Progressive supranuclear palsy (PSP), a rare neurodegenerative disorder of unknown origin, is pathologically characterized by abnormal tau deposition in the form of globose neuro-fibrillary tangles, tufted astrocytes, coiled bodies, and threads, with a predominance of 4-repeat (4R) tau isoforms (1, 2). Clinically, PSP is heterogeneous and may manifest various phenotypes, in which the most classical form is Richardson Syndrome (PSP-RS, also known as Steele-Richardson-Olszewski Syndrome), with symptoms such as vertical supranuclear gaze palsy, postural instability, and motor and cognitive deficits. Other forms of PSP have been increasingly recognized, including PSP with predominant parkinsonism (3), PSP with progressive gait freezing (4), PSP with predominant corticobasal syndrome (5), PSP with a predominant speech/language disorder (6), PSP with predominant frontal presentation (7), PSP with predominant cerebellar ataxia (5), and PSP with mixed pathology (8). Although PSP is generally considered sporadic, an increasing number of familial cases have drawn attention to its potential genetic basis (8–10). Among these, variants in the MAPT gene are most commonly associated with PSP (11, 12).

We identified a PSP family with an autosomal inheritance pattern, performed an exhaustive clinical, neuroimaging investigation of the proband, and further performed gene analysis of the proband and four relatives with or without PSP symptoms for the purpose of confirming the pathogenicity of potential gene variant. Additionally, we reviewed the literature on MAPT variants and their related disease.

We examined a newly identified Chinese family with a novel MAPT variant, displaying typical PSP features. Those features included recurrent falls, oculomotor challenges, and progressive cognitive impairment with short-term memory loss. Additionally, a literature review of previously reported MAPT-mutated PSP patients demonstrated the heterogeneity and complexity of the disease caused by different genetic mutations, which has broadened our knowledge of MAPT variants and disease with tau-pathology.

The MAPT gene, situated on chromosome 17q21, encodes the tau protein and comprises 16 exons. Exons 0 and 14 do not contribute to protein encoding. Inheritance is autosomal dominant (40, 41). Over 100 families worldwide have been identified with 50 distinct variants in the tau gene. Tau proteins exist in six isoforms, resulting from selective splicing in exons 2, 3, and 10. Depending on the splicing of exons 2 and 3, isoforms with 0, 1, or 2 N-terminal repeats (0 N, 1 N, 2 N) are produced. Selective splicing of exon 10 results in tau isoforms with either 3 or 4 microtubule-binding repeats (40). Disorders involving MAPT are primarily characterized by frontotemporal lobe dementia and/or clinical Parkinson’s syndrome, and less commonly by motor neuron disease (42). In case-control genome-wide association studies (GWAS), MAPT is the most significant risk locus for sporadic PSP, and is also the most common cause of familial PSP (11, 12).

The novel MAPT variant is deemed likely pathogenic based on criteria set forth by the American College of Medical Genetics and Genomics (ACMG) and the Society for Molecular Pathology (43). These criteria are as follows: the mutation resides in a functional structural domain (PM1). It is absent in healthy populations (PM2). The new missense alteration occurs at an amino acid residue (E342V) previously identified as pathogenic (PM5) (44, 45). The mutation co-segregates with the disease in multiple family lines (PP1). The affected gene is highly conserved across species, and computational analyses suggest the mutation is deleterious (PP3). Clinical presentation of patients supports a monogenic etiology for the disease (PP4).

The variant is situated in the fourth repeat, R4, of MAPT’s exon 11, which encodes the functional microtubule-binding domain (MTBD). Spanning from the latter part of exon 9 to exon 12 (amino acids 244–368), the MTBD contains four highly conserved 18-amino-acid repeats, separated by either 13 or 14 residues. MTBD plays a critical role in the interaction of tau with microtubules, promoting their assembly and stability (46, 47). The p.E342V variant in exon 11 has demonstrated an increase in 4R tau mRNA levels. This variant not only escalates the splicing of exon 10 but also decreases the inclusion of exons 2 and 3. At both RNA and protein levels, the E342V variant hampers the ability of tau to promote microtubule assembly. Additionally, the variant is hypothesized to diminish the affinity of tau for microtubules, thereby facilitating its release, self-assembly, and fibrillar aggregation (45). Pathological examination has unveiled notable frontotemporal lobe neuronal loss, intracytoplasmic tau aggregates, and paired helical tau filaments, thus confirming the variant’s deleterious effects. Moreover, exon 11 appears to influence the alternative splicing of other exons in the tau gene (44).

The MAPT gene is the most frequently implicated gene in hereditary forms of PSP. As shown in Table 2 and Figure 1, which contain variants in this patient’s genes, there were 20 different MAPT variants described in cases presenting with PSP (clinical or neuropathologic diagnosis). Variant prevalence varies regionally, potentially due to ethnic and environmental influences. The occurrence of MAPT variants in PSP patients ranges from 0.6 to 14.3% (25, 48–50). The most commonly observed MAPT variant in PSP is at codon 279, found in 10 patients. Families carrying the N296 variant tend to experience an earlier onset of the disease. Almost all patients with MAPT variants are heterozygous, with only one reported case of a homozygous N296 variant. That particular patient exhibited a more severe phenotype and disease progression than did those with heterozygous variants (23). The p.K298H299insQ variant in exon 10 represents the first reported insertion variant in the MAPT gene. Patients with MAPT variants typically exhibit a gradual disease onset and are more likely to present with Parkinsonian symptoms. Pathologically, these patients often manifest standard PSP or PSP-like conditions. Table 2 shows that the vast majority of patients with MAPT variants, with the exceptions of R5L, V363I, and V363A, have a family history of Parkinsonian syndrome, dementia, or other neurodegenerative diseases. This supports the previously published notion of familial clustering in PSP (27, 51). Clinical heterogeneity has been observed even among patients carrying the same variant, including those within the same family, underscoring the complex interaction of genetic and environmental factors in PSP (33, 34, 37).

