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1998 - Pediatrics - Inborn Errors of Metabolism in Infancy A Guide To Diagnosis
1998 - Pediatrics - Inborn Errors of Metabolism in Infancy A Guide To Diagnosis
Barbara K. Burton, MD
ABSTRACT. Recent advances in the diagnosis and 102/6/e69; inborn errors of metabolism, inherited metabolic
treatment of inborn errors of metabolism have improved disorders.
substantially the prognosis for many of these conditions.
This makes it essential that the practicing pediatrician be
familiar with the clinical presentation of these disorders. ABBREVIATIONS. CNS, central nervous system; THAN, transient
hyperammonemia of the newborn; OTC, ornithine transcarbamy-
A practical clinical approach to the recognition of inborn
lase; CoA, co-enzyme A; PDH, pyruvate dehydrogenase; GSD,
errors of metabolism in the young infant is presented in glycogen storage disease.
this review. Indications for specific laboratory studies are
discussed. Guidelines are provided for the stabilization
T
and emergency treatment of critically ill infants. This he number, complexity, and varied clinical
approach will identify those infants who will benefit presentation of inborn errors of metabolism
from additional evaluation and specific treatment. present a formidable challenge to the practic-
Many of the inborn errors of metabolism, including ing pediatrician. Yet, in many cases, prevention of
urea cycle defects, organic acidemias, and certain disor-
ders of amino acid metabolism, present in the young
death or permanent neurologic sequelae in patients
infant with symptoms of an acute or chronic metabolic with these disorders is dependent on early diagnosis
encephalopathy. Typical symptoms include lethargy, and institution of appropriate therapy. It is therefore
poor feeding, apnea or tachypnea, and recurrent vomit- incumbent on the pediatrician to be familiar with the
ing. Metabolic acidosis and/or hyperammonemia are ob- major signs and symptoms of inborn errors of me-
served in many of these conditions, but there are notable tabolism and with the basic laboratory studies nec-
exceptions, including nonketotic hyperglycinemia and essary to arrive at an initial diagnosis. Although the
molybdenum co-factor deficiency. Therefore, appropri- pediatrician may rarely be called on to be the sole
ate laboratory testing for metabolic disorders should be provider of long-term care to patients with these
performed in any infant who exhibits these findings. complex disorders, he or she will be responsible for
Although sepsis may be the initial consideration in a
neonate with these symptoms, inborn errors of metabo-
the emergency care and stabilization of the infants
lism should always be in the differential diagnosis, par- and children affected and should be familiar with the
ticularly in a full-term infant with no specific risk factors. fundamental aspects of such care.
Hypoglycemia may be the predominant finding in a It is the purpose of this review to define the con-
number of inborn errors of metabolism, including glyco- stellation of findings in the young infant that should
gen storage disorders, defects in gluconeogenesis, and alert the pediatrician to the possibility of inherited
fatty acid oxidation defects. The latter disorders, among metabolic disease. The discussion is confined to
the most common encountered, exhibit marked clinical those disorders that typically present in early infancy
variability and also may present as a sudden death, a and have potential life-threatening consequences.
Reye’s-like episode, or a cardiomyopathy. Jaundice or The many disorders that typically present in later
other evidence of hepatic dysfunction is the mode of
presentation of another important group of inborn errors
childhood, such as most lysosomal storage disorders,
of metabolism including galactosemia, hereditary ty- are not included. The laboratory tools used to eval-
rosinemia, neonatal hemochromatosis, and a number of uate infants suspected of having metabolic disease
other conditions. A subset of lysosomal storage disorders are described. Treatment of important groups of met-
may present very early with coarse facial features, orga- abolic disorders is addressed, focusing on the stabi-
nomegaly, or even hydrops fetalis. Specific patterns of lization and acute management of patients with
dysmorphic features and congenital anomalies character- these conditions. A more comprehensive discussion
ize yet another group of inherited metabolic disorders, of each of these topics can be found in recent editions
such as Zellweger syndrome and the Smith–Lemli–Opitz of reference textbooks.1,2
syndrome. Each of these symptom complexes, and the
appropriate evaluation of the affected infants, is dis-
cussed in more detail in this review. Pediatrics 1998; CLINICAL MANIFESTATIONS OF INBORN ERRORS
102(6). URL: http://www.pediatrics.org/cgi/content/full/ OF METABOLISM
Acute Metabolic Encephalopathy
From the Center for Medical Genetics, Michael Reese Hospital and Medical
Center, Division of Genetics and Metabolism, University of Illinois College Several groups of inherited metabolic disorders,
of Medicine, Chicago, Illinois. most notably the organic acidemias, urea cycle de-
Received for publication May 15, 1998; accepted Jul 15, 1998. fects, and certain disorders of amino acid metabo-
Reprint requests to (B.K.B) Center for Medical Genetics, Michael Reese lism, typically present with acute life-threatening
Hospital and Medical Center, Division of Genetics and Metabolism, Uni-
versity of Illinois College of Medicine, 2929 S Ellis Ave, Chicago, IL 60616.
