Severe phenotype of a patient with autosomal recessive centronuclear myopathy due to a BIN1 mutation

Abstract

Centronuclear myopathy (CNM) is a rare hereditary congenital myopathy characterized by muscular hypotonia and abnormal centralization of nuclei in muscle fibers. The autosomal recessive (AR) form presents from birth to childhood, followed by a mild progression of muscle weakness. Despite recently identified genetic loci in the AR form, genotype-phenotype correlations are poorly established. Our index case is a 17 year old boy with recessive CNM causing loss of ambulation at 13 years of age and requiring ventilatory assistance nightly. Recent genetic testing revealed a c.1723A > T mutation in the BIN1 gene. The phenotype of the index case contrasts to previously published cases, where recessive CNM patients have lost ambulation in their 20s and have not required ventilatory assistance. The disease severity of our index case, carrying a c.1723A > T mutation, widens the phenotypic spectrum of AR CNM to include earlier loss of ambulation and respiratory failure.

Figure 1

Pedigree of the family in this case study. Double line between parents indicates consanguinity. Half filled symbols indicate heterozygous carriers; filled symbol the index case.

Figure 2

Muscle biopsy findings at 6 (A-C) and 15 (D-G) years of age. In the initial biopsy (age 6 years) the fibres show a great variation in size. In some areas the fibres are rounded with a large central nucleus (A), while in other areas large fibres show severely abnormal morphology (B-C). In a few fibres a vacuole is present. The amount of connective tissue is increased. In the subsequent biopsy (age 15 years) the amount of adipose tissue is prominent in some areas (D). There is also an increased amount of connective tissue. Most fibres are rounded with centrally located nuclei (E). Many fibres contain a vacuole surrounded by increased activity of NADH (F). The walls of the vacuoles stain with antibodies against dystrophin, sometimes in continuity with the sarcolemma (G). A, B, D, E: H&E; C, F: NADH; G: Dystrophin (Dys 3, Novocastra, Newcastle-upon-Tyne, UK). Bars: D: 0,5mm; A-C, E-F: 0,1mm.