Most Frequently Encountered Inborn Errors of Metabolism


  • 1.

    Inborn errors of metabolism (IEMs) are inherited conditions that block metabolic pathways. As a group, these conditions could be identified in 1 out of every 1500 infants.

  • 2.

    We have suspected IEMs in infants during the early neonatal period if they have progressively worsening encephalopathy with lethargy, seizures, or coma that cannot be explained as due to asphyxia or infections; unexplained severe high anion-gap metabolic acidosis; or unexplained respiratory alkalosis associated with considerable and persistently increased serum ammonia levels.

  • 3.

    Infants with urea-cycle defects can present with lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, subclinical or clinically evident seizures, or coma.

  • 4.

    Congenital hypothyroidism is the most frequently detected abnormality in newborn screening programs, seen in 1 in 2000 to 4000 newborn infants.

  • 5.

    Congenital adrenal hyperplasia is a group of genetic disorders affecting adrenal steroid biosynthesis and can be seen in virilizing or salt-wasting clinical presentations.

  • 6.

    Infants with galactosemia have markedly elevated blood galactose and can present with subtle clinical signs such as jaundice, vomiting, and poor weight gain, lethargy and hypotonia, hepatomegaly, and sepsis, most often due to Escherichia coli .

  • 7.

    Organic acidemias typically present within the early neonatal period with poor feeding, vomiting, hypoglycemia, irritability, lethargy, hypotonia, and seizures. Hepatomegaly may be present. Patients with infantile or late-onset forms may have failure to thrive, developmental delay, seizures, and spasticity. Laboratory tests show metabolic acidosis, ketosis, hyperlactatemia, and hyperammonemia.

  • 8.

    Phenylketonuria is a rare autosomal-recessive disorder of phenylalanine (Phe) metabolism associated with Phe accumulation in the brain and other organs. The classic signs are microcephaly, hypotonia, motor deficits, eczematous rash, autism, seizures, and developmental problems.

  • 9.

    Neonates with classic maple syrup urine disease present within the first few weeks of life with feeding intolerance, urine with a maple syrup odor, seizures, coma, and death.

  • 10.

    Medium-chain acyl-coenzyme A (CoA) dehydrogenase deficiency is seen with altered mental status, lethargy, seizures, emesis, and even death.

  • 11.

    Citrullinemia presents after the first 24 hours of life with tachypnea and respiratory alkalosis, but if untreated, these infants develop worsening lethargy, seizures, coma, hepatomegaly with increased transaminases, and eventually death.

Inborn errors of metabolism (IEMs) are inherited conditions that block metabolic pathways. Even though these disorders may be rare at an individual level, genetic screening suggests that as a group, these conditions could be identified in 1 out of every 1500 infants. Disturbances in metabolic pathways usually cause a spectrum of systemic findings involving multiple organ systems. Early recognition is important because institution of definitive treatment, or at least palliation of the manageable aspects, can improve mortality and morbidity. ,

We have suspected IEMs in infants during the early neonatal period, before the screening reports become available, if they have progressively worsening encephalopathy with lethargy, seizures, or coma that cannot be explained as due to asphyxia or infections; unexplained severe high anion-gap metabolic acidosis; or unexplained respiratory alkalosis associated with considerable and persistently increased serum ammonia levels.

In the United States, the newborn screening (NBS) programs include up to 52 conditions (as described in the next chapter). To improve the clinical outcomes in IEMs, there may be two possible strategies. One may be focused on early diagnosis by expanding the NBS programs. There may be benefits in early institution of therapeutic measures, in supporting these families, and in finding help from social, religious, educational, and/or political leadership. The second strategy may be to strengthen the educational programs for healthcare providers for early diagnosis and management of these rare disorders. However, we still have not identified clear therapeutic measures for all these disorders. No NBS program will be sensitive enough to detect every single genetic variant of these diseases, and hence there may be a need for individualized interventions at multiple levels. We may not have the resources to do so.

