Autosomal recessive congenital methemoglobinemia (Autosomal recessive congenital methemoglobinemia) - Gen CYB5R3.
Congenital methemoglobinemia autosomal recessive is an inherited disease that primarily affects the function of erythrocytes. Specifically, the hemoglobin molecule, responsible for transporting oxygen to body tissues and cells altered. In affected people, of normal hemoglobin is replaced by a methemoglobin abnormally called, which is unable to carry oxygen to the body tissues. Because of this, the body's tissues do not receive oxygen, thereby causing cyanosis.
They described two forms of congenital methemoglobinemia autosomal recessive: types I and II. People with Type I have cyanosis from birth and may have weakness or shortness of breath related to oxygen deficiency in their tissues. People with type II have cyanosis and severe neurological problems. After months of seemingly normal development, children with type II type develop encephalopathy, dystonia and choreoathetosis. In addition, these individuals have microcephaly. People with type II have intense intellectual disability and impaired motor skills. In type II, growth decelerates frequently. Abnormal facial muscle movements can interfere with swallowing, which can lead to feeding difficulties and slower growth. People with congenital autosomal recessive methemoglobinemia have a normal life expectancy but often people with type II do not survive beyond adulthood.
This process is due to mutations in the gene CYB5R3, located on the long arm of chromosome 22 (22q13.2). This gene encodes the enzyme cytochrome b5 reductase 3, involved in the transfer of electrons from one molecule to another. This gene encodes two isoforms of this enzyme. The soluble isoform is present only in the erythrocytes and the membrane - bound isoform found in all other cell types. RBCs contain normal hemoglobin molecules containing iron, which provide oxygen to body tissues. Hemoglobin iron is ferrous (Fe2 +), but can become ferric (Fe3 +). Hemoglobin containing ferric iron, called methemoglobin, can not deliver oxygen. The soluble isoform Cytochrome b5 reductase 3 changes the ferric iron into ferrous iron so that hemoglobin can function. Normally, erythrocytes contain less than 2% methemoglobin. For its part, the membrane - bound isoform is embedded in the membranes of various cell compartments and is widely used in the body. This isoform is required for many chemical reactions, including decomposition and formation of fatty acids, cholesterol formation and decomposition of various molecules and drugs.
There have been more than 65 mutations in the gene responsible for congenital methemoglobinemia CYB5R3 autosomal recessive types I and II. Most of these genetic mutations lead to Type I. These mutations generally reduce the activity or stability of the enzyme. As a result, the enzyme can not efficiently change the ferric iron to ferrous iron, leading to an increase of 10% to 50% methemoglobin within erythrocytes. This increase of methemoglobin and the corresponding decrease of normal hemoglobin reduces the amount of oxygen delivered to the tissues. The altered enzyme activity affects only erythrocytes because other cells can compensate for a decrease in enzyme activity. On the other hand, mutations that lead to type II disease, typically result in a complete loss of enzyme activity. Cells can not compensate for a complete loss of Cytochrome b5 reductase 3, resulting in an increase of 10% to 70% methemoglobin inside the eritrocios. This increase in methemoglobin and a corresponding decrease in normal hemoglobin leads to cyanosis. The lack of enzyme activity in other cells leads to neurological features associated with type II. It is likely to neurological problems are caused by the fatty acid and the deterioration of the formation of cholesterol, which reduces the production of myelin. Myelin insulates nerve cells and promotes rapid transmission of nerve impulses. The hypomyelination leads to a loss of nerve cells, particularly in the brain. The loss of these cells probably contributes to the alterations of movement and encephalopathy characteristics autosomal recessive congenital methemoglobinemia type II.
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 autosomal recessive congenital methemoglobinemia, by complete PCR amplification of exons CYB5R3 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).