Treatment of many inherited liver enzyme deficiencies muscle. These mice exhibited hyperphenylalaninemia at requires the removal of toxic intermediate metabolites frombaseline, but serum phenylalanine levels decreased sigthe blood of affected individuals. We propose that circulatnificantly when the mice were supplemented with tetrahyding toxins can be adequately cleared and disease phenorobiopterin (BH 4 ), a required cofactor for PAH. This is the type influenced by enzyme expressed in tissues other than first demonstration that a liver-specific enzyme, when the liver. Phenylalanine hydroxylase (PAH) activity was expressed in a heterologous tissue and supplied with constitutively expressed in skeletal and cardiac muscle of necessary cofactors, can effectively clear toxic metabolites transgenic mice which carried the PAH cDNA under the from the circulation of individuals with inherited enzyme transcriptional control of the mouse muscle creatine kinase deficiency. This result suggests that gene therapy targeted promoter. Muscle PAH-expressing mice were bred to liver to heterologous tissues, such as muscle, will be effective PAH-deficient, hyperphenylalaninemic mice to yield proin the treatment of selected inborn errors of metabolism. geny that lack PAH activity in liver but express PAH in
Current dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxido-reductase, EC 1.1.1.211) deficiency (LCHADD) is based on avoiding fasting, and minimizing energy production from long-chain fatty acids. We report the effects of various dietary manipulations on plasma and urinary laboratory values in a child with LCHADD. In our patient, a diet restricted to 9% of total energy from long-chain fatty acids and administration of 1.5 g medium-chain triglyceride oil per kg body weight normalized plasma acylcarnitine and lactate levels, but dicarboxylic acid excretion remained approximately ten times normal. Plasma docosahexaenoic acid (DHA, 22:6n-3) was consistently low over a 2-year period; DHA deficiency may be related to the development of pigmentary retinopathy seen in this patient population. We also conducted a survey of metabolic physicians who treat children with LCHADD to determine current dietary interventions employed and the effects of these interventions on symptoms of this disease. Survey results indicate that a diet low in long-chain fatty acids, supplemented with medium-chain triclyceride oil, decreased the incidence of hypoketotic hypoglycaemia, and improved hypotonia, hepatomegaly, cardiomyopathy, and lactic acidosis. However, dietary treatment did not appear to effect peripheral neuropathy, pigmentary retinopathy or myoglobinuria.
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