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.

Keywords: Animal models; Congenital myopathy; Nemaline myopathy; Rod bodies; Rods; Z disc; Z line.

Fig. 1

Muscle biopsies from patients with a a mutation in ACTA1 (Gӧmӧri trichrome), b heterozygous mutations in NEB (Gӧmӧri trichrome), c heterozygous mutations in TNNT1 (haematoxylin and eosin), d, e heterozygous mutations in NEB (slow and fast myosin respectively), f control with no molecular defects causing a neuromuscular disorder (antibody to exon 143 of NEB). Note the variable number and distribution of nemaline rods in a and b, the pronounced connective tissue in c, the uneven distribution of fibre types in d and e with several fibres co-expressing both isoforms (*) and the three intensities of labelling of exon 143 of nebulin in f (most of the darker fibres express fast myosin)

Fig. 2

Electron micrographs of muscle biopsies from patients with nemaline myopathy caused by a a mutation in ACTA1, b homozygous mutation in CFL2, c heterozygous mutations in KLHL40 and dLMOD3. Note in a the variable size of the nemaline rods and irregularities of the Z line, in b the very small rods and accumulation of thin actin filaments (*) and in c and d the similar rectangular shape of the rods and the fringe-like filaments attached to many of them