In the following sections, we provide a brief summary of the most frequently seen IEMs, focusing on epidemiologic information, clinical features, available tools for diagnosis, and possible treatment(s). This chapter will have to be expanded in time as more information becomes available. We have assimilated findings from our own clinical experience with an extensive review of the literature, using key terms in multiple databases including PubMed, Embase, and ScienceDirect.

Diagnosis of Conditions With Early Neonatal Onset or Those Not Included in Screening Programs

As described above, we have suspected IEMs during the first few days after birth if there is worsening encephalopathy, unexplained severe high anion-gap metabolic acidosis, or unexplained respiratory alkalosis associated with high serum ammonia levels ( Fig. 75.1 ).

Fig. 75.1

Most Frequent Settings in Which to Suspect an Inborn Error of Metabolism Before the First Newborn Screening Reports Become Available .

MRI, Magnetic resonance imaging.

These clinical manifestations may appear in the most severe variants and in urea-cycle defects. In the following section, we describe the clinical approach to urea-cycle defects, which are mostly not included in NBS programs.

Urea Cycle Defect

The urea cycle is composed of five core enzymes, one activating enzyme, and one mitochondrial ornithine/citrulline antiporter (Krebs-Henseleit cycle) that convert waste nitrogen generated from protein catabolism into urea, which is then excreted from the body ( Fig. 75.2 ). Urea-cycle disorders (UCDs) result in the failure of conversion of ammonia into urea, resulting in accumulation of ammonia and other products. If not recognized and treated rapidly, this results in encephalopathy, coma, and death.

Fig. 75.2

The Urea Cycle .

These five reactions convert ammonia into urea ( encircled ). The deficiency of ornithine transcarbamylase (OTC; shown in red ) is most frequently associated with clinical manifestations. ATP, Adenosine triphosphate; HCO3, bicarbonate; NH3, ammonia.

The incidence of UCDs is estimated at 1 in 35,000 births. Existing information indicates that defects in ornithine transcarbamylase (OTC) constitute nearly 60% of all UCDs. In the United States, two UCDs, argininosuccinic synthetase and lyase deficiency, are currently detected by NBS; each of these accounts for approximately 15% of the UCDs. Argininosuccinate synthetase (AS) deficiency is described later in the chapter. Individuals with predicted attenuated forms of argininosuccinic aciduria seem to be overrepresented in the NBS group.

Severe deficiency or total absence of activity of any of the first four enzymes in the pathway (carbamoylphosphate synthetase [CPS], OTC, ASS, and argininosuccinate lyase [ASL]) or a cofactor producer (N-acetylglutamate synthase deficiency; not shown) results in the accumulation of ammonia and other precursor metabolites and can present very early, during the first few days of life, before the results of NBS become available. Because no effective secondary clearance system for ammonia exists, complete disruption of this pathway results in the rapid accumulation of ammonia and development of related symptoms.

Carbamoyl phosphate synthetase I (CPS1) deficiency is the most severe of the UCDs. Individuals with complete CPS1 deficiency rapidly develop hyperammonemia in the newborn period. Ornithine transcarbamylase deficiency in males can be as severe as CPS1 deficiency. Approximately 15% of carrier females develop hyperammonemia. ASS1 deficiency can also be associated with severe hyperammonemia.

Argininosuccinic aciduria (ASL deficiency) can also present with rapid-onset hyperammonemia in neonates. Some affected infants develop chronic hepatic enlargement and elevation of transaminases. Arginase deficiency is not typically characterized by rapid-onset hyperammonemia, but affected infants can present with spasticity and choreoathetosis. Ornithine translocase deficiency presents less frequently in neonates and has symptoms that evolve more slowly. Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis.

Clinical Features

Infants with a UCD may appear normal at birth and may have only nonspecific symptoms in the initial few days. Most newborns are discharged from the hospital within 1 to 2 days after birth, and the symptoms of a UCD often develop when the child is at home and may not be recognized in a timely manner by the care providers.

