Familial Dysautonomia

Updated: Jan 05, 2016
  • Author: Robert A D'Amico, MD, FACS; Chief Editor: Hampton Roy, Sr, MD  more...
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Overview

Background

Familial dysautonomia (FD) is an inherited disorder of the nervous system that affects the development and survival of autonomic and some sensory neurons. [1, 2] Originally reported by Riley et al in 1949, [3] familial dysautonomia is now recognized as one of several hereditary sensory and autonomic neuropathies. Evidence of the disorder may be noted from birth, although neurologic deterioration progresses with age. [1, 2] The transmission is autosomal recessive with complete penetrance, and with the exception of one patient, all proven cases have been of Ashkenazi Jewish extraction. [4, 5, 6]

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Pathophysiology

Pathologic studies have shown marked reduction in nonmyelinated neuronal populations as well as reduction in small diameter myelinated axons. [1, 7] This reduction seems to indicate a developmental arrest in the sensory and autonomic systems and, in the latter, principally in the sympathetic fibers. Sympathetic ganglia have been found to be one third of the normal size, and the neuronal population has been found to be one tenth of the normal number.

Hypersensitivity to sympathomimetic and parasympathomimetic drugs occurs. There is a unique pattern of plasma catechols with low plasma levels of dihydroxyphenylglycol (DHPG), high DOPA and dopamine (DA) levels, and high norepinephrine (NE):DHPG, DA:NE, and DOPA:DHPG ratios. [2] During physical and emotional stress, plasma norepinephrine and dopamine are elevated and autonomic storms or "crises" may develop.

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Epidemiology

Frequency

United States

Approximately 1 in 30 Ashkenazi Jews is presumed to be a carrier, which results in a potential disease incidence of 1 in 3600 live births to this population. However, since identification of the gene and institution of population screening, the actual birth rate has decreased.

International

Since its original description in 1949, more than 600 patients have been identified and registered with the Dysautonomia Center in New York, an international registry with patient distribution reflecting Jewish dispersion. Of these patients, 30% reside in the New York area, and 30% reside in Israel.

Mortality/Morbidity

With greater understanding of the disorder and development of treatment programs, survival statistics have improved markedly and increasing numbers of patients are reaching adulthood. [8] Survival statistics prior to 1960 reveal that there was a 50% probability of patients dying before age 5 years. [9] Current survival statistics indicate that a newborn with familial dysautonomia has a 50% probability of reaching age 40 years. [8]

Many adults with familial dysautonomia have been able to achieve independent function. Both men and women with familial dysautonomia have married and reproduced. All offspring have been phenotypically normal despite their obligatory heterozygote state. Although pregnancies were tolerated well, blood pressures were labile at time of delivery. [10]

Causes of death are less often related to pulmonary complications, indicating that aggressive treatment of aspirations has been beneficial. Of recent concern have been patients who have succumbed to unexplained deaths that may have been the result of unopposed vagal stimulation or a sleep abnormality. Some adult patients have died of renal failure. [8, 11]

Other clinical signs encountered include tachycardia, hypertension, delayed development and poor growth, drooling and dysphagia, breath-holding with cyanosis, spinal curvature, and progressive ataxia. These children usually have a pleasant personality and generally normal intelligence, although they may have excessive anxiety. [12, 13, 14] Neurologic function deteriorates with time. [15]

Race

Familial dysautonomia is an autosomal recessive disorder with complete penetrance but variable expression. With the exception of only one patient, all affected individuals have had both parents of Ashkenazi Jewish extraction. [4, 5, 6]

In 1993, using genetic linkage, the gene for familial dysautonomia was localized to the distal long arm of chromosome 9(q31) with sufficient DNA markers to permit prenatal diagnosis and carrier identification for families in which an individual had been affected. [16]

In 2001, mutations were discovered in the IKB kinase-complex-associated protein (IKBKAP) gene, with a major haplotype mutation located in the donor splice site of intron 20. [4, 6] This mutation can result in the skipping of exon 20 in the mRNA of specific subsets of cells, such as peripheral neurons.

The major haplotype accounts for more than 99.5% of the familial dysautonomia chromosomes, corresponding to a founder defect. The second mutation is a missense mutation that affects the phosphorylation of IKAP and has been identified in 4 unrelated patients heterozygous for the major splice mutation. [17, 18]

Because the 2 Jewish mutations causing familial dysautonomia have been identified, DNA diagnosis and general population screening for the Ashkenazi Jewish population are now feasible. If both members of a couple are shown to be carriers by genetic testing, prenatal diagnosis by amniocentesis (14-17 wk) or chorionic villus sampling (10-11 wk) is possible.

Sex

No sex predilection exists in either affected individuals or carriers. Both sexes have demonstrated capability to conceive, and pregnancies have been brought successfully to term.

Age

The disorder is present throughout life. Expression of the disease varies among individuals and even in the same individual at different ages. At the present time, more than 40% of the surviving patients are older than 20 years, and some patients have survived into their 50s.

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