Inborn Errors of Metabolism

Inborn Errors of Metabolism

Ayman W. El-Hattab

V. Reid Sutton

I. INTRODUCTION. Inborn errors of metabolism (IEMs) are a group of disorders each of which results from deficient activity of a single enzyme in a metabolic pathway. Although IEMs are individually rare, they are collectively common, with an overall incidence of more than 1:1,000. More than 500 IEMs have been recognized, with more than 100 of them that can present clinically in the neonatal period.

Neonates with IEMs are usually healthy at birth with signs typically developing in hours to days after birth. The signs are usually nonspecific and may include decreased activity, lethargy, poor feeding, vomiting, respiratory distress, or seizures. These signs are common to several other neonatal conditions, such as sepsis and cardiopulmonary dysfunction. Therefore, maintaining a high index of suspicion is important for early diagnosis and the institution of appropriate therapy, which are mandatory to prevent death and ameliorate complications from many IEMs.

The vast majority of IEMs are inherited in an autosomal recessive manner. Therefore, a history of parental consanguinity or a previously affected sibling should raise the suspicion of IEMs. Some IEMs, such as ornithine transcarbamylase (OTC) deficiency, are X-linked. In X-linked disorder, typically affected males have severe disease, whereas affected females are either asymptomatic or have a milder disease. So, the severely affected family member could be a maternal uncle or a brother, whereas the mildly affected member could be a mother or sister.

II. CLINICAL PRESENTATION. After an initial symptom-free period, neonates with IEMs can start deteriorating for no apparent reasons and do not respond to symptomatic therapies. The interval between birth and clinical symptoms may range from hours to weeks, depending on the enzyme deficiency. Neonates with IEMs can present with one or more of the following clinical groups:

A. Neurologic manifestations. Deterioration of consciousness is one of the common neonatal manifestations of IEMs that can occur due to metabolic derangements, including metabolic acidosis (see section IV), hyperammonemia (see section V), and hypoglycemia (see section VI). Neonates with these metabolic derangements typically exhibit poor feeding and decreased activity that progress to lethargy and coma. Other common neurologic manifestations of IEMs in the neonatal period are seizures (see section VII), hypotonia (see section VIII), and apnea (Table 60.1).

B. Liver dysfunction (see section IX). Galactosemia is the most common metabolic cause of liver disease in the neonate. Three main clinical groups of hepatic symptoms can be identified: hepatomegaly with hypoglycemia, cholestatic jaundice, and liver failure (jaundice, coagulopathy, elevated transaminases, hypoglycemia, and ascites) (Table 60.2).

C. Cardiac dysfunction (see section X). Some IEMs can present predominantly with cardiac diseases, including cardiomyopathy, heart failure, and arrhythmias (Table 60.3).

D. Other manifestations. An abnormal urine odor is present in some IEMs in which volatile metabolites accumulate (Table 60.4). Some IEMs can present with facial dysmorphism (Table 60.5), and others can present with hydrops fetalis (Table 60.6).

Table 60.1. Inborn Errors of Metabolism Associated with Neurologic Manifestations in Neonates

Deterioration in consciousness

▪ Metabolic acidosis

□ Organic acidemias

□ Maple syrup urine disease (MSUD)

□ Disorders of pyruvate metabolism

□ Fatty acid oxidation defects

□ Fructose-1,6-bisphosphatase deficiency

□ Glycogen storage disease type I

□ Mitochondrial diseases

□ Disorders of ketone body metabolism

▪ Hyperammonemia

□ Urea cycle disorders

□ Organic acidemias

□ Disorders of pyruvate metabolism

▪ Hypoglycemia

□ Fatty acid oxidation defects

□ Fructose-1,6-bisphosphatase deficiency

□ Glycogen storage disease type I

□ Organic acidemias

□ Mitochondrial diseases

□ Disorders of ketone body metabolism


▪ Biotinidase deficiency

▪ Pyridoxine-dependent epilepsy

▪ Pyridoxal phosphate-responsive epilepsy

▪ Glycine encephalopathy

▪ Mitochondrial diseases

▪ Zellweger syndrome

▪ Sulfite oxidase/molybdenum cofactor deficiency

▪ Purine metabolism disorders

▪ Disorders of creatine biosynthesis and transport

▪ Neurotransmitter defects

▪ Congenital disorders of glycosylation


▪ Mitochondrial diseases

▪ Zellweger syndrome

▪ Glycine encephalopathy

▪ Sulfite oxidase/molybdenum cofactor deficiency


▪ Glycine encephalopathy


▪ Urea cycle disorders

▪ Disorders of pyruvate metabolism

▪ Fatty acid oxidation defects

▪ Mitochondrial diseases

III. EVALUATION AND MANAGEMENT. Early diagnosis and the institution of appropriate therapy are mandatory in IEMs to prevent death and ameliorate complications. Management of suspected IEMs should be started even before birth.

