Congenital central hypoventilation; Ondine's curse; Síndome Haddad; Failure of autonomic control (central hypoventilation syndrome Congenital -CCHS-) - Genes PHOX2B, RET, EDN3, ASCL1, GDNF and BDNF.
Syndrome congenital central hypoventilation (CCHS) is a disorder that affects breathing. Breathing of affected individuals is characterized by shallow, especially during sleep, causing oxygen deficiency and an accumulation of carbon dioxide in the blood. Generally, the autonomic nervous system react to this imbalance by stimulating the individual to breathe more deeply or awakening, but in individuals with CCHS, this reaction does not happen and mechanical ventilation or diaphragm pacemaker is required. While some people need this support only at night, others need 24 hours a day.
CCHS symptoms usually appear shortly after birth. Affected children have cyanosis due to lack of oxygen in the blood. In some milder cases, the disease can be diagnosed later in life. Besides the problem of breathing, these people may have difficulty regulating your heart rate and blood pressure, for example, in response to exercise or changes in body position. These individuals may have abnormalities in the nerves that control the digestive tract, resulting in severe constipation, intestinal obstruction and an increased risk of developing neuroblastomas, Ganglioneuromas and ganglioneuroblastomas. Some people with learning difficulties or other neurological problems that can be aggravated by a lack of oxygen to support treatment if your breathing is not completely effective. Additional symptoms may include ocular abnormalities as decreased pupil response to light, decreasing pain perception, low body temperature and occasional episodes of profuse sweating. In addition, people with CCHS, especially children, may have a characteristic appearance with a short, wide face, somewhat flattened. Life expectancy and extent of cognitive disabilities depend on the severity of the disease at diagnosis and successful treatment.
This process is due to mutations in the PHOX2B, RET, EDN3, ASCL1, GDNF and BDNF genes.
The PHOX2B gene located on the short arm of chromosome 4 (4p12), encodes a protein which acts early in development to help promote the formation and regulate the differentiation of neurons. The protein is active in neural crest cells migrate to which part of the autonomic nervous system, which controls body functions such as breathing, blood pressure, heart rate and digestion. The neural crest cells also give rise to many tissues of the face and skull, and other cell types and tissues. The protein encoded by the gene PHOX2B contains two areas in which the amino acid alanine is repeated several times. These sections are known as alanine polyalanine extensions (poly-A). Most genetic mutations that lead to congenital central hypoventilation syndrome of (CCHS) add extra alanines at the PHOX2B protein. This type of mutation is called a polyalanine repeat expansion. They have identified other types of mutations in the 8 to 10% of people with this disease. It is considered that these mutations interfere with protein function in the formation and neuronal differentiation, especially in the autonomic nervous system, resulting in the characteristics of the disease.
The RET gene, located on the long arm of chromosome 10 (10q11.2), encodes a protein that is involved in signaling within cells. This protein appears to be essential for normal development of various types of nerve cells, including neurons and enteric autonomic nervous system. The RET protein is also required for normal kidney development and spermatogenesis.
The EDN3 gene, located on the long arm of chromosome 20 (20q13.2-q13.3), encoding the protein endothelin 3. family proteins are encoded endothelin in various cells and tissues, which are involved in development and function of blood vessels, the production of certain hormones and stimulation, growth and division of cells. Endothelin 3 acts through interaction with another protein, endothelin receptor type B (encoded gene from EDNRB), on the cell surface. In the early development before birth, endothelin and endothelin receptor 3 type B together play an important role in neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo, where many different types of cells giving rise. In particular endothelin receptor 3 and are essential for the formation of enteric nerves and melanocytes.
The ASCL1 gene, located on the long arm of chromosome 12 (12q23.2), encodes a member of the basic helix-loop-helix (bHLH) family of transcription factors. The protein activates transcription by binding to the E (5'-CANNTG-3 ') sequence. Dimerization is required with other bHLH proteins for efficient DNA binding. This protein plays a role in neuronal differentiation and generation of olfactory and autonomic neurons. Mutations in this gene can contribute to congenital central hypoventilation (CCHS) syndrome in rare cases.
The GDNF gene, located on the short arm of chromosome 5 (5p13.1-p12) encoding a highly conserved neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases dopamine uptake high affinity.
BDNF gene, located on the short arm of chromosome 11 (11p13), encoding a protein found in the brain and spinal cord called brain-derived neurotrophic factor. This protein promotes neuronal survival to play a role in growth, differentiation and maintenance of these cells. In the brain, BDNF protein is active at the synapse, where communication cell to cell occurs. BDNF protein helps regulate synaptic important for learning and memory plasticity. BDNF protein found in brain regions that control aspects such as eating, drinking, and body weight. Protein probably contributes to the management of these functions.
This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to result in the alteration. More than 90% of CCHS cases are due to new mutations in the gene PHOX2B and occur in people with no history of disease in your family. Occasionally an affected person inherits the mutation from an affected parent. About 5 to 10% inherit the mutation from a parent apparently unaffected by somatic mosaicism, meaning that some of the body 's cells have a genetic mutation PHOX2B, and others not.
Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with syndrome congenital central hypoventilation (CCHS), by complete PCR amplification of the exons of PHOX2B, RET, EDN3, ASCL1, GDNF and BDNF genes, respectively, 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).