Spinal Muscular Atrophy With Congenital Bone Fractures 2

A number sign (#) is used with this entry because of evidence that spinal muscular atrophy with congenital bone fractures-2 (SMABF2) is caused by homozygous mutation in the ASCC1 gene (614215) on chromosome 10q22. One such family has been reported.

For a discussion of genetic heterogeneity of SMABF, see SMABF1 (616866).

Clinical Features

Knierim et al. (2016) reported 2 sisters, born of consanguineous Turkish parents (family D), who were born with distal and proximal joint contractures consistent with arthrogryposis multiplex congenita (AMC), multiple prenatal fractures of the long bones, and generalized severe muscle atrophy. Reduced fetal movements were apparent during pregnancy, and both pregnancies were complicated by polyhydramnios. Deep tendon reflexes were absent, muscles did not contract upon electrical stimulation, and neurography was consistent with axonal neuropathy. The patients had neonatal respiratory distress with pulmonary hypoplasia, and fed poorly. Both patients also had patent foramen ovale and patent ductus arteriosus. The patients had global developmental delay, and brain imaging showed abnormal cortical gyration. Skeletal muscle biopsy showed muscle fiber immaturity, fiber size variation, and atrophic fibers, suggestive of spinal muscular atrophy. Sural nerve biopsy of 2 patients showed signs of unmyelinated axon loss. The children died from respiratory failure between 2 weeks and 16 months of age.

Inheritance

The transmission pattern of SMABF2 in the family reported by Knierim et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sisters, born of consanguineous Turkish parents, with SMABF2, Knierim et al. (2016) identified a homozygous truncating mutation in the ASCC1 gene (614215.0002). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed complete absence of the ASCC1 protein. Messenger RNA carrying the mutation was unable to rescue the motor defects in morpholino-knockout zebrafish embryos.

Animal Model

Knierim et al. (2016) found that morpholino knockdown of the ascc1 gene in zebrafish embryos resulted in a severe impairment of axonal outgrowth of alpha-motoneurons, as well as impaired formation of the neuromuscular junction and organization of the myotome. Mutant zebrafish showed compromised motor responses.