Positive response to nusinersen in a patient with motor neuron disease and 1 copy of SMN1 (5066)

Objective: To describe a positive response to nusinersen in patient with motor neuron disease and 1 copy of SMN1. Background: Most spinal muscular atrophy (SMA) cases are caused by biallelic deletions of exon 7. Remaining cases involve an exon 7 deletion and a pathogenic sequence variant. The number of SMN2 copies modifies the phenotype. Nusinersen, an antisense oligonucleotide, induces alternating splicing of SMN2, causing increased production of SMN protein. Design/Methods: The patient is a 5-year-old who presented at 3 months of age with hypotonia. Later he developed feeding difficulties and respiratory distress requiring G-tube and tracheostomy. Motor development was limited to head control and sitting without support. His exam had proximal weakness and absent reflexes. SMA testing revealed 1 copy of SMN1 and 1 copy of SMN2. No sequence variants in SMN1 were identified. Trio whole exome sequencing was unrevealing. Muscle biopsy demonstrated fiber type grouping and group atrophy consistent with motor neuron disease. As the patient best resembled type 2 SMA, nusinersen was trialed. Results: The patient underwent baseline CHOP INTEND, a validated scale for motor functioning in SMA patients, at 3 years of age with a score of 40/60. Nusinersen was initiated approximately nine months later. Five months after the start of nusinersen, the patient’s CHOP INTEND score was 20/60. Approximately six months later it had improved to 35/40. His mother noted improvement in extremity strength which was confirmed on clinical exam. Conclusions: A single exon 7 deletion and absence of SMN1 sequence variants is typically associated with carrier status for SMA. However, promotor and deep intronic variants are not detected by conventional testing nor exome sequencing and could cause SMA when paired with an exon 7 deletion or SMN1 sequence variant. In such cases where exome sequencing fails to demonstrate an alternative diagnosis, SMA-specific therapies such as nusinersen should be considered. Disclosure: Dr. Calame has nothing to disclose. Dr. Abid has nothing to disclose.