{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:14:21Z","timestamp":1789002861705,"version":"build-2803163510"},"reference-count":104,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,11]],"date-time":"2024-02-11T00:00:00Z","timestamp":1707609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Niemann\u2013Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure. In this sense, bronchoscopy with broncho-alveolar lavage or biopsy together with high-resolution computed tomography are fundamental diagnostic tools. Although several efforts have been made to find an effective therapy for NPD, to date, only limited therapeutic options are available. Enzyme replacement therapy with Olipudase \u03b1 is the first and only approved disease-modifying therapy for patients with ASMD. A lung transplant and hematopoietic stem cell transplantation are also described for ASMD in the literature. The only approved disease-modifying therapy in NPD type C is miglustat, a substrate-reduction treatment. The aim of this review was to delineate a state of the art on the genetic basis and lung involvement in NPD, focusing on clinical manifestations, radiologic and histopathologic characteristics of the disease, and available therapeutic options, with a gaze on future therapeutic strategies.<\/jats:p>","DOI":"10.3390\/biom14020211","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T03:50:27Z","timestamp":1707709827000},"page":"211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann\u2013Pick Disease: A Comprehensive Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4502-9902","authenticated-orcid":false,"given":"Claudio","family":"Tirelli","sequence":"first","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7057-5684","authenticated-orcid":false,"given":"Ornella","family":"Rondinone","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Italia","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Mira","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca Alessandro","family":"Belmonte","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"De Grassi","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8429-2154","authenticated-orcid":false,"given":"Gabriele","family":"Guido","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Maggioni","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Mondoni","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica Rosa","family":"Miozzo","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Centanni","sequence":"additional","affiliation":[{"name":"Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00408-016-9893-0","article-title":"Pulmonary Involvement in Niemann-Pick Disease: A State-of-the-Art Review","volume":"194","author":"Rodrigues","year":"2016","journal-title":"Lung"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e293","DOI":"10.1016\/j.chest.2020.11.074","article-title":"Bilateral Cystic Bronchiectasis as Novel Phenotype of Niemann-Pick Disease Type B Successfully Treated with Double Lung Transplantation","volume":"159","author":"Tirelli","year":"2021","journal-title":"Chest"},{"key":"ref_3","first-page":"12552","article-title":"Identification and Expression of Five Mutations in the Human Acid Sphingomyelinase Gene Causing Types A and B Niemann-Pick Disease. Molecular Evidence for Genetic Heterogeneity in the Neuronopathic and Non-Neuronopathic Forms","volume":"267","author":"Takahashi","year":"1992","journal-title":"J. Biol. Chem. Med. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s41065-023-00272-1","article-title":"SMPD1 expression profile and mutation landscape help decipher genotype\u2013phenotype association and precision diagnosis for acid sphingomyelinase deficiency","volume":"160","author":"Wang","year":"2023","journal-title":"Hereditas"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/humu.22923","article-title":"SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants","volume":"37","author":"Zampieri","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/humu.9353","article-title":"Functional in vitro characterization of 14 SMPD1 mutations identified in Italian patients affected by Niemann-Pick Type B disease","volume":"26","author":"Dardis","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_7","first-page":"125","article-title":"Molecular genetic characterization of novel sphingomyelin phosphodiesterase 1 mutations causing Niemann-Pick Disease","volume":"3","author":"Ritli","year":"2012","journal-title":"JIMD Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/humu.1380020414","article-title":"Type A Niemann-Pick Disease: A frameshift mutation in the acid sphingomyelinase gene (fsP330) occurs in Ashkenazi Jewish patients","volume":"2","author":"Levran","year":"1993","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1182\/blood.V80.8.2081.2081","article-title":"Identification and Expression of a Common Missense Mutation (L302P) in the Acid Sphingomyelinase Gene of Ashkenazi Jewish Type A Niemann-Pick Disease Patients","volume":"80","author":"Levran","year":"1992","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1172\/JCI115380","article-title":"Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype\/phenotype correlations in type A and B patients","volume":"88","author":"Levran","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1073\/pnas.88.9.3748","article-title":"Niemann-Pick Disease: A frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients","volume":"88","author":"Levran","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"982","DOI":"10.3389\/fphys.2017.00982","article-title":"Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease","volume":"8","author":"Torres","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ymgme.2016.12.008","article-title":"Types