Riley-Day Syndrome (Familial Dysautonomia or FD) is a rare, inherited disorder affecting the nervous system’s ability to control involuntary body functions. Classified as a hereditary sensory and autonomic neuropathy (HSAN type III), this progressive condition impairs the development and survival of sensory and autonomic neurons. Since the autonomic nervous system regulates functions like breathing, heart rate, digestion, and temperature control, the disorder causes widespread dysfunction. The condition is extremely uncommon, with only a few hundred cases known globally.
Genetic Basis and Inheritance
Riley-Day Syndrome arises from a genetic alteration in the ELP1 gene, formerly known as IKBKAP, located on chromosome 9. This gene provides instructions for making a protein that plays a role in the growth and survival of sensory and autonomic nerve cells. The pathogenic variant causes a problem with splicing, resulting in the production of a reduced amount of functional protein.
The disorder follows an autosomal recessive pattern of inheritance. This means that a child must inherit two copies of the altered gene—one from each parent—to be affected by the syndrome. Parents who carry only one copy of the altered gene are typically asymptomatic but have a 25% chance with each pregnancy of having a child with the disorder. The condition is seen almost exclusively in individuals of Ashkenazi Jewish descent, where the carrier frequency is estimated to be approximately one in 30 people.
Clinical Manifestations
The wide array of problems associated with Riley-Day Syndrome stems from the dysfunction of the sensory and autonomic nervous systems. The sensory neuron issues cause a reduced ability to perceive pain, temperature, and taste, which often results in frequent, unnoticed injuries like burns and bone fractures. The absence of the lingual fungiform papillae on the tongue contributes to an impaired sense of taste.
The most profound effects result from the autonomic instability, which disrupts the body’s ability to maintain a stable internal environment. Patients experience episodes of wildly fluctuating blood pressure, with sudden drops upon standing (postural hypotension) and spikes (hypertension) during periods of stress or excitement. Temperature regulation is also compromised, leading to inappropriate sweating (hyperhidrosis) and difficulty managing body temperature.
Gastrointestinal and respiratory issues pose a significant concern, often beginning in infancy with poor suckling and swallowing coordination. This difficulty with feeding and swallowing frequently leads to poor growth and chronic acid reflux. Aspiration of food or liquid into the lungs is common due to swallowing problems, making recurrent aspiration pneumonia a major cause of illness and hospital admission.
A hallmark symptom is the inability to produce overflow tears when crying emotionally, caused by autonomic nerve damage. Reduced corneal sensation affects the eyes, leading to frequent corneal abrasions, neurotrophic ulcers, and chronic damage due to dryness and reduced blinking. Patients often exhibit developmental delays, poor motor coordination, and hypotonia (low muscle tone), which contributes to an unsteady, broad-based gait and often leads to scoliosis.
Diagnostic Process
The path to diagnosis begins with a thorough clinical evaluation of characteristic symptoms. Strong clinical indicators include reduced or absent overflow tears, diminished or absent deep tendon reflexes, and a smooth appearance to the tongue.
Today, the definitive diagnosis is confirmed through molecular genetic testing. Genetic analysis identifies the specific pathogenic variants in the ELP1 gene. For individuals of Ashkenazi Jewish descent, targeted analysis for the most common gene variant can be performed first, as this single alteration accounts for the majority of cases in that population.
Supportive Care and Management Strategies
Since there is currently no curative treatment for Riley-Day Syndrome, management focuses entirely on alleviating symptoms and preventing complications across the affected systems. A multidisciplinary approach involving several specialists is necessary to address the various manifestations of the disorder.
Systemic Management
Managing autonomic instability requires personalized strategies, often including medications to regulate severe swings in blood pressure. During an acute autonomic crisis, specific medications control nausea and normalize blood pressure. Due to the lack of pain perception, careful monitoring is necessary to prevent self-mutilation and injuries.
Specialized Therapies
Ocular health requires constant attention because the lack of tears and reduced corneal sensation leaves the eyes vulnerable to damage. Frequent application of lubricating eye drops protects the cornea from ulceration and abrasion. To address the high risk of aspiration, swallowing therapy is employed, and sometimes tube feeding is necessary to ensure adequate nutrition and prevent recurrent lung infections. Physical and occupational therapy are routinely used to address low muscle tone, improve coordination, and manage orthopedic issues like scoliosis.