300 mg/kg/day IV or PO), which enhances secretion of organic acids, should be considered for patients with isovaleric acidemia Patients with holocarboxylase synthetase, biotinidase deficiency, or propionic acidemia may improve with biotin (10 to 40 mg/day given PO or NG), those with maple syrup urine disease may benefit from thiamine, and those with methylmalonic academia may benefit from hydroxocobalamin (vitamin B12 ; mg IM) It is usually not imperative that these cofactor therapies be administered in the ED Antibiotics should be administered as clinically indicated for infection Administration of an oral, broad-spectrum antibiotic to reduce gut flora, a significant source of organic acids, may be beneficial but usually is not initiated in the ED Efficacy of emergent treatment is monitored by ongoing assessment of mental status, fluid and cardiovascular status, signs of bleeding, and measurement of electrolytes, glucose, ammonia, and blood gas levels every to hours until the patient is stabilized Resolution of metabolic crisis usually takes days to weeks The New England Consortium of Metabolic Programs details treatment for specific organic acidemias on their website http://newenglandconsortium.org/for-professionals/acute-illness-protocols/organic-acid-disorders/ UREA CYCLE DEFECTS Goals of Treatment For urea cycle defects, the specific goals of acute treatment are to eliminate protein intake, avoid protein catabolism, remove ammonia, and treat any precipitating illness Current Understanding Disorders of the urea cycle result in toxic accumulation of ammonia generated by the catabolism of protein Urea cycle disorders include carbamoyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, citrullinemia, argininosuccinate lyase deficiency, and arginase deficiency Ammonia, in excess, is a neurotoxin that results in cerebral edema as well as brainstem dysfunction Clinical Considerations Assessment Patients with severe enzyme deficiency present within the first few days of life, following consumption of protein in breast milk or formula Those with partial deficiency usually present within the first few months of life, but may present even as adults, after intake of a quantity of protein that exceeds their metabolic capacity The most severe forms include carbamoyl phosphate synthetase deficiency and ornithine transcarbamylase deficiency, which is the most common urea cycle defect and the only one with X-linked inheritance Female carriers for ornithine transcarbamylase deficiency may manifest clinical disease due to skewed inactivation of their X chromosomes, but usually present later, including during adolescence The other urea cycle defects affect males and females similarly Arginase deficiency typically presents later in life, ranging from infancy to adulthood, as a neurologic syndrome with developmental delay and progressive neurologic abnormalities and usually less severe hyperammonemia Presentation even later in life can be acute, severe, and even life threatening Acute manifestations are anorexia, irritability, lethargy, vomiting, ataxia, seizures, progressing to coma, and death without appropriate emergent treatment Duration of coma is a better predictor of outcome than is serum ammonia concentration With late-onset forms, symptoms, although similar, are usually episodic and/or less severe and may include subtle findings such as failure to thrive in infants and learning and attention deficits, personality and behavioral disturbances, and migraine-like headaches in school-age children and adolescents Level of alertness and cardiorespiratory status must be assessed Potential precipitating factors, such as infection, should be investigated Hyperammonemia is a brainstem respiratory stimulant that results in tachypnea Respiratory alkalosis is common, sometimes with secondary metabolic acidosis Increased intracranial pressure due to hyperammonemia may produce bradycardia and elevated blood pressure Electrolytes, blood gas, glucose, AST, ALT, alkaline phosphatase, bilirubin, ammonia, plasma amino acid levels, CBC, and urinalysis should be obtained All labs except ammonia may be normal Even patients who are not lethargic may have significant hyperammonemia, masked by acclimatization to chronic elevations of ammonia Management Immediate treatment of hyperammonemia is important to prevent morbidity and mortality ( Table 95.7 ) Rapid consultation with an IEM specialist is crucial and central venous access may be needed Protein intake should be temporarily withheld (not longer than 36 to 48 hours) Although patients with urea cycle defects are usually not hypoglycemic, dextrose should be provided in IV fluids (along with IV lipids at to g/kg/day) at typically 1.5 times the maintenance rate in order