Familial dysautonomia, also known as Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III (HSAN III), is a rare genetic disorder that primarily affects the autonomic and sensory nervous systems. It is inherited in an autosomal recessive manner, meaning both parents must pass on a mutated gene for an individual to be affected. It is a disease almost exclusive to the Ashkenazi Jewish population, with an incidence of 1 case per 3.600 births.
Familial dysautonomia genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of familial dysautonomia include:
- Autonomic Dysfunction: Dysfunction of the autonomic nervous system, which controls involuntary bodily functions such as blood pressure, heart rate, digestion, and temperature regulation. This can lead to problems with blood pressure control, swallowing difficulties, and temperature instability.
- Sensory Impairments: Impairments in the sensory nervous system, causing reduced pain and temperature sensation. Individuals with familial dysautonomia may be less sensitive to pain and temperature changes, leading to an increased risk of injuries.
- Gastrointestinal Issues: Problems with digestion, including difficulty swallowing, gastroesophageal reflux, and episodes of vomiting.
- Breathing Difficulties: Respiratory problems, such as recurrent pneumonia and breath-holding episodes.
- Orthostatic Hypotension: Episodes of low blood pressure upon standing can lead to dizziness and fainting.
- Gait and Motor Difficulties: Coordination and gait problems may be present, and individuals with familial dysautonomia may exhibit unsteady and jerky movements.
Familial dysautonomia is caused by mutations in the IKBKAP gene located on chromosome 9. The IKBKAP gene provides instructions for making an IκB kinase complex-associated protein (IKAP) protein. The specific role of IKAP in causing the symptoms of familial dysautonomia is not fully understood.
There is currently no cure for familial dysautonomia, and treatment primarily focuses on managing symptoms and improving the quality of life for affected individuals. Supportive care may include physical therapy, occupational therapy, medications to address specific symptoms, and measures to prevent complications.
Due to the autosomal recessive inheritance pattern, individuals with familial dysautonomia typically have unaffected parents who are carriers of the mutated gene. Genetic counseling is crucial for families affected by familial dysautonomia, providing information about the risk of passing the condition to future generations and family planning options.
FD affects the development and survival of sensory, sympathetic, and parasympathetic neurons. However, neuronal deficits have also recently been detected in the central nervous system of these patients. As previously indicated, FD is due to pathogenic variants in the ELP1 gene. This gene codes for a protein part of the elongator complex in the cell nucleus and cytoplasm. This complex plays a crucial role in transcription and histone acetylation in the nucleus. In the cytoplasm, ELP1, either as a component of the complex or independently, is involved in various cellular functions, such as cell migration and adhesion, intracellular trafficking, among other processes.
The pathogenic variant c.2204+6T>C (also called IVS20+6T>C) in ELP1 affects a splicing site and leads to the deletion of exon 20. This is the most frequent variant in Ashkenazi patients, 1.3% of this population carries IVS20+6T>C which is in more than 95% of FD cases, highlighting its founder effect.
A second pathogenic variant found in this population is c.2087G>C (p.Arg696Pro), which produces an amino acid change affecting a highly conserved serine/threonine phosphorylation site. The presence in compound heterozygosis of IVS20+6T>C and c.2087G>C, i.e. having one copy of IVS20+6T>C and one copy of c.2087G>C, produces typical FD symptoms. No homozygous individual for c.2087G>C has been identified.
Familial dysautonomia genetic testing analyzes the 2 most frequent pathogenic mutations of the ELP gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
