Disorders derive from common molecular causes

There are a wide variety of diseases that impair the growth of the brain and nervous system, ranging from autism spectrum disorders to schizophrenia. With this large number of disorders comes an even larger number of treatments, from medications to therapies to surgeries. However, many of these seemingly different neurodevelopmental disorders may share a common cause. One treatment could be developed that would be effective for many different disorders.

Previous challenges in studying the genetic causes of neurodevelopmental disorders have resulted from the difficulty in pinpointing which cellular functions are affected by which genes. Mutations in a single gene can cause separate disorders with notably different symptoms; for example, the same deletion on a segment of chromosome 15 can cause either Angelman syndrome or Prader-Willi syndrome, depending on whether the maternal or the paternal chromosome is affected.

On the other hand, a single “umbrella” disorder can originate from a complex variety of genetic mutations and molecular changes. This is the case with Alzheimer’s disease, for which the familial variant has been linked with mutations in no fewer than three different chromosomes.

A study at McGill University, led by Carl Ernst and published in the American Journal of Human Genetics, has proposed that certain genetic mutations can have remarkably similar effects on the growth and development of the brain and central nervous system.

Ernst and his team focused specifically on two enzymes: transcription factor 4 (TCF4) and euchromatic histone methyltransferase 1 (EHMT1). When these enzymes are affected, their altered functions lead to two different autism spectrum disorders.

The two disorders, named 18q21 deletion syndrome and 9q34 deletion syndrome, lead to similar delays in intellectual development and correspond with increases in psychiatric conditions such as depression and anxiety. Nevertheless, the disorders have separate names because of differences in the physical characteristics of affected individuals, their frequency of occurrence and, most importantly, the chromosomes on which the mutations occur.

The researchers altered the activity of each enzyme in human fetal brain cells, which are undifferentiated. This means that all of their genes are still expressed, and as a result, the cells are less specialized. During normal development, cells become differentiated for more specific functions, such as fighting infections or transferring energy.

Changes in either TCF4 or EHMT1 both resulted in similar changes in molecular activity in the fetal cells. These changes resembled those expressed by more mature brain cells, suggesting that the deficiencies in neurodevelopmental disorders result from these cells’ attempts to differentiate prematurely.

The research points to the fact that seemingly different disorders induced by different genetic mutations can cause similar molecular changes within cells. This could allow for a more general classification of neurodevelopmental disorders based on the molecular functions that are affected. While the possibility of such a classification could greatly simplify the ways in which scientists can understand how genetics affect human development, it is only the first step in understanding why the final effects of neurodevelopmental disorders can be so diverse.