The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Catherine Y.H. Wagoner. This current second edition chapter is a revision and update of the original author’s work.
A term male infant is born to a healthy 24-year-old G2P1 mother after an uncomplicated pregnancy. All serology testing, maternal serum screening,, and fetal ultrasounds were unremarkable. The mother presented in labor at 39 weeks gestation had an uncomplicated spontaneous vaginal delivery with rupture of membranes 2 hours prior to delivery. Apgar scores were 8 and 9 at one and five minutes, respectively. Growth parameters were all normal with a birth weight of 3250 g, birth length of 51 cm and head circumference of 35 cm (AGA). The infant’s initial assessment and physical examination were unremarkable. He breast fed well and was discharged to home on the second day of life.
Once home, he began having difficulty feeding. He had to be awakened every 3 hours to breastfeed and was not latching on to the breast as well. He passed at least 4 meconium stools since birth and still had wet diapers every couple of hours. Mother was experienced at breastfeeding from her first child and tried a variety of techniques to encourage breastfeeding. After 24 hours at home he began to gag and vomited a small amount of nonbilious material. His family called the pediatrician and was instructed to take the baby to the Emergency Department.
Upon arrival to the Emergency Department, the infant was noted to be sleepy but still arousable with stimulation. Vital signs showed weight 3100 g, T 36.2 C (rectal), P 125 and regular, RR 44, BP 70/50. His physical examination was otherwise unremarkable with minimal jaundice. Anterior fontanelle was soft and flat. He did not have retractions or nasal flaring. No heart murmur was detected. Chest x-ray was unremarkable with a normal cardiothymic silhouette and no infiltrates. Laboratory studies showed an unremarkable CBC. Total bilirubin was mildly elevated at 5.0 mg/dL. Electrolytes were normal (no metabolic acidosis). Urinalysis was negative for blood, protein, glucose, ketones, leukocyte esterase, trace for urobilinogen. Blood and urine cultures were obtained, IV antibiotics were started and he was admitted to the pediatric ward.
Over the next 4 hours he became progressively more lethargic and difficult to arouse. Repeat VS included T 36 C (rectal), P 115, RR 36, BP 68/50. His physical examination did not show any new symptoms except for hypotonia, lethargy and irregular breathing pattern. Ammonia was checked and was significantly elevated at 2300 micromol/L (reference range 15 to 53 micromol/L). He was transferred to the PICU where he was intubated for apnea and central venous lines were placed. He received intravenous sodium phenylbutyrate, sodium phenylacetate, and arginine HCl with initial bolus and then continuous IV infusion. He was also given IVF with a high glucose concentration (20% dextrose). He was started on continuous veno-venous hemofiltration to quickly reduce the ammonia level. The newborn screening office was called to inquire about the results of the newborn screen; the results were normal. Plasma amino acids and urine for orotic acid were sent to a reference lab with results reported by phone 3 days later consistent with ornithine transcarbamylase (OTC) deficiency.
The infant was discharged after two weeks on a special formula prescription made up of only essential amino acids, carbohydrate, and lipid mixed with small amount of expressed maternal breast milk, oral ammonia scavenging medication, and citrulline. Molecular testing of the OTC gene detected a pathogenic mutation confirming the diagnosis of OTC deficiency. His mother was found to be a carrier of the mutation. The infant was referred to a liver transplant center, and received the transplant at 6 months of age. The couple had a subsequent pregnancy two years later with a male fetus that was negative for the OTC mutation in the family. Carrier testing of the asymptomatic older sister will be deferred until she is of child bearing age.
Inborn errors of metabolism (IEM) are a diverse group of disorders that are almost always due to mutations in specific enzymes that function within the various biochemical pathways responsible for the synthesis, degradation, excretion, or transport of complex molecules. Individually, each disorder may be rare, but taken together, these disorders are not uncommon. There is a wide range of functional activity for each enzyme within the population and only a small minority of individuals has a low enough enzyme activity level to manifest symptoms. Most of these conditions present in the newborn, infant, or childhood period, and the astute physician must recognize the signs and symptoms that suggest metabolic disease and include appropriate screening and diagnostic testing in their evaluation. Due to the sheer number of disorders classified as inborn errors of metabolism, literally hundreds with more being discovered each year, it would be impossible to give a comprehensive review of the subject in a single book chapter. However, there are several overriding principles and practices that are fundamental to the diagnosis and management of the patient with acute symptoms of an IEM.
