{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T17:07:49Z","timestamp":1778605669313,"version":"3.51.4"},"reference-count":23,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spinal muscular atrophy 5q (5q SMA) is one of the most prevalent autosomal recessive disorders globally. The underlying cause of 5q SMA is attributed to variants in SMN1. To date, there are no reported cases of gene-based therapy in rare patients with 5q SMA caused by subtle SMN1 variants of unknown clinical significance. We included 10 patients with the clinical manifestations of 5q SMA associated with intragenic variants in combination with a heterozygous SMN1 deletion in this retrospective study. Previously reported pathogenic or likely pathogenic variants were identified (e.g., c.*3+1del, c.815A&gt;G (p.Tyr272Cys), and c.821C&gt;T (p.Thr274Ile)). Variants of unknown clinical significance were also found, including a recurrent, previously unreported variant c.80A&gt;C (p.Gln27Pro). We also report detailed molecular genetic and clinical data on 9 patients with 5q SMA. In addition, we provide results from the cohort of patients with gene-based therapy, consistent with data from patients with a homozygous SMN1 deletion.<\/jats:p>","DOI":"10.3390\/ijms27104301","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:04:36Z","timestamp":1778601876000},"page":"4301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rare SMA Patients: A Comprehensive Look at Clinical Features, Genetic Profiles and Therapeutic Approaches"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0394-7801","authenticated-orcid":false,"given":"Kristina","family":"Mikhalchuk","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8876-7462","authenticated-orcid":false,"given":"Svetlana","family":"Artemieva","sequence":"additional","affiliation":[{"name":"Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, Taldomskaya Str. 2, Moscow 125412, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viktoria","family":"Zabnenkova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7244-9654","authenticated-orcid":false,"given":"Maria","family":"Akhkiamova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Dadali","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galina","family":"Rudenskaya","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9160-0794","authenticated-orcid":false,"given":"Peter","family":"Sparber","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Rybakova","sequence":"additional","affiliation":[{"name":"Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, Taldomskaya Str. 2, Moscow 125412, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulia","family":"Papina","sequence":"additional","affiliation":[{"name":"Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, Taldomskaya Str. 2, Moscow 125412, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasiya","family":"Monakhova","sequence":"additional","affiliation":[{"name":"Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, Taldomskaya Str. 2, Moscow 125412, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Shulyakova","sequence":"additional","affiliation":[{"name":"Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, Taldomskaya Str. 2, Moscow 125412, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitriy","family":"Saiko","sequence":"additional","affiliation":[{"name":"Republican Clinical Hospital named after M.I. Kalinin, Ilyich Av. 14, Donetsk 283003, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Zhiteneva","sequence":"additional","affiliation":[{"name":"State Budgetary Healthcare Institution of the Moscow Region \u201cLukhovitskaya Hospital\u201d, Lukhovitsy, Mira Str. 39\/5, Moscow 140500, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Polyakov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4905-1303","authenticated-orcid":false,"given":"Olga","family":"Shchagina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moskvorechye St. 1, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/344540a0","article-title":"Genetic Mapping of Chronic Childhood-Onset Spinal Muscular Atrophy to Chromosome 5q11.2\u201313.3","volume":"344","author":"Brzustowicz","year":"1990","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mikhalchuk, K., Shchagina, O., Chukhrova, A., Zabnenkova, V., Chausova, P., Ryadninskaya, N., Vlodavets, D., Kutsev, S.I., and Polyakov, A. (2023). Pilot Program of Newborn Screening for 5q Spinal Muscular Atrophy in the Russian Federation. Int. J. Neonatal Screen., 9.","DOI":"10.3390\/ijns9020029"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kiselev, A., Maretina, M., Shtykalova, S., Al-Hilal, H., Maslyanyuk, N., Plokhih, M., Serebryakova, E., Frolova, M., Shved, N., and Krylova, N. (2024). Establishment of a Pilot Newborn Screening Program for Spinal Muscular Atrophy in Saint Petersburg. Int. J. Neonatal Screen., 10.","DOI":"10.3390\/ijns10010009"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mikhalchuk, K., Polyakov, A., Zabnenkova, V.V., Ismagilova, O., and Shchagina, O. (2025). Exploring the Prevalence of SMN1 Duplication and Deletion in Russia and Its Impact on Carrier Screening. