Objective: To provide a comprehensive review of individual-level data and genotype-phenotype relationships for genes implicated in neurodegeneration with brain iron accumulation (NBIA) disorders.

Background: The Movement Disorder Society Genetic Mutation Database (MDSGene) serves as a platform for the systematic collection of individual-level data from published literature pertaining to movement disorder phenotypes associated with pathogenic gene variants. To date, the database encompasses over 2,500 publications.

NBIAs constitute a group of disorders characterized by highly diverse clinical and radiologic features [1]. Currently, pathogenic variants in 12 distinct genes are associated with NBIA.

Method: Following MDSGene literature search and data extraction protocols, we systematically abstracted and summarized the clinical and genetic features of reported individuals with NBIA linked to the following genes: PANK2, C9orf12, COASY, DCAF17, FAHN, FTL, ATP13A2, WDR45, REPS1, CRAT, and CP. The most recent search was conducted on 02/12/2024 with plans for subsequent updates. Genotype-phenotype correlation data for PLA2G6 was previously collected by a separate group (DYT-PARK). An updated search will be conducted to review PLA2G6-related articles published after the completion of the DYT-PARK study.

Results: We identified 2,811 unique records. After screening through titles/abstracts, 903 articles were included. Of these, 428 were deemed eligible for data extraction: PANK2 (133/428, 31%), WDR45 (88/428, 21%), ATP13A2 (52/428, 12%), c9orf12 (46/428, 11%), CP (37/428, 9%), FA2H (36/428, 8%), FTL (17/428, 4%), DCAF17 (13/428, 3%), and COASY (6/428, 1%). Data for 335/428 (78%) of eligible articles have been completely extracted after full-text screening, while 93/428 (22%) records are pending full-text screening and subsequent data extraction, including relevant articles for PANK2, c9orf12, CP, WDR45, REPS1, and CRAT.

Conclusion: We present the most comprehensive review of existing literature regarding genotype-phenotype relationships for all known NBIA genes. Findings from this study will be instrumental in addressing research and clinical practice gaps. Our systematic review will be made publicly available in the mdsgene.org domain in the future.

Table 1. Current Status of Systematic Review

References: 1. Hayflick SJ, Kurian MA, Hogarth P (2018) Neurodegeneration with brain iron accumulation. pp 293–305
2. Lill CM, Mashychev A, Hartmann C, et al (2016) Launching the movement disorders society genetic mutation database (MDSGene). Mov Disord 31:607–609. https://doi.org/10.1002/mds.26651

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genotype-phenotype-relations-in-neurodegeneration-with-brain-iron-accumulation-nbia-genes-mdsgene-systematic-review/