Acute presentations of metabolic disease
The acute presentation of many metabolic disorders is due to "intoxication" or accumulation of toxic compounds proximal to the enzyme that is deficient (1). There is typically a symptom-free interval of variable length depending on the severity of the deficiency. The symptoms can be acute, chronic, or intermittent, presenting within hours of birth to several years after birth. Metabolic disorders that present with intoxication include the amino acidopathies, organic acidemias, urea cycle defects, fatty acid oxidation disorders, and disorders of carbohydrate metabolism.
The symptoms of metabolic disease are often nonspecific and can include lethargy, irritability, poor feeding/anorexia, failure to thrive, vomiting, dehydration, respiratory distress, seizures, ataxia, and developmental delay. IEM can also present for the first time when the infant or child is sick with an intercurrent infection or other physiologic stressor, so it is important to remember IEM among the conditions in the differential diagnosis for any sick child.
The historical information obtained from the family or records can be very helpful. It is important to document the first onset and progression of symptoms, the feeding type (breast milk, formula, solid foods) and relationship of the symptoms to feeding (worse after feedings or before feedings, after fasting overnight, etc.), in addition to the important signs and symptoms noted above. The family history is important to document, especially unexplained neonatal or childhood deaths, deaths associated with viral illness or infection, etc. Most IEM are inherited as autosomal recessive traits, with the affected or at risk individuals restricted to the siblings of the affected patient, so lack of a family history does not rule out IEM. Since autosomal recessive disorders may be more frequent in a given population that is restricted geographically or culturally, the racial/ethnic background of both sides of the family should be documented.
Physical examination findings may also be subtle and nonspecific and include hypothermia, tachypnea (a sign of metabolic acidosis), tachycardia (a sign of dehydration), neurologic signs of abnormal tone, lethargy or coma, unusual odors (rare, but helpful), and hepatomegaly for some conditions. In the evaluation of a sick infant or child, routine laboratory testing may suggest an IEM, but are also nonspecific. Common laboratory presentations include hypoglycemia, unexplained metabolic acidosis, increased anion gap, ketosis/ketonuria, and hyperammonemia.
The initial laboratory evaluation should include CBC with differential, arterial blood gas, serum electrolytes, glucose, plasma lactate, ammonia, urinalysis with special attention to ketones, and reducing substances (2,3). If possible, the newborn screen results should be documented. Follow-up screening and diagnostic testing depends on the condition being considered, but in general, for most amino acid, organic acid, fatty acid oxidation, and urea cycle disorders, the diagnosis may be suggested by the combination of results from the screening tests in addition to plasma amino acids (quantitative), urine organic acids (qualitative), total and free carnitine and acylcarnitine profile. These should all be analyzed at the same biochemical laboratory so that the results can be interpreted together. Definitive diagnosis may require documentation of the enzyme deficiency in blood, skin fibroblasts, or other tissue, or molecular genetic testing.
There are many useful algorithms available for the diagnosis of IEM depending on the presenting laboratory abnormality (1,2,3). Although it may be possible to determine the general class of metabolic defect, it is often not possible to determine the exact enzyme which is defective or lacking without definitive testing. Some specific patterns of laboratory abnormalities can be useful in the differential diagnosis. Elevated ammonia without hypoglycemia suggests a urea cycle defect. Elevated ammonia with hypoglycemia suggests an organic acidemia or fatty acid oxidation defect Hypoglycemia without hyperammonemia suggests a carbohydrate metabolism defect (e.g., galactosemia, defect in gluconeogenesis, or a glycogen storage disease) or sometimes a fatty acid oxidation disorder. Elevated plasma and urine ketones (the latter easily tested on urine dipstick) are very helpful in the presence of hypoglycemia. Ketosis/ketonuria is consistent with an organic acidemia, while hypoketosis can suggest a fatty acid oxidation defect. Reducing substances in the urine support the possibility of classic galactosemia, but careful interpretation is necessary since there are a variety of medical conditions and drugs that yield positive reducing substances in the urine (4).
Urea cycle disorders
Any neonate, infant, child or adult that presents with unexplained lethargy or coma should be evaluated for hyperammonemia, which can have a variety of underlying causes. Hyperammonemia is critical to recognize and treat promptly to minimize brain damage and risk of death. Hyperammonemia can be associated with urea cycle disorders (UCD), organic acidemias, or fatty acid oxidation defects. The urea cycle functions to prevent accumulation of excess nitrogen by incorporating it into urea, which can be excreted by the kidney. In all five of the UCDs, the common toxin is ammonia (NH3) and therefore, the presentation of this group of defects is quite similar. Presenting signs and symptoms include vomiting, lethargy, poor feeding, decreased mental status, and even coma. Survivors may eventually develop spasticity, mental retardation, seizures and ataxia. These disorders usually present in the first few days to weeks of life as the ammonia waste product accumulates, leading to very high serum ammonia levels (>1000 micromol/L). The affected newborn very rapidly decompensates. Remember that symptoms in a neonate and quite nonspecific, and are much more likely to be due to infection/sepsis. It can be difficult to differentiate the two disease processes. However, the existence of these symptoms, along with low risk for a neonatal infection, may raise the index of suspicion that would lead the clinician to conduct a thorough laboratory evaluation for a metabolic condition along with the sepsis workup (2).
