Familial Dysautonomia (Riley-Day syndrome)

Definition And Genetics

Familial dysautonomia, also known as Riley-Day syndrome, is Hereditary Sensory and Autonomic Neuropathy type III (HSAN-III).
It is an autosomal recessive neurodevelopmental genetic disorder affecting the peripheral nerves.
It is regarded as a neurocristopathy because the abnormal tissues are largely derived from the neural crest.
The disorder is most common in Ashkenazi Jews, with an incidence of 1 in 10,000 to 20,000, making it the most common HSAN overall.
It is caused by variants in the IKBKAP or ELP1 gene at the 9q31-q33 locus.
This gene encodes elongator complex protein 1 (ELP1), a scaffold protein necessary for the transcription of neural key proteins and maturation of peripheral nerves.

The condition is characterised by a reduced number of small unmyelinated nerve fibres that carry pain, temperature, taste sensation, and mediate autonomic functions (including baroreceptors).
There is a loss of small and large myelinated fibres from peripheral nerves alongside small dorsal root ganglia with reduced neurons.
Fungiform and circumvallate papillae (taste buds) are classically absent or reduced on the tongue.

Identification typically occurs during infancy.
Presenting features include hypotonia, motor delay, feeding difficulties, breath-holding spells followed by syncope, and recurrent pneumonia leading to chronic lung disease.

System	Characteristic Findings
Autonomic	Alacrima (universal absence of tears with emotional crying), postural hypotension without compensatory tachycardia, extreme hypertension under stress, temperature dysregulation, and hyperhidrosis.
Sensory	Insensitivity to pain leading to frequent traumatic injuries, reduced temperature sensation, and a general inability to detect noxious stimuli.
Ocular	Corneal ulcerations resulting from decreased corneal sensation and xerophthalmia, optic nerve involvement impairing visual acuity.
Neuromuscular	Ataxic gait, delayed walking, absent deep tendon reflexes, and progressive scoliosis or kyphosis.
Other	Cardiac arrhythmias (prolonged QT interval, bradycardia), seizures in approximately 40% of cases, emotional lability, and short stature.

Crises typically begin after 3 years of age.
They are characterised by attacks of cyclic vomiting lasting 24-72 hours, retching, tachycardia, hypertension, profuse sweating, skin blotching, prominent gastric distention, and sometimes hematemesis.

The diagnosis is formed by a combination of clinical signs and confirmatory tests.

Modality	Diagnostic Findings
Clinical Triad	Alacrima Absent fungiform papillae Decreased patellar reflexes in a patient with Ashkenazi Jewish lineage.
Histamine Test	Absence of the normal axon flare response to an intradermal injection of histamine phosphate.
Methacholine Test	Instillation of 2.5% methacholine into the conjunctival sac produces miosis, indicating parasympathetic denervation.
Biochemical Markers	Decreased urinary Vanillylmandelic Acid (VMA), increased Homovanillic Acid (HVA), and diminished plasma dopamine beta-hydroxylase.
Genetic Testing	Confirms the diagnosis by identifying IKBKAP/ELP1 variants.

There is no curative therapy; management is purely symptomatic and supportive.
Use topical ocular lubricants to prevent corneal ulceration.
Provide strict respiratory and gastrointestinal support, including gastrostomy for recurrent aspiration, to prevent malnutrition and pneumonia.
Orthopedic management is required for progressive scoliosis and joint deformities.
Dysautonomic crises are managed with centrally acting medications such as diazepam and clonidine, along with carbidopa.
Prognosis is guarded, with sixty percent of patients dying before 20 years of age, usually due to chronic respiratory failure or aspiration.
Older surviving patients often develop chronic renal disease related to vasomotor instability and hypertension.