After completing this article, readers should be able to:
Delineate features of a medical history that should raise suspicion for an inborn error of metabolism.
Describe common ocular findings associated with inborn errors of metabolism.
List the primary clinical findings of inborn errors of metabolism associated with encephalopathy without metabolic acidosis.
Delineate the categories of inborn errors of metabolism associated with encephalopathy and metabolic acidosis.
The rapid deterioration of a previously healthy-appearing neonate is one of the most stressful scenarios in medicine. Unless appropriate therapy is initiated without delay, there is a high risk of morbidity or mortality, regardless of the etiology of the acute illness. Any infant who presents with feeding difficulties, vomiting, jaundice, failure to thrive, apnea or tachypnea, hypotonia or hypertonia, seizures, lethargy, or coma should be considered as suffering from diseases in one of two broad categories: 1) disorders resulting from causes such as infection, cardiopulmonary dysfunction or other causes of hypoxemia, toxins, trauma, or congenital structural brain abnormalities or 2) disorders caused by an inborn error of metabolism. Because metabolic diseases are individually rare, there is a tendency to consider them only after excluding more common causes of neonatal distress. However, the aggregate incidence of inborn errors of metabolism is relatively high, with as many as one child in every 1,000 births being affected. The clinician must consider these disorders in all neonates who have nonspecific features of distress upon initial presentation. In many cases, only rapid diagnosis and management can prevent death or significant morbidity. Appropriate laboratory investigations should be obtained immediately. Even simple tests such as measurement of blood gases, glucose, electrolytes, lactate, and ammonia and the evaluation of urine for ketones may provide valuable clues to the underlying diagnosis.
Most inborn errors of metabolism are inherited as autosomal recessive traits or, as in the case of ornithine transcarbamylase deficiency, are X-linked. A detailed family history may reveal an affected relative who has a similar illness, which is of great diagnostic importance. The affected relative typically is a sibling of either gender in the case of an autosomal recessive condition, but can be a maternal uncle, a brother, or a mildly affected mother or other female in X-linked disease. Some disorders are caused by mitochondrial DNA mutations, and maternal transmission to all children in a sibship is observed. Special attention should be given to stillbirths, unexplained deaths, and neurologic diseases or delayed development of any degree or severity. Maternal illness in pregnancy also has been associated with specific metabolic disorders and may yield a clue to the presence of an inborn error of metabolism in a neonate. For example, acute fatty liver of pregnancy and hypertension, elevated liver enzymes, low platelets (HELLP) syndrome may occur in a heterozygous mother carrying a fetus that has long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.
Signs and Symptoms
Symptoms of metabolic disease generally occur postnatally, appearing after an interval period of apparent good health and following a normal pregnancy. The interval may be as short as a few hours or be several days or even longer. The infant may do well until subjected to a catabolic insult (infection, fasting, dehydration) or an excessive protein or carbohydrate load. Following exposure to a stressor, the child may become strikingly ill very suddenly and can present as sudden infant death of unexplained etiology. On the other hand, the absence of a normal period does not exclude an inborn error from diagnostic consideration. Neonatal distress from asphyxia or complications of prematurity may constitute the environmental stress that unmasks an underlying metabolic disease.
Irritability and feeding difficulties may be associated with uncoordinated sucking and swallowing or abnormal muscle tone. Persistent and severe vomiting and convulsions may occur. In mildly affected neonates, symptoms can disappear, only to recur in days or weeks. More severely affected infants have inexorable progression from lethargy to coma to episodic apnea and death. More limited symptoms, often in the form of generalized or partial seizures, may occur in some instances. These can include staring spells, eye rolling or myoclonus, and various combinations of tone abnormalities, tremulousness, lethargy, and a weak cry. Electroencephalography may suggest nonspecific diffuse encephalopathy. Unless an inborn error is suspected, the child may be misdiagnosed as having hypoxic-ischemic encephalopathy, intraventricular hemorrhage, sepsis, heart failure, or a gastrointestinal illness, such as pyloric stenosis or intestinal obstruction.
A concomitant acquired disorder may confound the diagnosis of an inherited metabolic disease. For example, neutropenia may occur in an organic acidemia that has a neonatal presentation, but sepsis with leukocytosis (or neutropenia) also may be present because of an increased susceptibility to bacterial infection. Escherichia coli sepsis is frequent in infants who have galactosemia, and the inanition and jaundice of that disorder might be ascribed incorrectly solely to sepsis. Other examples of acquired conditions that may complicate the presentation of a metabolic disorder include pulmonary hemorrhage or primary respiratory alkalosis in urea cycle defects.