Hyperammonemia requires prompt treatment in the intensive care setting and includes intravenous "ammonia scavenger" medication (e.g. sodium phenylbutyrate, sodium phenylacetate) to provide an alternative pathway for excretion of waste nitrogen. Deficient urea cycle intermediates, citrulline or arginine, must also be provided. Hemodialysis or continuous veno-venous hemofiltration are used to rapidly decrease ammonia levels that are greater than 500 micromol/L. High glucose concentration fluids provided through central lines are critical to decrease further protein breakdown (catabolism) (5). This is one of the most important concepts in the treatment of most acute metabolic disease. Catabolism must be reversed by providing sufficient calories in the form of glucose. In UCD, lipids can also be used along with limited protein intake.
All of these conditions are inherited in an autosomal recessive pattern except for OTC deficiency, which is X-linked. However, OTC deficiency can present in females, often later in infancy or childhood, or may present for the first time in a woman during the postpartum period. The diagnosis of a UCD is typically suggested by plasma amino acids, with low citrulline associated with the proximal defects in the pathway and high citrulline in the more distal pathway deficiencies. Elevated urine orotic acid and low citrulline are suggestive of OTC deficiency. Since citrulline is the "target" in newborn screening, low levels are not detected, and therefore proximal UCDs are not detected by newborn screening. Definitive diagnosis is made either by molecular genetic testing or enzyme assay (liver tissue).
Long term treatment of UCD includes oral ammonia scavenging medication (e.g., sodium phenylbutyrate) and restriction of natural protein with supplementation of essential amino acids to decease the excess daily nitrogen load that must be processed by the defective urea cycle. Oral citrulline or arginine (depending on the specific defect) is needed to bypass the enzyme block for the urea cycle to function (6). Liver transplantation is considered for the severe defects since repeated episodes of hyperammonemia with intercurrent illness or other physiologic stress are common, placing the patient at high risk for repeated brain damage from ammonia toxicity.
A group of metabolic disorders related to the urea cycle defects is the organic acidemias. These are caused by defective processing of a single or related group of amino acids resulting in an accumulation of organic acid byproducts or lack of production of a necessary end product. An organic acid, by definition, does not contain a nitrogen containing "amino" group. The symptoms are very similar to the urea cycle defects; however, there are subtle laboratory differences. While urea cycle disorders result in hyperammonemia without acidosis and only occasionally hypoglycemia, the organic acidemias (as the name suggests) result in metabolic acidosis and hyperammonemia that is more on the order of 200 to 900 micromol/L. One of the best understood diseases from this class of metabolic diseases is maple syrup urine disease (MSUD).
MSUD is categorized as both an amino acidopathy and organic acidemia. It is caused by variable deficiency of the branched-chain ketoacid deyhydrogenase complex, which is made up of subunits encoded by 3 different genes. Classic MSUD becomes symptomatic in the immediate neonatal period, presenting with acute decompensation within the first 1 to 2 weeks of life. Symptoms are similar to most other metabolic disorders and can include lethargy, poor feeding, vomiting, seizures, opisthotonus, and respiratory failure, which can progress to cerebral edema, coma and death if untreated. Toxicity is related to elevated leucine levels in addition to the accumulation of branched chain hydroxy acids and ketoacids (7). Laboratory evaluation yields hypoglycemia, hyperammonemia (to a lesser degree than in urea cycle defects), anion gap acidosis, and ketosis/ketonuria. A characteristic odor of maple syrup may accumulate in cerumen and urine, so the diagnosis can be suspected sniffing the ears and smelling the diaper. The diagnosis is confirmed by plasma amino acids which show elevations of the branched chain amino acids leucine, isoleucine, and valine, and the presence of alloisoleucine, which is pathognomic for MSUD. Molecular genetic testing is available for further confirmation, and if a compound heterozygous or homozygous mutation is identified, prenatal diagnosis is available for subsequent pregnancies.