A and B Niemann-Pick Disease","volume":"120","author":"Schuchman","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1086\/345074","article-title":"The demographics and distribution of type B Niemann-Pick Disease: Novel mutations lead to new genotype\/phenotype correlations","volume":"71","author":"Simonaro","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13023-017-0572-x","article-title":"Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)","volume":"12","author":"McGovern","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"170009","DOI":"10.1183\/16000617.0009-2017","article-title":"The role of macrophages in interstitial lung diseases: Number 3 in the Series \u2018Pathology for the clinician\u2019 Edited by Peter Dorfm\u00fcller and Alberto Cavazza","volume":"26","author":"Rossi","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1212\/01.wnl.0000194208.08904.0c","article-title":"Natural history of Type A Niemann-Pick Disease: Possible endpoints for therapeutic trials","volume":"66","author":"McGovern","year":"2006","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/S0008-4182(05)80054-7","article-title":"\u2018Cherry-red spot\u2019 or \u2018perifoveal white patch\u2019?","volume":"40","author":"Ospina","year":"2005","journal-title":"Can. J. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.pediatrneurol.2007.04.011","article-title":"The \u2018cherry red\u2019 spot","volume":"37","author":"Leavitt","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e341","DOI":"10.1542\/peds.2007-3016","article-title":"A prospective, cross-sectional survey study of the natural history of Niemann-Pick Disease type B","volume":"122","author":"McGovern","year":"2008","journal-title":"Pediatrics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W12","DOI":"10.2214\/AJR.09.2871","article-title":"Imaging manifestations of Niemann-Pick Disease type B","volume":"194","author":"Simpson","year":"2010","journal-title":"AJR. Am. J. Roentgenol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1067\/mpd.2003.113","article-title":"Growth restriction in children with type B Niemann-Pick Disease","volume":"142","author":"Wasserstein","year":"2003","journal-title":"J. Pediatr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.jpeds.2006.06.034","article-title":"Acid sphingomyelinase deficiency: Prevalence and characterization of an intermediate phenotype of Niemann-Pick Disease","volume":"149","author":"Wasserstein","year":"2006","journal-title":"J. Pediatr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/j.ophtha.2003.10.034","article-title":"Ocular manifestations of Niemann-Pick Disease type B","volume":"111","author":"McGovern","year":"2004","journal-title":"Ophthalmology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.rmed.2012.06.014","article-title":"Different features of lung involvement in Niemann-Pick Disease and Gaucher disease","volume":"106","author":"Orhan","year":"2012","journal-title":"Respir. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/crj.13150","article-title":"Pulmonary involvement in selected lysosomal storage diseases and the impact of enzyme replacement therapy: A state-of-the art review","volume":"14","year":"2020","journal-title":"Clin. Respir. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"204","DOI":"10.23736\/S2784-8477.23.02087-9","article-title":"Exogenous lipoid pneumonia secondary to repetitive micro-aspiration of paraffin oils laxatives","volume":"62","author":"Tirelli","year":"2023","journal-title":"Minerva Respir. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ccm.2011.11.001","article-title":"Genetic interstitial lung disease","volume":"33","author":"Devine","year":"2012","journal-title":"Clin. Chest Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s13023-023-02686-6","article-title":"Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick Disease types A, B and A\/B)","volume":"18","author":"Geberhiwot","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/gim.2015.24","article-title":"Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann-Pick Disease type B (acid sphingomyelinase deficiency)","volume":"18","author":"McGovern","year":"2016","journal-title":"Genet. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ymgme.2015.05.013","article-title":"Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency","volume":"116","author":"Wasserstein","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.gim.2022.03.021","article-title":"A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results","volume":"24","author":"Wasserstein","year":"2022","journal-title":"Genet. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1038\/s41436-021-01156-3","article-title":"One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency","volume":"23","author":"Diaz","year":"2021","journal-title":"Genet. Med."},{"key":"ref_34","first-page":"9431751","article-title":"Pulmonary Type B Niemann-Pick Disease Successfully Treated with Lung Transplantation","volume":"2019","author":"Belousova","year":"2019","journal-title":"Case Rep. Transplant."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.healun.2019.01.002","article-title":"Successful lung transplantation in a patient with Niemann-Pick disease","volume":"38","author":"Ding","year":"2019","journal-title":"J. Heart Lung Transplant."