Two Japanese Patients With SMA Type 1 Suggest that Axonal-SMN May Not Modify the Disease Severity

Abstract Background Spinal muscular atrophy is caused by survival motor neuron gene SMN1 mutations. SMN1 produces a full-length SMN1 protein isoform encoded by exons 1–7, and an axonal-SMN protein isoform encoded by exons 1–3 and intron 3. The axonal-SMN protein is expressed only in the embryonic period and plays a significant role in axonal growth. However, there has been no report on contribution of axonal-SMN to spinal muscular atrophy severity until now. Patients Two Japanese boys with spinal muscular atrophy type 1 in our study presented with generalized muscle weakness and respiratory insufficiency soon after birth and required an artificial ventilator from early infancy. Patient 1 was compound heterozygous for two SMN1 mutations, whole-gene deletion, and an intragenic mutation (c.819_820insT). He retained one copy of SMN1 producing the N-terminal part of SMN1 including axonal-SMN. On the other hand, patient 2 was homozygous for SMN1 deletion. Both of them showed the same copy number of spinal muscular atrophy–modifying genes, NAIP and SMN2 . These findings suggested that the C-terminal domain of full-length SMN1 determined the severity, irrespective of presence or absence of axonal-SMN expression. Conclusion In patient 1, the C-terminal domain of full-length SMN1 determined spinal muscular atrophy severity, rather than the axonal-SMN, one copy of which could be present and intact. The presence or absence of axonal-SMN may not impact disease severity in spinal muscular atrophy type 1 patients.