Affected infants can rapidly develop lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma. Seizures are common in acute hyperammonemia and may result from cerebral damage, but subclinical seizures may also be common in neonates. Many infants may show hepatic dysfunction.


Hyperammonemia with plasma ammonia >150 μM/L should trigger evaluation. If the anion gap is >20 or if there is hypoglycemia, then urine organic acids, plasma amino acids, and acylcarnitine profile should be checked to exclude other disorders.

Quantitative plasma amino acid analysis can be used to arrive at a tentative diagnosis. (Because the liver is not fully mature at birth, affected newborns often have plasma amino acid concentrations that are quite different from those in older children and adults.) Plasma concentration of citrulline can help distinguish between proximal and distal urea-cycle defects, because citrulline is the product of the proximal enzymes and is absent or very low in deficiency of CPS1, OTC, and N-acetylglutamate synthase (NAGS). It is a substrate for the distal enzymes (ASS1 and ASL) and is elevated in defects in these enzymes. Plasma concentration of arginine is markedly elevated in arginase 1 deficiency. It may be reduced in other UCDs.

Urinary orotic acid is normal or low in CPS1 deficiency and significantly elevated in OTC deficiency. Urinary orotic acid excretion can also be increased in argininemia (ARG1 deficiency) and citrullinemia type I (ASS1 deficiency). Urine amino acid analysis can also be helpful.

Molecular genetic testing is the primary method of diagnostic confirmation for all UCDs. If molecular testing is uninformative, CPS1, NAGS, or OTC enzyme activity can be measured in hepatocytes; ASL, ASS1, or ornithine transporter in fibroblasts; and ARG1 in erythrocytes.

Imaging changes in acute hyperammonemia can resemble those seen in hypoxic-ischemic encephalopathy. Lesions show cerebral edema and are frequently seen in deep white matter, particularly in the parietal, occipital, and frontal regions. This is best appreciated on T 2 -weighted magnetic resonance imaging (MRI) sequences or on diffusion tensor imaging. MRI findings may lag behind clinical changes.


Infants with neurologic symptoms should be treated at a tertiary center with access to specialists. The removal of ammonia is critical with whichever treatment is available; intermittent hemofiltration (arteriovenous or venovenous) and hemodialysis, extracorporeal membrane oxygenation, or continuous renal replacement therapies can all work if instituted in a timely fashion.

Nitrogen scavenger therapy (sodium phenylacetate and sodium benzoate) can be used as an intravenous infusion for acute management and an oral preparation for long-term maintenance.

Deficient urea-cycle intermediates need to be replaced depending on the diagnosis; these can include arginine (intravenous infusion) and/or citrulline (oral preparation). Reduction of the catabolic state is important.

Clinical Approach to IEMs Detected in NBS Programs

Congenital Hypothyroidism


Congenital hypothyroidism is the most frequently detected abnormality in NBS programs, seen in 1 in 2000 to 4000 newborn infants. It involves insufficient production of the thyroid hormones with dysfunction of the hypothalamic–pituitary–thyroid axis at various levels; there may be abnormal development or function of the thyroid gland, low levels of upstream regulators produced in the hypothalamus and/or the pituitary gland, or impaired thyroid hormone action in the peripheral tissue.

Clinical Features

Congenital hypothyroidism may be completely asymptomatic in newborn infants. In some, symptoms may be seen or may appear in time. There may a goiter, poor feeding, constipation, hypothermia, bradycardia, edema, wide fontanelles, macroglossia, prolonged jaundice, umbilical hernia, poor growth, and developmental delay. Up to 10% of infants with congenital hypothyroidism have other congenital abnormalities if it occurs as a part of specific syndromes. If not detected timely, congenital hypothyroidism can cause neurodevelopmental delay and cognitive impairment.