A. Before or during pregnancy. When a previous sibling has a metabolic disorder or symptoms consistent with a metabolic disorder, the following steps should be taken:

1. Clinical reports and hospital charts should be reviewed.

2. Prenatal genetic counseling regarding the possibility of having an affected infant

3. The parents and relatives can be screened for possible clues of an IEM.

4. When a diagnosis is known, intrauterine diagnosis by measurement of abnormal metabolites in the amniotic fluid or by enzyme assay or DNA analysis of amniocytes or chorionic villus cells

Table 60.2. Inborn Errors of Metabolism Associated with Neonatal Hepatic Manifestations

Hepatomegaly with hypoglycemia

▪ Fructose-1,6-bisphosphatase deficiency

▪ Glycogen storage disease type I

Cholestatic jaundice

▪ Citrin deficiency

▪ Zellweger syndrome

▪ Alpha-1-antitrypsin deficiency

▪ Niemann-Pick disease type C

▪ Inborn errors of bile acid metabolism

▪ Congenital disorders of glycosylation

Liver failure

▪ Galactosemia

▪ Tyrosinemia type I

▪ Hereditary fructose intolerance

▪ Mitochondrial diseases

▪ Fatty acid oxidation defects

Table 60.3. Inborn Errors of Metabolism Associated with Neonatal Cardiomyopathy

Disorders of fatty acid oxidation

▪ Very long chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency

▪ Long chain hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency

▪ Trifunctional protein deficiency

▪ Carnitine transport defect

▪ Carnitine-acylcarnitine translocase (CAT) deficiency

▪ Carnitine palmitoyltransferase II (CPT II) deficiency

Glycogen storage disease type II (Pompe disease)

Tricarboxylic acid cycle defects: α-ketoglutarate dehydrogenase deficiency

Mitochondrial diseases

Congenital disorders of glycosylations

Table 60.4. Inborn Errors of Metabolism Associated with Abnormal Urine Odor in Newborns

Inborn Error of Metabolism


Glutaric acidemia type II

Sweaty feet

Isovaleric acidemia

Sweaty feet

Maple syrup urine disease

Maple syrup



Tyrosinemia type I



Boiled cabbage

Multiple carboxylase deficiency

Cat urine




Old fish

Dimethylglycine dehydrogenase deficiency

Old fish

Table 60.5. Inborn Errors of Metabolism Associated with Distinctive Facial Features


Dysmorphic Features

Zellweger syndrome

Large fontanelle, prominent forehead, flat nasal bridge, epicanthal folds, hypoplastic supraorbital ridges

Pyruvate dehydrogenase deficiency

Epicanthal folds, flat nasal bridge, small nose with anteverted flared alae nasi, long philtrum

Glutaric aciduria type II

Macrocephaly, high forehead, flat nasal bridge, short nose, ear anomalies, hypospadias, rocker bottom feet

Cholesterol biosynthetic defects (Smith-Lemli-Opitz syndrome)

Epicanthal folds, flat nasal bridge, toe 2/3 syndactyly, genital abnormalities, cataracts

Congenital disorders of glycosylation

Inverted nipples, lipodystrophy, very wide variety of findings among the nearly 100 disorders

Miller syndrome (dihydroorotate dehydrogenase deficiency)

Micrognathia, cleft lip/palate, malar hypoplasia, eyelid coloboma, downslanted palpebral fissures, and absence of fifth digits

Table 60.6. Inborn Errors of Metabolism Associated with Hydrops Fetalis

Lysosomal disorders

▪ Mucopolysaccharidosis types I, IVA, and VII

▪ Sphingolipidosis: GM1 gangliosidosis, Gaucher disease, Farber disease, Niemann-Pick disease type A, multiple sulfatase deficiency

