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Diseases involving the same metabolic pathways or organelles usually share similar features Thus, recognition and treatment does not require specific knowledge of IEMs, but rather a general understanding of diagnostic categories and disease pathways Most IEMs with potential for acute decompensation present in neonates or infants but may present in older children and adolescents Common clinical manifestations of acute decompensation include vomiting, lethargy, seizures, rapid deep breathing, hypothermia, or brief resolved unexplained event (BRUE) Metabolic acidosis, respiratory alkalosis, hypoglycemia, and/or hyperammonemia are laboratory hallmarks of IEM Pretreatment samples should be sent for testing when possible as laboratory studies may become normal with treatment Prompt emergency treatment of physiologic decompensation, using PALS or APLS guidelines, correction of metabolic derangements, as well of precipitant causes of decompensation are critical for optimizing outcome Current Understanding IEMs are usually caused by single gene defects that result in abnormalities in protein, carbohydrate, fat, or complex molecule metabolism Most are due to a defect in, or deficiency of, an enzyme, enzyme cofactor, or transport protein that results in a block in a metabolic pathway Clinical effects are the consequence of toxic accumulations of substrates before the block or intermediates from alternative metabolic pathways and/or defects in energy production and utilization due to deficiency of products beyond the block Common clinical presentations of IEMs are detailed in Table 95.1 In the ED, evaluation and management of patients with undiagnosed but suspected IEM is usually guided by suspicion of metabolic disease but does not require a specific diagnosis Categories of IEMs and their clinical and laboratory findings are detailed in Table 95.2 Patients with an organic acidemia, urea cycle defect, disorder of carbohydrate utilization or production, fatty acid oxidation defect, mitochondrial disorder, or peroxisomal disorder are at greatest risk of acute, life-threatening decompensation Patients with congenital adrenal hyperplasia, detailed in Chapter 89 Endocrine Emergencies , may also present with acute critical decompensation Toxic accumulation of substances results from disorders of protein metabolism (i.e., aminoacidopathies, organic acidemias, urea cycle defects), carbohydrate intolerance, and lysosomal storage disorders Defects in energy production or utilization result from disorders of glycogenolysis and gluconeogenesis, fatty acid oxidation defects, and mitochondrial disorders Peroxisomal disorders are a diverse group of IEMs caused by defects of single or multiple peroxisomal enzymes, or of peroxisomal biogenesis that result in toxic accumulations, energy deficiency, and/or defects in biosynthesis of complex molecules Other categories include disorders of metal metabolism, purine, and pyrimidine biosynthesis (e.g., Lesch–Nyhan syndrome); cholesterol biosynthesis, heme, bile acid, and bilirubin metabolism, lipoprotein metabolism, and glycosylation TABLE 95.1 COMMON PRESENTATIONS OF INBORN ERRORS OF METABOLISM a Acute neonatal catastrophe Septic appearing Temperature instability Apnea, tachypnea, cyanosis, respiratory failure Bradycardia, poor perfusion Irritability, lethargy, coma Seizures Poor feeding, vomiting Hypertonia, hypotonia Sudden infant death Neurologic disturbance Developmental delay, usually progressive, with or without loss of milestones Autism Learning disabilities, behavioral and/or emotional disturbances Hallucinations, delirium Ataxia, dizziness, headache Lethargy, coma Encephalopathy Seizures Movement disorder, posturing Peripheral neuropathy Stroke, stroke-like episode Vision, hearing, speech impairment Dementia Cardiac failure/myopathy Failure with cardiomegaly ± skeletal muscle weakness Cardiac arrhythmia, syncope, sudden death Pericardial tamponade, effusion Gastrointestinal/hepatic dysfunction, failure Poor feeding, food intolerances/aversion, failure to thrive Chronic intermittent vomiting, decompensation out of proportion to illness Chronic diarrhea Abdominal pain Pseudoobstruction Acute pancreatitis Hepatomegaly Liver failure/hepatocellular dysfunction—jaundice (direct and/or indirect), coagulopathy, elevated liver function tests Myopathy Muscle weakness, pain, cramping Exercise intolerance Psychiatric disturbance Anxiety Psychosis Personality changes Behavioral disturbances Depression Obsessive compulsive disorder Delirium, hallucinations, schizophrenia Biochemical disturbance Acidosis—chronic or acute recurrent Hyperammonemia with or without alkalosis Hypoglycemia with or without ketonuria, hypoketosis a Findings may be in isolation or combination and may be either intermittent or progressive over time Clinical Considerations Triage IEM should be considered in any neonate or infant who is critically ill without known etiology IEM can present at any age with recurrent syndromes (stupor, lethargy), failure to thrive, unusual odors, or unexplained neurologic findings Assessment History Poor feeding, frequent vomiting, failure to thrive, lethargy in the morning before feeding or with delayed feeding, intractable seizures, hypothermia, or acute life-threatening events are common presentations of acute decompensation episodes Unusual dietary preferences, particularly protein or carbohydrate aversion, or the waxing/waning of episodic symptomatology may indicate possible IEM in an otherwise healthy child Physiologic stressors such as fasting, fever, illness, trauma, or surgery may precipitate symptoms, especially if the stressor induces a catabolic state Intercurrent infection may result in decompensation out of proportion to the illness A history of multiple hospitalizations for lethargy and dehydration with improvement following intravenous (IV) fluids and glucose is common Psychomotor developmental delay, especially with loss of milestones, is also concerning for an IEM Certain findings suggest particular categories of IEMs Vomiting occurs with many IEMs but is a prominent feature of organic acidemias and urea cycle defects Lethargy progressing to coma is common with amino acid disorders, organic acidemias, urea cycle defects, fatty acid oxidation defects, and certain disorders of carbohydrate intolerance IEM should also be considered in any child with unexpected, unexplained sudden death, even without other history suggestive of IEM Cerebral edema is particularly common in maple syrup urine disease and disorders with elevated ammonia or severe hypoglycemia Rapid deep breathing resulting in respiratory alkalosis is a hallmark of urea cycle disorders while metabolic acidosis is more commonly seen in organic acidemias