Universal NBS is the most important tool for diagnosing congenital hypothyroidism. Most screening programs measure the blood concentrations of thyroid-stimulating hormone (TSH); in some programs, T4 is also measured routinely or is requested if TSH is elevated. Screening based on TSH levels is sensitive for detecting primary hypothyroidism. However, TSH measurements may not detect newborn infants with central hypothyroidism in whom TSH is not elevated despite low T4 levels. Screening programs that include T4 measurements may have some strengths. The optimal time for TSH screening may be between 48 and 72 hours after birth because there is often a transient surge in TSH levels in the first few hours after birth and early blood samples may result in erroneous results. Genetic tests with next-generation sequencing techniques have allowed early identification of patients at risk of or with congenital hypothyroidism.

Thyroid imaging (either by ultrasound or scintigraphy) may help establish a diagnosis of thyroid dysgenesis or ectopic thyroid. Measurements of serum thyroglobulin levels can provide useful information about the etiology of congenital hypothyroidism. Further evaluation may include MRI of the pituitary and hypothalamus and laboratory assessment of pituitary hormone function to investigate the possibility of central hypothyroidism. Causes of congenital hypothyroidism are summarized in Table 75.1 .

Table 75.1

Causes of Congenital Hypothyroidism

Thyroid dysgenesis (1 in 4500); isolated thyroid aplasia, hemiagenesis, hypoplasia, or ectopy
mutations in transcription factors PAX-8, TTF-1, FOXE1 (TTF-2), NKX2-5, SHH, and Tbx1
Defects in thyroid hormonogenesis (1 in 35,000)

  • Abnormal iodide uptake (NIS, SLC5A5), concentration, organification

  • Abnormal TPO enzyme

  • Abnormal H 2 O 2 generation (THOX, DUOX2)

  • Pendred syndrome (SLC26A4)

  • Defective Tg synthesis or transport

  • Abnormal iodotyrosine deiodinase (DEHAL1)

  • Abnormal thyroxine cerebral transport (MCT8)

Secondary and/or tertiary hypothyroidism (1 in 50,000–100,000)

  • Isolated TSH deficiency

  • TRH deficiency

Multiple hypothalamic hormone deficiencies

  • Isolated hypothalamic defect

  • Associated with other midline facial/brain structural defects such as septo-optic dysplasia, cleft lip/palate

Pituitary abnormality

  • Isolated TSH deficiency (IGSF1), TRH resistance, abnormal TSHβ molecule

  • Multiple pituitary hormone deficiencies with eutopic posterior pituitary gland (transcription factor defect, e.g., POU1F-1, PROP1, LHX3) or ectopic posterior pituitary gland (idiopathic, transcription factor defect, e.g., HESX1, SOX3, LHX4, OTX2)

TSH resistance with mutations in the TSH receptor gene, possible postreceptor defect
Thyroid hormone resistance (1 in 100,000) TPPO, Triphenylphosphine oxide; TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone.


Any abnormal result on NBS should prompt immediate confirmation by measuring serum concentrations of TSH and free thyoxine (FT4). Pediatric endocrinologists should be consulted as soon as possible, and treatments should be initiated. If the screening TSH level is greater than 40 mIU/L, treatment should be started without waiting for the confirmatory test results. Levothyroxine (LT4) is the standard treatment for congenital hypothyroidism at a recommended dose of 10 to 15 mg/kg. ,

Delayed initiation of treatment is associated with poor neurodevelopmental outcomes. The goal of treatment is to achieve euthyroidism rapidly. Normalization of serum TSH and FT4 levels within 2 weeks after starting therapy seems to improve cognitive outcomes. The treatment of congenital hypothyroidism is monitored by measuring serum TSH and FT4 concentrations.

Congenital Adrenal Hyperplasia


Congenital adrenal hyperplasia (CAH) is a group of genetic disorders affecting adrenal steroid biosynthesis, resulting in decreased cortisol production from the fasciculate layer of the adrenal gland. The most frequently seen genetic defects result in decreased expression of the enzyme 21-hydroxylase (21-OH), which leads to low levels of cortisol. The consequent interruption of the normal feedback inhibition loops stimulates the pituitary to produce more adrenocorticotropic hormone (ACTH) and causes hyperplasia of the adrenal glands. The incidence has been estimated to be about 1 in 8000 newborn infants.

