Down syndrome is the most common chromosomal disorder affecting the nervous system in humans. A genetic condition, Down syndrome is recognized by impaired cognitive and physical development. People with the condition have long been known to face higher rates of many other illnesses, including heart disease and immune disorders. Research in the past has focused mainly on how Down syndrome affects the central nervous system, but a new study out of Johns Hopkins has delved into a less researched side of the problem.

Rejji Kuruvilla, an associate professor in the Johns Hopkins department of biology, believes that focusing on the central nervous system only is leaving a lot out. Dysfunction of the peripheral nervous system is also a common manifestation with Down syndrome, and impairment could contribute to diabetes, heart disease, and immune disorders.

“There’s been a whole aspect of the nervous system that has been ignored in Down syndrome and perhaps in other neurological disorders,” Kuruvilla said in a press release.

Kuruvilla’s lab aimed to understand the connection between Down syndrome and the peripheral nervous system at a molecular and cellular level. The team examined both mice, engineered to approximate a human Down syndrome genetic profile, and human organ tissues from Down syndrome patients. They found stunted peripheral nerve growth early in life for both mice and human pancreatic and spleen tissue. But the researchers still had one question: why?

Focusing on nerve growth factor, or NGF, they eventually targeted a particular gene (RCAN1) as the culprit for smothering NGF’s actions, and consequently, nerve development in Down syndrome patients. In these patients’ tissues, the gene appeared in three times the number that would be found in normal chromosomes. In a mouse model, tripling RCAN1 alone caused a loss of neurons and nerve growth, and reducing the extra dose of RCAN1 improved the survival rate of neurons. Basically, too much RCAN1 began a series of reactions that resulted in impaired peripheral nervous system development.

Kuruvilla cited the findings, published in Nature Communications, as raising even more questions: questions her team plans to pursue. One of these is how RCAN1 affects neurons in the basal forebrain, a portion of the brain that also responds to NGF. The basal forebrain is the area of the brain that deteriorates in Alzheimer’s disease patients. The researchers also planned to look into possible treatments, since peripheral nervous system dysfunction is associated with an array of medical conditions, including cardiovascular problems.

“When you think about therapeutic interventions that could affect life quality, it’s important to not ignore this important aspect of the nervous system,” Kuruvilla said.

Source: Patel A, Yamashita N, Ascano M, Bodmer D, Boehm E, Kuruvilla R, et al. RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome. Nature Communications. 2015.