Inborn Errors of Metabolism

Background

Inborn errors of metabolism (IEMs) are a large group of rare genetic diseases most commonly resulting from a defect in an enzyme or transport protein that causes a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, abnormal molecule transport, or a combination of these metabolic deviations. While the central nervous system (CNS) is often affected, leading to neurologic disease, any organ system can be impacted.^{[1, 2, 3, 4, 5]}

The incidence of IEMs, collectively, is estimated to be 1 in 800 to 1 in 2500 live births,^[1]  with wide variation across IEMs and populations. Phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, with respective incidences of 1 in 10,000 and 1 in 20,000, are among the most prevalent.^[6]  The incidence within different racial and ethnic groups varies with predominance of certain IEMs within particular groups (eg, cystic fibrosis, 1 per 1600 people of European descent; sickle cell anemia, 1 per 365 people with greater than 90% African descent; Tay-Sachs, 1 per 3500 Ashkenazi Jews).

Presentation is usually in the neonatal period or infancy but can occur at any time, even in late adulthood, with increasingly more neurologic and psychiatric conditions being recognized as due to IEMs. Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases. An understanding of the major clinical manifestations of IEMs provides the basis for knowing when to consider the diagnosis. A high index of suspicion is most important in making the diagnosis.

Goals of treatment for patients with IEMs are prevention of further accumulation of harmful substances, correction of metabolic abnormalities, and elimination of toxic metabolites. For patients with suspected or known IEMs, successful emergency treatment depends on prompt institution of therapy aimed at metabolic stabilization. Even the apparently stable patient with mild symptoms may deteriorate rapidly with progression to death within hours. Early recognition and appropriate treatment is critical to optimize outcome. With appropriate therapy, patients may completely recover from metabolic crisis without long-term sequelae. Asymptomatic neonates with newborn screening results positive for an IEM may require emergent evaluation, including confirmatory testing, and, as appropriate, initiation of disease-specific management.

Ongoing, families and patients should be supported by a team of IEM and subspecialty experts who provide education and support regarding disease manifestations, course of disease, medical care, and psychosocial challenges, and offer genetic counseling to discuss recurrence risks, screening of other family members, and prenatal diagnosis. Professional and peer support groups exist for many IEMs. The National Organization for Rare Disorders (NORD) can direct families to resources for numerous IEMs.

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Pathophysiology

Single-gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. As previously stated, most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway. Effects are due to toxic accumulations of substrates before the block, intermediates from alternative metabolic pathways, defects in energy production and use caused by a deficiency of products beyond the block, or a combination of these metabolic deviations. Nearly every metabolic disease has several forms that vary in age of onset, clinical severity, and, often, mode of inheritance.

Categories of IEMs are as follows:

• Disorders that result in toxic accumulation - Disorders of protein metabolism (eg, aminoacidopathies, organic acid disorders, urea cycle defects), disorders of carbohydrate intolerance, lysosomal storage disorders
• Disorders of energy production, utilization - Fatty acid oxidation defects; disorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis); mitochondrial disorders
• Disorders of complex molecule storage and/or substrate accumulation in organelles - Lysosomal storage disorders, peroxisomal disorders

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Etiology

Inborn errors of metabolism describes a class of over 1000 inherited disorders caused by mutations in genes coding for proteins that function in metabolism. Most of the disorders are inherited as autosomal recessive, but some are autosomal dominant or X-linked.

IEMs were initially thought to be caused by a specific single-gene mutation, but genetic characterization of variation in clinical manifestations led to the understanding that IEMs can be caused by different gene mutations that result in the same or similar diagnostic biochemical abnormalities.

The presentation of specific IEMs as a spectrum of disease phenotypes in which a clear correlation between the severity of mutation at the affected locus and the phenotype (genotype-phenotype correlation) is often lacking and impacts the ability to predict disease course.^[7] For example, phenylketonuria (PKU) was originally thought to be caused by mutations at the human phenylalanine hydroxylase locus (PAH) but was subsequently found to arise from different genetic defects (eg, tetrahydrobiopterin homeostasis) and to be influenced by dietary protein intake. The PAH genotype alone failed to consistently predict the extent of cognitive and metabolic phenotypes in PKU.

