No CrossRef data available.
Article contents
A Novel Homozygous Variant in the MCOLN1 Gene Associated With Severe Oromandibular Dystonia and Parkinsonism
Published online by Cambridge University Press: 27 March 2024
Abstract
Background:
Mucolipidosis type IV (MLIV) is a rare, progressive lysosomal storage disorder characterized by severe intellectual disability, delayed motor milestones and ophthalmologic abnormalities. MLIV is an autosomal recessive disease caused by mutations in the MCOLN1 gene, encoding mucolipin-1 which is responsible for maintaining lysosomal function.
Objectives and Methods:
Here, we report a family of four Iranian siblings with cognitive decline, progressive visual and pyramidal disturbances, and abnormal movements manifested by severe oromandibular dystonia and parkinsonism. MRI scans of the brain demonstrated signal abnormalities in the white matter and thinning of the corpus callosum.
Results and Conclusions:
Whole-exome sequencing identified a novel homozygous variant, c.362C > T:p. Thr121Met in the MCOLN1 gene consistent with a diagnosis of MLIV. The presentation of MLIV may overlap with a variety of other neurological diseases, and genetic analysis is an important strategy to clarify the diagnosis. This is an important point that clinicians should be familiar with. The novel variant c.362C > T:p. Thr121Met herein described may be related to a comparatively older age at onset. Our study also expands the clinical spectrum of MLIV associated with the MCOLN1 variants and introduces a novel likely pathogenic variant for testing in MLIV cases that remain unresolved.
Résumé
Un tout nouveau variant homozygote du gène MCOLN1 associé à une dystonie oromandibulaire grave et au parkinsonisme
La mucolipidose de type IV (ML IV) est une maladie de surcharge lysosomale rare et évolutive, qui se caractérise par un déficit intellectuel grave, un retard des étapes du développement moteur et des anomalies oculaires. La ML IV est une maladie autosomique récessive, causée par des mutations du gène MCOLN1, qui code la mucolipine1, responsable du maintien de la fonction lysosomale.
Sera présentée, dans l’article, l’histoire d’une famille iranienne, comptant une fratrie de quatre membres atteints d’un déclin cognitif, de troubles visuels et pyramidaux progressifs et de mouvements anormaux qui se manifestent par une dystonie oromandibulaire grave et du parkinsonisme. Les examens par IRM du cerveau ont révélé des anomalies de la transmission des signaux dans la substance blanche et un amincissement du corps calleux.
Grâce au séquençage de l’exome entier, l’équipe a découvert un tout nouveau variant homozygote, c.362C>T :p. Thr121Met, du gène MCOLN1, qui se montre compatible avec le diagnostic de la ML IV. Le tableau clinique de la ML IV peut coïncider avec celui de plusieurs autres maladies du système nerveux, et une analyse génétique représente une stratégie primordiale afin de clarifier le diagnostic. Il s’agit là d’un point important que devraient bien connaître les médecins. Le tout nouveau variant c.362C>T :p. Thr121Met ici décrit pourrait commencer à se manifester à un âge plus avancé que d’autres gènes du groupe. L’étude a aussi permis d’élargir le champ clinique de la ML IV associée aux variants MCOLN1 et présente un tout nouveau variant, probablement pathogène, à soumettre à des tests dans les cas non résolus de ML IV.
