Familial Dysautonomia (FD), also known as Riley-Day syndrome, is a rare genetic disorder that primarily affects the development and function of the autonomic nervous system (ANS) and sensory neurons. The ANS controls involuntary actions such as digestion, breathing, tear production, and regulation of blood pressure and body temperature.Â
FD is characterized by a wide range of symptoms, including insensitivity to pain, unstable blood pressure, recurrent pneumonia, and difficulty swallowing. This rare condition is almost exclusively found in individuals of Ashkenazi Jewish descent, with a carrier frequency estimated at 1 in 30 within this population.
ELP1 gene (Elongator Complex Protein 1) contains instructions for making a protein that’s part of the Elongator complex. The Elongator complex is a group of proteins that help with the process of building other proteins in our cells.
The protein encoded by the ELP1 gene is crucial for the development and function of our nervous system, particularly the nerves that control automatic body functions like breathing, digestion, and blood pressure. Familial Dysautonomia is caused by mutations in the ELP1 gene, formerly known as IKBKAP (gene for the Inhibitor of κ-B Kinase-Associated Protein).Â
Approximately 99.5% of FD cases are due to a specific mutation known as the IVS20(+6T>C) or c.2204+6T>C splice-site mutation. This mutation affects the splicing of the ELP1 mRNA, leading to reduced levels of functional ELP1 protein in neuronal tissues.Â
A second, rarer mutation, R696P (c.2087G>C), accounts for most of the remaining cases. Both mutations result in a significant decrease in the ELP1 protein within neurons, impairing the development and survival of sensory and autonomic neurons.
FD is inherited in an autosomal recessive manner. This means that an individual must inherit two copies of the mutated gene—one from each parent—to manifest the disease. Carriers, who have only one copy of the mutation, typically do not show symptoms but can pass the mutation to their offspring.
In 2011 researchers studied how the ELP1 (IKBKAP) gene is spliced using stem cells derived from the nasal tissue of FD patients. These cells are known as human olfactory ecto-mesenchymal stem cells (hOE-MSCs). By examining how alterations in the splicing of ELP1 mRNA influence gene expression across the entire genome, they discovered that the gene expression patterns in FD are closely linked to the development of the nervous system.
The researchers also investigated the effects of kinetin, a plant compound that can correct the splicing error in the IKBKAP (ELP1) gene. They found that kinetin increases the levels of IKAP/hELP1 protein and may regulate the factors involved in splicing. This provided new evidence that kinetin can specifically correct splicing errors in the genetic sequence.
The c.2204+6T>C mutation in ELP1 creates a defective splice donor site, resulting in exon skipping during mRNA processing. This splicing defect is tissue-specific, predominantly affecting neural tissues while sparing others. This specificity contributes to the neurological symptoms observed in FD patients.
The reduced expression of the ELP1 protein leads to defective neuronal development, particularly affecting the autonomic and sensory neurons. The Elongator complex, of which ELP1 is a part, is essential for the proper modification of tRNA (the RNA that is involved in making proteins) molecules, which in turn affects protein synthesis. The impaired function of this complex disrupts the production of proteins necessary for neuron growth and survival, leading to the degeneration of nerve cells.
Individuals with FD exhibit a range of symptoms due to the dysfunction of the autonomic and sensory nervous systems:
The severity and combination of symptoms can vary among individuals, but the condition is progressive and can lead to significant morbidity.
Early diagnosis of FD is crucial for managing symptoms and improving quality of life. Clinical evaluation includes assessing characteristic features such as lack of tears when crying, poor muscle tone, and feeding difficulties.
Definitive diagnosis is achieved through genetic testing to identify mutations in the ELP1 gene. Given the high prevalence of the common c.2204+6T>C, or IVS20+6T>C mutation among Ashkenazi Jews, targeted mutation analysis is often effective among them.
FD is most prevalent among individuals of Ashkenazi Jewish descent due to a founder effect, where a small ancestral population contributed a higher frequency of the mutation. The carrier rate in this population is approximately 1 in 30, making genetic screening particularly important.
Community-wide carrier screening programs have been implemented to identify carriers and provide genetic counseling. This has led to a significant reduction in the incidence of FD through informed reproductive choices.
For couples who are both carriers, there is a 25% chance with each pregnancy to have an affected child, a 50% chance to have a child who is a carrier, and a 25% chance to have a child who neither has the disease nor is a carrier.
Options for carrier couples include:
Genetic counseling also provides psychosocial support to families, helping them understand the implications of carrier status and make informed decisions.
Research is ongoing to develop therapies that increase the production of functional ELP1 protein.Â
These are small molecules that modify splicing mechanisms to increase correct ELP1 mRNA production. One example of this is kinetin as discussed in an earlier section.Â
In 2020, researchers discovered a new compound called BPN-15477 that fixes the most common splicing error mutation in the ELP1 gene responsible for familial dysautonomia (IVS20+6T>C). Using machine learning, they investigated whether BPN-15477 could correct splicing defects in other genetic diseases. By analyzing treated cell samples, they identified patterns in gene sequences that respond to the compound, particularly at certain splice sites. They predicted and confirmed that BPN-15477 could repair splicing errors in 155 other disease-related genes, including those linked to cystic fibrosis and Lynch syndrome.
In 2021, researchers discovered another small molecule that can bypass the IVS20+6T>C mutation. This is called RECTAS. The RECTAS molecule essentially corrects the splicing error created by the IVS20+6T>C mutation. This has been demonstrated in various FD disease models and offers a new approach for treating diseases caused by splicing errors.
Other therapeutic approaches include gene therapy (strategies to deliver functional copies of the ELP1 gene to affected neurons) and the use of neuroprotective agents (compounds that promote neuron survival and function).
Familial Dysautonomia is a severe genetic disorder with a well-characterized genetic basis involving rare mutations in the ELP1 gene. The autosomal recessive inheritance pattern and high carrier frequency in the Ashkenazi Jewish population highlight the importance of genetic screening and counseling.
Advances in understanding the molecular mechanisms of FD have opened avenues for potential therapies, offering hope for improved outcomes. Continued research is essential to develop effective treatments and support affected individuals and their families.