Phenotypic variation also results from cofactor defects that may affect multiple enzymes. As an example, biotinidase deficiency, due to a defect in the enzyme that recycles the cofactor biotin, impacts metabolic pathways of four different carboxylase enzymes, but there are also IEMs caused by single-gene defects impacting only one of the carboxylases. Furthermore, defects in different subunits of an enzyme can result in different IEMs.  Additional genes and environmental, epigenetic, and microbiome factors are also potential modifying etiologic factors in individual IEMs.^[6]

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Epidemiology

United States data

Individual IEMs are very rare diseases, with incidence ranging 1:10,000 (PKU) to 1:250,000 or less (guanidinoacetate methyltransferase [GAMT] deficiency).^[8] The prevalence of lysosomal storage disorders (approximately 60 diseases and growing) is significant when the group is considered as a whole, varying from 1 case in every 4000-13,000 births across different studies and projected to increase as data emerging from newborn screening programs is reported.^[9] The incidence of IEMs, collectively, is estimated to be as high as 1 in 800 live births.^[1]

International data

The overall incidence and the frequency for individual diseases varies based on racial and ethnic composition of the population and on the extent of screening programs.^[10] Overall rates are in a range similar to that of the United States.

A report from the Society for the Study of Inborn Errors of Metabolism (SSIEM), which looked at 15 centers specializing in the management of adults with IEMs, found that PKU was the most common disease (19.6%) among the study patients.^[11]

Race-,ethnicity-, sex-, and age-related data

Race

The incidence within different racial and ethnic groups varies with predominance of certain IEMs within particular groups (eg, cystic fibrosis, 1 per 1600 people of European descent; sickle cell anemia, 1 per 365 people of Black or African descent, with greater than 90% of those having it being of African descent [and with it also being prevalent in the Hispanic population]; Tay-Sachs, 1 per 3500 Ashkenazi Jews). In addition to Tay-Sachs disease, Gaucher disease type 1, Niemann-Pick disease type A, and mucolipidosis IV all have a higher prevalence in the Ashkenazi Jewish population, and patients of Finnish descent have been reported to have an increased frequency of infantile neuronal ceroid lipofuscinosis, Salla disease, and aspartylglucosaminuria .^[9]

Sex

The mode of inheritance determines the male-to-female ratio of affected individuals.

Many IEMs have multiple forms that differ in their mode of inheritance.

The male-to-female ratio is 1:1 for autosomal recessive and autosomal dominant transmission. It is also 1:1 for X-linked dominant if transmission is from mother to child. Autosomal recessive X-linked IEMs are more prevalent in males, since they only have one X-linked chromosome.

Age

Age of presentation of clinical symptoms varies for individual IEMs and variant forms within the IEM, with presentation from within hours of life to very late in adulthood. The timing of presentation depends on significant accumulation of toxic metabolites or on the deficiency of substrate.

The onset and severity may be exacerbated by environmental factors such as diet and intercurrent illness.

Disorders of protein or carbohydrate intolerance and disorders of energy production tend to present in the neonatal period or early infancy and have a tendency to be unrelenting and rapidly progressive. Less severe variants of these diseases usually present later in infancy or childhood and tend to be episodic.

Fatty acid oxidation defects, glycogen storage, and lysosomal storage disorders tend to present in infancy or childhood. Disorders manifested by subtle neurologic or psychiatric features often do not present or go undiagnosed until adulthood.

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Prognosis

Prognosis varies based on the individual IEM and may differ for different forms of a particular IEM. IEMs can affect any organ system and usually affect multiple organ systems, resulting in morbidity due to acute and/or chronic metabolic derangement and/or organ dysfunction.

