Inborn Errors of Metabolism

Inborn errors of metabolism: Pearls and Pitfalls

Author: Brit Long, MD, CAPT (EM Resident Physician at SAUSHEC; USAF) // Edited by: Jennifer Robertson, MD and Alex Koyfman, MD (@EMHighAK)

Case:

It is your last night shift of the month in the emergency department (ED). So far, the night has been quiet until about 1:30 am when paramedics arrive with a distressed five day old female.  The infant’s mother reports that the baby has not been tolerating feeds and has been vomiting repeatedly. She also notes that the baby has been intermittently tachypneic and “floppy.”  The infant’s initial vital signs include an afebrile rectal temperature, a respiratory rate (RR) of 78, a heart rate (HR) of 178, and an oxygen saturation (SpO2) of 98% on room air. The nurses are working on obtaining a blood pressure. The infant appears mottled and has poor tone. You order laboratory work and attempt to remember pediatrics facts from medical school and residency training. In addition to the laboratory work, you obtain a lumbar puncture and four limb oxygen saturations and blood pressures, all of which are normal.

The infant’s laboratory results return, showing an ammonia level of 296, with positive serum ketoacids. The patient’s liver enzymes are also elevated, which raises concern for a possible inborn error of metabolism.

 Background

Inborn errors of metabolism can be divided into four parts, based on the defect of a metabolic pathway. These separate parts include: (1) Ineffective or missing transport proteins or complexes that normally allow for passage of a needed substance across cell membranes, (2) Lack of  catalyzing enzyme (s) for an essential pathway, (3) Blockage of a primary metabolic pathway, requiring the use of an alternative pathway and (4) Deficient cofactor for a metabolic pathway.  (1-7)

 Presentation

Patients with inborn errors of metabolism may present in two different time periods: (1) the neonatal period and (2) months to years after birth. Neonatal presentations correlate with an absence of or complete block of the metabolic pathway, while presentations later in life are usually due to a partial or incomplete blockage of the affected pathway. (1-5)

In the neonatal period, patients usually present anytime between three days to one week of life.  They often present with vomiting, tachypnea, gasping, altered mental status, and lethargy. A study by Waber found that more than 90% of patients have neurologic symptoms and/or vomiting. (5)  Most commonly, infants present with an abnormal neurologic complaint such as poor tone, lethargy, jitteriness, seizures, poor feeding, strange odor, and/or exaggerated primitive reflexes. Unfortunately, at this age, infants are unable to communicate and thus, making the diagnosis may be difficult.

If an incomplete blockage or absence of protein/cofactor is present, the patient may present later in life. Usually, patients present in the setting of an acute stressor such as acute gastroenteritis or upper respiratory infection. (1-3) Infections that normally are self-limited in healthy children could potentially cause septic shock in these patients.

Ultimately the diagnosis comes down to clinical suspicion. When should you suspect these disorders, and how can you definitively diagnose an inborn error?

When should an inborn error of metabolism be suspected?

The following situations should raise your suspicion of a metabolic disorder: symptoms that worsen or emerge in a normally self-limited illness, recurrent vomiting despite multiple formula changes, symptoms when an switches to formula, symptoms that start with a new food, family history of metabolic disease, history of unexplained neonatal death, or history of consanguinity. Physical exam and laboratory findings that assist in the diagnosis may include organomegaly, abnormal tone, abnormal mental status, neutropenia, thrombocytopenia, hyperpnea, dysrhythmia, liver failure, cataracts, abnormal hair, and unusual rashes.

If older patients have recurrent severe presentations in the setting of normally self-limited illnesses such as gastroenteritis, suspect an inborn error of metabolism.

Diagnosis, Management and Treatment

“THE MISFITS”

The above historical factors and physical exam findings can occur in a multitude of childhood illnesses and thus, one must keep a wide differential when evaluating for inborn errors of metabolism and other life threats. To assist in evaluating ill children, a pneumonic called “THE MISFITS” can help ensure that all life threats are evaluated for and ruled out in the neonate or infant. (3-11)

T-Trauma (non-accidental and accidental)

H-Heart disease / hypovolemia / hypoxia

E-Endocrine (congenital adrenal hyperplasia, thyrotoxicosis)

M-Metabolic (electrolyte imbalance)

I-Inborn errors of metabolism: Metabolic emergencies

S-Sepsis (meningitis, pneumonia, urinary tract infection)

F-Formula mishaps (under- or over-dilution)

I-Intestinal catastrophes (volvulus, intussusception, or necrotizing enterocolitis)

T-Toxins

S-Seizures

When evaluating an infant you are concerned for an inborn error of metabolism, several steps should be taken. The ABCDEs (airway, breathing, circulation, disability and exposure) should always be addressed first. If the patient needs airway protection, address this first. At times, these patients have been tachypneic for an extended period to compensate for a metabolic acidosis, and thus, they may soon tire. Thus, patients may require mechanical ventilation. In addition, these patients are often volume depleted due to vomiting, diarrhea and insensible losses from tachypnea, so a fluid bolus will be beneficial. Ensure blood glucose testing is obtained, as most patients will be hypoglycemic. Look for signs of infection and rash when you expose the patient.

