Expanding MAPT p.V363I Mutation Phenotype: An Overlapping of PSP‐CBS and Posterior Cortical Atrophy

Mutations in the microtubule‐associated protein tau gene (MAPT) are associated with heterogeneous clinical and pathological manifestations, and their pathogenicity is based on two different mechanisms: missense and splicing mutations, leading to aggregates of insoluble filaments of tau. ¹ This letter describes the phenotype of a patient carrying the rare variant MAPT p.V363I mutation and explores the clinical presentation through multimodal imaging biomarkers.

A 49‐year‐old woman presented a 2‐year history of progressive slowed gait, visuospatial difficulties, rigidity, and dexterity impairment. Neurologic examination demonstrated asymmetric left‐sided parkinsonism, left upper limb dystonia, and vertical supranuclear gaze palsy with slowed horizontal saccades (Video 1). She had bilateral ideomotor apraxia, worse on the left arm (Video 1), and presented all Balint syndrome components (Video 2). She also demonstrated left spatial hemineglect (Video 2). There were no behavioral disturbances. Concerning family history, her parents were not consanguineous and had no neurologic symptoms. Her mother was 70 years old, and her father died at 80 years of age due to cardiac causes. She has two healthy brothers and two healthy children.

Video 1.

Segment 1 displays asymmetric left‐sided bradykinesia on the finger‐tapping test and left upper limb dystonia. Segment 2 shows vertical ophthalmoplegia on the vertical pursuit and vertical saccades, which is more prominent to upgaze than downgaze, and normal oculocephalic reflex. Segment 3 displays bilateral upper limb ideomotor apraxia, worse on the left arm.

Video 2.

Segment 4 demonstrates the Balint syndrome components, such as simultanagnosia through the description of the cookie theft figure, optic ataxia when the patient shows difficulty reaching the key without sound, and oculomotor apraxia, worse to the left gaze. Visual left hemineglect is also observed during the description of the cookie theft figure.

Therefore, she was clinically diagnosed with probable corticobasal syndrome (CBS), ² overlapping with possible progressive supranuclear palsy (possible PSP‐OM). ³ She also fulfilled the criteria for posterior cortical atrophy (PCA). ⁴ A comprehensive investigation was performed. Laboratory findings were normal. Brain magnetic resonance imaging (MRI) disclosed atrophy in the mesencephalon and right parieto‐occipital regions (Fig. 1). [¹⁸F] Fluorodeoxyglucose‐positron emission tomography (PET) showed an asymmetric hypometabolism in the right frontal, parietal and occipital lobes and right striatum. She tested negative for cortical amyloid deposition on a [¹¹C] Pittsburgh compound‐B‐PET scan (Fig. 1). A commercial genetic panel (Invitae Hereditary Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Alzheimer's Disease Panel) identified that she was heterozygous for a pathogenic variant in the MAPT gene p.V363I (Supporting Information 1). Additionally, we performed the same genetic panel on her mother. Interestingly, we identified that she was also heterozygous for the MAPT gene p.V363I variant (Supporting Information 2).

FIG. 1.

(A) FDG‐PET 3D‐stereotactic surface projection (3D‐SSP, Cortex ID suite software, GE Healthcare): moderate to severe hypometabolism on right frontal and parietal areas, including the supplementary motor cortex and less severely the primary sensory and motor cortex, with metabolic impairment in a lesser extension on the contralateral (left) side. Severe right occipital and temporo‐occipital hypometabolism is also seen. (B) 3D‐SSP Z score map of the FDG‐PET highlights the areas with metabolic impairment compared to an age‐matched control group (Cortex ID Suite, Z score threshold of −2.0 SD). (C) Transaxial FDG‐PET images: mild to moderate hypometabolism on the right striatum and thalamus (yellow arrows). (D) T1w MRI (weighted magnetic resonance imaging): mild volumetric reduction of the mesencephalon, more prominent on the right side (white arrow). (E) Fused PET/MRI images of PIB‐PET and a T1w MRI scan showing an absence of amyloid deposition on gray matter and physiological uptake of the tracer on white matter tracts (negative amyloid PET), with mild asymmetric atrophy of the frontoparietal, posterior parietal, and occipital cortex (worst on the right side) and in the right insula. FDG‐PET, [18F] Fluorodeoxyglucose‐positron emission tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; PIB‐PET, [¹¹C] Pittsburgh compound‐B‐positron emission tomography

Different phenotypes have been associated with autosomal‐dominant MAPT mutations at the V363 codon, including behavioral, cognitive, and parkinsonian syndromes. ¹ , ⁵ The p.V363I variant is a missense mutation located in the MAPT microtubule‐binding domain on chromosome 17, confirmed as pathogenic and a cause of corticobasal degeneration pathology. ⁵

Clinical syndromes previously related to the p.V363I variant were semantic dementia, ⁶ primary progressive aphasia, ¹ behavioral variant frontotemporal dementia, ⁷ CBS, ⁵ and PCA. ¹ Some individuals had more than one syndrome at presentation. ⁵ This variant has only been described in nine patients ⁵ and is not related to PSP yet. However, a single case presented a PSP syndrome carrying a mutation in the same residue (p.V363A). ⁵ Moreover, none of the previous descriptions displayed PSP, CBS, and PCA phenotypes on the same subject. ¹ , ⁵

The fact that her mother was positive for this mutation, but asymptomatic reinforces prior studies that suggested its incomplete penetrance. ¹ Additionally, imaging findings are congruent with the presentation and previous case reports. ⁵ We also excluded Alzheimer's disease co‐pathology, another cause of PCA.

Finally, we described a patient with the MAPT p.V363I variant presenting a unique PSP‐CBS and PCA clinical syndrome, which might aid in understanding the clinical heterogeneity and genetic underpinnings of this rare mutation.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review, and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review, and C. Critique.

J.B.P.: 1A, 1B, 1C, 3A.

A.M.C.: 1A, 1B, 1C, 3B.

T.G.G.: 1B, 1C.

J.Y.: 1B, 1C.

L.T.T.: 1B, 1C.

R.N.: 3B, 3C.

E.R.B.: 3B, 3C.

S.M.D.B.: 3B, 3C.

Disclosures

Ethical Compliance Statement: The ethical committee of the University of Sao Paulo approved the investigation procedure and informed consent under protocol number 2.046.113. The patient provided written informed consent for the study. We confirm that we have read the Journal's position on ethical publication issues and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This report is part of research supported by the São Paulo Research Foundation (FAPESP) in Brazil, reference number 2017/10033‐4. The authors report no disclosures and no conflicts of interest.

Financial Disclosure for the Previous 12 Months: The authors report no disclosures.

Supporting information

Figure S1. Pedigree chart.

Appendix S1. Supporting information.

Appendix S2. Supporting information.