Many diseases develop over a long period, either due to outside effects on the body or slow changes in the interior physiology. This case is an example of the opposite situation: a disease that appears rapidly at birth. What kind of disease is this, and how are they evaluated?
The case: A 5-day old child, born 6 weeks premature, was lethargic with difficult breathing. He had required breathing support for his first 3 days of life, but standard treatments with surfactant let him breathe normally thereafter. During his fifth day, he went from normal breathing to being completely dependent on machine ventilation; he also had a seizure that was stopped with phenobarbital.
Diagnostic tests included CBC blood count, lumbar puncture and blood cultures to detect infection, head ultrasound, and a large set of blood chemistry tests to determine metabolic problems.
What was found on blood chemistry tests?
The baby's electrolytes were initially normal, but by his fifth day, blood gas analysis showed him to be retaining carbon dioxide. The acidity of his blood was corrected with breathing support. His shallow breathing and seizure were found to be caused by a high and rapidly rising level of ammonia. Samples of blood and urine were immediately sent to a nearby pediatric laboratory, where levels of many amino acids were elevated.
How should an ammonia level be checked?
Ammonia is a gas at room temperature, and therefore must be collected in a similar manner to other blood gases. Either arterial or venous blood is acceptable. The tube should be drawn without a tourniquet, as levels will be falsely elevated by any change to blood flow in nearby tissues. To keep ammonia levels accurate, the sample should be placed on ice for transport to the lab and analyzed immediately on arrival. Any high value should be confirmed by repeating the analysis immediately.
What causes hyperammonemia?
In adults, high ammonia levels can be briefly caused by exercise or breakdown of protein (including blood cell breakdown); various drugs (alcohol, narcotics, smoking, diuretics, and antibiotics) can raise or lower ammonia. However, very high ammonia levels in newborns are most often caused by inborn errors of metabolism related to one of several basic biochemical functions: processing of fatty acids, amino acids, or other organic acids containing nitrogen. Diseases caused by these errors arise as soon as the baby is cut off from the mother's ability to conduct the chemical reactions through the placenta. They are caused by genetic mutations that disable an enzyme required to convert a commonly used organic molecule.
Most cases of inborn error of metabolism are inherited from parents that are carriers of mutations, but have at least one functional copy of the enzyme. These are more common in cases of marriage between relatives, as the chances of both parents carrying the same mutation are increased.
How are inborn errors of metabolism detected?
Each U.S. state/Canadian province and many other jurisdictions mandate testing newborns within the first few days of life for a panel of inborn errors of metabolism. The exact number and types of mandated tests vary from place to place, with a typical panel of 20-30 tests screening for 30-50 diseases. The American College of Medical Genetics and the Federal Department of Health and Human Services provide lists of priorities for testing for specific inborn errors -- particularly those for which treatment must be immediate. Each test detects a mutation in a specific enzyme by testing for the molecule(s) on which that enzyme acts. A set of metabolic enzymes are like an assembly line in a factory; if a molecule cannot be processed by the proper enzyme, the molecules prior to that enzyme "pile up" waiting to be processed.
Figure 1: Urea cycle. An inborn error of metabolism for any of the boxed enzymes results in elevated levels of the molecules previous to it, including ammonia.
What was the inborn error of metabolism in this patient?
The urea cycle is a set of enzymes that processes ammonia and amino acids into urea, the primary component of urine. Inborn errors of metabolism in any of the urea cycle enyzmes can produce hyperammonemia. In this case, urine and blood samples tested by the state department of public health and the local pediatric hospital showed elevated levels of citrulline, argininosuccinate, and glutamine, but not arginine or ornithine. Consulting the figure above, the enzyme responsible for this patient's inborn error of metabolism can be identified as argininosuccinate lyase.
Back to the patient: Inborn errors of metabolism must be rapidly treated to prevent damage to brain, kidneys, and other organs, which can cause coma and rapid death. The immediate hyperammonemia created by the newborn's urea cycle disorder was treated by dialysis and plasma exchange. Feeding was stopped for 1-2 days, then restarted at a lower level to prevent muscle breakdown from starvation. A month afterward, our newborn was stable and continuing treatment in the neonatal intensive care unit at the local pediatric hospital, where his feeding, breathing, and metabolism were carefully monitored.
Depending on the severity and type of inborn errors of metabolism, prognosis for patients with this class of diseases can range from good (if the enzyme's target molecule can be avoided in the diet) to very poor (for severe cases involving key molecules).
Dr. Bryan received his medical degree at Harvard Medical School, and PhD at Massachusetts Institute of Technology. Now he is a first-year resident in the Department of Pathology at Beth Israel Deaconess Medical Center in Boston, MA.
For further reading:
- - Rosenthal P. Assessing liver function and hyperbilirubinemia in the newborn. Clinical Chemistry 43(1): 228-234 (1997)
- - Smith LD, Uttam G. The urea cycle disorders and hyperammonemias. Laboratory diagnosis of inherited metabolic diseases. AACC Press, 2012.
- - Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 11:823(2009).
- - Broomfield A, Grunewald S. How to use serum ammonia. Arch Dis Child Educ Pract Ed. 97(2):72(2012).
- - Wappner R. Biochemical diagnosis of genetic diseases. Pediatr Ann 22(5):282(1993).
- - Saudubray JM, Chappentier C. Clinical phenotypes: Diagnosis/algorithms. Metabolic and molecular bases of inherited disease, McGraw-Hill, New York 2001. p.1327.