Riley-Day Syndrome (Familial Dysautonomia, Hereditary and Sensory Autonomic Neuropathy Type III)

Incidence: 1:3700 live births among American and Israeli Jews.

Since original description in 1949, more than 600 pts have been identified and registered with the Dysautonomia Center at New York University.

Prior to 1960 there was a 50% probability of death before age 5 y; currently a newborn with FD has 50% probability of reaching age 40 y, although many require multiple surgical interventions.

Mortality is primarily due to pulmonary complications (26%, decreasing with aggressive treatment of aspirations). Some deaths are unexplained (38%, possibly due to unopposed vagal stimulation or sleep abnormality). Others are due to sepsis (11%), bradycardia/CHB, hyponatremia, or renal failure.

Labile blood pressures exacerbated by physical and/or emotional stress

Dysrhythmias, especially bradycardia, which can lead to asystole/CHB

Compromised respiratory function at baseline due to chronic aspirations and severe thoracic kyphosis/scoliosis

Hyponatremic seizures secondary to hypertensive vomiting, which is associated with excessive secretion of vasopressin and water retention

Advancing renal failure due to progressive denervation of renal arteries, leading to poor regulation of RBF during paroxysmal hypertensive and hypotensive episodes

FD is characterized by poor development and poor survival of autonomic and sensory neurons; motor neurons are typically spared; intelligence is usually normal.

Signs and symptoms of FD are usually apparent at birth and tend to progress with age.

Diagnosis is based on documentation of mutation(s) in the IKBKAP gene. There is high suspicion for disease if five cardinal criteria are present: Absence of overflow emotional tears (after age 7 mo), absent lingual fungiform papillae, depressed patellar reflexes, lack of an axon flare following intradermal histamine, documentation of Ashkenazi Jewish extraction.

Affected individuals are hypersensitive to sympathomimetic and parasympathomimetic drugs (due to upregulation of adrenergic and cholinergic receptors) but have decreased endogenous catecholamine levels at baseline.

During physical and emotional stress, plasma epinephrine, NE, and DA are relatively elevated and precipitate dysautonomic crises: intractable emesis, diaphoresis, tachycardia, Htn, and personality changes.

Additionally there is a decreased response to temperature and somatic pain (palms, soles of feet, neck, and genital areas are spared). Visceral pain perception is normal or heightened.

Pts also experience orthostatic and paroxysmal Htn (due to failure of the afferent baroreflex), arrhythmias/CHB, prolonged QT interval, erythematous skin rash, central sleep apnea/disordered sleeping, altered response to hypoxia and hypercarbia (due to malfunctioning chemoreceptors), dry-eye optic neuropathy with retinal injury, decreased blink rate, ocular anesthesia and corneal damage, oropharyngeal incoordination, GI dysfunction and bleeding, progressive glomerulosclerosis, hypotonia (in infants) and gait ataxia (in adults), and spinal deformities.

Fixed Htn can develop chronically, secondary to advancing renal failure.

Hyponatremic seizures may occur with hypertensive vomiting, excessive sweating, and poor fluid/salt intake. 10% of pts have a seizure disorder.

Autosomal recessive disease with complete penetrance, but variable expression.

Relatively low carrier frequency (1:3000) in non-Jewish individuals; significantly higher carrier frequency (∼1:30) among people of Ashkenazi/Eastern European Jewish ancestry.

Single noncoding mutation (base pair 6 change from T to C on chromosome 9q31) in the IKBKAP gene leads to expression of truncated IKAP (I κ B kinase–associated protein), responsible for >99% of all cases of FD.

IKAP is believed to regulate gene transcription and expression during neuronal development and myelination in embryogenesis.