Familial Dysautonomia

Familial dysautonomia (hereditary sensory and autonomic neuropathy type III, Riley-Day syndrome) is an autosomal recessive disorder caused by splicing variants in ELP1 (IKBKAP), almost exclusively in people of Ashkenazi Jewish descent (carrier frequency about 1 in 30). Incidence is about 1 in 3,700 in this population.

Pathophysiology. Reduced ELP1 protein causes developmental and progressive loss of sensory and autonomic neurons, with impaired baroreflex function.

Neonatal hypotonia, poor feeding and suck, aspiration, reflux, absent overflow tears, absent fungiform papillae of the tongue, reduced pain and temperature perception, areflexia, autonomic crises (vomiting, hypertension, tachycardia, sweating and agitation), labile blood pressure with orthostatic hypotension, recurrent pneumonia, scoliosis, delayed growth, kidney disease and optic neuropathy. Sleep apnoea and temperature instability occur.

Red flags.

• Autonomic crisis with severe vomiting and haemodynamic instability.
• Aspiration pneumonia or respiratory failure.

Genetic testing of ELP1 (founder variants) confirms the diagnosis. Clinical criteria: Ashkenazi ancestry, absent overflow tears, absent fungiform papillae, absent deep tendon reflexes and absent axon flare after intradermal histamine. Assess swallowing, reflux, lung function, spine, renal function and eyes.

Differential diagnosis.

• Other hereditary sensory and autonomic neuropathies, congenital insensitivity to pain.
• Neonatal hypotonia due to other causes, and cyclic vomiting.

Care is multidisciplinary at specialist centres.

Autonomic crises. Diazepam 0.1 to 0.2 mg/kg IV or rectal, clonidine 1 to 5 microgram/kg orally, ondansetron for nausea, hydration and treatment of triggers (infection, pain). Avoid hypotension and hypoglycaemia.

Blood pressure. Fludrocortisone, midodrine and salt for orthostatic hypotension, and clonidine for hypertensive surges.

Feeding and reflux. Thickened feeds, gastrostomy and fundoplication for reflux and aspiration, antireflux drugs (omeprazole).

Respiratory. Chest physiotherapy, antibiotics for pneumonia and vaccination.

Eyes. Lubricants to prevent corneal ulcers, and tarsorrhaphy where required.

Orthopaedic. Scoliosis monitoring and bracing or surgery.

Perioperative. Careful anaesthetic planning with cardiovascular monitoring.

Other. Renal and neurodevelopmental support, and genetic counselling and carrier screening.

Monitoring. Growth, pulmonary and renal function, spine, vision and blood pressure.

Referral and escalation. Refer to specialist dysautonomia centres.