},{"key":"ref_36","first-page":"5428381","article-title":"Double-Lung Transplantation in a Patient with Pulmonary Type B Niemann-Pick Disease: A Valid Treatment Option","volume":"2022","author":"Mora","year":"2022","journal-title":"Case Rep. Transplant."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1016\/j.transproceed.2015.10.051","article-title":"Liver Transplantation in Patients with Niemann-Pick Disease--Single-Center Experience","volume":"47","author":"Coelho","year":"2015","journal-title":"Transplant. Proc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1002\/lt.25457","article-title":"The Effects of Liver Transplantation in Children with Niemann-Pick Disease Type B","volume":"25","author":"Liu","year":"2019","journal-title":"Liver Transpl."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1023\/B:BOLI.0000009950.81514.c8","article-title":"Niemann-Pick Disease: Sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant","volume":"26","author":"Victor","year":"2003","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1097\/00007890-199804150-00005","article-title":"Biochemical, pathological, and clinical response to transplantation of normal bone marrow cells into acid sphingomyelinase-deficient mice","volume":"65","author":"Miranda","year":"1998","journal-title":"Transplantation"},{"key":"ref_41","first-page":"775","article-title":"Combined bone marrow and intracerebral mesenchymal stem cell transplantation leads to synergistic visceral and neurological improvements in Niemann\u2013Pick disease mice","volume":"26","author":"Jin","year":"2003","journal-title":"Mol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.ymthe.2005.03.011","article-title":"AAV8-mediated hepatic expression of acid sphingomyelinase corrects the metabolic defect in the visceral organs of a mouse model of Niemann-Pick Disease","volume":"12","author":"Barbon","year":"2005","journal-title":"Mol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.expneurol.2008.10.021","article-title":"Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann-Pick A disease","volume":"215","author":"Dodge","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1038\/sj.gt.3301300","article-title":"Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick Disease","volume":"7","author":"Miranda","year":"2000","journal-title":"Gene Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature08710","article-title":"Hsp70 stabilizes lysosomes and reverts Niemann-Pick Disease-associated lysosomal pathology","volume":"463","author":"Kirkegaard","year":"2010","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1183\/16000617.0363-2020","article-title":"Interstitial lung disease in lysosomal storage disorders","volume":"30","author":"Borie","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"ref_47","first-page":"680","article-title":"Growth hormone, insulinlike growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease","volume":"21","author":"Donaghy","year":"1995","journal-title":"Hepatology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ymgme.2016.05.001","article-title":"Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick Disease type B and B variant): Literature review and report of new cases","volume":"118","author":"Cassiman","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1002\/ajmg.a.33077","article-title":"Psychosocial aspects of patients with Niemann-Pick Disease, type B","volume":"149A","author":"Henderson","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1016\/j.febslet.2006.06.008","article-title":"Lipid imbalance in the neurological disorder, Niemann-Pick C disease","volume":"580","author":"Vance","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1159\/000112178","article-title":"Type C Niemann-Pick Disease: Biochemical aspects and phenotypic heterogeneity","volume":"13","author":"Vanier","year":"1991","journal-title":"Dev. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1086\/301931","article-title":"The Nova Scotia (type D) form of Niemann-Pick Disease is caused by a G3097-->T transversion in NPC1","volume":"63","author":"Greer","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1399-0004.2007.00782.x","article-title":"Niemann-Pick C disease: Functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2","volume":"71","author":"Verot","year":"2007","journal-title":"Clin. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1086\/302626","article-title":"Niemann-Pick C1 disease: The I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype","volume":"65","author":"Millat","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.bbalip.2013.09.010","article-title":"Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann-Pick type C disease","volume":"1841","author":"Ramirez","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1086\/320606","article-title":"Niemann-Pick C1 disease: Correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop","volume":"68","author":"Millat","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1086\/302620","article-title":"Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain","volume":"65","author":"Greer","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1086\/320599","article-title":"Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1","volume":"68","author":"Sun","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/humu.10255","article-title":"Identification of 58 novel mutations in Niemann-Pick Disease type C: Correlation with biochemical phenotype and importance of PTC1-like domains in NPC1","volume":"22","author":"Park","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1126\/science.290.5500.2298","article-title":"Identification of HE1 as the second gene of Niemann-Pick C