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DISORDERS OF FATTY ACID METABOLISM

Neonatal coma due to a disorder of fatty acid oxidation may occur with any of the following conditions: (1) deficiency of short-chain, medium-chain, or long-chain acyl-CoA dehydrogenases; (2) multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia II) More about... 73; (3) hydroxymethylglutaryl-CoA dehydrogenase deficiency; and (4) carnitine cycle defects. The characteristic features of fatty acid oxidation disorders are mild metabolic acidosis, nonketotic hypoglycemia, low or normal total carnitine blood levels, dicarboxylic aciduria. Mild hyperammonemia and slight elevation of liver transaminases may also be present with fatty acid oxidase disorders. Final diagnosis is established by demonstration of the enzymatic defect in leukocytes and fibroblasts. Treatment consists of stopping fat intake, correcting hypoglycemia with glucose, and providing oral carnitine at 100 mg/kg per day. Riboflavin at 50 to 750 mg daily is recommended. Fasting should be avoided.

DISORDERS OF CARBOHYDRATE METABOLISM

Coma due to an inborn error in the metabolism of carbohydrates occurs in fructose-1-6 diphosphate deficiency and in fructose-1-phosphate aldolase deficiency (hereditary fructose intolerance). Fructose-1-6 diphosphate deficiency produces accumulation of lactic and pyruvic acids, increased ketosis, and hypoglycemia. Treatment consists of continuous glucose supplementation to avoid gluconeogenesis. Hereditary fructose intolerance presents with vomiting after the introduction of fruit juice or table sugar to the neonatal diet. Continuous vomiting leads to coma. Carbohydrate abnormalities are diagnosed by finding reduced enzyme activity in the liver. Treatment consists of eliminating fructose from the diet and correcting hypoglycemia.

RETT SYNDROME

Rett syndrome is produced by mutations in methyl-CpG-binding protein 2 (MECP2), located at the Xq28. Rett syndrome produce neonatal encephalopathy in boys. The encephalopathy is characterized by seizures, cortical myoclonus, hypotonia and central apnea. Rett syndromes in male neonates may occur in families with females siblings affected by Rett syndrome or not. The study of choice is DNA for Rett syndrome. Genetic evaluation for parents is warranted.


EVALUATION OF A NEONATE WITH A SUSPECTED METABOLIC DISORDER


To help establish a prompt diagnosis of a metabolic disorder in a neonate with a suspected metabolic disorder, group them according to the results of the most readily available blood test: blood pH, glucose, lactate and ammonia, and urine ketones. Neonates with ketoacidosis and hypoglycemia are likely to have a metabolic error that involves the leucine pathway, propionic or methylmalonic acidemias, or a disorder of carbohydrate metabolism. Neonates with hyperammonemia and respiratory alkalosis usually have a urea cycle defect. Neonates with low urinary ketones and hypoglycemia usually have a disorder of mitochondrial fatty acid oxidation. Neonates with lactic acidosis are likely to have pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, or a respiratory chain enzyme defect, but other disorders are frequently occurs in this group. The evaluation of neonates with lactic acidosis is complicated since elevated lactic acids frequently occur in a large number of disorders.
Inborn errors of metabolism that present with lactic acidosis in neonates can be grouped according to the results of the urine organic acids. Lactic acidosis and organic aciduria occur with fatty acid oxidative defects, biotinidase and multiple carboxylase deficiencies and in organic acidemias. Lactic acidosis without organic aciduria occurs in pyruvate dehydrogenase, glucogenic enzymes, pyruvate carboxylase, and respiratory chain defects.
Inborn errors of metabolism that present with lactic acidosis without organic acidemia can be further grouped according to the lactate/pyruvate ratio and the pyruvate concentration. The normal lactate (0.8 to 2.2 mmol/L) to pyruvate (0.04 to 0.01 mmol/L) blood concentration ratio is less than 25 (lactate 25: pyruvate 1). The lactate/pyruvate ratio depends on the state of tissue oxygenation (lactate = pyruvate multiplied by the state of tissue oxygenation [x]). The state of tissue oxygenation x depends on the amount of NADH2 and NAD in the cytosol (NADH2/NAD). So a metabolic disorder associated with lactic acidosis and a high number in x will have a high serum lactate level despite low serum pyruvate levels (increased lactate/pyruvate ratio [lactate >35: pyruvate 1]); whereas diseases with lactic acidosis and a lower x will have a high serum lactate level at the expense of a high pyruvate level (low lactate/pyruvate level [lactate <25: pyruvate 1]).

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Volpe, 1995 Stanley, 1990 Baerlocher, 1990 Leuzzi, 2004 Odievre, 1990 Schanen NC, 1998 Evans, 1989 Would you like to know more these enzymes? Would you like to know about canitine and  beta-oxidation?