{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T23:28:31Z","timestamp":1793748511125,"version":"4.6.1"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"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>Background\/Objectives: The genetic underpinnings of Parkinson\u2019s disease (PD) and parkinsonism have drawn increasing attention in recent years. Mutations in the Factor-Induced Gene 4 (FIG4) have been implicated in various neurological disorders, including Charcot-Marie-Tooth disease type 4J (CMT4J), amyotrophic lateral sclerosis (ALS), and Yunis-Var\u00f3n syndrome. This review aims to explore the association between FIG4 mutations and parkinsonism, with a specific focus on the rare missense mutation p.Ile41Thr (I41T). Methods: We identified 12 cases from 10 different families in which parkinsonism was reported in conjunction with CMT4J polyneuropathy. All cases involved the I41T mutation in a compound heterozygous state, combined with a FIG4 loss-of-function mutation. Data from clinical observations, neuroimaging studies, and genetic analyses were evaluated to understand the characteristics of parkinsonism in these patients. Results: In all 12 cases, parkinsonism developed either concurrently or following the onset of CMT4J neuropathy, but was never observed in isolation. Cases of both early- and late-onset parkinsonism were identified, reflecting similarities to genetic forms of parkinsonism with autosomal recessive inheritance. Imaging studies, including Dopamine transporter Single Photon Emission Computed Tomography (DaTscan) and brain magnetic resonance imaging (MRI), revealed abnormalities indicative of neurodegeneration, consistent with findings in other neurodegenerative disorders. Conclusions: The co-occurrence of parkinsonism with CMT4J in patients carrying the I41T mutation suggests an expanded spectrum of FIG4-related disorders, potentially implicating the same molecular mechanisms seen in other neurodegenerative disorders. Further research into FIG4-mediated pathways may offer valuable insights into potential therapeutic targets for disorders of both the central and peripheral nervous systems.<\/jats:p>","DOI":"10.3390\/genes15101344","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T03:57:09Z","timestamp":1729483029000},"page":"1344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature"],"prefix":"10.3390","volume":"15","author":[{"given":"Iro","family":"Boura","sequence":"first","affiliation":[{"name":"School of Medicine, University of Crete, Crete, 70013 Heraklion, Greece"},{"name":"Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King\u2019s College London, London SE5 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene Areti","family":"Giannopoulou","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Crete, Crete, 70013 Heraklion, Greece"},{"name":"Department of Neurology, University General Hospital of Heraklion, Crete, 71500 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Pavlaki","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Crete, Crete, 70013 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Xiromerisiou","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Thessaly, 41500 Larissa, Greece"},{"name":"Department of Neurology, University General Hospital of Larissa, 41334 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9089-4954","authenticated-orcid":false,"given":"Panayiotis","family":"Mitsias","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Crete, Crete, 70013 Heraklion, Greece"},{"name":"Department of Neurology, University General Hospital of Heraklion, Crete, 71500 Heraklion, Greece"},{"name":"Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA"},{"name":"School of Medicine, Wayne State University, Detroit, MI 48202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9824-6620","authenticated-orcid":false,"given":"Cleanthe","family":"Spanaki","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Crete, Crete, 70013 Heraklion, Greece"},{"name":"Department of Neurology, University General Hospital of Heraklion, Crete, 71500 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bandres-Ciga, S., Diez-Fairen, M., Kim, J.J., and Singleton, A.B. (2020). Genetics of Parkinson\u2019s disease: An introspection of its journey towards precision medicine. Neurobiol. Dis., 137.","DOI":"10.1016\/j.nbd.2020.104782"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1055\/s-0037-1601567","article-title":"Genetic Forms of Parkinson\u2019s Disease","volume":"37","author":"Kim","year":"2017","journal-title":"Semin. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"648588","DOI":"10.3389\/fneur.2021.648588","article-title":"Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings","volume":"12","author":"Guadagnolo","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.tins.2018.11.001","article-title":"Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson\u2019s Disease","volume":"42","author":"Nguyen","year":"2019","journal-title":"Trends Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13195-023-01244-3","article-title":"Shared genetic risk loci between Alzheimer\u2019s disease and related dementias, Parkinson\u2019s disease, and amyotrophic lateral sclerosis","volume":"15","author":"Wainberg","year":"2023","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1141","DOI":"10.1002\/mgg3.1141","article-title":"Whole exome sequencing establishes diagnosis of Charcot\u2013Marie\u2013Tooth 4J, 1C, and X1 subtypes","volume":"8","author":"Michaelidou","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1093\/brain\/awr148","article-title":"Distinctive genetic and clinical features of CMT4J: A severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4","volume":"134","author":"Nicholson","year":"2011","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/acn3.525","article-title":"Charcot Marie Tooth disease type 4J with complex central nervous system features","volume":"5","author":"Orengo","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.parkreldis.2020.03.021","article-title":"FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Var\u00f3n syndrome","volume":"74","author":"Zimmermann","year":"2020","journal-title":"Park. Relat. