Inborn Errors of Metabolism
Ayman W. El-Hattab
V. Reid Sutton
I. INTRODUCTION.
Infants with inborn errors of metabolism (IEM) are usually normal at birth with signs typically developing in hours to days after birth. The signs are usually nonspecific and may include respiratory distress, hypotonia, poor sucking, vomiting, lethargy, or seizures. These signs are common to several other neonatal conditions, such as sepsis and cardiopulmonary dysfunction; therefore, it is important to maintain a high index of suspicion of IEM in sick neonates, since most of these disorders can be lethal unless diagnosed and treated immediately.
Although IEM are individually rare, their overall incidence is as high as 1 in 2,000. About 100 different IEM may present clinically in the neonatal period. Most IEMs are transmitted as autosomal recessive genetic diseases. A history of parental consanguinity or previous sibling with unexplained neonatal death or severe illness should raise the suspicion for an IEM. Some IEM, such as the urea cycle disorder (UCD) ornithine transcarbamylase (OTC) deficiency, are X-linked. As in any X-linked disorder, the severely affected family member could have been a maternal uncle, or a brother, or perhaps a mildly affected mother, sister, or maternal aunt.
II. CLINICAL PRESENTATION.
Newborns with IEMs can present with one or more of the following clinical groups:
Neurologic deterioration (lethargy/coma). Poor sucking and decreased activity may progress to lethargy, coma, muscle tone changes, involuntary movements, apnea, bradycardia, and hypothermia. IEMs associated with neurologic deterioration may be subdivided as follows to narrow the differential diagnosis:
IEMs with metabolic acidosis: Maple syrup urine disease (MSUD), organic acidurias, fatty acid oxidation defects, and primary lactic acidemias (defects of gluconeogenesis, pyruvate metabolism, and mitochondrial respiratory chain function) (see IV.)
IEMs with hypoglycemia: Organic acidurias, defects of fatty acid oxidation, and defects of gluconeogenesis (see V.)
IEMs with hyperammonemia: UCD, propionic acidemia (PPA), and methylmalonic acidemia (MMA) (see VI.)
Seizures may be the presenting symptom in pyridoxine-responsive seizures, pyridoxal phosphate-responsive seizures, nonketotic hyperglycinemia (NKH), sulfite oxidase/molybdenum cofactor deficiency, disorders of creatine biosynthesis and transport, and peroxisomal disorders (see VII.).
Hypotonia. Severe hypotonia is a common symptom in sick neonates. Few IEMs present as predominant hypotonia in the neonatal period. These disorders include
mitochondrial respiratory chain defects, peroxisomal disorders, sulfite oxidase/molybdenum cofactor deficiency, and NKH (see VIII.).
Liver dysfunction. Galactosemia is the most common metabolic cause of liver disease in the neonate (see IX.). Three main clinical groups of hepatic symptoms can be identified.
Hepatomegaly with hypoglycemia suggest gluconeogenesis defects (e.g., glycogen storage diseases).
Liver failure (jaundice, coagulopathy, elevated transaminases, hypoglycemia, and ascites) occurs in hereditary fructose intolerance, galactosemia, tyrosinemia type I, fatty acid oxidation defects, and mitochondrial respiratory chain defects.
Cholestatic jaundice with failure to thrive is observed primarily in alantitrypsin deficiency, Byler disease, inborn errors of bile acid metabolism, peroxisomal disorders, citrin deficiency, and Niemann-Pick disease type C.
Cardiac dysfunction. Long-chain fatty acid oxidation defects and mitochondrial respiratory chain defects can present with cardiomyopathy, arrhythmias, and hypotonia in neonates. The neonatal form of Pompe disease, a lysosomal disorder with glycogen storage, presents with generalized hypotonia, failure to thrive, and cardiomyopathy (Table 60.1).
Table 60.1 Inborn Errors of Metabolism Associated with Neonatal Cardiomyopathy
Disorders of fatty acid oxidation
Carnitine uptake deficiency
Carnitine-acylcarnitine translocase (CAT) deficiency
Carnitine palmitoyltransferase II (CPT II) deficiency
Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
Trifunctional protein deficiency
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency
Mitochondrial respiratory chain disorders
Tricarboxylic acid cycle defects
α-Ketoglutarate dehydrogenase deficiency
Glycogen storage diseases
Pompe disease (glycogen storage disease type II)
Phosphorylase b kinase deficiency
Lysosomal storage disorders
I-cell disease
Table 60.2 Inborn Errors of Metabolism Associated with Abnormal Urine Odor in Newborns
Inborn error of metabolism
Odor
Glutaric acidemia type II
Sweaty feet
Isovaleric acidemia
Sweaty feet
Maple syrup urine disease
Maple syrup
Hypermethioninemia
Boiled cabbage
Multiple carboxylase deficiency
Tomcat urine
Apnea in the neonatal period can be the presenting sign in NKH and long-chain fatty oxidation defects.
Abnormal urine odor. An abnormal urine odor is present in some diseases in which volatile metabolites accumulate (Table 60.2).
Dysmorphic features. Several IEM can present with facial dysmorphism (Table 60.3).
Hydrops fetalis. Congenital disorders of glycosylation and most lysosomal storage diseases can present with hydrops fetalis (Table 60.4).