A paucity of abnormal physical findings is the general rule in heritable metabolic diseases. Nevertheless, certain components of the physical examination should be emphasized. A detailed ocular examination is essential; corneal clouding, cataracts, optic nerve abnormalities, and macular or retinal pigmentary changes may be helpful in establishing a diagnosis (Table 1⇓ ). Hepatomegaly can occur in carbohydrate disorders (galactosemia, glycogen storage disease, hereditary fructose intolerance), peroxisomal disorders, tyrosinemia, Niemann-Pick disease, Gaucher disease, inborn errors of bile acid metabolism, neonatal hemochromatosis, some forms of congenital lactic acidosis (mitochondrial respiratory chain defects), and other organic acidemias and fatty acid oxidation defects that may have a Reye syndrome-like presentation. Abnormal, brittle hair may be seen in some urea cycle defects (argininosuccinic aciduria, citrullinemia), holocarboxylase synthetase deficiency, and Menkes syndrome (pili torti). An unusual body or urine odor has been associated with several organic acidemias, including branched-chain ketoaciduria (maple syrup), isovaleric acidemia or multiple acyl-CoA dehydrogenase deficiency (sweaty feet), and 3-methylcrotonyl-CoA carboxylase deficiency (cat-like) (Table 2⇓ ). Ketosis accompanies many of these conditions and will cause the sweet odor of ketone bodies in the urine. An unusual urine color also may signal some inborn errors (Table 3⇓ ).
Encephalopathy Without Metabolic Acidosis
A number of inborn errors of metabolism are associated with encephalopathic findings or isolated seizures in the newborn period (Table 4⇓ ). The nonspecific features of these conditions are similar to those of hypoxic-ischemic encephalopathy. However, unlike acute asphyxia, generally there is no history of birth trauma, and patients appear normal for at least a short time. If the degree of encephalopathy appears greater than would be expected from careful review of the perinatal history, an inborn error should be considered strongly.
Maple Syrup Urine Disease (MSUD)
Infants who have MSUD typically develop symptoms in the first few days to weeks of life after appearing normal at birth. Poor feeding and vomiting may be the initial symptoms, but lethargy and progressive neurologic deterioration supervene. The child may be hypotonic or appear markedly hypertonic with opisthotonus. Not all infants develop a “maple syrup” smell. Although ketosis is prominent, metabolic acidosis is not often present until later in the course of disease.
Mevalonic aciduria is a disorder of cholesterol biosynthesis that usually is not associated with metabolic acidosis. Severe neurologic involvement may occur in neonates, but patients often have other findings, such as dysmorphic features, hepatosplenomegaly, recurrent fevers, and anemia.
Urea Cycle Defects
The early clinical course of patients who have urea cycle defects is similar to that in MSUD, except that hypotonia typically is more severe, and a respiratory alkalosis is common. Severe hyperammonemia is the hallmark of these conditions. However, sepsis often is suspected initially, and unless an ammonia level is evaluated, these infants may die of unknown cause early in the newborn period. Aside from the X-linked ornithine transcarbamylase deficiency, these are autosomal recessive disorders.
Transient hyperammonemia of the newborn (THAN) is an important consideration in the differential diagnosis of these conditions. THAN tends to occur in the first day of life; urea cycle disorders typically present after 1 or 2 days. Other inborn errors, including pyruvate carboxylase deficiency, organic acidemias, fatty acid oxidation defects, lysinuric protein intolerance, and the hyperammonemia-hyperornithinemia-homocitrullinuria syndrome, can cause marked hyperammonemia by secondary inhibition of urea cycle function. Standard metabolic investigations are usually sufficient to diagnose these conditions.
Infants who have peroxisomal disorders (Zellweger syndrome, neonatal adrenoleukodystrophy) often exhibit severe neonatal features, including craniofacial dysmorphism, neuronal migration defects, pigmentary retinopathy, profound hypotonia, seizures, hepatomegaly, jaundice, and renal cysts. Short limbs, joint contractures, and epiphyseal stippling are characteristic of rhizomelic chondrodysplasia punctata. Evidence of hepatocellular dysfunction is common.
A growing list of metabolic disorders are associated with isolated seizures or progressive encephalopathy without obvious biochemical abnormalities on routine metabolic screening (Table 4⇑ ). It is important to save a sample of cerebrospinal fluid (CSF) for specialized testing in case a common cause for neonatal seizures is not identified.
