Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic, CBS : Pathogenic, Globular Glial Tauopathy : Pathogenic
Clinical Phenotype: Corticobasal Syndrome, Frontotemporal Dementia, Globular Glial Tauopathy
Position: (GRCh38/hg38):Chr17:46010388 C>A
Position: (GRCh37/hg19):Chr17:44087754 C>A
dbSNP ID: rs63751438
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to ACG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This was the third mutation discovered at the 301 codon in MAPT. It was identified in a 57-year-old man with a two-year history of cognitive decline, gait disturbances, behavioral changes, apathy, speech difficulties, and falls. MRI showed mild global atrophy that was more prominent in the frontal and temporal lobes. Four family members had similar symptoms, but genetic analysis was not possible and segregation could not be assessed (Lladó et al., 2007).

Subsequently the P301T mutation was found in two additional families from the Navarra region of northern Spain (Erro et al., 2019). The clinical presentations of afflicted individuals varied, but neuropathological findings support a diagnosis of familial globular glial tauopathy (GGT).

Two members of the first family, a mother and son, received clinical evaluations. The mother was diagnosed with corticobasal syndrome at age 68, and she died four years later. Imaging studies prior to death revealed atrophy of the left parietal and temporal cortices. Her son started showing gait disturbances at age 45, and after neurological examination, he received a diagnosis of primary lateral sclerosis syndrome. As his disease progressed, he exhibited speech difficulties, cognitive decline, and abnormal behavior. MRI revealed atrophy of frontotemporal cortex, left hippocampus, and mesencephalon, as well as white-matter lesions. He died at age 49. The son was found to be heterozygous for the MAPT P301T mutation; genetic data were not available from the mother. Additionally, the father of the female patient was reported to have died at age 53, after experiencing rapid cognitive decline.

Three siblings from the second family were clinically evaluated and genotyped. Two brothers were diagnosed with corticobasal syndrome in their 40s, while their sister was diagnosed with frontotemporal dementia at age 55. The average disease duration among these patients was five to six years. MRI revealed frontotemporal atrophy in one brother, posterior parietal atrophy and white-matter involvement in the other brother, and white-matter lesions in the sister. All three siblings were heterozygous for the MAPT P301T mutation. Family history included several other relatives who reportedly suffered from neurological deficits, including the mother of the three siblings, who died at age 54 after a period of rapid cognitive decline.

Neuropathology

Neuropathological data are available from four of the five patients in the case series reported by Erro and colleagues (Erro et al., 2019). The most striking finding was the presence of globular deposits composed of four-repeat tau in astrocytes and oligodendrocytes in all of the cases examined. Other findings include neuron loss in frontal cortex, substantia nigra, and spinal cord; spongiosis and astrogliosis in cortex and subcortical regions; neurofibrillary tangles; and demyelination of the corticospinal tracts.

Biological Effect

Unknown.

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References

Paper Citations

1. Lladó A, Ezquerra M, Sánchez-Valle R, Rami L, Tolosa E, Molinuevo JL. A novel MAPT mutation (P301T) associated with familial frontotemporal dementia. Eur J Neurol. 2007 Aug;14(8):e9-10. PubMed.
2. Erro ME, Zelaya MV, Mendioroz M, Larumbe R, Ortega-Cubero S, Lanciego JL, Lladó A, Cabada T, Tuñón T, García-Bragado F, Luquin MR, Pastor P, Ferrer I. Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings. J Neurol. 2019 Oct;266(10):2396-2405. Epub 2019 Jun 12 PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database