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Familial dysautonomia


Types

There are a number of types - the most common type occurs in Ashkenazi Jews. The other types are less common and occur in all the other ethnic groups.

Clinical signs

Familial dysautonomia is a severe hereditary disease that mainly affects the functioning of the autonomic nervous system, which is responsible for the regulation of heat, blood pressure, pulse, response to pain, tear secretion etc.

The clinical picture can vary greatly. The disease manifests in infancy as recurrent pneumonia due to the aspiration of food into the lungs because of abnormal functioning of the swallowing mechanism.

There is considerable secretion from the respiratory tract.

The secretions of saliva and sweat are also extensive, but tear production is significantly reduced.

Other manifestations include significant flushing of the face when excited, disorders of urination, varying levels of hypertension, and impaired regulation of body temperature with episodes of increased temperature.
There are also sensory disorders including absence of the sense of taste and absence of feeling of pain. This may cause patients to harm themselves without feeling it, leading to damage such as burns. The lack of tears and corneal sensitivity can result in corneal ulcers, which can be prevented by continuous treatment with artificial tears. Occasionally there is delayed development. Speech difficulties and emotional lability are common. Patients need medical supervision including physiotherapy, and recurrent pneumonia occasionally leads to death at a young age. Because of the improvement in medical treatment, the lifespan of these patients has increased, but there is still significant mortality in the third decade of life.

Inheritance pattern

Autosomal recessive

Penetrance

Full

Associated features that can be demonstrated in tests performed during pregnancy

There are no specific ultrasound signs and no associated defects.

What is the risk of recurrence in a subsequent pregnancy?

For a couple who has already had an affected child, the risk is 25% in every subsequent pregnancy. This also applies to a couple where both partners have been found to carry mutations for familial dysautonomia. When only one parent carries the abnormal gene, there is no risk that any of their offspring will have the disease; however, in such families there is a 50% chance that the infant will be a carrier, but he himself will be healthy, like the carrier parent.

The risk for more distant relatives depends on the degree of relationship between the relatives and the affected individuals, the ethnic groups of their partners, the presence of family members with familial dysautonomia in the partners' families, consanguinity between the parents, if present, etc. and is established within genetic counseling.

Molecular genetic information

The gene for the disease


The gene for the disease is called IKAP, and the mutation is found mainly in Ashkenazi Jews.

Location


Chromosome 9.

Genetic testing

Diagnostic testing

A direct test can be performed to identify the mutation in the gene by testing for the common mutations. See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal recessive diseases.

Carrier testing

The carrier frequency in the healthy Ashkenazi Jewish population is between 1:30 and 1:25. In this population there are two specific mutations in the IKAP gene on chromosome 9 - the mutation 2507+6T→C causes the disease in more than 99.5% and the mutation R696P in less than 0.5%. By testing these two mutations in Ashkenazi Jews, laboratories in Israel can identify approximately 99% of Ashkenazi Jewish carriers, but in Jews of other ethnic groups, carriers cannot be identified.

In view of this, it is very important to ascertain the ethnic origins of the couple, and it is advisable to examine (carrier DNA testing) those couples where both partners are even partially of Ashkenazi origin. More recently, it has been found that Jews from other regions, such as the Balkans and possibly North Africa, may also carry the same mutation as Ashkenazi Jews, and therefore it is advisable to offer carrier testing to Jews from these ethnic groups as well.

Carrier status testing in relatives of patients with familial dysautonomia

It is important that relatives of patients with familial dysautonomia clarify which mutations are present in the patient or parents in their family in order to ascertain that they are included in the battery of mutations routinely tested for - otherwise it will be necessary to expand the list of mutations tested for and/or examine the partner. This will be discussed in genetic counseling. See also: Introduction to cystic fibrosis, Gaucher disease, Canavan disease, familial dysautonomia, Bloom syndrome and Fanconi anemia.

Fetal testing

Same as the diagnostic test.

Prenatal diagnosis (amniocentesis) can also be offered to each couple who has had an affected child. The best way is after identifying the mutations in the parents, but if these are not found, indirect linkage analysis can be performed. See: Indirect testing for genetic markers in a family that has one or more patients - when there is only one gene that can cause the disease - autosomal recessive diseases.

Preimplantation diagnosis (before the embryonic cells implant in the uterine wall) can also be offered for this disease - this is performed in special centers, mainly overseas, and in special cases this can be considered within genetic counseling.
 
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