Riley-Day syndrome is inherited as an autosomal recessive trait, which means that a person must inherit the defective gene from both parents in order to develop the condition.

It is found predominantly in people of European Jewish descent (Ashkenazi Jews). The disease is caused by mutation of the IKBKAP gene on chromosome 9. It is rare in the general population, but not amongst Ashkenazi Jews, where the incidence is estimated to be 1 in 3,700 people.

Infants with this condition have feeding problems and develop pneumonia caused by breathing their formula and food into their airways. Vomiting and sweating spells begin as the infant matures. Young children may also have breath-holding spells that produce unconsciousness, since they can hold their breath for long enough to pass out without feeling the discomfort that normal children would.

A hallmark of Riley-Day syndrome is insensitivity to pain. This leads to unnoticed injuries or injuries that might not have occurred had the child sensed discomfort. Children do not feel the normal sensations that generally warn of impending injury, such as drying of the eyes, pressure over pressure points, and chronic rubbing and chaffing. Bone and skin pain, including burns, are also poorly perceived. However, they can feel visceral pain, like menstrual cramps.

Seizures occur in almost 50% of affected children. They have acute problems with high and low blood pressure. They may have problems regulating their body temperature.