Familial dysautonomia (Familial dysautonomia) - IKBKAP gene.

Familial dysautonomia is a genetic disorder that affects the development and survival of certain nerve cells. This condition alters the cells in the autonomic nervous system that controls involuntary actions such as digestion, breathing, tear production, regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls the activities related to the senses, such as taste and perception of pain, heat and cold.

Problems related to this disorder first appear in childhood. Signs and symptoms include hypotonia, feeding difficulties, poor growth, lack of tears, frequent lung infections and difficulty maintaining body temperature. Older infants and young children with familial dysautonomia can hold their breath for extended periods of time, which can lead to cyanosis and fainting. Overall, this behavior ceases apnea at 6 years old. Some activities like walking and talking, often delayed, although some affected individuals show no signs of developmental delay.

Other signs and symptoms include additional enuresis, episodes of vomiting, decreased sensitivity to changes in temperature and pain, lack of balance, scoliosis, ossification deficiency with an increased risk of fractures, kidney and heart problems. Affected individuals also have a poor regulation of blood pressure, orthostatic hypotension may present which can lead to dizziness, blurred vision and fainting. Likewise, they may have episodes of high blood pressure when they are nervous or excited, or during episodes of vomiting. About one third of children with the disease have learning problems with short attention spans, requiring special education classes. In adulthood, affected individuals often have increasing difficulty with balance and walking unassisted. Other problems that may occur in adolescence or early adulthood include lung damage due to repeated infections, renal failure and atrophy of the optic nerves.

Familial dysautonomia is due to mutations in the IKBKAP gene, located on the long arm of chromosome 9 (9q31). This gene encodes a protein called IKK - associated protein complex (IKAP). This protein is found in a variety of cells throughout the body, including brain cells. It is part of a complex of six proteins called elongation complex, which plays a key role in transcription. It is believed that this complex is important for transcription of proteins that affect the cytoskeleton and cell motility, essential for the growth and development of cells. For example, the cytoskeleton plays a critical role in growth of nerve cells, particularly axons and dendrites that are required for transmission of nerve impulses axons. Cell motility is crucial for the movement of nerve to their correct locations in the brain cells.

Almost all individuals with familial dysautonomia have two copies of the same mutation in the IKBKAP gene in every cell. This mutation may affect how the information is reconstructed in the IKBKAP gene to encode IKAP protein. As a result, a reduced amount of normal protein is encoded. However, this mutation behaves inconsistently. Some cells encode normal amounts of the protein, and other cells, particularly brain cells have very small amounts of the protein. Critical activities in brain cells is probably altered by small amounts or absence of IKAP protein, leading to signs and symptoms of familial dysautonomia. In a small number of reported cases of familial dysautonomia, other mutations have been identified that change amino acids in the IKAP protein. In these cases, the amino acid arginine is replaced by the amino acid proline at position 696 (Arg696Pro), or the amino acid proline the amino acid leucine is substituted in position 914 (Pro914Leu). Together, these mutations alter the IKAP protein.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with familial dysautonomia, by complete PCR amplification of exons IKBKAP gene, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).