Infantile Tauopathies: Changing How We Think of Neurodegeneration

When we think of the term, “neurodegeneration,” the classic pictures of Alzheimer’s or Parkinson’s Diseases typically come to mind. We may envision an older person who exhibits memory loss, maybe psychosis, or has some sort of progressive motor disorder, all of which ultimately leads to medical complications and eventually death.


Little do we think of neurodegeneration in infancy or childhood. And yet current research indicates neurodegeneration can occur at any age.

Granted, infantile neurodegeneration doesn’t share the same course as senile or even adult neurodegenerative disorders. Even though symptoms may worsen over time, neurodegeneration in infancy often isn’t fatal. Instead, it generally causes various forms of developmental delay/intellectual disability and sometimes seizures.

Although it’s early days, the dynamic duo, Harvey Sarnat and his wife, Laura Flores-Sarnat, have brought attention to the existence of “tauopathies” in infancy and childhood. Tau proteins are vital in helping to stabilize the cytoskeletal network within cells, which is the mobile skeleton of the cell. You may have heard them mentioned in relation to Alzheimer’s pathogenesis, as they comprise the pathologic “tangles” partly characteristic of the disease.

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Taken from Sarnat et al. (2012).

Conditions that the Sarnats have helped to identify/confirm as infantile tauopathies include:

  • tuberous sclerosis
  • hemimegalencephaly
  • focal cortical dysplasia type 2b
  • ganglioglioma

Each of these conditions overexpresses the phosphorylated form of tau, which is also linked with senile forms of neurodegeneration (phospho-tau is misshapen and therefore can’t form bonds properly with microtubules in order to help them stabilize). Each of these conditions also displays overactivation of the mTOR pathway, which is a major cell growth-related pathway, and they exhibit certain cellular malformations within the brain, such as balloon cells (see below). Finally, they are all the result of mosaic mutations, meaning that only certain organs of the body, such as the brain, have these mutations.


Examples of balloon cells seen in both focal cortical dysplasia 2b (FCD IIb) and tuberous sclerosis (TSC). Borrowed from Iyer et al. (2013).

Iyer et al. (2013) have also reported finding an abundance of the beta-amyloid precursor protein in the brains of those with focal cortical dysplasia 2b and tuberous sclerosis, which, as the name suggests, is the precursor to the beta-amyloid protein found in plaques in Alzheimer’s disease.

The existence of these infantile tauopathies can teach us some valuable lessons: Not only does it illustrate the pleiotropy— different symptoms– resultant of tauopathies, it also suggests that other neurodegenerative proteopathies may exist in infancy and childhood, which we have yet to identify. There are a variety of protein inclusions linked with senile neurodegeneration, such as alpha-synuclein bodies in Parkinson’s, Lewy Body Dementia, and multiple system atrophy, and TAR DNA binding protein 43 (TBP43) and tau in frontotemporal lobar dementia. TBP43 is also found in some cases of amyotrophic lateral sclerosis (Lou Gehrig’s disease).

Ultimately, we may find that many of the common senile proteopathies share infantile counterparts and are responsible for certain types of intellectual disability, developmental delay, seizure disorders, and even perhaps some types of autism. Currently, I am actively engaged in investigating the latter, with promising results that support the idea that a subset of rare forms of autism may in fact be proteopathies. Clearly, that’s the case for the autism-associated, tuberous sclerosis. And time will tell whether more types of autism share similar features.

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