▪ Lipid storage disorders: Wolman disease, Niemann-Pick disease type C

▪ Oligosaccharidosis: galactosialidosis, sialic acid storage disease, mucolipidoses I (sialidosis), mucolipidoses II (I cell disease)

Zellweger syndrome

Glycogen storage disease type IV

Congenital disorders of glycosylation

Mitochondrial diseases

Neonatal hemochromatosis

5. Planning to deliver the baby in a facility equipped to handle potential metabolic or other complications

B. Initial evaluation. When an IEM is suspected in a neonate, a careful physical examination seeking any of the signs of IEM needs to be performed; nonmetabolic causes of symptoms such as infection, asphyxia, or intracranial hemorrhage need to be evaluated; and the newborn screening program should be contacted for the results of the screening and for a list of the disorders screened. Initial laboratory studies should be obtained immediately once IEMs are suspected (Table 60.7). The results of these tests can help to narrow the differential diagnosis and determine which specialized tests are required.

1. 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.

2. 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. Most metabolic conditions result in acidosis in late stages as encephalopathy and circulatory disturbances progress. A persistently high anion gap metabolic acidosis with normal tissue perfusion may suggest an IEM (e.g., organic acidemia or pyruvate metabolism defects). A mild respiratory alkalosis in nonventilated babies suggests hyperammonemia. However, in late stages of hyperammonemia, vasomotor instability and collapse can cause metabolic acidosis.

3. Glucose. Hypoglycemia is a critical finding in some IEMs.

Table 60.7. 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

Plasma amino acids

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

CSF neurotransmitters

Sulfocysteine in urine

Very long chain fatty acids

4. Plasma ammonia level should be determined in all neonates suspected of having an IEM. Early recognition of severe neonatal hyperammonemia is crucial because irreversible damage can occur within hours.

5. 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 mitochondrial diseases. Some IEM (fatty acid oxidation disorders, organic acidemias, and urea cycle disorders [UCDs]) 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 because use of tourniquet during venous sampling may result in a spurious increase in lactate.

6. Liver function tests. Some IEMs are associated with liver dysfunction.

7. 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 <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.

8. Plasma amino acid analysis. 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.

9. Urine organic acid analysis is indicated for patients with unexplained metabolic acidosis, seizures, hyperammonemia, hypoglycemia, and/or ketonuria.

10. Plasma carnitine and acylcarnitine profile. Carnitine transports long-chain fatty acids across the inner mitochondrial membrane. An elevation of carnitine esters may be seen in fatty acid oxidation defects (FODs), organic acidemias, and ketosis. In addition to patients with inherited disorders of carnitine uptake, low carnitine levels are common in preterm infants and neonates receiving total parenteral nutrition (TPN) without adequate carnitine supplementation. Several metabolic diseases may cause secondary carnitine deficiency.

C. Management of acute metabolic decompensation. Several IEMs can present with acute metabolic decompensation during the neonatal period, such as urea cycle defects and organic acidemias. The principles of managing acute metabolic decompensation are as follows:

1. Decrease production of the toxic intermediates by holding enteral intake for 24 to 48 hours and suppressing catabolism. Reversal of catabolism and promotion of anabolism can be achieved by the following:

a. Providing adequate caloric intake

b. Administering insulin. Insulin is a potent anabolic hormone and can be administered as a continuous infusion (0.05 to 0.1 unit/kg/hour) with adjusting the intravenous (IV) glucose to maintain a normal blood glucose.

c. Providing adequate hydration and treating infections aggressively

d. Introducing enteral feeding as early as possible. The period of enteral feed restriction should not exceed 24 to 48 hours; after that, a special formula appropriate for the suspected IEM should be introduced if there are no contraindications for enteral feeding.

2. Elimination of toxic metabolites by the following:

a. IV hydration, which can promote renal excretion of toxins

b. The use of specific medications that create alternative pathways. For example, carnitine can bind organic acid metabolites and enhance their excretion in urine in organic acidemias. Another example is
sodium benzoate, which is used in glycine encephalopathy and urea cycle defects, because it binds to glycine-forming hippurate, which is excreted in urine.

c. Hemodialysis/hemofiltration may be employed in cases of unresponsive hyperammonemia (>500 mg/dL) in urea cycle defects and hyperleucinemia in maple syrup urine disease (MSUD).