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26051984"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/gim.2013.84","article-title":"An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy","volume":"16","author":"Luo","year":"2014","journal-title":"Genet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gug, M., Andreescu, N., Caba, L., Popoiu, T.-A., Mozos, I., and Gug, C. (2025). The Landscape of Genetic Variation and Disease Risk in Romania: A Single-Center Study of Autosomal Recessive Carrier Frequencies and Molecular Variants. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262210912"},{"key":"ref_7","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). Spinal Muscular Atrophy. GeneReviews\u00ae, University of Washington, Seattle."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/humu.20092","article-title":"Molecular Analysis of SMA Patients without Homozygous SMN1 Deletions Using a New Strategy for Identification of SMN1 Subtle Mutations","volume":"24","author":"Clermont","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/cge.14714","article-title":"Rare Cause 5q SMA: Molecular Genetic and Clinical Analyses of Intragenic Subtle Variants in the SMN Locus","volume":"108","author":"Mikhalchuk","year":"2025","journal-title":"Clin. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00439-008-0598-1","article-title":"Mutation Update of Spinal Muscular Atrophy in Spain: Molecular Characterization of 745 Unrelated Patients and Identification of Four Novel Mutations in the SMN1 Gene","volume":"125","author":"Bernal","year":"2009","journal-title":"Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.nmd.2007.03.003","article-title":"Analysis of Point Mutations in the SMN1 Gene in SMA Patients Bearing a Single SMN1 Copy","volume":"17","author":"Kalina","year":"2007","journal-title":"Neuromuscul. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Day, J.W., Howell, K., Place, A., Long, K., Rossello, J., Kertesz, N., and Nomikos, G. (2022). Advances and Limitations for the Treatment of Spinal Muscular Atrophy. BMC Pediatr., 22.","DOI":"10.1186\/s12887-022-03671-x"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/s12031-014-0483-4","article-title":"Novel Splice-Site Mutation in SMN1 Associated with a Very Severe SMA-I Phenotype","volume":"56","author":"Ronchi","year":"2015","journal-title":"J. Mol. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and Characterization of a Spinal Muscular Atrophy-Determining Gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1093\/hmg\/6.5.821","article-title":"Missense Mutations in Exon 6 of the Survival Motor Neuron Gene in Patients with Spinal Muscular Atrophy (SMA)","volume":"6","author":"Hahnen","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.cell.2011.06.043","article-title":"Structure of a Key Intermediate of the SMN Complex Reveals Gemin2\u2019s Crucial Function in snRNP Assembly","volume":"146","author":"Zhang","year":"2011","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1042\/BJ20120241","article-title":"Solution Structure of the Core SMN-Gemin2 Complex","volume":"445","author":"Sarachan","year":"2012","journal-title":"Biochem. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11122","DOI":"10.1074\/jbc.M609297200","article-title":"Gemin2 Plays an Important Role in Stabilizing the Survival of Motor Neuron Complex","volume":"282","author":"Ogawa","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1212\/WNL.0000000000006502","article-title":"Evidence in Focus: Nusinersen Use in Spinal Muscular Atrophy [RETIRED]: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology","volume":"91","author":"Michelson","year":"2018","journal-title":"Neurology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1056\/NEJMoa1710504","article-title":"Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy","volume":"378","author":"Mercuri","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1134\/S1022795415080128","article-title":"SMN1 Gene Point Mutations in Type I\u2013IV Proximal Spinal Muscular Atrophy Patients with a Single Copy of SMN1","volume":"51","author":"Zabnenkova","year":"2015","journal-title":"Russ. J. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:10:38Z","timestamp":1778602238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":23,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104301"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104301","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]}}}