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Familial Dysautonomia is an autosomal recessive disorder, which means that an individual must inherit two copies of an FD mutation in order to be affected.  Individual with only one copy of the mutation are called carriers. One out of every 25 to 30 Ashkenazi (or Eastern European) Jews carries the most common Familial Dysautonomia mutation and one out of every 625-900 Jewish couples is at risk for having a child with FD.

Chromosomes:

Chromosomes are the blueprint for how a body’s cells develop and function. Every person has 23 pairs of chromosomes. One chromosome of each pair is inherited from one’s mother and the other chromosome is inherited from one’s father. Chromosomes are made up of strands of a molecular substance called DNA. Sections of the DNA strands which make proteins are called genes. It is our genes that determine how certain traits will be expressed and tell our body’s cells how to function. When there is an error within a portion of a gene’s DNA, it is called a mutation and the gene does not function the way it should.
 

Chromosomes have many different functions. The part of the chromosome that makes up the genes are only a small portion of the total DNA in the chromosomes. These gene sections are called exons. Between the exons are sections of DNA called introns, enhancers, 3’-UTR, promoter, and other regions, which tell the chromosome important things like when to turn a gene on and off. The intron regions, previously thought to be “junk” DNA, are now believed to hold information like how an individual reacts to certain drugs.

Familial Dysautonomia mutation:

In January, 2001, the gene affected in Familial Dysautonomia was identified as the IKBKAP gene, which encodes for the IKAP protein.  There have been three mutations in IKBKAP identified in individuals with FD.  Two of these are found exclusively among individuals of Eastern European descent and a third was found in a single individual.  Every individual diagnosed with FD to date carries at least one copy of the "major" mutation, which has the carrier rate of 1 in 25-30.  Individuals who have a copy of  the second or third mutation are called "heterozygous"; they have two different mutations.

The most common FD mutation is found in an intron region of DNA.  It controls where the gene product is cut and spliced.  The mutation causes an exon (an important piece of DNA) to be cut out of the final protein product.  One of the things that makes Familial Dysautonomia unique is that some cells are able to ignore the error message and produce regular, full-length protein.  Most cells types are able to do this on a regular basis (although they all still produce abnormal protein some of the time).  Unfortunately, nerve cells are more likely to produce the shortened, abnormal protein (although they too are able to produce normal protein some of the time).

One of the exciting areas of FD research is the search for products (drugs, nutritional products, etc) that will increase the amount of normal protein produced by FD cells.  In May, 2003, an article by Drs. Rubin and Anderson of the Laboratory for Familial Dysautonomia Research at Fordham University, suggested that tocotrienols, a variant of Vitamin E, increase IKBKAP gene expression, producing increased amounts of normal protein.  This research, funded in part by FD Hope, promises much hope for the care of those with FD.
 

Estimating A Family Member's Risk for Being a Familial Dysautonomia Carrier
We know that the parents of a child with Familial Dysautonomia are each carriers (one normal chromosome and one with the IKAP mutation). The child with familial dysautonomia has inherited the chromosome containing the DYS mutation from each parent. In any future pregnancy, there are four possible outcomes: inheriting mom's normal and dad's DYS, inheriting mom's DYS and dad's normal, inheriting normal chromosomes from both, or inheriting the DYS mutation from both. Therefore the chance of having any one of the above possibilities is one in four (25%). Since we know that unaffected siblings have not inheritied the DYS mutation from both parents (or else they would have FD), they have only three possible chromosome combinations (DYS from mom, normal dad or normal mom, DYS from dad). Carrier status is seen with two of these possibilities. Therefore, siblings of individuals with FD have a two in three chance of being carriers (67%). The following table states the risk of being an FD carrier for family members of different levels of relation to an individual with FD. 

This table assumes that all relatives are Ashkenazi Jews and therefore includes the baseline 1 in 30 risk from each parent unrelated to the affected individual. If non-Ashkenazi Jews are included in your family tree, then the risk would be less.

Gene Information:

OMIM entry on Familial Dysautonomia: #223900

OMIM Gene Database # 603722

INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE COMPLEX-

ASSOCIATED PROTEIN; IKBKAP

Also known as: IKK COMPLEX-ASSOCIATED PROTEIN; IKAP

Gene map locus 9q31

Bibliography:

1. Anderson SL, Qiu J, Rubin BY.  Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochem Biophys Res Commun. 2003 Jun 20;306(1):303-9.

2. Leyne M, Mull J, Gill SP, Cuajungco MP, Oddoux C, Blumenfeld A, Maayan C, Gusella JF, Axelrod FB, Slaugenhaupt SA. Identification of the first non-Jewish mutation in Familial Dysautonomia.  Am J Med Genet 2003 May 1; 118A(4):305-8.

3. Cuajungco MP, Leyne M, Mull J, Gill SP, Lu W, Zagzag D, Axelrod FB, Maayan C, Gusella JF, Slaugenhaupt SA. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am J Hum Genet. 2003 Mar;72(3):749-58. Epub 2003 Feb 06.
4. Holmberg C, Katz S, Lerdrup M, Herdegen T, Jaattela M, Aronheim A, Kallunki T. A novel specific role for I kappa B kinase complex-associated protein in cytosolic stress signaling. J Biol Chem. 2002 Aug 30;277(35):31918-28. Epub 2002 Jun 10.
5. Dong J, Edelmann L, Bajwa AM, Kornreich R, Desnick RJ.  Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews. Am J Med Genet. 2002 Jul 1;110(3):253-7.
6. Slaugenhaupt SA.Genetics of familial dysautonomia. Tissue-specific expression of a splicing mutation in the IKBKAP gene. Clin Auton Res. 2002 May;12 Suppl 1:I15-9.
7. Coli R, Anderson SL, Volpi SA, Rubin BY. Genomic organization and chromosomal localization of the mouse IKBKAP gene. Gene. 2001 Nov 14;279(1):81-9.
8. Cuajungco MP, Leyne M, Mull J, Gill SP, Gusella JF, Slaugenhaupt SA. Cloning, characterization, and genomic structure of the mouse Ikbkap gene. DNA Cell Biol. 2001 Sep;20(9):579-86.
9. Gilbert F Familial dysautonomia and the expansion of the Ashkenazi Jewish carrier screening panel. Genet Test. 2001 Summer;5(2):83-5.
10. Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA, Ekstein J, Rubin BY. Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet. 2001 Mar;68(3):753-8. Epub 2001 Jan 22.
11. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet. 2001 Mar;68(3):598-605. Epub 2001 Jan 22.