to maintain hydration and prevent catabolism IV Ammonul (sodium phenylacetate and sodium benzoate) is given via central line as a bolus followed by 24-hour infusion in order to correct hyperammonemia Arginine may also be used (except those with arginase deficiency) and citrulline is used in CPS1 and OTC deficiencies to correct hyperammonemia Sodium chloride (not Ringer lactate) can be used to correct dehydration but should be used with extreme caution when giving Ammonul, which is high in sodium and/or arginine, which is high in chloride Although patients with urea cycle defects have low levels of carnitine and may be taking L carnitine as a routine medication, patients should not receive L -carnitine while being treated with Ammonul because it conjugates and inactivates sodium benzoate For treatment of seizures, valproic acid should be avoided because it decreases urea cycle activity and may therefore worsen hyperammonemia The New England Consortium of Metabolic Programs details treatment for specific urea cycle defects on their website http://newenglandconsortium.org/for-professionals/acute-illness-protocols/urea-cycledisorders/ FATTY ACID OXIDATION DEFECTS Goals of Treatment Goals specific for the treatment of the patient with a fatty acid oxidation defect are to correct acidosis and hypoglycemia which should correct hyperammonemia, if present Clinical Understanding Disorders include enzyme deficiencies involving metabolism of short, medium, long, and very long-chain fatty acids and carnitine transport defects Medium-chain acyl-CoA dehydrogenase deficiency is not only the most common fatty acid oxidation defect but also one of the most common IEMs with an incidence of approximately 1/10,000 Patients with a fatty acid oxidation defect usually present in infancy between ages months and years due to longer overnight fasts as the infant begins sleeping through the night or due to increased metabolic demand caused by intercurrent illness, often gastroenteritis, recent surgery, or, particularly in children and adolescents, vigorous exercise Normally in these scenarios, inadequate glucose availability to meet caloric demands results in catabolism of fatty acids, which are oxidized in the mitochondria to acetyl CoA, which is used to produce ketones to meet energy needs In fatty acid oxidation defects, accumulation of fatty acid metabolites inhibits gluconeogenesis, causes metabolic acidosis and has hepatotoxic effects Inadequate energy leads to impairment of skeletal and cardiac muscle Current Considerations Assessment Early manifestations of decompensation may include lethargy, dehydration, vomiting and/or diarrhea, hepatomegaly, and usually hypoglycemia with absent or inappropriately low ketones (except in patients with short-chain acyl-CoA deficiency who often produce ketones) Decompensation may progress within hours to encephalopathy, coma, cardiac dysfunction (heart failure or pericardial effusion), liver dysfunction, hypotonia, seizures, metabolic acidosis, and hyperammonemia Patients with very longchain acyl-CoA dehydrogenase deficiency or long-chain L -3-hydroxyacyl-CoA dehydrogenase deficiency may have exercise-induced rhabdomyolysis Patients may be normal between episodes of decompensation or may have chronic manifestations of disease that can include failure to thrive, developmental delay, chronic peripheral neuropathy, motor deficits (with long-chain L -3-hydroxyacylCoA dehydrogenase deficiency), retinitis pigmentosa (with glutaric acidemia type II), cardiac dysfunction, and dysmorphic facial features Patients with a fatty acid oxidation defect are at risk for SIDS and cardiac arrest due to hypertrophic cardiomyopathy and/or cardiac arrhythmia Women who are pregnant with a fetus affected with long-chain L -3-hydroxyacyl-CoA dehydrogenase deficiency are, as carriers, at risk for HELLP syndrome During decompensation, laboratory assessment should include electrolytes, BUN, creatinine, blood gas, glucose, AST, ALT, alkaline phosphatase, PT, PTT, bilirubin, ammonia, carnitine, and creatinine phosphokinase Management After administration of bolus fluid and correction of any hypoglycemia, D10 in ½ normal saline should be continued at to 1.5 times maintenance, along with insulin, if needed, to maintain serum glucose level at 120 to 170 mg/dL Sodium bicarbonate should be administered for bicarbonate less than 16 mg/dL In patients with fatty acid oxidation defects, correction of acidosis and hypoglycemia usually corrects hyperammonemia Administration of L -carnitine is controversial because in excess, long-chain acylcarnitine may produce cardiac arrhythmias; therefore, L -carnitine should be administered only after consulting a metabolism specialist Drugs that induce hypoglycemia and