Mortality can be very high for certain IEMs, particularly those that present in neonates, but initial presentation of an IEM even in adults may result in death. Progression may be unrelenting, with rapid life-threatening deterioration over hours; episodic, with intermittent decompensations and asymptomatic intervals; or insidious, with slow degeneration over decades, or it may not manifest even until late in adulthood. Diet or physiologic stress (ie, from intercurrent illness, trauma, surgery, or immunization) may precipitate episodic decompensation. A high index of suspicion is critical for early diagnosis and treatment of IEM.

For IEMs that result in chronic organ dysfunction, interventions that support and ideally preserve organ function to optimize physical and cognitive abilities should be initiated as soon as the IEM is recognized.

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Patient Education

Education regarding inborn errors should include public education regarding newborn screening, risk factors, and screening based on family history, and if diagnosed, education regarding medical care, genetic counseling, and resources for psychosocial support. 

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History

The history varies with age at presentation and is a function of the age at which various IEMs manifest clinically. Any organ system can be affected, including dermatologic, ophthalmologic, cardiac, pulmonary, gastrointestinal, musculoskeletal, neurologic, and hematologic. The central nervous system (CNS) is most often affected, followed by the gastrointestinal (GI) system.^{[3, 4]}

Symptoms can range from abrupt in onset and episodic to chronic and progressive. Disorders of intermediary metabolism, including amino and organic acidopathies, urea cycle defects, and disorders of fatty oxidation or carbohydrate metabolism, often present with acute, life-threatening decompensation. Triggers may include changes in diet, fasting, dehydration, illness, medications, strenuous activity, trauma, childbirth, or surgery.

Neurotransmitter disorders may present with neurologic dysfunction or encephalopathy. Mitochondrial, peroxisomal, and storage disorders may manifest as progressive organ dysfunction or motor and/or neurologic dysfunction.

The patient’s history may also include the following:

• Developmental delay, sometimes with loss of milestones
• Poor feeding, vomiting, failure to thrive, lethargy
• Onset of symptoms with change in diet and unusual dietary preferences, particularly protein or carbohydrate aversion
• Decompensation out of proportion to what would be expected from intercurrent infection or longer-than-expected duration of illness
• Similar findings of unexplained neonatal, sudden infant deaths or early childhood deaths due to neurologic, cardiac, or hepatic dysfunction in siblings or maternal male relatives; a negative family history does not rule out an IEM
• Parental consanguinity increases the likelihood of autosomal recessive IEM

Neonate

Consider an IEM in any critically ill neonate. Frequently, the most important clue is a history of deterioration, often life-threatening, after an initial period of apparent good health ranging from hours to weeks, usually following an uncomplicated pregnancy and delivery in a term infant.  A few IEMs cause abnormalities in pregnancy and perinatally that include decreased fetal movement, prolonged labor, nonimmune hydrops, and HELLP (hemolysis, elevated liver function tests, low platelets) syndrome. In term infants without risk for sepsis who develop the symptoms of sepsis, metabolic disease may be nearly as common as sepsis. 

Nearly all states and many countries test newborns for a core set of 35 diseases, and many test for more than 50 diseases, nearly all of which are IEMs, using tandem mass spectrometry. Tests screened for by each state are provided by the Newborn Screening Information Center.^[2]  It usually takes a few days and sometimes weeks until results are available. A negative newborn screen result does not exclude diagnosis of metabolic disease. False-negative findings can result from screening too early, from medications, from transfusions, and from sample collection and handling. For every true positive newborn screen result, 12-60 false-positive results occur depending on the IEM.^[12]  Cut-off values have been deliberately set to yield a low rate of false-negative results.

Infants and young children (1 mo to 5 yr)

Onset of symptoms may coincide with what are normally developmentally appropriate changes in diet that result in increased intake of protein and carbohydrates or with increased duration of fasting as infants begin sleeping through the night. Carbohydrate or protein aversion may also be manifestations of IEM.

The patients may have a history of recurrent episodes of vomiting, diarrhea, ataxia, seizures, lethargy, coma, or fulminant hepatoencephalopathy.

