{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T07:42:21Z","timestamp":1777794141056,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320, ORPHA:98920) is a rare autosomal recessive congenital motor neuron disease. It is caused by variants in the IGHMBP2 gene. Clinically, it presents with respiratory failure due to diaphragmatic paralysis, progressive muscle weakness starting in the distal parts of the limbs, dysphagia, and damage to sensory and autonomic nerves. Unlike spinal muscular atrophy (SMA), SMARD1 has a distinct genetic etiology and is not detected in the population newborn screening programs. Most children with SMARD1 do not survive beyond the first year of life due to progressive respiratory failure. Artificial ventilation can prolong survival, but no specific treatment is available. Therapy focuses on mechanical ventilation and improving the patient\u2019s quality of life. Research into gene therapy is ongoing. We report three female patients with SMARD1, including twins from a triplet pregnancy. In twin sisters (patient no. 1 and patient no. 2), two heterozygous variants in the IGHMBP2 gene were identified: c.595G&gt;C\/p.Ala199Pro and c.1615_1623del\/p.Ser539_Tyr541del. In patient no. 3, a variant c.1478C&gt;T\/p.Thr493Ile and a variant c.439C&gt;T\/p.Arg147* in the IGHMBP2 gene were detected. Our findings underscore the variability of clinical presentations, even among patients sharing the same pathogenic variants in the IGHMBP2 gene, and emphasize the importance of early genetic diagnosis in patients presenting with respiratory failure, with or without associated diaphragmatic muscle paralysis.<\/jats:p>","DOI":"10.3390\/genes15080997","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T15:26:53Z","timestamp":1722526013000},"page":"997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Clinical Heterogeneity of Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1)\u2014A Report of Three Cases, Including Twins"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0760-5120","authenticated-orcid":false,"given":"Alicja","family":"Le\u015bniak","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2859-7200","authenticated-orcid":false,"given":"Marta","family":"Gli\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5981-6456","authenticated-orcid":false,"given":"Micha\u0142","family":"Patalan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iwona","family":"Ostrowska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"\u015awirska-Sobolewska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaja","family":"Gi\u017cewska-Kacprzak","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Oncological Surgery, Urology and Hand Surgery, Pomeranian Medical University in Szczecin, Prof. Tadeusz Soko\u0142owski University Clinical Hospital No. 1, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agata","family":"Kotkowiak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Le\u015bniak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mieczys\u0142aw","family":"Walczak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-9549","authenticated-orcid":false,"given":"Robert","family":"\u015amigiel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Gi\u017cewska","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e148","DOI":"10.1542\/peds.2011-0544","article-title":"The Natural Course of Infantile Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1)","volume":"129","author":"Guenther","year":"2012","journal-title":"Pediatrics"},{"key":"ref_2","unstructured":"(2024, April 16). Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 1. Available online: https:\/\/www.omim.org\/entry\/604320."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1542\/peds.53.1.33","article-title":"Respiratory distress as the initial manifestation of Werdnig-Hoffmann disease","volume":"53","author":"Mellins","year":"1974","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/ajmg.1320330309","article-title":"Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: A variant of infantile spinal muscular atrophy","volume":"33","author":"Bertini","year":"1989","journal-title":"Am. J. Med. Genet."},{"key":"ref_5","unstructured":"(2024, April 16). Spinal Muscular Atrophy, Type I. Available online: https:\/\/www.omim.org\/entry\/253300."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1086\/302636","article-title":"Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form is linked to chromosome 11q13-q21 [2]","volume":"65","author":"Grohmann","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/ng703","article-title":"Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1","volume":"29","author":"Grohmann","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_8","unstructured":"(2024, April 16). Charcot-Marie-Tooth Disease, Axonal, Type 2s. Available online: https:\/\/www.omim.org\/entry\/616155."