A Look into Life Without the Cerebellum: Cerebellar Agenesis (by Danielle Steinbach)
Jan 26, 2026Throughout the history of life, it is often the case that animals must wait for an advantageous mutation to come along that saves the species and allows them to survive their environment. Among the billions of species that have lived and languished and thrived on the face of this Earth, there has been one common thread, and that is helplessness when met with the changing winds of the world.
Humans, however, seem to be an anomaly among the other species. We are not born quite as fixed and rigid. Our brains, once born, are not done developing–they are malleable pieces of clay for the world to imprint itself on. One’s behavior can be fine-tuned and calibrated to their surroundings. Thus, birth only marks the beginning of a rapid growth period in the brain. Indeed, one particular section of the brain develops at a particularly fast-tracked pace, roughly doubling in size within the first few months–the cerebellum. Proprioception, balance, and motor learning are all controlled by the cerebellum. As an infant observes the world, their understanding of themselves in space and how to perform necessary sequences of movement expands exponentially. At least, in most cases.
Every once in a while, though, an outlier comes around, as it did in the year 1993. It was this year that the parents of a young boy named Jonathan Keleher began to develop concerns about their son. For years, their son seemed to be on a delayed timeline of motor skill development. Coordinated movements such as picking up a fork and standing were less easily learned and perfected. Wanting to understand how to help their son, Keleher’s parents took him to the hospital for extensive scans and tests. As it turned out, Jonathan’s condition did not stem from the presence of some pathogen or malignant growth–rather, it stemmed from the lack of something. Roughly 10% of Jonathan’s brain was missing. Upon scan results, Jonathan was quickly diagnosed with cerebellar agenesis–that is, he was born without a cerebellum. Jonathan became one of less than twenty patients in the world with this condition.
Given that cerebellar agenesis is a congenital condition, in order to discover its root causes, one must look to embryonic development. In the initial days of embryonic development, three germ layers (which can be considered tissue precursors) emerge. From innermost to outermost, these layers are the endoderm, mesoderm, and ectoderm. It is from the ectoderm that the full nervous system arises in a complex orchestra of signaling chemicals, radial glia that act as scaffolds, and newly developed neurons. But that particular story of development is another blog for another day.
For now, what is important to know about the ectoderm is that it eventually folds in on itself to form a structure called a neural tube. This neural tube will then further divide into distinct sections that will form different regions of the brain, including the forebrain, midbrain, hindbrain, and spinal cord. Within the hindbrain region of the neural tube–known as the rhombencephalon–a substructure of tissue called the metencephalon develops. It is from the metencephalon that we get the cerebellum and a brainstem structure called the pons. Generally, genes in the cells making up the metencephalon will receive chemical signals from their surroundings that alter their gene expression in such a way that causes differentiation into cerebellar cells. However, there exist exceedingly rare cases in which an early mutation in the PTF1A gene occurs that throws off this precise process.
Researchers working with mouse models have leveraged a technique referred to as genetic fate mapping to fluorescently tag cells expressing PTF1A. These experiments suggest that PTF1A plays a critical role in preventing early cerebellar cells from migrating further back to the brainstem (Millen et al., 2014). When PTF1A expression is disturbed, the cerebellum becomes underdeveloped or completely absent as more cells venture and settle further back into the brainstem.
What we just covered is a purely genetic explanation for cerebellar agenesis. We must not neglect the potential for environmental factors though, as a growing fetus–despite being seemingly shielded from the outside world–is arguably most vulnerable to changes in its immediate surroundings. In this case, the fetus’ environment is determined largely by the composition of the mother’s bloodstream. When pathogens like Zika virus and cytomegalovirus (CMV) cross the placenta through the mother’s blood and reach the fetus, the effects can sometimes be seen in cerebellar development. In order to defend the fetus against the pathogen, immune cells will initiate an inflammatory response that may partially disrupt circulation to the metencephalon. This drought of blood–and particularly the oxygen it carries–could stagnate or, in extreme cases, arrest the growth of cells in the cerebellum. As a result, in very few cases, cerebellar agenesis may result from fetal exposure to infections.
However, there is certainly always hope, and I’d like now to come back around to where we began, with young Jonathan Keleher. Since his diagnosis at the age of five, Keleher has lived over thirty years working, deepening relationships, forming new ones, and building on his motor skills. And this is the amazing capacity of the human brain and the human species to continue supporting a productive life in the face of loss and change.
-- Danielle Steinbach
Sources
https://rarediseases.org/rare-diseases/cerebellar-agenesis/
https://www.sciencedirect.com/science/article/pii/S1930043324006459
https://www.ncbi.nlm.nih.gov/books/NBK557414/#:~:text=Structure%20and%20Function,%5D%5B5%5D%5B6%5D