Approximately two thirds of patients who have nonketotic hyperglycinemia exhibit symptoms within 48 hours of delivery. Infants typically present with lethargy, apnea, profound hypotonia, feeding difficulty, hiccups, and intractable seizures. The only consistent abnormalities are elevated urine, plasma, and CSF glycine levels. A CSF-to-plasma glycine ratio of greater than 0.08 confirms the diagnosis. CSF and blood samples for glycine analysis must be obtained as near to simultaneously as possible for accurate calculation of the glycine ratio.
Sulfite oxidase deficiency may occur in isolation or combined with xanthine oxidase deficiency. The combined defects are secondary to molybdenum cofactor deficiency. Patients have seizures that are recalcitrant to therapy starting in the first few days of life. A low uric acid level may be noted in molybdenum cofactor deficiency, but other laboratory findings are normal. A specific assay for elevation of plasma or urine S-sulfocysteine is required to make the diagnosis.
Infants who have pyridoxine-dependent seizures may present as early as the first day of life with flaccidity, abnormal eye movements, and irritability. The diagnosis is clinical and is based on documented response of seizures to intravenous pyridoxine (vitamin B6).
The enzyme 4-aminobutyrate aminotransferase (GABA transaminase) catalyzes the initial step in the conversion of GABA, a central nervous system inhibitory neurotransmitter, to succinic acid. Elevated GABA concentrations in the central nervous system result in neonatal seizures, lethargy, hypotonia, hyperreflexia, and a high-pitched cry.
Folinic acid-responsive seizures is a newly described disease of unknown etiology. Seizures occur as early as 2 hours after birth. High-performance liquid chromatography documents a characteristic peak. Infants respond to folinic acid supplementation.
Patients who have guanidinoacetate methyltransferase deficiency, a recently identified disorder of creatine metabolism, usually present in infancy with seizures, developmental delay, and extrapyramidal signs, but symptoms have been described in neonates. Low plasma creatinine levels and elevated guanidinoacetate are characteristic.
A reduced CSF glucose concentration (hypoglycorrhachia) is present in the GLUT-1 deficiency syndrome (glucose transporter defect). This autosomal dominant disorder causes severe clinical symptoms, including seizures, acquired microcephaly, and developmental delay. Patients have become symptomatic as early as the third week of life, but it is unclear whether symptoms may occur earlier because of the paucity of reported cases.
Encephalopathy With Metabolic Acidosis
Inborn errors of metabolism that are characterized by a nonspecific encephalopathy with associated metabolic acidosis include organic acidemias, fatty acid oxidation defects, and primary congential lactic acidoses (Table 5⇓ ). Distinctive clinical features are often absent.
Organic acidemias that present in the newborn period with encephalopathy and severe metabolic acidosis are virtually indistinguishable clinically. Hyperammonemia may be severe, with ammonia levels similar to those encountered in urea cycle disorders. In addition, neutropenia and thrombocytopenia are common, and sepsis or a bleeding diathesis may supervene. Distinctive odors may be present in some of these conditions (Table 2⇑ ), but often only the nonspecific sweet smell of ketone bodies is noticeable.
Fatty acid oxidation disorders may have a Reye syndrome-like presentation. Approximately 5% to 10% of unexplained sudden infant deaths may be attributed to these conditions. Although encephalopathy may dominate the clinical picture, multiorgan system involvement is common, with infants showing various degrees of cardiac, skeletal muscle, ophthalmologic, and hepatic involvement. Hyperammonemia and lactic acidosis may occur. Cardiomyopathy is particularly common in long-chain defects (Table 6⇓ ). Hepatomegaly and hepatocellular dysfunction are typical of these conditions when they occur in neonates. A pigmentary retinopathy is often present in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, but it tends to develop later in childhood.
Disorders of pyruvate metabolism and mitochondrial disorders may cause congenital lactic acidosis. Many infants who have pyruvate dehydrogenase deficiency exhibit dysmorphic features. Brain abnormalities, including cerebral and cerebellar atrophy, agenesis of the corpus callosum, and Leigh syndrome, may be present. Patients who have the neonatal form of pyruvate carboxylase deficiency have hepatomegaly, hyperammonemia, citrullinemia, and ketosis. Infants who have mitochondrial disease often have lactic acidosis with an elevated lactate-to-pyruvate ratio. Virtually any organ system may be affected, either in isolation or in any combination, in patients who have mitochondrial disease. However, involvement of the neuromuscular systems is especially common.