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.ajhg.2014.10.002","article-title":"Truncating and Missense Mutations in IGHMBP2 Cause Charcot-Marie Tooth Disease Type 2","volume":"95","author":"Cottenie","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"113802","DOI":"10.1016\/j.celrep.2024.113802","article-title":"RNA helicase IGHMBP2 regulates THO complex to ensure cellular mRNA homeostasis","volume":"43","author":"Prusty","year":"2024","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e164608","DOI":"10.1172\/jci.insight.164608","article-title":"ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity","volume":"8","author":"Vadla","year":"2023","journal-title":"JCI Insight"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1093\/hmg\/ddab317","article-title":"The Ighmbp2 D564N mouse model is the first SMARD1","volume":"31","author":"Smith","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.nmd.2018.10.002","article-title":"Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study","volume":"29","author":"Viguier","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_14","unstructured":"(2024, April 16). Knowledge on Rare Diseases and Orphan Drugs. Available online: https:\/\/www.orpha.net\/en\/disease\/detail\/98920."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jns.2014.09.010","article-title":"The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: A systematic review","volume":"346","author":"Porro","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"364","DOI":"10.24953\/turkjped.2020.2012","article-title":"Spinal muscular atrophy with respiratory distress type 1 (SMARD1): A rare cause of hypotonia, diaphragmatic weakness, and respiratory failure in infants","volume":"1","author":"Pekuz","year":"2022","journal-title":"Turk. J. Pediatr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1111\/jcmm.14874","article-title":"Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights","volume":"24","author":"Saladini","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1177\/0883073807310989","article-title":"Spinal muscular atrophy with respiratory distress type 1 (SMARD1)","volume":"23","author":"Kaindl","year":"2008","journal-title":"J. Child Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1055\/s-2007-973741","article-title":"Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: Further delineation on the basis of SMN gene deletion findings","volume":"27","author":"Forkert","year":"1996","journal-title":"Neuropediatrics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1007\/s00018-020-03492-0","article-title":"Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1)","volume":"77","author":"Perego","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_21","first-page":"183","article-title":"Severe Phenotypes of SMARD1 Associated with Novel Mutations of the IGHMBP2 Gene and Nuclear Degeneration of Muscle and Schwann Cells","volume":"18","author":"Mierzewska","year":"2013","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.nmd.2013.03.002","article-title":"Clinical and mutational characteristics of spinal muscular atrophy with respiratory distress type 1 in the Netherlands","volume":"23","author":"Stalpers","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"58","DOI":"10.5414\/NP300902","article-title":"Spinal muscular atrophy with respiratory distress type 1 (SMARD1): Report of a Spanish case with extended clinicopathological follow-up","volume":"35","author":"Millan","year":"2016","journal-title":"Clin. Neuropathol."},{"key":"ref_24","unstructured":"(2024, April 16). Simple ClinVar. Available online: https:\/\/simple-clinvar.broadinstitute.org\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1093\/brain\/awg278","article-title":"Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1","volume":"126","author":"Pitt","year":"2003","journal-title":"Brain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1002\/pd.952","article-title":"Prenatal diagnosis of spinal muscular atrophy with respiratory distress (SMARD1) in a twin pregnancy","volume":"24","author":"Chen","year":"2004","journal-title":"Prenat. Diagn."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1046\/j.1471-0528.2003.00012.x","article-title":"Neonatal complications following preterm birth","volume":"110","author":"Ward","year":"2003","journal-title":"BJOG"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1542\/peds.111.6.1253","article-title":"International small for gestational age advisory board consensus development conference statement: Management of short children born small for gestational age, April 24\u2013October 1, 2001","volume":"111","author":"Lee","year":"2003","journal-title":"Pediatrics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4137\/CMPed.S40070","article-title":"Intrauterine Growth Restriction: Antenatal and Postnatal Aspects","volume":"10","author":"Sharma","year":"2016","journal-title":"Clin. Med. Insights Pediatr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2147\/TACG.S239603","article-title":"Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance","volume":"14","author":"Keinath","year":"2021","journal-title":"Appl. Clin. Genet."},{"key":"ref_31","first-page":"e2103","article-title":"Systematic Literature Review of the Natural History of Spinal Muscular Atrophy: Motor Function, Scoliosis, and Contractures","volume":"101","author":"Ribero","year":"2023","journal-title":"Neurology"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/997\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:26:11Z","timestamp":1760109971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/997"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,30]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["genes15080997"],"URL":"https:\/\/doi.org\/10.3390\/genes15080997","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,30]]}}}