Most cases, more than 90%, with low 21-OH expression are related to autosomal-recessive (AR) mutations in the gene encoding cytochrome P450 family 21 subfamily A member 2 protein ( CYP21A2 ). This causes the accumulation of its substrate, 17-hydroxyprogesterone (OHP), and increases androgen production with masculinization of the female newborn and virilization of affected males.

Depending on the severity of the enzyme deficiency, infants with 21-OH deficiency are classified into the following categories:

  • 1.

    Classic (severe adrenal hyperplasia): Further subdivided into virilizing or salt-wasting forms. Many individuals with mild loss-of-function mutations present with androgen excess rather than adrenal insufficiency, which leads to an ascertainment bias that favors diagnosis in females.

  • 2.

    Nonclassic (relatively milder).

Patients with the classic or symptomatic nonclassic forms can be treated with glucocorticoids to suppress the excessive secretion of the corticotrophin-releasing hormone and ACTH. Recent studies suggest that there may be an advantage of detecting CAH through molecular genotyping ( CYP21A2 mutations) of fetal cells obtained by chorionic villous sampling, possibly as early as at 9 to 11 weeks’ gestation. Identification of satellite DNA markers from an amniocentesis sample obtained at 15 to 18 weeks or by analyzing cell-free fetal DNA in maternal circulation can increase the diagnostic accuracy.

In mothers with CAH, the sex of the fetus can be determined as early as 7 weeks’ gestation, which can reduce parental anxiety and facilitate treatment planning. Gonadal hormones, particularly androgens, affect certain aspects of brain development and have permanent influences on the psychosexual identity of the patient. Hence, early detection of CAH can facilitate early initiation of treatment, even in utero. Early detection of CAH in infants born to mothers with nonclassic adrenal hyperplasia due to 21-OH deficiency can reduce the severity of abnormalities in the infants (approximately 2.5%, from 14.8%, respectively). Prenatal treatments for mothers with CAH, to prevent fetuses from developing ambiguous genitalia, are also available. However, some studies have discussed the long-term effects of antenatal dexamethasone treatment on verbal working memory and certain aspects of self-perception. Some researchers recommend a flexible clinical approach.

Clinical Features

Excessive androgen production is the hallmark of this disorder. In the severe classic form, genital ambiguity is present in affected female infants. This virilization of the female fetus may begin before 11 to 12 weeks’ gestation, and this disorder may be the most common cause of ambiguous genitalia in a genetically female fetus. The phenotypic virilization ranges from simple clitoromegaly, with or without partial fusion of the labioscrotal folds, to the appearance of a penile urethra. Although the genitalia of a female born with the severe form of the disease may be indistinguishable from those of a male, the important differentiating points are the absence of testes and the presence of a normal uterus and ovaries. The internal genitalia (uterus and fallopian tubes) that arise from the Müllerian duct are also normal.

Males with 21-OH deficiency do not manifest genital abnormalities at birth but may have subtle penile enlargement and some hyperpigmentation of external genitalia. These infants may continue to show accelerated virilization during childhood. The aldosterone deficiency can predispose them to salt-wasting crises.


The initial laboratory evaluation should include the measurements of blood glucose, electrolytes, and a liver function panel; arterial blood gases; serum levels of cortisol ACTH, and 17-OHP; pelvic ultrasonography; karyotype; and comprehensive mutation analysis of CYP21A2 . Genotype–phenotype correlations associated with CYP21A2 mutations and clinical presentations are described in Table 75.2 .

Sep 9, 2023 | Posted by in PEDIATRICS | Comments Off on Most Frequently Encountered Inborn Errors of Metabolism

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