Long term history of a congenital core-rod myopathy with compound heterozygous mutations in the Nebulin gene

Abstract

Mutations in the Nebulin gene (NEB) may cause core-rod myopathy. The large size of the gene so far prevented inclusion of its routine analysis by didesoxy resequencing methodology in the diagnostic regime for muscular dystrophy cases. Here we report a 54-year-old female with a rare histological myopathy presentation of co-occurring cores and rods. The patient reported early childhood onset weakness. Muscle-MRI showed mainly proximal muscle involvement. We identified two compound heterozygous non-sense mutations in NEB (c.19653G > A, p.W6551^* exon 127 and c.25441C > T, p.R8481^* exon 182) using a comprehensive next generation sequencing (NGS)-based approach named Mendeliome Sequencing. The p.W6551^* mutation has not been reported elsewhere. Early diagnosis by NGS shall be chased since even a scoliosis surgery at the age of 18 years had failed to initiate a neurological workup. Rather, cosmetic surgery for facial weakness had been performed recently, albeit with an unsatisfactory outcome.

Keywords: Mendeliome; Nebulin; core-rod myopathy; cosmetic surgery; muscle magnetic resonance imaging.

Figure 1.

Pedigree of the patient (II:1) shows two heterozygous frameshift mutations in the nebulin (NEB) gene c.19653 G > A in exon 127 causing p.W6551* and c.25441 C > T in exon 182 causing p.R8481*. The bioinformatics analysis showed that the aberrant amino acid changes are located on the super repeats (S15-S21) and serine-rich domains of the protein. The variants were confirmed by Sanger sequencing, which revealed that the mother (I:1) and the daughter (III:2) have a recessive allele in exon127 (p.W6551*). Furthermore, the son (III:1) has a recessive allele in exon 182 (p.R8481*). The mother and the children were clinically unaffected (A). Muscle magnetic resonance imaging of the lower limbs showing predominant proximal involvement, within the thigh the ischiocrural and medial muscles shows fatty atrophic changes (B).

Figure 2.

Muscle biopsy showed variation in fiber size and increased internalization of nuclei on H&E staining (A). Modified Gomori trichrome staining revealed fuchsinophilic rods in most of the fibers (B). NADH staining showed numerous cores with absent enzyme activity in several fibers (C), while mATPase staining was inconspicuous (D).

Figure 3.

The presence of rods and cores were confirmed by electron microscopy, up to 5 µm long rods could be identified preferentially around nuclei. Numerous muscle fibers harbored core-like disintegration of myofibrils associated with breakup of Z bands (A-C). Many muscle fiber mitochondria were enlarged and contained paracrystalline inclusions, several muscle fiber nuclei showed prominent lobulation (D).