epinephrine, which stimulates lipolysis, should be avoided, and if they must be given, glucose concentration should be maintained with dextrose Medium chain triglyceride (MCT) oil is beneficial for children with Very Long Chain Acyl Dehydrogenase (VLCADD) Deficiency but it is dangerous for other fatty acid oxidation defects Clinical and laboratory parameters should be monitored until the patient is stabilized and tolerating fluid well Long-term patients may be on a high-carbohydrate, low-fat diet that includes a complex carbohydrate such as cornstarch to avoid hypoglycemia Asymptomatic siblings and parents should be tested The New England Consortium of Metabolic Programs details treatment for specific fatty acid oxidation defects on their website http://newenglandconsortium.org/for-professionals/acute-illness-protocols/fatty-acidoxidation-disorders/ CARBOHYDRATE DISORDERS Disorders of Carbohydrate Intolerance Galactosemia Classic galactosemia, characterized by less than 1% galactose-1-phosphate uridyltransferase activity, results in clinical symptoms usually within the first week of life, often within the first to days, and may be rapidly fatal Goals of Treatment Treatment goals specific for galactosemia are to eliminate galactose from the diet and recognizing and treating possible sepsis Clinical Considerations Assessment Manifestations include poor feeding, vomiting, diarrhea, failure to thrive, bulging fontanelle lethargy that may progress to coma, jaundice and coagulopathy due to liver disease, and/or sepsis, classically with E coli, which may be the initial manifestation Most newborns will have cataracts although they may only be appreciated by slit lamp examination Urine dip will be positive for non–glucose-reducing substances, that is, positive Clinitest, and have negative or trace of glucose with glucose oxidase strip, that is, Clinistix or Glucostix CBC will reveal hemolysis Electrolytes may be remarkable for hyperchloremic metabolic acidosis due to renal tubular dysfunction LFTs are expected to reveal markedly elevated bilirubin level, initially indirect and after to weeks direct, alkaline phosphate and mild to moderately elevated AST and ALT, and markedly elevated PT and PTT Given that most patients present as neonates, those with a known diagnosis will likely have received the diagnosis based on NBS Definitive diagnosis requires measurement of erythrocyte enzyme activity, and particularly in patients with less severe presentation, it may reveal more benign forms Management In addition to correction of dehydration, metabolic derangements, and infection, treatment requires complete lifelong exclusion of galactose from the diet In neonates, breast milk and cow milk must be replaced with lactose-free soy formula, (e.g., Nutramigen, Pregestimil) Even when galactose-free diet is initiated early, those who survive the neonatal period often have developmental delay or learning disabilities Disorders of Carbohydrate Production or Utilization Glycogen Storage Disorders Goals of Treatment Treatment goals specific for glycogen storage disorders are to correct hypoglycemia if present and provide supportive care for organ dysfunction or failure most notably for GSD II heart and liver, GSD IV liver, GSD V renal Current Understanding Glycogen storage disorders are due to defects in glycogen synthesis, degradation, or regulation GSD 0, I, III, IV, VI, IX, which primarily involve liver, and GSD II, which involves skeletal and cardiac muscle, account for the vast majority of cases in the United States and Europe Clinical Considerations Assessment GSD is the most likely to result in acute decompensation, usually due to hypoglycemia during intercurrent illness when patients are unable to take cornstarch, the mainstay of therapy Presentation is similar to that for fatty acid oxidation defects Patients with GSD I, III, VI, IX may also present with symptoms of hypoglycemia Hepatomegaly is seen with GSD 0, I, III, IV, VI, IX Manifestations of skeletal muscle involvement include weakness and potentially renal failure due to rhabdomyolysis Depending on type, other findings can include cardiomyopathy, cardiac arrhythmias, hemolysis, and jaundice Laboratory findings, depending on the organ systems involved, may include hypoglycemia, elevated liver transaminases, ketosis, elevated CPK, myoglobinuria, elevated BUN, creatinine, anemia, neutropenia, coagulopathy, elevated LDH and bilirubin EKG may reveal arrhythmia or findings consistent with cardiomegaly Management Correction of hypoglycemia with glucose and glucose-containing fluids is the same as for fatty acid oxidation defects Enzyme replacement therapy is now available for a subset of GSDs NEONATE WITH POSITIVE NEWBORN SCREEN CLINICAL PEARLS AND PITFALLS