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.parkreldis.2020.10.011","article-title":"CMT4J, parkinsonism and a new FIG4 mutation","volume":"81","author":"Posada","year":"2020","journal-title":"Park. Relat. Disord."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1002\/mdc3.13855","article-title":"Imaging in FIG 4\u2014Related Parkinsonism","volume":"10","author":"Silva","year":"2023","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_12","first-page":"1355","article-title":"Clinical and genetic features of patients suffering from CMT4J","volume":"271","author":"Morales","year":"2023","journal-title":"J. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1055\/s-0042-1747934","article-title":"Clinical and Genetic Aspects of Childhood-Onset Demyelinating Charcot-Marie-Tooth\u2019s Disease in Brazil","volume":"12","author":"Machado","year":"2023","journal-title":"J. Pediatr. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature05876","article-title":"Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J","volume":"448","author":"Chow","year":"2007","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lenk, G.M., Ferguson, C.J., Chow, C.Y., Jin, N., Jones, J.M., Grant, A.E., Zolov, S.N., Winters, J.J., Giger, R.J., and Dowling, J.J. (2011). Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002104"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/acn3.51175","article-title":"Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients","volume":"8","author":"Lafontaine","year":"2021","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1002\/ana.25198","article-title":"Myelin abnormality in Charcot-Marie-Tooth type 4J recapitulates features of acquired demyelination","volume":"83","author":"Hu","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ajhg.2008.12.010","article-title":"Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS","volume":"84","author":"Chow","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/ejhg.2016.186","article-title":"FIG4 variants in central European patients with amyotrophic lateral sclerosis: A whole-exome and targeted sequencing study","volume":"25","author":"Osmanovic","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/ana.24306","article-title":"Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes","volume":"77","author":"Cady","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4609","DOI":"10.1007\/s10072-024-07542-4","article-title":"FIG4-associated disease manifesting as rapidly progressive amyotrophic lateral sclerosis","volume":"45","author":"Caetano","year":"2024","journal-title":"Neurol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1111\/ene.13559","article-title":"New FIG4 gene mutations causing aggressive ALS","volume":"25","author":"Bertolin","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/BF02250923","article-title":"Tendon jerks in Parkinson\u2019s disease","volume":"8","author":"Hammerstad","year":"1994","journal-title":"J. Neural. Transm. Park Dis. Dement Sect."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/ana.10613","article-title":"How much phenotypic variation can be attributed to parkin genotype?","volume":"54","author":"Lohmann","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1093\/brain\/awn114","article-title":"Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration","volume":"131","author":"Zhang","year":"2008","journal-title":"Brain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/humu.23720","article-title":"Cerebral hypomyelination associated with biallelic variants of FIG4","volume":"40","author":"Lenk","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/ajmg.a.63084","article-title":"T2 olivary nuclei hyperintensities: A characteristic neuroimaging finding in FIG4-related leukoencephalopathy","volume":"191","author":"Sait","year":"2023","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.pneurobio.2012.11.001","article-title":"FIG4 deficiency: A newly emerged lysosomal storage disorder?","volume":"101\u2013102","author":"Martyn","year":"2013","journal-title":"Prog. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1093\/hmg\/ddy145","article-title":"Protective role of the lipid phosphatase FIG4 in the adult nervous system","volume":"27","author":"Mironova","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/s41573-022-00582-5","article-title":"Beyond PI3Ks: Targeting phosphoinositide kinases in disease","volume":"22","author":"Burke","year":"2023","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1093\/jnen\/nlx062","article-title":"A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade","volume":"76","author":"Gentil","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1091\/mbc.E18-01-0015","article-title":"PI(3,5)Pcontrols vacuole potassium transport to support cellular osmoregulation","volume":"29","author":"Wilson","year":"2018","journal-title":"Mol. Biol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/neup.12056","article-title":"ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases","volume":"34","author":"Kon","year":"2014","journal-title":"Neuropathology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"137159","DOI":"10.1172\/JCI137159","article-title":"AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model","volume":"131","author":"Presa","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S233","DOI":"10.1016\/S1353-8020(08)70008-7","article-title":"Genetics of parkinsonism","volume":"13","author":"Bonifati","year":"2007","journal-title":"Park. Relat. Disord."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/10\/1344\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:17:17Z","timestamp":1760113037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/10\/1344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,21]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["genes15101344"],"URL":"https:\/\/doi.org\/10.3390\/genes15101344","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,21]]}}}