inborn error of metabolism

Misconceptions (from Fanaroff & Martin's Neonatal & Perinatal Medicine)

• Inherited metabolic diseases are rarely a cause of disease in the neonate and should, therefore, be considered diagnostically as a last resort. 

  • Incidence is > 1/2,000, so not rare enough to not at include on the differential for a neonate presenting with vague, non-specific symptoms.

• It is difficult to know when to suspect that a sick newborn infant may have a metabolic disorder, because presentation of such disorders often mimics that of sepsis in the newborn infant. 

  • Because the neonate with an IEM may present with sepsis like symptoms is exactly why IEM should be on the differential. The newborn septic workup is specifically designed to be broad enough to identify newborns who may have an underlying IEM.

• Many metabolic diseases are detectable in the neonatal period, and it is difficult to remember the presentation of each one. 

  • This misses the forest for the trees; the goal is not to remember the individual presentations. Because there is great redundancy in their clinical presentations, the workup can become simplified to certain routine lab tests and algorithms (see below).

• The biochemical pathways and nomenclature of inborn errors of metabolism are impossible to remember. 

  • Yes, they are numerous and difficult/impossible to remember for the general neonatologist. However, that is not the expectation. The goal is to develop a systematic approach (much simpler!) to help identify whether there is or is not an underlying IEM.

• It is difficult to diagnose a metabolic disease. 

  • The goal is not to diagnose a metabolic disease with one round of testing. The goal is to develop a staged approach that leads the clinician down the right diagnostic pathway. The subsequent step once an IEM is identified is to recruit the expertise of a specialist. 

Most newborn infants with an inborn error of metabolism present have relatively few types of presentation:

• Encephalopathy

• Seizures

• Hypotonia

• Eye anomalies (cataracts, corneal clouding, retinal anomalies - highlights the importance of a thorough eye exam at birth/on admission)

• Poor feeding

• Lethargy

• Jaundice

• Hepato/splenomegaly

• Respiratory failure

• Cardiomyopathy 

• Cytopenias/Pancytopenia

So, the presentation is very vague and almost all of the above symptoms could be attributed to sepsis, so IEM should be on your differential if sepsis is!

Most newborn infants with an inborn error of metabolism have one or more of only a handful of strategic laboratory findings, so look for these in the undifferentiated neonate: 

• Metabolic acidosis

• Lactic acidemia (high anion gap)

• Hypoglycemia

• Hyperammonemia

Any combination of the above laboratory findings should prompt you to think of/consider an IEM when building your differential.

Blood:

• CBC

• BMP (electrolytes, glucose, BUN, Cr)

• Hepatic panel (AST/ALT and bilirubin)

• Blood gas

• Lactate, pyruvate

• Ketones (β-hydroxybutyrate and acetoacetate) 

• Ammonia

• Uric acid

Urine:

• UA (pH, ketones)

• Urine organic acids

• Odor (set some aside and leave at infant's bedside, smell later)

CSF:

• Glucose

• Lactate

• Pyruvate

Note 1: high ammonia with otherwise normal labs (normal glucose, minimal/no acidosis, normal ketones) should prompt you to think about urea cycle disorders:

• Obtain plasma/urine amino acids and urine orotic acid

Note 2: high ammonia with multiple other derangements (hypoglycemia, lactic acidosis, ketosis, +/- cytopenias) should prompt you to think about organic acidemias:

• Obtain urine organic acids