3. Correction of metabolic acidosis. If the infant is acidotic (pH <7.22) or the bicarbonate level is <14 mEq/L, sodium bicarbonate can be given at dose of 1 to 2 mEq/kg as a bolus followed by a continuous infusion. If hypernatremia is a problem, potassium acetate can be used in the maintenance fluid.

4. Correction of hypoglycemia (see Chapter 24)

5. Calories. Provided calories during a period of decompensation, in order to support anabolism, should be at least 20% greater than that needed for ordinary maintenance. Adequate calories can be achieved parenterally by IV glucose and intralipid and enterally by giving protein-free formula or special formula appropriate for the IEM. One must remember that withholding natural protein from the diet also eliminates this source of calories, which should be replaced using other dietary or nutritional (nonnitrogenous) sources.

6. Lipids. To supply extra calories, the neonate can be supplied with lipids in the form of oral medium-chain triglycerides (MCTs) or parenteral intralipid. However, before feeding MCT, it is very important to be certain that the infant does not have a medium-chain acylcoenzyme A dehydrogenase (MCAD) deficiency; otherwise, this could provoke a very severe metabolic reaction.

7. Protein. All natural protein should be withheld for 24 hours while the patient is acutely ill. Afterward, amino acid supplementation may be very beneficial in facilitating clinical improvement by promoting anabolism, but it should be implemented only under the supervision of a physician/dietitian with expertise in IEMs. Special parenteral amino acid solutions and specialized formulas are available for many disorders when individuals with IEMs require prolonged parenteral nutrition.

8. L-Carnitine. Free carnitine levels are low in organic acidemias because of increased esterification with organic acid metabolites. Carnitine supplementation (100 to 300 mg/kg/day) may facilitate excretion of these metabolites. Diarrhea is the primary adverse effect of oral carnitine.

9. Antibiotics. For certain organic acidemias (propionic acidemia [PA] and methylmalonic acidemia [MMA]), gut bacteria are a significant source of organic acid synthesis (propionic acid). Eradicating the gut flora with a short course of a broad-spectrum antibiotic (e.g., neomycin, metronidazole) enterally may speed the recovery of a patient in acute metabolic decompensation.

10. Cofactor supplementation. Pharmacologic doses of appropriate cofactors may be useful in cases of vitamin-responsive enzyme deficiencies, e.g., thiamine in MSUD.

11. Treatment of precipitating factors. Infection should be treated as per usual protocols. Excess protein ingestion should be discontinued.

D. Monitoring the patient. Neonates with IEMs should be monitored closely for any mental status changes, overall fluid balance, evidence of bleeding (if thrombocytopenic), and symptoms of infection (if neutropenic). Biochemical parameters need to be followed including electrolytes, glucose, ammonia, blood gases, complete blood cell count, and urine for ketones.

E. Recovery and initiation of feeding

1. The neonate should be kept nothing by mouth (NPO) until his or her mental status is more stable. Anorexia, nausea, and vomiting during the acute metabolic decompensation period make significant oral intake unlikely.

2. If the neonate is not significantly neurologically compromised, consideration should be given to providing the neonate (orally or by nasogastric/gastric tube) with a modified formula preparation containing all but the offending amino acids. When the neonate is able to take oral feedings, a specific diet must be used. The diet will be individualized for each child and his or her metabolic defect, e.g., in galactosemia, the infant should be fed a lactose-free formula.

F. Long-term management. Several IEMs require dietary restrictions (e.g., leucine-restricted diet in isovaleric acidemia [IVA]). If hypoglycemia occurs, then frequent feeding and the use of uncooked cornstarch are advised. Cofactors are used in vitamin-responsive IEMs (e.g., pyridoxine in pyridoxine-dependent epilepsy). Examples of other oral medications used in chronic management of IEMs are carnitine for organic acidemias, sodium benzoate for urea cycle defects, and nitisinone (NTCB) in tyrosinemia type I.

IV. INBORN ERROR OF METABOLISM WITH METABOLIC ACIDOSIS. Metabolic acidosis with a high anion gap is an important laboratory feature of many IEM including MSUD, organic acidurias, fatty acid oxidation disorders, disorders of pyruvate metabolism, glycogen storage diseases, and mitochondrial diseases (Table 60.1). The presence or absence of ketosis in metabolic acidosis can distinguish certain groups of disorders from each other (Fig. 60.1).

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Oct 27, 2018 | Posted by in PEDIATRICS | Comments Off on Inborn Errors of Metabolism

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