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At a glance

Familial dysautonomia is a genetic disorder that affects involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. Problems related to this disorder first appear during infancy. Early symptoms include hypotonia, feeding difficulties, poor growth, lack of tears, frequent lung infections, and difficulty maintaining body temperature. Other features include alterations of the taste and the perception of pain, heat, and cold. Older infants and young children with familial dysautonomia show cyanosis when these infants hold their breath which may cause a bluish appearance of the skin or lips or fainting. This breath-holding behavior usually stops by age 6. Developmental milestones, such as walking and speech, are usually delayed, although some affected individuals show no signs of developmental delay.

Synonyms

Familial Dysautonomia; Riley-Day Syndrome; Hereditary Sensory Neuropathy Type III (HSN III).

History

Peripheral nerve degeneration involving unmyelinated fibers. First reported in 1949 by American pediatricians Conrad Milton Riley and Richard Lawrence Day.

Incidence

Incidence is 1:3,800 in Eastern European Jews. Only reported in individuals of Ashkenazi Jewish descent (classified as one of the Jewish genetic diseases). The familial dysautonomia gene is carried in 1:30 individuals of Eastern European Jewish ancestry.

Genetic inheritance

Autosomal recessive with complete penetrance. Chromosome 9 (9q31). Two mutations of the familial dysautonomia gene (IKBKAP) can cause the disease: (1) a mutation in intron 20 (99% of cases) in which the gene product IKAP is not expressed in the brain (but is in lymphoblasts), and (2) a missense mutation in exon 19 that causes a disruption of a phosphorylation site of IKAP, which decreases its activity.

Pathophysiology

Loss of small unmyelinated nerve fibers carrying pain, temperature, and central autonomic nervous control.

Diagnosis

Nerve biopsy shows a loss of unmyelinated fibers. Muscle biopsies show loss of Golgi tendon organs. Tongue has few or no papillae. Urinary catecholamines and metabolites excretion are decreased. Definitive diagnosis established by molecular biology (DNA analysis by genetic linkage testing). Prenatal diagnosis and carrier genetic testing (when there is a family history) is available.

Clinical aspects

In early infancy, there is poor swallowing with pharyngeal dyscoordination and aspiration. Poor sucking. Swallowing difficulties remain the main problem, leading to significant failure to thrive. Sweating during meals. Delayed and ataxic walking is reported. Ataxia is secondary to loss of feedback by muscle spindles. Progressively, pain and thermal sensation are lost. When children are 2 to 6 years old, painless corneal ulcerations and numerous painless traumatic injuries occur frequently. Tendon stretch reflexes are absent. Skeletal deformity and scoliosis are often present. Generalized convulsions can be observed in 40% of these patients. Autonomic crises begin between 3 and 6 years. They include ...

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