Objective: To describe the phenotypic continuum and genotypic spectrum of microtubule-associated protein tau (MAPT)-associated parkinsonism in a multi-ethnic Malaysian cohort.

Background: Carriers of pathogenic MAPT variants exhibit significant phenotypic heterogeneity, including syndromes resembling PD, PSP, CBS, or frontotemporal dementia (FTD)(ref 1-4). However, genotypic profiles and clinical presentation remain underreported in Asian populations. We investigated the genetic variation and phenotypic diversity of MAPT-associated parkinsonism in a Malaysian cohort.

Method: An international, multi-centre collaboration facilitated MAPT mutational screening via WGS or WES in 2,029 patients with parkinsonism. Additional screening was performed on affected family members (n=3) of patients carrying pathogenic or likely pathogenic MAPT variants. Medical records of patients with pathogenic or likely pathogenic MAPT variants were reviewed to integrate longitudinal clinical phenotyping, neuroimaging findings, and WGS/WES data.

Results: Refer Table1 & Table2: The cohort comprised 10 adults (4 Chinese, 4 Indians, 2 Malays; 6:4 males:females) with a median age at onset of 45 (range: 34-71) years and median follow-up of 4.5 (range: 2-16) years. Ethnic-specific segregation of alleles was observed: the c.2013T>G (p.Asn671Lys) variant predominantly clustered in 5 patients (4 Indian, 1 Malay), while distinct variants including c.14G>A (p.Arg5His), c.1693G>A (p.V565M), and c.2038G>A (p.V680I) segregated within the Chinese. Phenotypically, 50% (n=5) initially exhibited a PD phenotype with favourable response to levodopa. There was phenotypic conversion in 10% (n=1). Currently, 40% (n=4) have retained a PD phenotype, 50% (n=5) a PSP-like phenotype, and 10% (n=1) remained as FTD. Key features associated with conversion to atypical parkinsonism included the emergence of supranuclear gaze palsies, prominent axial features, and diminished response to levodopa.

Conclusion: This cohort demonstrates allele-specific ethnic clustering of MAPT variants with corresponding phenotypes in Malaysia. It also highlights a diagnostic challenge: MAPT variant carriers may initially manifest as clinical PD before evolving into more debilitating PSP-like syndrome. Our findings offer clinical pearls (Table3) while broadening the genotypic and phenotypic spectrum of MAPT mutations in the Asian populations.

Table 1: Demographics and phenotypic data

Table 2: Genotypic spectrum

Table 3: Clinical pearls from this cohort

References: 1. Villa C, Pellencin E, Romeo A, Giaccone G, Rossi G, Prioni S, Caroppo P. Dissecting the Clinical Heterogeneity and Genotype-Phenotype Correlations of MAPT Mutations: A Systematic Review. Front Biosci (Landmark Ed). 2024 Jan 16;29(1):12. doi: 10.31083/j.fbl2901012. PMID: 38287807.
2. Leveille E, Ross OA, Gan-Or Z. Tau and MAPT genetics in tauopathies and synucleinopathies. Parkinsonism Relat Disord. 2021 Sep;90:142-154. doi: 10.1016/j.parkreldis.2021.09.008. Epub 2021 Sep 14. PMID: 34593302; PMCID: PMC9310195.
3. Mao C, Dong L, Li J, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Cui L, Gao J. Phenotype Heterogeneity and Genotype Correlation of MAPT Mutations in a Chinese PUMCH Cohort. J Mol Neurosci. 2021 May;71(5):1015-1022. doi: 10.1007/s12031-020-01723-4. Epub 2020 Oct 1. PMID: 33006106.
4. Ramakrishnan S, Arshad F, Keerthana BS, Bosco S, Gokul Pon A, Ganaraja VH, Madhusudhan D, Mahima R, Arunachal G, Kulanthaivelu K, Alladi S. Clinical profile, atrophy and inheritance patterns of pathogenic MAPT gene mutations in Frontotemporal dementia detected using whole exome sequencing: a single-center first report from India. BMC Neurol. 2025 Aug 27;25(1):353. doi: 10.1186/s12883-025-04336-9. PMID: 40859209; PMCID: PMC12382150.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phenotypic-and-genotypic-spectrum-of-mapt-associated-parkinsonism-in-a-multi-ethnic-malaysian-cohort/