P.221 Improvement in respiratory and bulbar function in two patients with SMALED2B

Abstract

Pathogenic variants in <i>BICD2</i> are implicated in lower extremity predominant spinal muscular atrophy type 2B (SMALED2B). Here we report two patients with SMALED2B due to <i>de novo</i> pathogenic variants in <i>BICD2</i>. The first patient had poor fetal movement. She was born full term and noted to have arthrogryposis, low birth weight, dysmorphic features, bilateral femur fractures and hip dislocations, congenital vertical talus and scoliosis. Electrodiagnostic studies showed chronic axonal motor neuropathy. A muscle biopsy of the gastrocnemius showed extensive fibrofatty replacement. Electron microscopy of the sural nerve showed axonal degeneration and regeneration. Brain MRI showed mild cerebellar atrophy, enlargement of the frontal horns, and reduced size of the optic nerves and chiasm. Additional features included intellectual disability, kyphosis, tremors, choreiform movements and exotropia. Whole exome sequencing (WES) revealed a c.2080C>T variant in <i>BICD2</i>. The second patient had arthrogryposis and polyhydramnios identified prenatally. He was born at 33 weeks and noted to have micrognathia, a large anterior fontanelle and bilateral femur fractures. Electrodiagnostic studies showed low compound muscle action potential amplitudes, likely due to diffuse muscle hypoplasia. MRI of musculature and brain showed near complete absence of skeletal muscles in the extremities and bifrontal white matter volume loss. Additional features included intellectual disability, facial weakness, ptosis, bilateral undescended testes, conductive hearing loss and scoliosis. WES identified a c.1636_1638del variant in <i>BICD2</i>. Both patients had gastrostomy and tracheostomy placement shortly after birth. Patient 1 is now 20 years old. She now only requires nocturnal BiPAP and feeds orally with supplementation via gastrojejunostomy tube. Patient 2 is 7 years old and has not required assisted ventilation since he was 5, but is still fed via gastrostomy. Despite severe <i>in utero</i> presentations, these patients demonstrate that the long-term clinical course for patients with SMALED2B may be more favorable than previously reported.