symptoms of an encephalopathy. These symptoms
PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Acad- are the result of toxic effects of accumulating metab-
emy of Pediatrics. olites on the central nervous system (CNS). Because
than those associated with inborn errors of metabo- born errors of metabolism and in most other condi-
lism and THAN can be observed in a variety of other tions producing metabolic acidosis in the neonate. In
conditions associated with liver dysfunction, includ- contrast, the differential diagnosis of metabolic aci-
ing sepsis, generalized herpes simplex infection, and dosis with a normal anion gap is essentially limited
perinatal asphyxia. Liver function studies should be to two conditions, diarrhea and renal tubular acidosis.
obtained in evaluating the significance of moderate Among the inborn errors, the largest group typically
elevations of plasma ammonia. However, even in associated with overwhelming metabolic acidosis in
cases of severe hepatic necrosis, it is rare for ammo- infancy is the group of organic acidemias, including
nia levels to exceed 500 mmol/L.4 Mild transient such entities as methylmalonic acidemia, propionic
hyperammonemia with ammonia levels as high as acidemia, and isovaleric acidemia.
twice normal is relatively common in the newborn, In addition to specific organic acid intermediates,
especially in the premature infant, and is usually plasma lactate often is elevated in organic acidemias
asymptomatic. It appears to be of no clinical signifi- as a result of secondary interference with co-enzyme
cance, and there are no long-term neurologic se- A (CoA) metabolism. Neutropenia and thrombo-
quelae. cytopenia are commonly observed and further un-
derscore the clinical similarity of these disorders to
Metabolic Acidosis neonatal sepsis. Hyperammonemia, sometimes as
The second important laboratory feature of many dramatic as that associated with urea cycle defects, is
of the inborn errors of metabolism during acute commonly but not uniformly seen in clinically ill
episodes of illness is metabolic acidosis with an infants with organic acidemias.
increased anion gap, readily demonstrable by mea- Defects in pyruvate metabolism or in the respira-
surement of arterial blood gases or serum electro- tory chain may lead to primary lactic acidosis pre-
lytes and bicarbonate. A flowchart for the evaluation senting as severe metabolic acidosis in infancy.5 Un-
of infants with this finding is presented in Fig 2. An like most of the other conditions presenting acutely
increased anion gap ($16) is observed in many in- in the newborn, clinical features of these disorders
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are unrelated to protein intake. Disorders in this medical center genetics units. It is important to insist
group should be considered in patients with lactic that any reference laboratory used for this purpose
acidosis who have normal urine organic acids. Dif- provide prompt test results and reference ranges and
ferentiation of the various disorders in this group can provide interpretation of abnormal results.
be facilitated by measuring plasma pyruvate and A summary of the inborn errors of metabolism
calculating the lactate/pyruvate ratio. A normal ratio most likely to be associated with symptoms of an
(#25) suggests a defect in pyruvate dehydrogenase acute encephalopathy is presented in Table 2. The
(PDH) or in gluconeogenesis, and an elevated ratio typical laboratory findings in each condition or
($25) suggests PC deficiency, a respiratory chain group of conditions are also listed.
defect, or a mitochondrial myopathy.
Not all infants with life-threatening metabolic dis- Emergency Treatment of the Infant With an Acute
ease have metabolic acidosis or hyperammonemia. Metabolic Encephalopathy
For example, nonketotic hyperglycinemia typically When an inborn error of metabolism, such as an
presents in the neonatal period with evidence of organic acidemia or urea cycle defect, is suspected in
severe and progressive CNS dysfunction, but with a critically ill infant, immediate treatment should be
neither metabolic acidosis nor hyperammonemia. initiated, even if a definitive diagnosis may not yet
The same is true of molybdenum co-factor de- be established. Within 48 to 72 hours, the results of
ficiency, which on the surface may be virtually amino acid and organic acid analysis should be avail-
indistinguishable from hypoxic–ischemic encepha- able, allowing diagnostic confirmation in most cases.