MSUD is an excellent example of variability in a given IEM as there are intermediate or intermittent forms that present later in infancy, childhood, or adulthood that lead to milder chronic symptoms of poor growth, developmental delay, or normal early development but with intermittent encephalopathic symptoms that may not be recognized as due to an IEM (7). Intermittent MSUD may not be detected on the newborn screen.
The treatment of MSUD and other organic acidemias typically involves utilization of medical food/formula that has the specific offending amino acids removed, restriction of natural protein intake, and avoidance of catabolism during illness or other stress. Involvement of a registered dietician in all patients with IEM is critical to ensure adequate nutrition since dietary restriction can lead to malnutrition, vitamin, and/or mineral deficiencies. Levocarnitine is often used to bind toxic metabolites for excretion in the urine. Vitamin co-factors are used for selective disorders; in the case of MSUD, some cases seem to be responsive to thiamine (7).
Galactosemia is one of the commonly occurring disorders of carbohydrate metabolism, and also one of the first conditions included in newborn screening programs. This disease occurs from a deficiency of galactose-1-phosphate uridyltransferase (GALT). Over time, there is an accumulation of galactose-1-phosphate, which manifests as failure to thrive, prolonged vomiting, lethargy, diarrhea, cataracts, developmental delay and intellectual disability, liver, and kidney disease. In galactosemia, there is an increased likelihood of sepsis from gram negative organisms that may cause death in the neonatal period. There are many variant forms of galactosemia due to less severe deficiency of GALT activity; Duarte galactosemia is one common variant. Most of the variant forms of galactosemia do not require galactose restriction (8).
Although Phenylketonuria (PKU), due to deficiency of the enzyme phenylalanine hydroxylase (PAH), does not present with acute metabolic derangement, it does need to be diagnosed and treated promptly to avoid long term neurologic damage. The enzyme deficiency leads to accumulation of phenylalanine that is toxic to brain growth and nerve myelination. Symptoms include acquired microcephaly, seizures, severe to profound intellectual disability, abnormal behaviors, skin rashes (eczema) and "musty" or "mousy" odor. In addition, the PAH enzyme is necessary to convert phenylalanine to tyrosine which is required for melanin synthesis. With a defective enzyme, the individual is unable to produce proper levels of tyrosine which results in deficient pigmentation of skin and hair. Treatment includes restriction of natural protein intake with supplementation of medical food/formula that is phenylalanine free. Phenylalanine and tyrosine levels are used to monitor response to treatment and the need for tyrosine supplementation. Recently, novel treatments have been developed for PKU including oral sapropterin dihydrochloride, an important cofactor of PAH that increases enzyme activity and protein tolerance in some individuals. Another novel treatment blocks phenylalanine update in the brain by providing competing large neutral amino acids; this is primarily used for patients who are unable to achieve dietary compliance. Finally, clinical trials are ongoing for an injectable enzyme similar to PAH that can metabolize phenylalanine (9).
All U.S. States and Territories, the District of Columbia, and many other countries, have newborn metabolic screening programs. Recent advances in testing technology, particularly tandem mass spectrometry, have enabled laboratories to quickly and simultaneous screen for many IEM (10). In the US, a standard panel of screening tests was recommended by the Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (11,12), and as of April 2013 includes 31 core conditions including many hemoglobinopathies, endocrine disorders, and IEM, but also important heritable conditions such as cystic fibrosis and severe combined immunodeficiency (11). This rapid expansion in the number of disorders included in the screen has also led to increases in public outreach to educate parents (13) and health care providers. The latter effort includes easily available ACTion (ACT) sheets and confirmatory algorithms for the primary care physician (14).
The State of Hawaii began screening for PKU in 1963, and gradually more conditions were added. The Hawaii Newborn Metabolic Screening (NBMS) program is responsible for oversight, management and quality assurance of newborn screening statewide, follow-up and tracking of results ensuring that babies with positive screens are treated promptly, and lastly, the development of educational materials for families and health care practitioners (15). Hawaii was one of the first states to adopt the recommended expanded newborn screening panel in 2003. The Hawaii NBMS program has a manual available to the primary care physicians (online and printed versions) in addition to other related resources (15,16). The Oregon Public Health Laboratory performs the testing for all infants born in Hawaii and many other western states. Normal results are reported out to the primary care provider within 2 weeks of the testing. Abnormal results are called or faxed to the physician, depending on urgency, with instructions for treatment and diagnostic testing.
It is important to remember that screening tests, including newborn screening, may have both false positive and false negative results, and the specific reasons for both may be unique for the different disorders. For IEM, the goal is to detect serious disease at an early treatable stage. More subtle or later onset forms of the same conditions included in the screening may yield normal results in the newborn.
