A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-5 (LCCS5) is caused by homozygous mutation in the DNM2 gene (602378) on chromosome 19p13. One such family has been reported.

Heterozygous mutation in the DNM2 gene can also cause a form of autosomal dominant Charcot-Marie-Tooth disease (606482) and autosomal dominant centronuclear myopathy (CNM1; 160150).

For a general phenotypic description and a discussion of genetic heterogeneity of LCCS, see LCCS1 (253310).

Koutsopoulos et al. (2013) reported 3 sibs, born of consanguineous Pakistani parents, with a lethal congenital neuromuscular syndrome. All exhibited decreased fetal movements, polyhydramnios, and decreased birth weight. At birth, all showed severe hypotonia with respiratory insufficiency, lack of reflexes, joint contractures, and thin ribs and bones. In addition, all had retinal hemorrhages and 2 had evidence of intracranial bleeding (subdural hematoma and blood in the subarachnoid cavity). Muscle biopsy of 1 patient showed small rounded fibers with some centralized nuclei, suggestive of a congenital myopathy component, whereas muscle biopsy of another patient showed atrophic fibers without obvious centralization of nuclei. EMG studies of 1 patient suggested a myopathy or lower motor neuron disease, whereas in the other 2 patients, EMG revealed low nerve conduction velocities, suggesting a hypomyelinating neuropathy or anterior horn disease. Death occurred at ages 5 days, 19 days, and 4 months. Both parents showed decreased reflexes on examination, and skeletal muscle biopsy of the mother showed fiber size variation and centralized nuclei, suggestive of a mild form of centronuclear myopathy.

The transmission pattern of a lethal congenital contracture syndrome in the family reported by Koutsopoulos et al. (2013) was consistent with autosomal recessive inheritance.

In 3 sibs, born of consanguineous Pakistani parents, with a lethal congenital contracture syndrome, Koutsopoulos et al. (2013) identified a homozygous missense mutation in the DNM2 gene (F379V; 602378.0013). The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder and was not present in controls. Studies on patient cells and in vitro functional analysis indicated that the mutation was hypomorphic. Animal studies in mice and zebrafish suggested a role for Dnm2 in the development of muscle fibers and vasculature.

Koutsopoulos et al. (2013) found that morpholino knockdown of Dnm2 in zebrafish embryos resulted in lethality in 10% and bent tails in 20%. Morphants showed mild misalignment of muscle fibers; muscular innervation appeared normal. There were also defects in the endothelium of the vascular system. The findings suggested that Dnm2 has a pleiotropic role during development.