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Clinical and neuropathological variability in the rare IVS10 + 14 tau mutation
Selena P Maxwell1, Meghan K Cash1, Kenneth Rockwood2
1Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract:
Mutations in the microtubule-associated protein tau gene are known to cause progressive neurodegenerative disorders with variable clinical and neuropathological phenotypes, including the intronic 10 + 14 (IVS10 + 14) splice site mutation. Three families have been reported with the IVS10 + 14 microtubule-associated protein tau mutation. Here, we describe the clinical and neuropathological data from an additional family. Neuropathological data were available for 2 of the 3 cases, III-4, and III-5. While III-5 had widespread tau deposition and atrophy, III-4 exhibited more mild neuropathological changes except for the substantia nigra. The previously reported families that express the IVS10 + 14 mutation exhibited significant interfamilial heterogeneity, with symptoms including amyotrophy, dementia, disinhibition, parkinsonism, and breathing problems. In addition to expressing many of these symptoms, members of this fourth family experienced profound sensory abnormalities and sleep disturbance. Although there were probable clinicopathological correlates for the symptoms expressed by the earlier families and III-5 from our cohort, pathology in III-4 did not appear sufficient to explain symptom severity. This indicates the need to explore alternate mechanisms of tau-induced brain dysfunction.
Insights
A novel microtubule-associated protein tau (MAPT) mutation, IVS10 + 14, causes varied neurodegenerative symptoms. This fourth family shows unique sensory and sleep issues, suggesting alternative tau dysfunction mechanisms beyond direct pathology.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Microtubule-associated protein tau (MAPT) gene mutations are linked to neurodegenerative diseases.
- The intronic 10 + 14 (IVS10 + 14) splice site mutation in MAPT has been identified in three families.
- Clinical and neuropathological heterogeneity is observed in families with MAPT mutations.
Purpose of the Study:
- To report the clinical and neuropathological findings of a fourth family with the IVS10 + 14 MAPT mutation.
- To compare the phenotype and pathology of this family with previously reported cases.
- To investigate potential alternative mechanisms of tau-induced neurodegeneration.
Main Methods:
- Clinical data collection from affected family members.
- Neuropathological examination of brain tissue from deceased individuals (Cases III-4 and III-5).
- Comparison of findings with existing literature on MAPT mutations.
Main Results:
- The fourth family presented with symptoms including amyotrophy, dementia, disinhibition, parkinsonism, breathing problems, sensory abnormalities, and sleep disturbances.
- Case III-5 showed widespread tau deposition and atrophy.
- Case III-4 exhibited milder neuropathological changes, primarily affecting the substantia nigra, which did not fully correlate with symptom severity.
Conclusions:
- The IVS10 + 14 MAPT mutation leads to significant interfamilial and intrafamilial clinical heterogeneity.
- While some symptoms in Case III-5 correlated with pathology, Case III-4's symptom severity suggests other factors contributing to tau-induced brain dysfunction.
- Further research is needed to explore alternative mechanisms driving neurodegeneration in MAPT mutation carriers.
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