Gene Discovery in Neurological Disorders

Public Health Burden
The burden of neurological disorders affects people of all ages. There are hundreds of neurological disorders ranging from extremely rare disorders to much more common diseases. Genetic factors contribute to many neurological disorders, and identification of disease-causing genes is often the first step toward understanding disease susceptibility, onset, and progression. Identification of genetic pathways also opens the door to study gene function, investigate disease pathophysiology, and explore strategies for therapeutic intervention.

Identification of Gene Defects Linked to Complex Neurological Diseases and Disorders
During the last decade, researchers have identified the gene defects responsible for many single-gene neurological disorders, that is, diseases caused by mutations in a single gene. For some diseases, mutations in one of several different genes can be the cause, and for other diseases, defects in multiple genes can affect susceptibility to environmental factors that lead to disease. These complexities increase the difficulties of identifying genetic factors. Researchers supported by NINDS ARRA funds have made progress toward identifying genetic factors contributing to several neurological disorders, including these more complex genetic contributions.

  • Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease): Researchers at the University of Massachusetts Medical School collaborated with international researchers to identify mutations in two large families with an inherited form of Amyotrophic lateral sclerosis (ALS). ALS, or Lou Gehrig's disease, is a rapidly progressive, fatal neurological disease that attacks the nerve cells responsible for controlling voluntary muscles. The researchers identified several different mutations in the gene for the protein profilin (PFN1) in the affected families. The mutant protein disrupts the proper growth of axons, the long processes of nerve cells. Mutant profilin also accumulates in clumps in the cells further affecting the cell’s normal function. Identification of this genetic mutation supports existing studies, which suggest that disruptions in the cells’ structure plays a role in ALS and point to possible common pathways to target for therapeutic intervention.1
  • Tourette Syndrome: A genome-wide association study recently identified possible gene variants (alterations in the genetic sequence) involved in Tourette syndrome. Tourette syndrome (TS) is a neurological disorder characterized by repetitive, stereotyped, involuntary movements or vocalizations called tics. The study, led by investigators at Massachusetts General Hospital, analyzed gene variants in a large number of individuals with and without Tourette syndrome. This study lays the groundwork for the precise identification of genes that confer susceptibility to Tourette and helps to provide a more complete understanding of how genes contribute to this disorder.2
  • Gliomas: A study led by researchers at the Mayo Clinic has further honed in on a region of the genome that increases the risk of certain types of brain tumors. The researchers identified seven gene variations in the region that are strongly associated with the risk for certain sub types of gliomas. Gliomas are among the most difficult of all tumors to treat. In general, the identification of specific gene mutations that lead to different types of tumors opens opportunities for understanding the molecular causes and developing more precisely targeted treatments.3

Identification of Genes that Contribute to Brain Malformations and Developmental Disorders
Mutations that disrupt the normal development of the brain contribute to many types of developmental disabilities. For example, mutations that affect the movement of newly generated nerve cells to their correct location in the brain may prevent the formation of appropriate brain connections. Using ARRA funds, NINDS-funded researchers have made important steps towards understanding the genetic basis of brain malformations.

  • Developmental Brain Abnormalities in the Cerebral Cortex: “Exome sequencing” is a method that capitalizes on improvements in gene sequencing technology to identify genes associated with rare disorders. Using this technique, researchers found that mutations at a single location in the genome, called WDR62, can lead to several types of developmental brain abnormalities in the cerebral cortex, the outermost layer of the brain. These irregularities, known as malformations of cortical development (MCD), may manifest as a smaller cortex, a cortex with either more or fewer folds than typical, or pockets of fluid in the brain. Children with MCDs often have severe intellectual disabilities and may not reach developmental milestones. The identification of these mutations will advance research toward understanding the mechanisms of these disorders and the search for treatment options. The information can also help couples assess the risk of passing genetic disorders on to their children.4
  • Cerebellum Development: Building on previous work, researchers at the University of Chicago identified and further characterized genes involved in the development of a part of the brain called the cerebellum. Malformations in the cerebellum result in disorders such as Dandy-Walker syndrome, which may include cognitive and intellectual deficits as well as lack of muscle coordination and other motor problems. Using mouse models, the research team identified a gene, FOXC1, required for normal cerebellar development, and found that mutations in this gene lead to a cerebellar malformation known as cerebellar vermis hypoplasia (CVH). Using human brain imaging data, they showed that patients with a mutation in this gene also have CVH.5 The researchers went on to show that FOXC1 likely plays a role, together with other previously identified genes, in the development of Dandy-Walker syndrome and other related cerebellar malformations.6 An improved understanding of the developmental and genetic causes of these malformations will provide valuable diagnostic information and lead to better understanding of brain development and its disorders.

Contributing NIH Institutes & Centers

  • National Institute of Neurological Disorders and Stroke (NINDS)