Somatic mosaicism in TPM2-related myopathy with nemaline rods and cap structures

Abstract

The TPM2 gene encodes for beta-tropomyosin. Dominant mutations in TPM2 are associated with different congenital myopathies, including nemaline and cap myopathy [8]. In one family, a TPM2 mutation (p.Glu41Lys) has been reported to cause a myopathy with nemaline rods in the mother and cap structures in the daughter [7]. We describe a family with two siblings affected by congenital myopathy showing both rods and cap-like structures caused by a TPM2 mutation. Their clinically asymptomatic father was a somatic mosaic for the mutation. The proband, a 15-year-old girl, presented with slowly progressing muscle weakness in the first decade. At age 13, she developed rapidly progressing scoliosis and respiratory failure, leading to hypercapnic coma, with subsequent tracheostomy. On examination, she had moderate diffuse weakness more pronounced in ankle extensors, long narrow face, scoliosis and rigid spine. CK level and cardiological examinations were normal. Her 14-year-old brother displayed a similar, although milder, phenotype. He had elongated face, high arched palate, rigid spine and mild scoliosis. Ankle extensors, neck flexors, supra and infraspinatus muscles were weak. Forced vital capacity was 60 % of predicted value. Their parents were reported to be healthy. Muscle MRI features are shown in Fig. 1. Given the clinical and radiological phenotype and the possibly recessive pattern of inheritance, SEPN1 mutations were ruled out. Muscle biopsy disclosed in both patients the presence of nemaline rods, cap structures (Fig. 1d–i) and type 1 fiber predominance. These findings prompted us to examine the TPM2 gene, and a heterozygous deletion, c.412_414delGAG (p.E138del) in exon 4, was found (Fig. 1k). When their parents were examined, the 47-year-old father, who did not complain of any neuromuscular symptom and routinely practiced mountaineering, did not show any obvious weakness or contractures but had mild scoliosis and high arched palate. EMG displayed some polyphasic, short amplitude motor unit potentials. Muscle MRI showed features consistent with those of the siblings (Fig. 1c). Muscle biopsy showed mild myopathic features, with cap structures in rare fibers (Fig. 1j) and no nemaline rods. The electropherogram of the TPM2 gene revealed a relatively low level of the mutation in blood DNA suggesting a somatic mosaicism. SNaPshot analysis [1] confirmed the presence of mosaicism (Fig. 1k). The p.E138del pathogenic deletion found in the family has been previously reported only in pure cap disease [3, 5]. Our findings further substantiate the concept that nemaline rods and cap structures belong to the same spectrum of pathological alterations [4] and, although both nemaline myopathy and cap disease are genetically heterogeneous entities, the coexistence of both features should suggest investigating TPM2 first [7]. In the family, the proband’s father had the mildest phenotype so far reported in association with TPM2 G. Tasca G. Silvestri Don Carlo Gnocchi Onlus Foundation, Milan, Italy