Important laboratory tests include a venous blood gas (VBG), electrolytes, a complete blood count (CBC), a renal function panel, a urine dipstick, an ammonia level, ketones, lactate, and liver function (LFTs) testing. In the setting of a sick neonate, an ECG, chest X-ray, four limb oxygen saturations, blood pressures, blood cultures, and a lumbar puncture should also be obtained. (2,4,10)

 Ammonia levels will usually be above 180 if a true inborn error is present. A sick neonate may have an ammonia level around 80, however this is not necessarily consistent with an inborn error of metabolism. If a tourniquet is used for blood collection, hemolysis can occur and lead to falsely elevated ammonia levels as well. Hypoglycemia may be present, though this is usually a later finding. CBC may show neutropenia. (4-10)

There are a multitude of laboratory tests that can assist with inpatient physicians, but the most critical laboratory tests include an ammonia level, cortisol and growth hormone levels, an insulin level, and ketoacids. Most pediatric critical care physicians will want these labs drawn before glucose is provided, as these tests will help definitively diagnose the mechanism and condition.

Other laboratory tests include urine reducing substances, urine orotic acid, urine organic acids, serum organic acids, serum acylcarnitine, amino acids of blood/urine/CSF, and comprehensive newborn screen. These tests will not return quickly and in this setting, it may be helpful to ask the inpatient physicians what additional laboratory tests should be drawn in the ED.(1-8)

Treatment

The first goal is to stop metabolism of the toxin. Make sure that the patient is nothing by mouth (NPO) as it is essential to remove protein sources from the diet as soon as possible.  The next step is to stop catabolism by giving dextrose 10% (D10) with 0.25 normal saline (NS) at 1.5 x maintenance fluid infusion. Finally, in conjunction with the inpatient physicians, consider removing the toxin and metabolites. For hyper-ammonemia, sodium phenyl acetate at 250mg/kg intravenous (IV) bolus or sodium benzoate at 0.25g/kg IV over 2 hours may be given. Dialysis is also an option to assist in removal of the toxin (s).  Arginine at 200-600mg/kg IV and/or carnitine at 100-200mg/kg IV x 1 should be given in the setting of a urea cycle defect with no acidosis. If a neonate is seizing, pyridoxine at 1mg intramuscularly (IM) should be given. Importantly, the above treatments should be given after consulting with the pediatric intensive care team. (1,6-11)

Consultations are vital in the definitive management of patient suffering from an inborn error of metabolism. Call the pediatric intensive care unit (PICU) as soon as possible to discuss the patient, testing, and management. A genetics and or metabolism consultation can also assist in correct testing and management. Finally, nephrologists can be helpful if dialysis is necessary for refractory hyperammonemia. In fact, early dialysis in these patients is associated with improved neurologic development as well as improved morbidity and mortality. (3,4,10,11)

Summary:

1. Presentation of inborn errors of metabolism occurs in two different phases of life: (1) neonatal if a complete enzymatic block exists or complex enzyme is absent or (2) later if a child has an incomplete blockage of a metabolic pathway.
2. Go through “THE MISFITS” differential when assessing an ill infant or young child.
3. Obtaining a CBC, VBG, renal function panel, LFTs, ketones, ammonia level, lactate, and urinalysis are the most important tests to obtain during initial assessment
4. Stop toxin metabolism, stop catabolism, provide glucose, and remove the toxin.
5. Consult the PICU, genetics, and nephrology as early as possible.

References / Further Reading

1. Ward JC. Inborn errors of metabolism of acute onset in infancy. Pediatr Rev. 1990;11(7):205-216.
2. Lindor NM, Karnes PS. Initial assessment of infants and children with suspected inborn errors of metabolism. Mayo Clin Proc. 1995;70(10):987-988.
3. Kwon KT, Tsai VW. Metabolic emergencies. Emerg Med Clin North Am. 2007;25(4):1041-1060, vi.
4. Harris GD, Perkin RM, Sacchetti A. Inborn errors of metabolism in infants: recognition, diagnosis, and management. Pediatr Emerg Med Rep. 2002;7(1):1-12.
5. Waber L. Inborn errors of metabolism. Pediatr Ann. 1990;19(2):105-109, 112-113, 117-118.
6. Saudubray JM, Nassogne MC, de Lonlay P, Touati G. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol. 2002;7(1):3-15.
7. Weiner DL. Metabolic emergencies. In: Fleisher GR, Ludwig S, Henretig FM, Ruddy RM, Silverman BK, eds. Textbook of Pediatric Emergency Medicine. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:1193-1206.
8. Walter JH. Investigation and initial management of suspected metabolic disease. Curr Paediatr. 2002;12(2):110-116.
9. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998;102(6):E69.
10. Claudius I, Fluharty C, Boles R. The emergency department approach to newborn and childhood metabolic crisis. Emerg Med Clin North Am. 2005;23(3):843-883.
11. Wong KY, Wong SN, Lam SY et al. Ammonia clearance by peritoneal dialysis and continuous arteriovenous hemodialysis filtration. Pediatr Nephrol. 1998 12:589-591.