Keywords
- Type
- Original Article
- Information
- Copyright
- © The Author(s), 2024. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation
References
Al-Alawi, B, Harikrishna, B, Al-Thihli, K, et al. Mucolipidosis type IV in Omani families with a novel MCOLN1 mutation: search for evidence of founder effect. Genes. 2022;13:248.CrossRefGoogle ScholarPubMed
Chen, CS, Bach, G, Pagano, RE. Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc Natl Acad Sci US Am. 1998;95:6373–8.CrossRefGoogle ScholarPubMed
Tuysuz, B, Goldin, E, Metin, B, Korkmaz, B, Yalcinkaya, C. Mucolipidosis type IV in a Turkish boy associated with a novel MCOLN1 mutation. Brain Dev. 2009;31:702–5.CrossRefGoogle Scholar
Misko, AL, Wood, LB, DeBono, M, et al. Cross-sectional observations on the natural history of mucolipidosis type IV. Neurol Genet. 2022;8:e662.CrossRefGoogle ScholarPubMed
Misko, A, Wood, L, Kiselyov, K, Slaugenhaupt, S, Grishchuk, Y. Progress in elucidating pathophysiology of mucolipidosis IV. Neurosci Lett. 2021;755:135944.CrossRefGoogle ScholarPubMed
Saijo, H, Hayashi, M, Ezoe, T, et al. The first genetically confirmed Japanese patient with mucolipidosis type IV. Clin Case Rep. 2016;4:509–12.CrossRefGoogle ScholarPubMed
Mirabelli-Badenier, M, Severino, M, Tappino, B, et al. A novel homozygous MCOLN1 double mutant allele leading to TRP channel domain ablation underlies mucolipidosis IV in an Italian child. Metabolic Brain Dis. 2015;30:681–6.CrossRefGoogle Scholar
Bassi, MT, Manzoni, M, Monti, E, Pizzo, MT, Ballabio, A, Borsani, G. Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet. 2000;67:1110–20.CrossRefGoogle ScholarPubMed
Hayashi, T, Hosono, K, Kubo, A, et al. Long-term observation of a Japanese mucolipidosis IV patient with a novel homozygous p.F313del variant of MCOLN1. Am J Med Genet A. 2020;182:1500–5.CrossRefGoogle ScholarPubMed
Wakabayashi, K, Gustafson, AM, Sidransky, E, Goldin, E. Mucolipidosis type IV: an update. Mol Genet Metab. 2011;104:206–13.CrossRefGoogle ScholarPubMed
Yamaguchi, N, Ban, K, Suzuki, A, et al. Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum. Brain Dev. 2020;42:298–301.CrossRefGoogle Scholar
AlBakheet, A, Qari, A, Colak, D, Rasheed, A, Kaya, N, Al-Sayed, M. A novel mutation in a large family causes a unique phenotype of mucolipidosis IV. Gene. 2013;526:464–6.CrossRefGoogle Scholar
Davarzani, A, Shahrokhi, A, Hashemi, SS, et al. The second family affected with a PRDM8-related disease. Neurol Sci. 2022;43:3847–55.CrossRefGoogle ScholarPubMed
Chaer, L, Harissi-Dagher, M, Soucy, JF, Ellezam, B, Hamel, P. Mucolipidosis type IV in a child. J AAPOS. 2018;22:469–71.CrossRefGoogle ScholarPubMed
Boudewyn, LC, Walkley, SU. Current concepts in the neuropathogenesis of mucolipidosis type IV. J Neurochem. 2019;148:669–89.CrossRefGoogle ScholarPubMed
Mills, E, Dong, X-P, Wang, F, Xu, H. Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. Future Med Chem. 2010;2:51–64.CrossRefGoogle ScholarPubMed
Fine, M, Li, XJEV-DCC. A structural overview of TRPML1 and the TRPML family. Handb Exp Pharmacol. 2023;278:181–98.CrossRefGoogle ScholarPubMed
Jezela-Stanek, A, Ciara, E, Stepien, KM. Neuropathophysiology, genetic profile, and clinical manifestation of mucolipidosis IV—A review and case series. Int J Mol Sci. 2020;21:4564.CrossRefGoogle ScholarPubMed
Zerem, A, Ben-Sira, L, Vigdorovich, N, et al. White matter abnormalities and iron deposition in prenatal mucolipidosis IV-fetal imaging and pathology. Metab Brain Dis. 2021;36:2155–67.CrossRefGoogle ScholarPubMed
Metin, B, Korkmaz, B, Tuysuz, B, Yalcinkaya, C, E., G. Mucolipidosis type IV in a Turkish boy associated with a novel MCOLN1 mutation. Brain Dev. 2009;31:702–5.Google Scholar
Ghasemi et al. supplementary material 1
Ghasemi et al. supplementary material
File
598 KB
Ghasemi et al. supplementary material 2
Ghasemi et al. supplementary material
File
23.5 MB
Ghasemi et al. supplementary material 3
Ghasemi et al. supplementary material
File
13.7 MB
Ghasemi et al. supplementary material 4
Ghasemi et al. supplementary material
File
20.9 MB