1. True/False: Infants with an inborn metabolic defect are always symptomatic within the first two weeks of life.
2. A 4 week old female born on a remote Pacific island presents with failure to thrive, lethargy, and vomiting. Hepatomegaly and jaundice are noted on examination. Appropriate initial laboratory testing should include (choose all that apply):
. . . . . a. CBC and differential
. . . . . b. urinalysis including reducing substances
. . . . . c. electrolytes
. . . . . d. liver function testing
. . . . . e. blood, urine, and CSF cultures
3. An infant male is now being discharged at 4 weeks of age with the diagnosis of OTC deficiency. His long term management will include (choose all that apply):
. . . . . a. protein restriction
. . . . . b. medical food/formula
. . . . . c. ammonia scavenging medication
. . . . . d. supplementation of urea cycle intermediates (citrulline or arginine)
. . . . . e. thiamine supplementation
4. An 18 month old female is evaluated for developmental delay and hypotonia, and is seen in the Emergency Department for acute ataxia associated with a febrile illness. She has mild hypoglycemia, metabolic acidosis with anion gap of 17 and 3+ ketones in her urine. Ammonia was minimally elevated at 70 micomol/L. Her newborn screen was normal. The most likely diagnosis is:
. . . . . a. OTC deficiency
. . . . . b. Classic MSUD
. . . . . c. Galactosemia
. . . . . d. Intermediate MSUD
. . . . . e. Glycogen storage disease type 1
5. Newborn screening programs are designed with which of the following principles in mind (choose all that apply):
. . . . . a. To identify all infants with the diseases that is included in the screening panel.
. . . . . b. To allow for early treatment of disease to reduce morbidity and mortality.
. . . . . c. To screen for all possible metabolic diseases.
. . . . . d. To ensure early screening of future offspring for the family of affected infants.
. . . . . e. To educate the public and physicians about the newborn screening process and the conditions included in the screening panel.
1. Fernandes J, Saudubray J-M, van den Berghe G, Walter JH (Eds). Inborn Metabolic Diseases: Diagnosis and Treatment, 4th Ed. 2006, Heidelberg: Springer Medizin Verlag, pp. 5-10.
2. Burton BK. Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. Pediatrics 1998;102(6):e69.
3. Banta-Wright SA and Steiner RD. Not so rare: errors of metabolism during the neonatal period. Newborn Infant Nurs Rev 2003;3:143-155.
4. Vasudevan DM, Sreekumari S, Vaidyanathah. Textbook of Biochemistry for Medical Students, 6th Ed. 2011, New Delhi: Jaypee Brothers Medical Publishers (P) Ltd, p. 279.
5. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001;138:S30-s39.
6. The Urea Cycle Disorders Group. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr 2001;138:S1-S5.
7. Strauss KA, Puffenberger EG, Morton DH. Maple Syrup Urine Disease. 2006 Jan 30 (Updated 2013 May 9). In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ (Internet). Seattle (WA): University of Washington, Seattle; 1993. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1319/ Accessed 5/22/13.
8. Elsas LJ II. Galactosemia. 2000(Updated 2010 Oct 26). In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ (Internet). Seattle (WA): University of Washington, Seattle; 1993-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1518/ Accessed 5//26/13.
9. Mitchell JJ. Phenylalanine Hydroxylase Deficiency. 2000(Updated 2013 Jan 31). In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ (Internet). Seattle (WA): University of Washington, Seattle; 1993-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1504/ Accessed 5/26/13.
10. Wilcken B. Recent advances in newborn screening. J Inherit Metab Dis 2007:30:129-133.
11. Available at: http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendedpanel/uniformscreeningpanel.pdf Accessed 5/26/13.
12. Available at: http://www.cdc.gov/newbornscreening/ Accessed 5/26/13.
13. Available at: http://www.babysfirsttest.org/ Accessed 5/26/13.
14. ACMG ACT Sheets and Confirmatory Algorithms (Internet). Bethesda (MD): American College of Medical Genetics; 2001-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK55832/ Accessed 5/26/13.
15. Available at: http://health.hawaii.gov/genetics/programs/nbshome/
16. The Northwest Regional Newborn Screening Program Hawaii Practitioners Manual, 9th edition. 2011. Available at: http://health.hawaii.gov/genetics/files/2013/04/NSM_Hawaii2012_rev_052313.pdf Accessed 5/26/13.
1. False, some can present for the first time in adulthood.
2. a,b,c,d,e. Many IEM and other conditions are possible with this presentation.