Long-chain fatty acid oxidation defects are a significant cause of neonatal cardiomyopathy. Although cardiomyopathy may occur in mitochondrial disorders, onset is often in early infancy. The infantile form of Pompe disease presents between birth and 6 months of age with muscle weakness and a rapidly progressive cardiomyopathy. Electrocardiography may show very large QRS complexes and a short PR interval due to the electrical conductive properties of glycogen. Phosphorylase b kinase deficiency is another glycogen storage disorder that rarely causes cardiomyopathy. Several of the lysosomal storage disorders may be associated with cardiomyopathy, but this tends to develop after the newborn period (Table 6⇑ ).
Neonates who have classic galactosemia often have a history of persistent hyperbilirubinemia, hepatomegaly, and hepatocellular dysfunction. The hyperbilirubinemia tends to be unconjugated initially, but it becomes mostly conjugated in later untreated disease. Patients who have alpha-1-antitrypsin deficiency also may exhibit persistent neonatal jaundice that may progress to cirrhosis over several months.
Severe hepatocellular dysfunction is common in fatty acid oxidation defects and is characteristic of hereditary tyrosinemia type I and neonatal hemochromatosis. Hereditary fructose intolerance may present in the newborn period with acute liver dysfunction if an affected infant is exposed to fructose. Hepatomegaly associated with hypoglycemia (without encephalopathy) is characteristic of glycogen storage disease type I and some disorders of gluconeogenesis. Causes of neonatal liver disease are shown in Table 7⇓ .
An increasing number of inborn errors are being recognized that may be associated with dysmorphic features (Table 8⇓ ). Infants who have peroxisomal disorders may have striking facial dysmorphism and structural anomalies. Pyruvate dehydrogenase deficiency, cholesterol biosynthetic disorders (mevalonic aciduria, Smith-Lemli-Opitz syndrome), 3-hydroxyisobutyric aciduria, multiple acyl-CoA dehydrogenase deficiency (glutaric aciduria type II), D-2-hydroxyglutaric aciduria, and mitochondrial disorders also may be associated with dysmorphic features. Children who have congenital disorders of glycosylation (formerly carbohydrate deficient glycoprotein syndrome) typically exhibit inverted nipples and an unusual distribution of fat, often with suprailiac fat pads and buttock lipodystrophy. The coarse features characteristic of lysosomal storage disorders usually evolve in infancy and early childhood, but some of these conditions may present in the neonatal period with hydrops. Therefore, the presence of dysmorphic features does not exclude an inborn error of metabolism from diagnostic consideration.
Nonimmune Fetal Hydrops
Inborn errors of metabolism may be associated with nonimmune fetal hydrops (Table 9⇓ ). Although the association of metabolic disorders that cause anemia with fetal hydrops is clear, the cause of the massive generalized edema that may accompany many of these conditions remains obscure.
In aggregate, inborn errors of metabolism are a significant cause of neonatal distress. A presumptive diagnosis, or at least a narrow differential diagnosis, may be apparent after taking into account family history, clinical features, and results of basic laboratory studies. The consideration of these conditions in any infant who has nonspecific signs of distress may lead to rapid diagnosis and provide the best chance of decreasing the morbidity and mortality associated with metabolic diseases.
- Copyright © 2001 by the American Academy of Pediatrics
Blau N, Duran M, Blaskovics ME, eds. Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. 1996 Chapman and Hall London, England
Clarke JTR. Acute metabolic illness in the newborn. In: A Clinical Guide to Inherited Metabolic Diseases. 1996:176-204 New York, NY.: Cambridge University Press
Packman S. Metabolic encephalopathies. Berg B, eds. Child Neurology: A Clinical Manual. 1994:51-59 JB Lippincott Co Philadelphia, Pa
Packman S. Approach to inherited metabolic disorders that present in the newborn period and infancy. Rudolph AM, Hoffman JIE, Rudolph CD, eds. Rudolph’s Pediatrics. 1996:291-294 Appleton and Lange Stamford, Conn
Saudubray, J-M, Charpentier C. Clinical phenotypes: diagnosis/algorithms. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 2001:1327-1403 McGraw-Hill New York, NY
Ward JC. Inborn errors of metabolism of acute onset in infancy. Pediatr Rev. 1990;11:205-216