Nemaline myopathies: a current view

Abstract

Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adult onset have an autoimmune-related myopathy with a progressive course. The wide application of massively parallel sequencing methods is increasing the number of known causative genes and broadening the range of clinical phenotypes. Nemaline myopathies are identified by the presence of structures that are rod-like or ovoid in shape with electron microscopy, and with light microscopy stain red with the modified Gömöri trichrome technique. These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. Additional pathological features such as caps, cores and fibre type disproportion are associated with the same genes as those known to cause the presence of rods. Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living.

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

“…Patient muscle biopsies show accumulation of Z-disc and thin filament associated proteins into aggregates called nemaline bodies, usually accompanied by disorganization of the muscle Z discs [14,80,83]. There can be large variation in clinical severity, from in utero presentation and early neonatal death, through to milder forms with later onset [77,86].…”

Cofilin loss inDrosophilacontributes to myopathy through defective sarcomerogenesis and aggregate formation during muscle growth

“…These phenotypes can be rescued with the human CFL genes, indicating a strong conservation between the Drosophila and human proteins. While the protein aggregates in our DmCFL-knockdown muscle fibers do not completely mimic the electron dense nemaline bodies seen in NM patients, they do have similar protein compositions (F-actin, Zasp, and a-actinin) and subsarcolemmal localization (Sewry et al, 2019).…”

“…Nemaline bodies, the diagnostic feature of NM, are protein aggregates containing Z-disc proteins such as α-Actinin, along with other sarcomeric proteins including actin, tropomyosin, and nebulin (Agrawal et al, 2007;Ilkovski et al, 2001;Sewry et al, 2019). Nemaline bodies either diffusely distribute in the cytoplasm, cluster under the cell membrane, localize near nuclei, or in lines within muscle fibers (Sewry et al, 2019). To determine if the aberrant aggregates observed in our DmCFL-knockdown muscles were nemaline bodies, we examined and found co-localization of the F-actin aggregates and α-Actinin in our Drosophila model ( Figure 2D).…”

“…Mutations in CFL2 have been identified in three isolated cases of NM (Agrawal et al, 2007;Ockeloen et al, 2012;Ong et al, 2014). NM is a slowly progressing myopathy characterized by muscle weakness and the presence of nemaline bodies containing both actin and a-actinin (Sewry et al, 2019). Mouse models of Cfl2 recapitulate aspects of the disease such as the degeneration of muscle fibers, presence of actin and a-actinin positive nemaline bodies, sarcomeric disruptions, actin accumulations and muscle weakness Gurniak et al, 2014b).…”

Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function

“…Nemaline myopathy is a rare congenital disease that disrupts the skeletal muscle sarcomeres and results in muscle weakness. This disease was originally identified by, and named for, the thread-like protein aggregates found in muscle biopsies [1,2]. Patients diagnosed with nemaline myopathy exhibit a wide range of disease severities from manageable symptoms to severe disruptions to quality of life; while most patients exhibit a mild phenotype, in severe nemaline myopathy, muscle weakness can lead to respiratory failure and death.…”