Phenotypes of SMA patients retaining SMN1 with intragenic mutation

• Main Authors: Wijaya, Y.O.S., Ar Rohmah, M., Niba, E.T.E., Morisada, N., Noguchi, Y., Hidaka, Y., Ozasa, S., Inoue, T., Shimazu, T., Takahashi, Y., Tozawa, T., Chiyonobu, T., Shiroshita, T., Yokoyama, A., Okamoto, K., Awano, H., Takeshima, Y., Saito, T., Saito, K., Nishio, H., Shinohara, M.
• Format: Article PeerReviewed
• Published: 2021
• Subjects: Neurosciences
• Online Access: https://repository.ugm.ac.id/279108/; https://www.scopus.com/inward/record.uri?eid=2-s2.0-85104783455&doi=10.1016%2fj.braindev.2021.03.006&partnerID=40&md5=3614e7990714fd782ab010078c61646b
• Institution: Universitas Gadjah Mada

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with intragenic SMN1 mutation, the relationship between phenotype and SMN2 copy number remains unclear. Methods: We have analyzed a total of 515 Japanese patients with SMA-like symptoms (delayed developmental milestones, respiratory failures, muscle weakness etc.) from 1996 to 2019. SMN1 and SMN2 copy numbers were determined by quantitative polymerase chain reaction (PCR) method and/or multiplex ligation-dependent probe amplification (MLPA) method. Intragenic SMN1 mutations were identified through DNA and RNA analysis of the fresh blood samples. Results: A total of 241 patients were diagnosed as having SMA. The majority of SMA patients showed complete loss of SMN1 (n = 228, 95), but some patients retained SMN1 and carried an intragenic mutation in the retaining SMN1 (n = 13, 5). Ten different mutations were identified in these 13 patients, consisting of missense, nonsense, frameshift and splicing defect-causing mutations. The ten mutations were c.275G > C (p.Trp92Ser), c.819820insT (p.Thr274Tyrfs*32), c.830A > G (p.Tyr277Cys), c.5C > T (p.Ala2Val), c.826 T > C (p.Tyr276His), c.79C > T (p.Gln27*), c.188C > A (p.Ser63*), c.422 T > C (p.Leu141Pro), c.835-2A > G (exon 7 skipping) and c.835-3C > A (exon 7 skipping). It should be noted here that some patients with milder phenotype carried only a single SMN2 copy (n = 3), while other patients with severe phenotype carried 3 SMN2 copies (n = 4). Conclusion: Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers. © 2021 The Japanese Society of Child Neurology