reduced at the DmCFL KD postsynapse as well, which may be due to sequestering of Tmod at the cell poles as we have previously reported (Balakrishnan et al, 2020).…”

“…NM diagnosis is based on myopathic clinical disease hallmarks, including hypotonia and proximal muscle weakness, as well as the presence of actin-rich accumulations (known as nemaline rods or bodies) and myofibrillar disruption on pathology. CFL2 NM patients have generalized muscle weakness; delayed motor skills; stiff spine; kyphoscoliosis; and joint contractures (Agrawal et al, 2007; Fattori et al, 2018; Ockeloen et al, 2012; Ong et al, 2014). Mutations in CFL2 have been described as recessive and hypomorphs and lead to reduced levels of cofilin activity in muscle.…”

Clinical-genetic features and peculiar muscle histopathology in infantileDNM1L-related mitochondrial epileptic encephalopathy

“…Specimens were dehydrated in a graded series of ethanol and embedded in epon resin. Thin sections were evaluated with a transmission electron microscope (EM 109 Zeiss; Fattori et al, ).…”

The Role of Muscle Biopsy in Diagnostic Process of Infant Hypotonia: From Clinical Classification to the Genetic Outcome

“…The first patient had a mutation in TNNT1 gene that encodes the slow twitch skeletal muscle isoform of troponin T; the second patient had a very rare mutation in CFL2 gene that encodes Cofilin 2, a member of a group of proteins that regulate actin-filament dynamics. Nemaline bodies can be absent at the early stage of the disease, and sometimes, a second biopsy is required (18).…”