On Oct. 10, 2023, the University of Wisconsin-Madison researchers announced a new study published in the journal Neuron showed that FMRP, a protein deficient in individuals with fragile X syndrome, has a role in the function of mitochondria, part of a cell that produces energy, during prenatal development. Their results fundamentally change how scientists understand the developmental origins of fragile X syndrome and suggest a potential treatment for brain cells damaged by the dysfunction.

Fragile X syndrome, the most common form of inherited intellectual disability, may be unfolding in brain cells even before birth, despite typically going undiagnosed until age 3 or later. Individuals with FXS may present developmental delays — not sitting, walking or talking at expected ages — as well as mild to severe intellectual disability, learning disabilities and social and behavioral problems. About half are also diagnosed with autism spectrum disorder.

In previous research, Zhao found that mitochondria in mice with an FMRP deficiency that imitates FXS were smaller and unhealthy. Diving deeper, they also discovered that FMRP regulates genes involved in mitochondria fission-fusion, a process in which mitochondria fuse into a bigger shape in order to produce more energy for the cell.

For the study, researchers grew brain cells called neurons grown from induced pluripotent stem cells. Because the stem cells came from people with FXS, the researchers could study the development of the disorder at a cellular level, determining whether mitochondria in human cells experienced issues similar to those in mice.

Although it has long been known that FMRP is deeply involved in FXS, the new discovery pinpoints a role for the protein in early development of the condition.

Symptoms of FXS present long after the baby is born. Many babies appear to be developing typically before showing slower development, autistic features or developmental deficits. Children with FXS are typically diagnosed at three years of age or older.

Using cultured neurons derived from individuals with FXS to screen for drugs, the researchers found a drug called leflunomide that corrected mitochondrial deficits. The treatment improved mitochondrial function and reduced the neurons’ hyperexcitability.