lördag 28 februari 2009

Dikarboksyylihapot betaoksidaatiohäiriössä: Adipiini, suberiini ja sebasiinihappo

Lipid Storage Myopathies Due to Fatty Acid Oxidation Defects

Dicarboxylic Acids

Dicarboxylic acids (DCAs) (e.g. adipic, suberic, sebacic acids) are found in all identified intramitochondrial β-oxidation defects.185 Hale and Bennett39 point out several limitations to the value of these compounds in the recognition of FAO defects.

 (i) These DCAs may be seen in children receiving certain formulas containing medium-chain triglycerides or in children who are seriously ill (e.g. with diabetic ketoacidosis)186 or who are receiving certain medications which interfere with FAO such as valproic acid.187 It should, however, be noted that in each of the above conditions, the amount of ketone exceeds the amount of DCA whereas in the intramitochondrial FAO defects, the amount of DCA equals or exceeds the amount of ketones when the children are fasting. Furthermore, the pattern of the DCAs is usually easily distinguished, in experienced metabolic laboratories, from the pattern of the pathological DCAs that is associated with FAO defects.

 (ii) These DCAs are not present when children are not in a catabolic state and are well and eating regularly or are receiving intravenous glucose at rates in excess of normal hepatic glucose production rates, thereby decreasing the dependence on FAO and the production of fatty acid metabolites.

 (iii) Increased concentrations of DCA in the urine are generally not seen in the disorders involving the transport of fats into the mitochondria.

Therefore, an FAO defect can be suspected in the presence of an excess of DCA relative to ketones. However, the absence of DCAs does not necessarily exclude a defect.

The site of defect may be suggested by the organic acid pattern. For example, children with LCAD/LVCAD deficiency excrete primarily medium- and long-chain saturated DCAs in contrast to children with trifunctional protein deficiency, who excrete almost equimolar amounts of the saturated and the 3-hydroxydicarboxylic acids.188
 However, it should be noted that the presence of 3-hydroxy compounds is not specific for trifunctional protein deficiency as they may also be seen in toxic reactions with acetaminophen and with intrinsic liver disease.189
Advances in stable-isotope dilution mass spectrometry have improved the ability to detect metabolites in very small quantities in plasma or urine.190

 Acylglycines that are consistently excreted in small quantities in the urine do not appear to have the same limitations as DCAs. Useful glycine metabolites have been identified for several defects including MCAD, SCAD, ETF, and ETF-coenzyme Q oxidoreductase deficiencies. There are increased concentrations of hexanoyl-, suberyl-, and 3-phenyl propionyl glycine in the urine in MCAD deficiency.191

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