Instituto Valenciano de Microbiología
(IVAMI)

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
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Genetic Testing - aciduria hydroxyglutaric variety D-2 (types I and II), L-2, and D, L-2- (2-hydroxiglutaric aciduria D-2, L-2, and D, L-2) - Genes D2HGDH (D-2, type I), IDH2 (D-2, type II), L2HGDH (L-2) and SLC25A1

Aciduria hydroxyglutaric variety D-2 (types I and II), L-2, and D, L-2- (2-hydroxiglutaric aciduria D-2, L-2, and D, L-2) - Genes D2HGDH (D-2 , type I), IDH2 (D-2, type II), L2HGDH (L-2), and SLC25A1 (D, L-2)  

Hydroxyglutaric aciduria the (2-hydroxyglutaric aciduria) is a process that causes progressive brain damage. Three varieties of this process: the hydroxyglutaric aciduria D-2 (D-2-hydroxyglutaric aciduria; D-2-HGA), the hydroxyglutaric aciduria L-2 (L-2-hydroxyglutaric aciduria, L-2-HGA), and hydroxyglutaric aciduria combined D, L-2 (D, L-2-hydroxyglutaric aciduria, D, L-2-HGA).

Major events of the variety D-2-HGA are late development, seizures, hypotonia and abnormalities in the brain. This strain D-2-HGA is subdivided into two types, type I and type II, differentiated by their genetic cause and the inheritance pattern, with some differences in the signs and symptoms as type II often begins before and cause more problems the type I, and affects the myocardium (cardiomyopathy), not found in type I. type I is due to mutations in the gene D2HGDH, whereas type II is caused by mutations in the gene IDH2.

The D2HGDH gene, located on the long arm of chromosome 2 (2q37.3), encoding the enzyme D-2-hydroxyglutarate dehydrogenase. Inside of the mitochondria, the enzyme involved in the reactions that produce energy for cellular activities. Specifically, the D-2-hydroxyglutarate dehydrogenase converts the compound D-2-hydroxyglutarate 2-ketoglutarate. A number of additional enzymes processed more 2-ketoglutarate to produce energy. There are more than 30 mutations in people with D2HGDH hydroxyglutaric aciduria D-2-HGA type I mutations in this gene reduce the activity of the enzyme D-2-hydroxyglutarate dehydrogenase, increasing the concentration of these compounds in the cells. When there are high concentrations of D-2-hydroxyglutarate cellular damage that causes cell death is induced. The brain seems to be the most vulnerable to the toxic effects of this compound body, which may explain why the signs and symptoms of D-2-HGA type I primarily involve the brain.

Meanwhile, the IDH2 gene, located on the long arm of chromosome 15 (15q26.1), encodes the enzyme isocitrate dehydrogenase 2. Inside of the mitochondria, the enzyme involved in the reactions that produce energy for cellular activities. Specifically, isocitrate isocitrate dehydrogenase 2 becomes a 2-ketoglutarate. A number of additional enzymes processed more 2-ketoglutarate to produce energy. The conversion reaction also produces one molecule of NADPH needed for many cellular processes and helps protect cells from reactive oxygen species. They described at least two mutations in the gene responsible for IDH2 hydroxyglutaric aciduria D-2-HGA type II. These mutations prevent the enzyme isocitrate dehydrogenase 2 to carry out its normal activity, the conversion of isocitrate to 2-ketoglutarate. Instead, the altered enzyme acquires a new abnormal function, the production of compound D-2-hydroxyglutarate, which is described as a mutation gain function. In people with D-2-HGA type II, this compound accumulates abnormally in the cells, which can damage them and cause cell death. Brain cells appear to be the most vulnerable to the toxic effects of this compound, which may explain why the signs and symptoms of D-2-HGA type II primarily involve the brain. However, some people with this form of the disease also have cardiomyopathy. It is unclear why a accumulation of D-2-hydroxyglutarate may be associated with Cardiomyopathy.

Variety L-2-HGA affects the cerebellum, and consequently affected individuals suffering from muscular incoordination and balance (ataxia). They also have delayed development of seizures, speech difficulties and macrocefalia. Signs and symptoms begin in infancy or early childhood. This condition worsens over time and usually causes severe disability in early adulthood.

The L-2-HGA variety is caused by mutations in the gene L2HGDH, located on the long arm of chromosome 14 (14q21.3). This gene encodes the enzyme L-2-hydroxyglutarate dehydrogenase. Inside of the mitochondria, the enzyme involved in the reactions that produce energy for cellular activities. Specifically, L-2-hydroxyglutarate dehydrogenase converts L-2-hydroxyglutarate 2-ketoglutarate. A number of additional enzymes processed more 2-ketoglutarate to produce energy. There are more than 70 mutations in the gene that cause L2HGDH hydroxyglutaric aciduria L-2 (L-2-HGA). Some gene mutations L2HGDH change amino acids in the enzyme L-2-hydroxyglutarate dehydrogenase, which probably alter its function. Other mutations inserted or deleted genetic material in the gene or coding result of an abnormally short, nonfunctional version of the enzyme. Functional enzyme deficiency, because it does not spoil L-2-hydroxyglutarate and accumulated in cells. At high concentrations, this compound can damage cells and cause cell death. Brain cells appear to be the most vulnerable to the toxic effects of this compound, which may explain why the signs and symptoms of L-2-HGA primarily involve the brain.

The combined variety D, L-2-HGA causes intense brain abnormalities that occur in early childhood. Affected children suffer from severe seizures, hypotonia, respiratory and feeding difficulties. Generally, affected individuals only survive in infancy or early childhood. This variety, is caused by mutations in the SLC25A1 gene.

The SLC25A1 gene, located on the long arm of chromosome 22 (22q11.21), encodes a protein that carries citrate outside the mitochondria, in exchange for malate, which is conveyed into. Inside the mitochondrion, malate citrate as both participate in reactions that produce energy for cellular activities. The citrate is transported out of the mitochondrion, and also has important functions in other parts of the cell. In particular, the citrate is involved in lipid production and regulation of glycolysis. Described at least 12 SLC25A1 gene mutations responsible for hydroxyglutaric aciduria combined D, L-2. Each of the SLC25A1 gene mutations known function reduces SLC25A1 protein greatly. Consequently, citrate and malate can not be transported in and out of the mitochondrion, which interrupts power production within the cells. Through processes that are not fully understood, deficiency of citrate and malate transport allows other compounds as D-2-hydroxyglutarate and L-2-hydroxyglutarate, accumulate inside cells.  

The hydroxyglutaric aciduria D-2-HGA type I, L-2-HGA, and D combined, L-2-HGA all have an autosomal recessive pattern of inheritance, which means that both copies of the gene in every cell must have mutations so that the 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. However, hydroxyglutaric aciduria D-2-HGA type II is considered an autosomal dominant disease because a copy of the altered gene in each cell is sufficient to express the disease. Often the hydroxyglutaric aciduria D-2-HGA type II is due to a new mutation in the gene IDH2 and occurs in people with no history of disease in your family.  

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with genes involved in the different varieties of hydroxyglutaric aciduria, by complete PCR amplification of the exons of D2HGDH genes (D-2-HGA type I) and L2HGDH ( L-2-HGA), IDH2 (D-2-HGA type II), SLC25A1 (D, L-2-HGA), 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).