Genetic Disorders with Tau Pathology: A Review of the Literature and Report of Two Patients with Tauopathy and Positive Family Histories

Abstract

Background: Tauopathies are a group of neurodegenerative disorders characterized by the pathological accumulation of hyperphosphorylated and insoluble tau protein within neurons and glia. Although most cases are sporadic, hereditary tauopathies have also been reported.

Summary: In this article, we review genetic disorders in which tau pathology has been reported and present two novel families with primary tauopathies. Mutations in the microtubule-associated protein tau gene (MAPT) cause a small subset of primary tauopathies. Mutations in 21 other genes and an 18q deletion syndrome have also been reported to be associated with tau pathology reminiscent of Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease or Pick's disease. In 8 of the 21 genes, tau pathology was only seen in cases with some 'specific' mutations. In the remaining genes, tau pathology, often in the form of Alzheimer-type neurofibrillary lesions, was a common finding but was 'not mutation specific'. The probands of the two families were diagnosed with progressive supranuclear palsy based on clinicopathological evaluation. Their family histories were relevant for parkinsonism in 3 siblings of family 1 and 1 brother and the father from family 2, but these were not autopsy-confirmed. DNA from the brains of the probands from these families was screened for MAPT and leucine-rich repeat kinase 2 gene mutations, but no mutations were identified.

Key messages: MAPT mutations are a cause of familial tauopathies, but other genes have also been associated with tau pathology. Novel genes still await discovery.

Figure 1. Pedigree of Family 1 (Figure 1A) and Family 2 (Figure 1B)

Round symbols indicate women; squares indicate men; numbers inside symbols indicate number of children; diagonal lines indicate that the individual is deceased. The arrow indicates the proband. A caret indicates an autopsy was completed. Black symbols indicate individual with progressive supranuclear palsy; black and white symbols indicate individuals with parkinsonism.

Figure 2. Semiquantitative assessment of tau pathology in two probands

The pattern of neuronal and glial tau pathology is similar in the probands. Number and shading represents lesion density score: 0 = none; 1 = sparse; 2 = moderate; 3 = frequent.