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A rare hereditary sensory and autonomic neuropathy characterized by decreased pain and temperature perception, absent deep tendon reflexes, proprioceptive ataxia, afferent baroreflex failure and progressive optic neuropathy.
ORPHA:1764Classification level: Disorder
- Hereditary sensory and autonomic neuropathy type 3
- Hereditary sensory and autonomic neuropathy type III
- Riley-Day syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Childhood, Infancy, Neonatal
- ICD-10: G90.1
- OMIM: 223900
- UMLS: C0013364
- MeSH: D004402
- GARD: 7581
- MedDRA: 10039179
The disease affects individuals of Ashkenazi Jewish ancestry. The prevalence at birth in the Ashkenazi Jewish population is estimated at 1/10,000 in North America and 1/3,700 in Israel.
The disease is present at birth and is progressive. Initial symptoms (from birth to 3 years) include swallowing problems, aspiration pneumonia, hypotonia, temperature and blood pressure instability, and delayed development. Lack of fungiform papilla on the tongue and absence of tears with emotional crying are classic features, but not easily recognized (the tongue appears inconspicuous and lack of overflow tears is normal until about seven months of age). No obvious dysmorphism is present at birth, but a characteristic facial expression develops over time. Pain and temperature perception are decreased, but not absent. Proprioception and vibration sense are markedly decreased. Deep tendon reflexes are absent. Feeding difficulties due to gastrointestinal dysmotility (oropharyngeal incoordination, abnormal esophageal peristalsis, erratic gastric emptying, gastroesophageal reflux) occur early and may persist throughout life. Episodes of protracted vomiting attacks and hypertension termed 'autonomic crises'' can be recurrent. Forty percent of the patients manifest a cyclical crisis pattern that can occur daily, weekly, or monthly with personality changes ranging from irritability and withdrawal to general excitation. Chronic lung disease (secondary to repeated aspirations), restrictive lung disease (imposed by scoliosis), and chemoreceptor dysfunction (resulting in blunted responses to hypoxemia) are frequent. Orthostatic hypotension without compensatory tachycardia is always present, as well as episodic hypertension in response to emotional stress or visceral pain. Chronic renal failure is common. Progressive optic neuropathy and neurotrophic keratopathy result in severe visual loss. There is ample phenotypic variation particularly in cognitive abilities. Severe kyphoscoliosis and short stature are common.
The disease is due to a founder mutation in the ELP1 gene (9q31), encoding elongator-1 protein, resulting in a truncated unstable protein. ELP1 is implicated in the migration, survival, and myelination of neurons during development and, in humans, the mutation affects the development of primary sensory and autonomic neurons.
Diagnosis is based upon clinical recognition of both sensory and autonomic dysfunction as well as alacrima, absent fungiform papillae, and abnormal histamine test with absent axon flare. Genetic testing provides a definitive diagnosis.
Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN). Normal or increased sweating easily distinguishes familial dysautonomia (FD) from HSAN4, also hypertensive crises are unique to FD and not present in other HSANs. Deep tendon reflexes are absent in FD.
Prenatal diagnosis is possible in families where the pathogenic variant has previously been identified.
The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers.
Management and treatment
Management should be tailored for each patient, as the clinical expression varies considerably. It is supportive and mainly directed towards protecting the cornea, and management of gastrointestinal dysfunction, respiratory dysfunction, and blood pressure lability.
Average age of death is in the third decade of life but patients may live into the seventh decade.