ピルビン酸脱水素酵素複合体欠損症、ピルビン酸デヒドロゲナーゼ複合体欠損症
出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/06 09:39:44」(JST)
| Pyruvate Dehydrogenase Complex Deficiency | |
|---|---|
| Classification and external resources | |
| ICD-10 | E74.4 |
| ICD-9 | 271.8 |
| OMIM | 312170 |
| DiseasesDB | 30060 |
| eMedicine | ped/1969 |
| MeSH | D015325 |
Pyruvate Dehydrogenase Deficiency (PDH) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. ""PDH deficiency"" is an X-linked disease that shows heterogeneous characteristics in both clinical presentation and biochemical abnormality. The ""PDH Complex"" is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria.
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The most commonly seen form of “”Pyruvate Dehydrogenase Complex Deficiency”” is caused by mutations in the X-linked E1 alpha gene and is approximately equally prevalent in both males and females. However, a greater severity of symptoms tends to affect males more often than heterozygous females. This can be explained by x-inactivation, as females carry one normal and one mutant gene. Cells with a normal allele active can metabolize the lactic acid that is released by the PDH deficient cells. They cannot, however, supply ATP to these cells and, therefore, phenotype depends largely on the nature/severity of the mutation.[1][2]
“”Pyruvate Dehydrogenase Complex Deficiency”” is generally present in one of two forms. The metabolic form appears as lactic acidosis and a blood lactate concentration of approximately >10 mmol/L. The neurological form of “”PDH deficiency”” contributes to hypotonic, poorly fed, lethargic and structurally abnormal in the brain patients who later may develop seizures and/or neuropathological spasms. These presentation of the disease usually progresses to mental retardation, microcephaly, blindness and spasticity.[1]
Females with residual “”PDH”” activity will have no uncontrollable systemic lactic acidosis and few, if any, neurological symptoms. Conversely, females with little to no enzyme activity will have major structural brain abnormalities and atrophy. Males with mutations that abolish, or almost abolish, enzyme activity presumably die in utero because brain cells are not able to generate enough ATP to be functional viable. It is expected that most cases will be of mild severity and a clinical presentation involving lactic acidosis.[2]
Prenatal onset may be presented with non-specific signs such as low Apgar scores and small for gestational age. Metabolic disturbances may also be considered with poor feeding and lethargy out of proportion to a mild viral illness, and especially after bacterial infection has been ruled out.[1]
Direct treatment that stimulates the pyruvate dehydrogenase complex (PDC), provides alternative fuels, and prevents acute worsening of the syndrome. However, some correction of acidosis does not reverse all the symptoms. CNS damage is common and limits a full recovery.
Ketogenic diets, with high fat and low carbohydrate intake have been used to control or minimize lactic acidosis but have shown marginal success.
There is some evidence that dichloroacetate reduces the inhibitory phosphorylation of pyruvate dehydrogenase complex and thereby activates any residual functioning complex. Resolution of lactic acidosis is observed in patients with E1 alpha enzyme subunit mutations that reduce enzyme stability. However, treatment with dichloroacetate does not improve neurological damage.[1]
Oral citrate is often used to treat acidosis.
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| リンク元 | 「ピルビン酸デヒドロゲナーゼ複合体欠損症」 |
| 関連記事 | 「disease」「deficiency」「complex」「complexed」「complexes」 |