lopathy. Even patients with galactosemia may rarely Appropriate and aggressive treatment before the
present with symptoms of CNS toxicity, which may confirmation of a diagnosis may be life-saving and
progress to cerebral edema, when galactose-1-phos- may avert or reduce the neurologic sequelae of some
phate levels rise precipitously. Therefore, the series of these disorders. The immediate treatment of in-
of laboratory studies listed in Table 1 should be fants with disorders in this group has two primary
obtained for any infant with clinical findings sug- goals. The first is the removal of accumulating me-
gesting an inborn error of metabolism, even if met- tabolites such as organic acid intermediates or am-
abolic acidosis and hyperammonemia are not monia. At the first suspicion of a disorder associated
present. Most of the tests on this list are self-explan- with protein intolerance, protein intake should be
atory. Although not available in many hospital lab- discontinued immediately. In critically ill infants
oratories, amino acid and organic acid analysis can with hyperammonemia, arrangements should be
be obtained in any part of the country through ref- made for hemodialysis. Although peritoneal dialysis,
erence laboratories or through referral of samples to continuous arteriovenous hemoperfusion, and ex-
change transfusion all have been used in the past to of complete protein restriction. Essential amino acids
lower plasma ammonia levels, all are substantially or total protein can be provided orally or intrave-
less effective than hemodialysis. In infants who are nously at an initial dose of 0.5 g protein/kg/24
comatose or ventilator-dependent, or who exhibit hours. This should be increased incrementally to 1.0
evidence of cerebral edema, dialysis should be insti- g/kg/24 hours and held at that level until the diag-
tuted immediately without waiting to determine nostic evaluation is complete and plans can be made
whether there is a response to dietary manipulation, for definitive long-term therapy. Therapy should be
medication, or other less aggressive therapy. Maxi- planned in conjunction with a geneticist or specialist
mal supportive care should be provided simulta- in metabolic disease. Until then, supplemental calo-
neously. In patients suspected of having a urea cycle ries and nutrients can be provided orally using pro-
defect because of significant hyperammonemia with- tein-free diet powder (product 80056, Mead Johnson,
out acidosis, an infusion of 6 mL/kg of 10% arginine Evansville, IN or Prophree, Ross Laboratories, Co-
HCL (0.6 g/kg) can be given intravenously over 90 lumbus, OH). Once a definitive diagnosis is estab-
minutes. In patients with citrullinemia and arginino- lished, commercial products formulated for individ-
succinic aciduria, this often results in a precipitous ual diseases can be instituted.
drop in the plasma ammonia level. An intravenous
arginine preparation is available commercially and Hypoglycemia
should be readily accessible to any hospital phar- Hypoglycemia and its associated symptoms occa-
macy. sionally may be seen in infants with disorders of
If an organic acidemia is suspected, vitamin B12 (1 protein intolerance, but it is seen more commonly in
mg) should be given intramuscularly in case the disorders of carbohydrate metabolism or fatty acid
patient turns out to have a B12-responsive form of oxidation. Among the best known inborn errors of
methylmalonic acidemia. Biotin (10 mg) should be metabolism associated with hypoglycemia are the
given orally or by nasogastric tube, because some hepatic glycogen storage diseases (GSD). The hypo-
patients with multiple carboxylase deficiency are glycemia in these disorders is related to the inability
biotin-responsive. If acidosis exists, intravenous bi- of the liver to release glucose from glycogen, and it is
carbonate should be administered liberally. Calcula- most profound during periods of fasting. Hypogly-
tions of bicarbonate requirements appropriate for the cemia, hepatomegaly, and lactic acidosis are promi-
treatment of other conditions are rarely adequate in nent features of these disorders. Hypoglycemia is not
these disorders because of ongoing production of a feature of GSD type II (Pompe disease) because
organic acids or lactate. The acid-base status should cytoplasmic glycogen metabolism and release are
be monitored frequently, with therapy adjusted ac- normal in this disorder in which glycogen accumu-
cordingly. Dialysis should be considered for severely lates within lysosomes as a result of deficiency of the
acidotic neonates with organic acidemias, regardless enzyme acid maltase. Clinical manifestations of this
of whether hyperammonemia is present. disorder include macroglossia, hypotonia, cardio-
After removing toxic metabolites, the second ma- megaly with congestive heart failure, and hepato-
jor goal of therapy in infants with inborn errors of megaly. Cardiomegaly is the most striking feature
metabolism should be to prevent catabolism. Intra- and may be apparent in the neonatal period. Con-
venous glucose should be administered liberally to gestive heart failure is the cause of death in most
provide as many calories as possible. Intravenous cases. Hypoglycemia may be a prominent feature of
lipids can be given to infants with urea cycle defects both galactosemia and hereditary fructose intoler-
and other disorders in which dietary fat plays no ance, although symptoms of the latter disorder occur
role. Protein should not be withheld indefinitely. If only after fructose (sucrose) has been introduced in
clinical improvement is observed and a final diagno- the diet.
sis has not been established, some amino acid intake A number of inherited defects in fatty acid oxida-
should be provided after a maximum of 2 to 3 days tion have been identified in infants presenting with
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TABLE 3. Inborn Errors of Metabolism Associated With Neonatal Liver Disease and Laboratory Studies Useful in Diagnosis
Disorder Laboratory Studies References
Galactosemia Urine reducing substances; RBC galactose-1-phosphate uridyl transferase 13
Hereditary tyrosinemia Plasma quantitative amino acids; urine succinylacetone 14
a1-Antitrypsin deficiency Quantitative serum a1-antitrypsin; protease inhibitor typing 15
Neonatal hemochromatosis Serum ferritin; liver biopsy 16
Zellweger syndrome Plasma very long-chain fatty acids 17
Niemann–Pick disease type C Skin biopsy for fibroblast culture; studies of cholesterol esterification and 18
accumulation
GSD type IV (brancher deficiency) Liver biopsy for histology and biochemical analysis or skin biopsy with assay 19
of branching enzyme in cultured fibroblasts
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