Table 60.3 Inborn Errors of Metabolism Associated with Dysmorphic Features | ||||||||||||||
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Table 60.4 Inborn Errors of Metabolism Associated with Hydrops Fetalis | ||||||||||||||||||||||||||||||||||
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III. EVALUATION OF A NEONATE WITH SUSPECTED IEM
The laboratory evaluation of a neonate with suspected IEM is summarized in Table 60.5. The initial laboratory studies should be obtained immediately once IEM is suspected. The results of these tests can help to narrow the differential diagnosis and determine which specialized tests are required. For neonatal seizures, additional tests are needed (Table 60.5).
Complete blood cell count. Neutropenia and thrombocytopenia may be associated with a number of organic acidemias. Neutropenia may also be found with glycogen storage disease type Ib and mitochondrial diseases such as Barth syndrome and Pearson syndrome.
Electrolytes and blood gases are required to determine whether an acidosis or alkalosis is present and, if so, whether it is respiratory or metabolic and if there is an increased anion gap. The organic acidemias and primary lactic acidosis cause
metabolic acidosis with a raised anion gap in early stages. Most metabolic conditions result in acidosis in late stages as encephalopathy and circulatory disturbances progress. A persistent metabolic acidosis with normal tissue perfusion may suggest an organic acidemia or a primary lactic acidosis. A mild respiratory alkalosis in nonventilated babies suggests hyperammonemia. However, in late stages of hyperammonemia, vasomotor instability and collapse can cause metabolic acidosis. A flowchart for the investigation of metabolic acidosis in patients with suspected IEM is presented in Figure 60.1.
Table 60.5 Laboratory Studies for a Newborn Suspected of Having an Inborn Error of Metabolism
Initial laboratory studies
Complete blood count with differential
Serum glucose and electrolytes
Blood gases
Liver function tests and coagulation profile
Plasma ammonia
Plasma lactate and pyruvate
Plasma amino acids, quantitative
Plasma carnitine and acylcarnitine profile
Urine reducing substances, pH, ketones
Urine organic acids
Additional laboratory studies considered in neonatal seizures
Cerebrospinal fluid (CSF) amino acids
Cerebrospinal fluid (CSF) neurotransmitters
Sulfocysteine in urine
Very long chain fatty acids
Glucose. Hypoglycemia is a critical finding in some IEMs. Ketones are useful in developing a differential diagnosis for newborns with hypoglycemia (Fig. 60.2). Nonketotic hypoglycemia is the hallmark of defects of fatty acid oxidation. Hypoglycemia associated with metabolic acidosis and ketones suggests an organic acidemia or defect of gluconeogenesis (glycogen storage disease type I or fructose-1,6-bisphosphatase deficiency).
Figure 60.1. Approach to the investigation of neonatal metabolic acidosis. FBPase = fructose-1,6-bisphosphatase deficiency; GSD I = glycogen storage disease type I; PC = pyruvate carboxylase; HCS = holocarboxylase synthetase; MSUD = maple syrup urine disease; PDH = pyruvate dehydrogenase; FAO = fatty acid oxidation. Note that while a significant hyperlactatemia is more associated with mitochondrial respiratory chain defects and pyruvate metabolism disorders, milder lactate elevations can be seen in organic acidurias and MSUD.
Figure 60.2. Approach to the investigation of persistent hypoglycemia in the newborn with suspected inborn errors of metabolism (IEM). FBPase = fructose-1,6-bisphosphatase deficiency; GSD I = glycogen storage disease type I; FAO = fatty acid oxidation.
Plasma ammonia level should be determined in all neonates suspected of having an IEM. Early recognition of severe neonatal hyperammonemia is crucial since irreversible damage can occur within hours. Hyperammonemia is the major indicator for urea cycle disorders. However, hyperammonemia with ketoacidosis suggests an underlying organic acidemia. Figure 60.3 summarizes the approach to neonatal hyperammonemia.
Plasma lactate level. A high plasma lactate can be secondary to hypoxia, cardiac disease, infection, or seizures, whereas primary lactic acidosis may be caused by disorders of gluconeogenesis, pyruvate metabolism, and respiratory chain defects. Some IEM (fatty acid oxidation disorders, organic acidemias, and urea cycle disorders) may also be associated with a secondary lactic acidosis. Persistent increase of plasma lactate above 3 mmol/L in a neonate who did not suffer from asphyxia and who has no evidence of other organ failure should lead to further investigation for an IEM. Specimens for lactate measurement should be obtained from a central line or through an arterial stick, since the use of tourniquet during venous sampling may result in a spurious increase in lactate.
Liver function tests (LFTs). Galactosemia is the most common metabolic cause of liver dysfunction in the newborn period. Other causes of abnormal LFTs in the newborn include tyrosinemia, α1-antitrypsin deficiency, neonatal hemochromatosis, mitochondrial respiratory chain disorders, and Niemann-Pick disease type C.
Urine for reducing substances, pH, and ketones. Reducing substances are tested by the Clinitest reaction that detects excess excretion of galactose and glucose but not fructose. A positive reaction with the Clinitest should be investigated further with the Clinistix reaction (glucose oxidase) that is specific for glucose. Reducing substances in urine can be used as screening for galactosemia; however, this test is not very reliable because of high false-positive and false-negative rates. Urine pH below 5 is expected in cases of metabolic acidosis associated with IEM; otherwise, renal tubular acidosis is a consideration. In neonates, the presence of ketonuria is always abnormal and an important sign of metabolic disease.
Plasma amino acid analysis is indicated for any infant suspected of having IEM. Recognition of patterns of abnormalities is important in the interpretation of the results.
Urine organic acid analysis is indicated for patients with unexplained metabolic acidosis, seizures, hyperammonemia, hypoglycemia, and/or ketonuria.
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