In the family we studied, the mean age at onset was 53.7 years. This is higher than the mean age at onset in the general PSP population with MAPT variants, which is approximately 45.8 years. The family’s mean duration of the disease was 13.3 years. This is longer than the mean disease duration in the general PSP population with MAPT variants, which is approximately 8.4 years. The older age at onset and longer disease duration in this family could suggest the presence of family-specific genetic or environmental factors that modulate the course of the disease. Also of interest is the presence of a genetic variant in IV-9 without clinical manifestations, which may be related to the fact that the patient was very young at the time of the present study. Future follow-up of this patient is needed to further understand this disease.

The predominance of postural instability as the initial symptom in this family aligns with observations from the broader PSP population with MAPT variants. This could have implications for early diagnosis and intervention strategies. The presence of amnesia as an initial symptom in one individual emphasizes clinical heterogeneity, even within families carrying the same MAPT variants. Memory disorder is seldom found to be one of the main symptoms of PSP, but has been described in association with MAPT variants in PSP (Table 2). The differences in age at onset and disease duration between this family and the general PSP population call for more in-depth genetic and environmental studies to uncover the reasons behind these discrepancies.

The hummingbird and morning-glory-flower signs on MRI, previously established as markers of midbrain pathology, effectively distinguish patients with PSP from those with Parkinson’s disease and multiple-system atrophy. The hummingbird sign has a 99.5% diagnostic specificity, and the morning-glory sign a 97.7% diagnostic specificity for PSP. As depicted in Figure 2 (52), our patient exhibited pronounced hummingbird and morning-glory signs. The patient’s MRI also revealed a notably small midbrain, which is indicative of a classic PSP-RS phenotype. This significant midbrain atrophy aligns well with the clinical manifestations commonly observed in patients with sporadic PSP-RS. In summary, the patient’s MRI findings are consistent with established literature, reinforcing their diagnosis as a case of PSP-RS (53–55).

Studies have indicated that ¹⁸F-Fluorodeoxyglucose PET often reveals hypometabolism in specific regions like the midbrain, basal ganglia, thalamus, and frontal lobes in patients with PSP-RS (56, 57).The most frequently observed sites of hypometabolism are the thalamus (100%), caudate nucleus (86%), midbrain (86%), and frontal lobes (71%) (58). In line with these findings, our patient also exhibited hypometabolism in these regions, as well as in the bilateral temporal poles. Uniquely, our patient exhibited hypometabolism in the bilateral temporal poles. Kanel et al. posited that a greater loss of cholinergic activity in the superior temporal poles could explain this observation in patients with PSP (59).

Although structural MRI did not reveal significant atrophy in our patient, the functional deficits were evident. Prior research has identified focal, bilateral cortical thinning in patients with PSP, predominantly in the prefrontal/precentral cortex and the temporal pole. Even in the absence of structurally significant changes in our case, the patient did present with clinically relevant cognitive deficits (60). These additional findings contribute to the complexity of the PSP clinical picture. The hypometabolism in the bilateral temporal poles could serve as another layer of diagnostic criteria, potentially distinguishing subsets of PSP patients or highlighting disease severity. Moreover, although the absence of significant cortical thinning may limit the utility of structural MRI in some PSP cases, functional markers such as hypometabolism can provide valuable insights into the disease process, especially when aligned with clinical manifestations like cognitive deficits.

Our proband demonstrated tau protein deposition in the bilateral thalamus and brainstem. The most commonly used tau tracer, ¹⁸F-AV-1451, typically shows increased uptake in multiple brain regions in PSP-RS, including the pallidum, chiasma, caudate nucleus, and thalamus (61, 62). Previous research has consistently noted increased ¹⁸F-AV-1451 uptake in the globus pallidus, putamen, and caudate nucleus, among other regions, when comparing PSP-RS with controls. Quantitative analyses have found that the best differentiation between PSP-RS and control groups is achieved through evaluating globus pallidus retention and thalamic activity (63, 64). Our proband’s tau-PET results, which showed tau protein deposits in the bilateral thalamus and brainstem, align with previous studies (65). These imaging markers further substantiate the diagnosis of PSP and contribute to our understanding of this disorder.

The key constraints of our study include the limited size of our cohort and the relatively few documented cases of PSP and PSP-like conditions with MAPT variants in existing literature. Such limitations could introduce publication or selection bias, as well as inconsistencies in symptom reporting and grading across different studies. To fully grasp the complex clinical heterogeneity observed in patients with MAPT variants, larger sample sizes are needed.

Ethical constraints also prevented further genetic studies among other family members to clarify the gene’s pathogenicity, though we plan to pursue this in future research. Additionally, the review may be subject to publication bias, particularly because genetic screening is not commonly performed in some rural areas of China. To affirm the prevalence of MAPT variants in China, broader multicenter genetic studies are necessary.

The PSP pedigree caused by the novel MAPT (E342K) variant have been expanding the mutational spectrum of MAPT. The findings in the present study may be helpful for the development of targeted therapeutic interventions of PSP.

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2022), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA006913) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.

This study was approved by the ethical review board of Peking Union Medical College Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

HL: Writing – original draft, Writing – review & editing, Data curation, Investigation. QL: Writing – original draft, Writing – review & editing. QW: Writing – original draft, Writing – review & editing, Software. RC: Writing – original draft, Writing – review & editing. T-CY: Writing – original draft, Writing – review & editing, Resources. YL: Writing – original draft, Writing – review & editing, Funding acquisition, Project administration, Resources, Supervision.