Muscular Dystrophy, Congenital, Davignon-Chauveau Type

A number sign (#) is used with this entry because of evidence that the Davignon-Chauveau type of congenital muscular dystrophy (MDCDC) is caused by homozygous mutation in the TRIP4 gene (604501) on chromosome 15q22. One such family has been reported.

Clinical Features

Davignon et al. (2016) reported a large consanguineous family from eastern France in which 4 individuals had a severe form of congenital muscular dystrophy. One patient died of respiratory failure at age 16 months. The other patients, aged 25, 24, and 10 years, were wheelchair-bound and required full assistance for all daily life activities. The patients presented at birth with neonatal hypotonia, head lag, poor antigravity limb movements, severe respiratory insufficiency necessitating tracheostomy in 2, and feeding difficulties. None had congenital contractures. Motor development was severely delayed, and only 1 patient was able to achieve independent ambulation between ages 4 and 11 years. All had severe muscle weakness leading to poor head control, rigid cervical spine, and severe scoliosis. Other features included generalized joint laxity and dry skin with follicular hyperkeratosis. Two patients had learning difficulties. Serum creatine kinase was normal or slightly elevated, and EMG showed a myopathic pattern with normal nerve conduction velocities. Muscle biopsies showed fiber size variability, rounded fibers, adipose replacement, minicore lesions, centralized nuclei, angular fibers, and cap lesions, reminiscent of a myopathy. Electron microscopy showed subsarcolemmal accumulations of disorganized sarcomere components lacking thick filaments.

Inheritance

The transmission pattern of congenital muscular dystrophy in the family reported by Davignon et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from a consanguineous French family with congenital muscular dystrophy, Davignon et al. (2016) identified a homozygous truncating mutation in the TRIP4 gene (W297X; 604501.0003). The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in the family. Patient cells showed no detectable TRIP4 protein and significantly decreased mRNA, suggesting that the mutation results in nonsense-mediated mRNA decay. Cultured patient-derived muscle cells showed normal proliferation and fusion in early differentiation, but had abnormally thick branching myotubes. Knockdown of the Trip4 gene using siRNA in a murine myoblastic cell line (C2C12) affected late myogenic differentiation and/or myotube growth, manifest as reduced levels of the contractile protein myosin heavy chain, similar to patient cells. Early myogenic differentiation was not affected. The findings indicated that the TRIP4 gene plays a role in late myogenic differentiation and that defects in myotube growth likely contributed to the disorder.