Familial Dysautonomia (FD), also known as Riley-Day syndrome, is a rare, inherited disorder of the nervous system. This condition is present from birth and is classified as a hereditary sensory and autonomic neuropathy (HSAN type III). The disorder is progressive, impacting the development and survival of specific nerve cells. FD is overwhelmingly found in individuals of Ashkenazi Jewish descent, making it a founder mutation disease within that population.
Defining Familial Dysautonomia
The underlying issue in Familial Dysautonomia involves the malfunction of two major components of the peripheral nervous system: the autonomic nervous system (ANS) and the sensory nervous system. The ANS controls all involuntary actions that the body performs without conscious thought. This includes essential functions like breathing, heart rate, digestion, blood pressure regulation, and body temperature control.
The sensory neurons are responsible for gathering information from the body, such as the perception of pain, temperature, and body position. In FD, the development and survival of these sensory and autonomic neurons are compromised. This means the body struggles to perform basic self-regulatory processes and cannot properly sense the external or internal environment.
Major Clinical Manifestations
The widespread nerve dysfunction in FD results in a broad and complex array of symptoms that often present starting in infancy. A hallmark of the disorder is the altered sensitivity to pain and temperature, often leading to a reduced ability to perceive injury. Affected individuals can sustain burns or fractures without realizing the extent of the damage, which poses a significant safety risk.
Gastrointestinal (GI) issues are nearly universal and highly problematic, including poor coordination of the mouth and throat muscles for feeding (oropharyngeal incoordination). This can cause severe feeding difficulties, poor growth, and recurrent aspiration pneumonia from inhaling food or stomach contents. Esophageal dysmotility and gastroesophageal reflux disease (GERD) are also common due to the lack of proper autonomic control over the digestive tract.
Autonomic instability is a defining feature, manifesting as extreme fluctuations in blood pressure and body temperature. Patients frequently experience orthostatic hypotension, a sharp drop in blood pressure upon standing, which can cause dizziness and fainting. Conversely, they may also suffer from episodic hypertension during times of stress or excitement.
Dysautonomic Crises
The most dramatic autonomic events are known as “dysautonomic crises.” These involve episodes of protracted vomiting, profuse sweating, skin blotching, and dramatically high blood pressure. These crises can be triggered by stresses like infection, emotional upset, or a full bladder, and can last for days.
Ocular and Motor Symptoms
A distinct ocular sign is the absence of overflow tears during emotional crying (alacrima). This, combined with reduced corneal sensation, often leads to dry eyes and corneal damage. Motor coordination is also affected, resulting in hypotonia (poor muscle tone) in infancy and a progressively unsteady gait (ataxia) in older individuals.
Genetic Basis and Inheritance
Familial Dysautonomia is caused by mutations in the ELP1 gene (previously IKBKAP). This gene provides instructions for making the Elongator-1 protein, which is important for the proper development and function of nerve cells. The most common mutation disrupts how genetic information is processed, resulting in a reduced amount of functional ELP1 protein, especially in the brain.
The condition is inherited in an autosomal recessive pattern. This means a child must inherit two copies of the mutated ELP1 gene—one from each parent—to be affected. Parents who carry one copy of the mutated gene are typically healthy carriers, but they have a one in four chance of having an affected child with each pregnancy. Genetic testing confirms the diagnosis by identifying pathogenic variants in the ELP1 gene.
Management and Supportive Care
Since there is no cure for Familial Dysautonomia, treatment focuses on managing symptoms and preventing complications. Management requires a multidisciplinary team, including neurologists, pulmonologists, and gastroenterologists. A primary focus is controlling blood pressure lability, which may involve medications like midodrine or fludrocortisone for low blood pressure and antihypertensives for high blood pressure.
Autonomic crises are managed acutely with interventions like benzodiazepines to reduce vomiting and retching, alongside aggressive hydration. Gastrointestinal support is frequently needed to manage feeding difficulties and aspiration risk, often necessitating the use of feeding tubes (gastrostomy) to ensure adequate nutrition and protect the lungs. Respiratory care is crucial, as chronic lung disease from repeated aspiration pneumonia is a leading cause of illness and death.
Physical and occupational therapies address motor and sensory deficits, helping patients maintain mobility and independence. Orthopedic issues like scoliosis are common and require monitoring and treatment, sometimes involving surgery, to prevent restrictive lung disease. Regular monitoring of eye health is essential, with measures taken to keep the eyes moist due to the lack of overflow tears.