{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:32:55Z","timestamp":1790839975487,"version":"4.1.0"},"reference-count":25,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T00:00:00Z","timestamp":1641859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>NALCN mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of limbs and face, hypotonia, and developmental delay (CLIFAHDD), which are recessively and dominantly inherited, respectively. We present a patient in whom congenital myasthenic syndrome (CMS) was suspected due to the occurrence of hypotonia and apnea episodes requiring resuscitation. For this reason, treatment with pyridostigmine was introduced. After starting the treatment, a significant improvement was observed in reducing the apnea episodes and slight psychomotor progress. In the course of further diagnostics, CMS was excluded, and CLIFAHDD syndrome was confirmed. Thus, we try to explain a possible mechanism of clinical improvement after the introduction of treatment with pyridostigmine in a patient with a mutation in the NALCN gene.<\/jats:p>","DOI":"10.3390\/ijerph19020775","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T14:05:07Z","timestamp":1641909907000},"page":"775","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Central Apneas Due to the CLIFAHDD Syndrome Successfully Treated with Pyridostigmine"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8551-3419","authenticated-orcid":false,"given":"Anna","family":"Winczewska-Wiktor","sequence":"first","affiliation":[{"name":"Chair and Department of Developmental Neurology, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam Sebastian","family":"Hirschfeld","sequence":"additional","affiliation":[{"name":"Chair and Department of Medical Genetics, Poznan University of Medical Sciences, 60-352 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Badura-Stronka","sequence":"additional","affiliation":[{"name":"Chair and Department of Medical Genetics, Poznan University of Medical Sciences, 60-352 Poznan, Poland"},{"name":"Centers of Medical Genetics GENESIS, 60-529 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-1499","authenticated-orcid":false,"given":"Irena","family":"Wojsyk-Banaszak","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Pediatric Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Sobkowiak","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Pediatric Allergy and Clinical Immunology, Poznan University of Medical Sciences, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4950-2346","authenticated-orcid":false,"given":"Alicja","family":"Bartkowska-\u015aniatkowska","sequence":"additional","affiliation":[{"name":"Department of Pediatric Anesthesiology and Intensive Therapy, Poznan University of Medical Sciences, 60-572 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeriia","family":"Babak","sequence":"additional","affiliation":[{"name":"Chair and Department of Medical Genetics, Poznan University of Medical Sciences, 60-352 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9839-8162","authenticated-orcid":false,"given":"Barbara","family":"Steinborn","sequence":"additional","affiliation":[{"name":"Chair and Department of Developmental Neurology, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6323","DOI":"10.1038\/ncomms7323","article-title":"The NCA sodium leak channel is required for persistent motor circuit activity that sustains locomotion","volume":"6","author":"Gao","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.ajhg.2013.08.001","article-title":"Mutations in NALCN Cause an Autosomal-Recessive Syndrome with Severe Hypotonia, Speech Impairment, and Cognitive Delay","volume":"93","author":"Albakheet","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ajhg.2015.01.003","article-title":"De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay","volume":"96","author":"Chong","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3389\/fphar.2019.00259","article-title":"Compound Heterozygous CHAT Gene Mutations of a Large Deletion and a Missense Variant in a Chinese Patient With Severe Congenital Myasthenic Syndrome With Episodic Apnea","volume":"10","author":"Liu","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s00415-017-8689-3","article-title":"Congenital myasthenic syndrome with episodic apnoea: Clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients","volume":"265","author":"McMacken","year":"2017","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/cne.902810107","article-title":"Brainstem projections to the major respiratory neuron populations in the medulla of the cat","volume":"281","author":"Smith","year":"1989","journal-title":"J. Comp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/j.neuron.2015.08.001","article-title":"Neural Control of Breathing and CO2 Homeostasis","volume":"87","author":"Guyenet","year":"2015","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev-physiol-040510-130049","article-title":"Understanding the Rhythm of Breathing: So Near, Yet So Far","volume":"75","author":"Feldman","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4732","DOI":"10.1523\/JNEUROSCI.2114-20.2021","article-title":"Unraveling the Mechanisms Underlying Irregularities in Inspiratory Rhythm Generation in a Mouse Model of Parkinson\u2019s Disease","volume":"41","author":"Oliveira","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8272","DOI":"10.1523\/JNEUROSCI.1475-05.2005","article-title":"Ionic Mechanisms Underlying Autonomous Action Potential Generation in the Somata and Dendrites of GABAergic Substantia Nigra Pars Reticulata Neurons In Vitro","volume":"25","author":"Atherton","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41586-020-2570-8","article-title":"Structure of the human sodium leak channel NALCN","volume":"587","author":"Kschonsak","year":"2020","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.cell.2007.02.041","article-title":"The Neuronal Channel NALCN Contributes Resting Sodium Permeability and Is Required for Normal Respiratory Rhythm","volume":"129","author":"Lu","year":"2007","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8174","DOI":"10.1523\/JNEUROSCI.1096-16.2016","article-title":"NALCN Is a \u201cLeak\u201d Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing","volume":"36","author":"Shi","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5831","DOI":"10.1038\/s41467-020-19667-z","article-title":"Structure of the human sodium leak channel NALCN in complex with FAM155A","volume":"11","author":"Xie","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"691","DOI":"10.2165\/11593300-000000000-00000","article-title":"Treatment of Myasthenia Gravis: Focus on pyridostigmine","volume":"31","author":"Maggi","year":"2011","journal-title":"Clin. Drug Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.bbr.2009.05.002","article-title":"Gulf War illness: Effects of repeated stress and pyridostigmine treatment on blood\u2013brain barrier permeability and cholinesterase activity in rat brain","volume":"203","author":"Amourette","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1038\/nm1296-1382","article-title":"Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response","volume":"2","author":"Friedman","year":"1996","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1093\/toxsci\/69.1.157","article-title":"Acute and Repeated Restraint Stress Have Little Effect on Pyridostigmine Toxicity or Brain Regional Cholinesterase Inhibition in Rats","volume":"69","author":"Song","year":"2002","journal-title":"Toxicol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1006\/taap.2000.8906","article-title":"Stress Does Not Enable Pyridostigmine to Inhibit Brain Cholinesterase after Parenteral Administration","volume":"164","author":"Grauer","year":"2000","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/30741","article-title":"Acute stress facilitates long-lasting changes in cholinergic gene expression","volume":"393","author":"Kaufer","year":"1998","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0014-4886(02)00016-X","article-title":"Pyridostigmine enhances glutamatergic transmission in hippocampal CA1 neurons","volume":"179","author":"Pavlovsky","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.brainres.2012.05.057","article-title":"Stress-induced altered cholinergic\u2013glutamatergic interactions in the mouse hippocampus","volume":"1472","author":"Pavlovsky","year":"2012","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s002100000382","article-title":"Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors","volume":"363","author":"Lockhart","year":"2001","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/embor.2009.125","article-title":"The NALCN ion channel is activated by M3 muscarinic receptors in a pancreatic \u03b2-cell line","volume":"10","author":"Swayne","year":"2009","journal-title":"EMBO Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/jhg.2015.163","article-title":"De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia","volume":"61","author":"Fukai","year":"2016","journal-title":"J. Hum. Genet."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/2\/775\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:02:00Z","timestamp":1760364120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/19\/2\/775"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,11]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijerph19020775"],"URL":"https:\/\/doi.org\/10.3390\/ijerph19020775","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,11]]}}}