disease","volume":"290","author":"Naureckiene","year":"2000","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1086\/324068","article-title":"Niemann-Pick Disease type C: Spectrum of HE1 mutations and genotype\/phenotype correlations in the NPC2 group","volume":"69","author":"Millat","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1750-1172-5-16","article-title":"Niemann-Pick Disease type C","volume":"5","author":"Vanier","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13023-018-0785-7","article-title":"Consensus clinical management guidelines for Niemann-Pick Disease type C","volume":"13","author":"Geberhiwot","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1002\/mgg3.1906","article-title":"Adult-onset Niemann-Pick Disease type C masquerading as spinocerebellar ataxia","volume":"10","author":"Vo","year":"2022","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1097\/01.nrl.0000094627.78754.5b","article-title":"A riddle wrapped in a mystery: Understanding Niemann-Pick Disease, type C","volume":"9","author":"Patterson","year":"2003","journal-title":"Neurologist"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1034\/j.1399-0004.2003.00147.x","article-title":"Niemann-Pick Disease type C","volume":"64","author":"Vanier","year":"2003","journal-title":"Clin. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ymgme.2009.06.008","article-title":"Recommendations on the diagnosis and management of Niemann-Pick Disease type C","volume":"98","author":"Wraith","year":"2009","journal-title":"Mol. Genet. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1002\/ppul.20725","article-title":"Lung disease in Niemann-Pick Disease","volume":"42","author":"Guillemot","year":"2007","journal-title":"Pediatr. Pulmonol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1399-0004.2009.01325.x","article-title":"Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis","volume":"77","author":"Griese","year":"2010","journal-title":"Clin. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s00261-007-9331-0","article-title":"Echinococcosis of the liver","volume":"33","author":"Czermak","year":"2008","journal-title":"Abdom. Imaging"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"194","DOI":"10.12688\/f1000research.12361.1","article-title":"Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC","volume":"7","author":"Benussi","year":"2018","journal-title":"F1000Res"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1053\/rmed.2000.0942","article-title":"Pulmonary involvement in Niemann-Pick Disease: Case report and literature review","volume":"94","author":"Minai","year":"2000","journal-title":"Respir. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1016\/j.radcr.2020.08.012","article-title":"CT-guided biopsy in the differential diagnosis of Sjogren syndrome associated cystic lung disease: A case of lung nodular AL-k amyloidosis","volume":"15","author":"Tirelli","year":"2020","journal-title":"Radiol. Case Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.ejrad.2004.07.003","article-title":"Metabolic lung disease: Imaging and histopathologic findings","volume":"54","author":"Chung","year":"2005","journal-title":"Eur. J. Radiol."},{"key":"ref_75","first-page":"5","article-title":"Pulmonary surfactants and their role in pathophysiology of lung disorders","volume":"51","author":"Akella","year":"2013","journal-title":"Indian J. Exp. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0163-7827(87)90004-X","article-title":"Lung surfactant","volume":"26","author":"Harwood","year":"1987","journal-title":"Prog. Lipid Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1194\/jlr.M700125-JLR200","article-title":"Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C disease","volume":"48","author":"Liu","year":"2007","journal-title":"J. Lipid Res."},{"key":"ref_78","first-page":"71","article-title":"Niemann-Pick Disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: Morphological findings in lung and nervous tissue","volume":"14","author":"Bjurulf","year":"2008","journal-title":"Med. Sci. Monit."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1007\/s004280100407","article-title":"Pulmonary storage with emphysema as a sign of Niemann-Pick type C2 disease (second complementation group). Report of a case","volume":"439","author":"Elleder","year":"2001","journal-title":"Virchows Arch."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.arcped.2005.01.015","article-title":"Fatal neonatal respiratory distress in Niemann-Pick C2 and prenatal diagnosis with mutations in gene HE1\/NPC2","volume":"12","author":"Morisot","year":"2005","journal-title":"Arch. Pediatr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s004310050764","article-title":"Early-lethal pulmonary form of Niemann-Pick type C disease belonging to a second, rare genetic complementation group","volume":"157","author":"Schofer","year":"1998","journal-title":"Eur. J. Pediatr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s10072-005-0456-z","article-title":"Lung involvement in Niemann-Pick Disease type C1: Improvement with bronchoalveolar lavage","volume":"26","author":"Palmeri","year":"2005","journal-title":"Neurol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"L919","DOI":"10.1152\/ajplung.00383.2011","article-title":"Characterization of the Niemann-Pick C pathway in alveolar type II cells and lamellar bodies of the lung","volume":"302","author":"Roszell","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Roszell, B.R., Tao, J.Q., Yu, K.J., Gao, L., Huang, S., Ning, Y., Feinstein, S.I., Vite, C.H., and Bates, S.R. (2013). Pulmonary abnormalities in animal models due to Niemann-Pick type C1 (NPC1) or C2 (NPC2) disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067084"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Ramirez, C.M., Liu, B., Le, L., Lopez, A.M., and Weinberg, A.G. (2013, January 13\u201315). Progression of pulmonary disease and related changes in lung cholesterol metabolism in mice Niemann-Pick type C1 deficiency. Proceedings of the Lysosomal Disease Network\u2019s WORLD SymposiumTM, Orlando, FL, USA. Abstract 144.","DOI":"10.1016\/j.ymgme.2012.11.158"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1007\/s00431-018-3219-6","article-title":"Pulmonary involvement in Niemann-Pick C type 1","volume":"177","author":"Aviram","year":"2018","journal-title":"Eur. J. Pediatr."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Tirelli, C., Pesenti, C., Miozzo, M., Mondoni, M., Fontana, L., and Centanni, S. (2022). The Genetic and Epigenetic Footprint in Idiopathic Pulmonary Fibrosis and Familial Pulmonary Fibrosis: A State-of-the-Art Review. Diagnostics, 12.","DOI":"10.3390\/diagnostics12123107"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"18932","DOI":"10.1073\/pnas.1110439108","article-title":"Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding","volume":"108","author":"Deffieu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/s41573-019-0036-1","article-title":"Lysosomes as a therapeutic target","volume":"18","author":"Bonam","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1080\/14656566.2023.2215386","article-title":"Current advancements in therapy for Niemann-Pick Disease: Progress and pitfalls","volume":"24","author":"Schneider","year":"2023","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ijdevneu.2017.11.007","article-title":"Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients","volume":"66","author":"Hammerschmidt","year":"2018","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/S1474-4422(07)70194-1","article-title":"Miglustat for treatment of Niemann-Pick C disease: A randomised controlled study","volume":"6","author":"Patterson","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13023-015-0377-8","article-title":"Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat","volume":"10","author":"Abel","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1177\/0883073809344222","article-title":"Long-term miglustat therapy in children with Niemann-Pick Disease type C","volume":"25","author":"Patterson","year":"2010","journal-title":"J. Child Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"E1716","DOI":"10.1212\/WNL.0000000000009287","article-title":"Imaging of neuroinflammation in adult Niemann-Pick type C disease: A cross-sectional study","volume":"94","author":"Walterfang","year":"2020","journal-title":"Neurology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ymgme.2009.11.007","article-title":"Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick Disease type C: A case series","volume":"99","author":"Pineda","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_97","first-page":"429","article-title":"Novel imaging technologies for genetic diagnoses in the inborn errors of metabolism","volume":"4","author":"Gropman","year":"2020","journal-title":"J. Transl. Genet. Genom."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1007\/s00415-021-10535-4","article-title":"Brain hypometabolic changes in 14 adolescent-adult patients with Niemann-Pick Disease type C assessed by 18F-fluorodeoxyglucose positron emission tomography","volume":"268","author":"Lau","year":"2021","journal-title":"J. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s00415-016-8051-1","article-title":"Normalisation of brain spectroscopy findings in Niemann-Pick Disease type C patients treated with miglustat","volume":"263","author":"Sedel","year":"2016","journal-title":"J. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1001\/jamaneurol.2020.3241","article-title":"Association of Miglustat with Swallowing Outcomes in Niemann-Pick Disease, Type C1","volume":"77","author":"Solomon","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s13023-018-0844-0","article-title":"Miglustat in Niemann-Pick Disease type C patients: A review","volume":"13","author":"Pineda","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"fcaa148","DOI":"10.1093\/braincomms\/fcaa148","article-title":"Acetyl-leucine slows disease progression in lysosomal storage disorders","volume":"3","author":"Kaya","year":"2021","journal-title":"Brain Commun."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Monahan, P.E., Negrier, C., Tarantino, M., Valentino, L.A., and Mingozzi, F. (2021). Emerging immunogenicity and genotoxicity considerations of adeno-associated virus vec- tor gene therapy for hemophilia. J. Clin. Med., 10.","DOI":"10.3390\/jcm10112471"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3389\/fmed.2020.00011","article-title":"Multidisciplinary Approach in the Early Detection of Undiagnosed Connective Tissue Diseases in Patients with Interstitial Lung Disease: A Retrospective Cohort Study","volume":"7","author":"Tirelli","year":"2020","journal-title":"Front. Med"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/2\/211\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:58:32Z","timestamp":1760104712000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/2\/211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,11]]},"references-count":104,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["biom14020211"],"URL":"https:\/\/doi.org\/10.3390\/biom14020211","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,11]]}}}