Infants may appear and act normal between episodes or have a history of poor feeding, failure to thrive, fussiness, and decreased activity/lethargy and/or developmental delay, sometimes with loss of milestones.

With routine illnesses, infants with an IEM may become more severely symptomatic, develop symptoms more rapidly, or require longer to recover than unaffected children.

Older children (>5 yr), adolescents

Undiagnosed metabolic disease should be considered in older children (>5 yr), adolescents, or even adults, with protein or carbohydrate aversion, muscle cramping with exercise, and subtle neurologic or psychiatric abnormalities (including, but not limited to, anxiety; personality changes; decreased school performance; autism, especially with seizures; self-injurious behavior; paranoia; catatonia).

Many individuals have been previously diagnosed as having birth injury or atypical forms of psychiatric disorders or medical diseases, such as multiple sclerosis, cerebral palsy,^[8] migraines, or stroke. Though, uncommon children with parkinsonism-like movements may have undiagnosed IEM, as may adults with a diagnosis of parkinsonism.^[3]  Historically, many patients with the now rarely diagnosed Reye syndrome actually had an IEM. 

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Physical Examination

The physical examination findings are nonspecific in most patients with IEMs, and examination findings may be normal. When present, physical findings provide important clues to the presence of an IEM, the category, and, occasionally, the specific metabolic disease.^[13]

Examination findings usually relate to major organ dysfunction or failure, most commonly hepatic and/or neurologic and, less commonly, cardiac or pulmonary. 

Abnormalities include failure to thrive; jaundice, dysmorphic features; abnormalities of hair, skin, skeleton, or all three; abnormal odor of cerumen, breath and/or urine; organomegaly; and abnormal muscle tone, weakness, and/or spastic diplegia.

Findings may be indistinguishable from those of sepsis, respiratory illness, cardiac disease, GI obstruction, renal disease, and CNS problems. The presence of these conditions does not rule out the possibility of an IEM.

Neonate

Symptoms for inborn errors of substrate and intermediary metabolism develop once a significant amount of toxic metabolites accumulate following the initiation of feeding and may include the following: poor feeding, vomiting, diarrhea, and/or dehydration; temperature instability; tachypnea; apnea; bradycardia; poor perfusion; irritability; involuntary movement; posturing; abnormal tone; seizures; and altered level of consciousness.

Certain IEMs, including galactosemia during the newborn period and certain organic acid disorders, result in an increased risk of sepsis.

For neonates with inborn errors of substrate and intermediary metabolism, the physical examination findings are usually unremarkable.

For IEMs of energy deficiency, symptoms usually develop within 24 hours of birth and are often present at birth. Neonates with inborn errors that result in defects in energy production and use often have dysmorphic features, skeletal malformations, cardiopulmonary compromise, organomegaly, and severe, generalized hypotonia.

IEMs most likely to cause acute decompensation in the neonate include certain amino and organic acidemias, urea cycle defects, fatty acid oxidation defects, and carbohydrate disorders.

Infants and young children

In infants and young children, symptoms may include recurrent episodes of vomiting, ataxia, seizures, lethargy, coma, and fulminant hepatoencephalopathy. Patients may have dysmorphic or coarse features, skeletal abnormalities, abnormalities of the hair or skin, poor feeding, failure to thrive, dilated or hypertrophic cardiomyopathy, hepatomegaly, jaundice, and liver dysfunction. In addition, patients may display developmental delay, occasionally with loss of milestones; ataxia, hypotonia, or hypertonia; and visual and auditory disturbances.

Older children, adolescents, and adults

Common findings include mild-to-profound intellectual disability, autism, learning disorders, behavioral disturbances, hallucinations, delirium, aggressiveness, agitation, anxiety, panic attacks, seizures, dizziness, ataxia, exercise intolerance, muscle weakness, and paraparesis.

Some manifestations may be intermittent, precipitated by the stress of illness, changes in diet, exercise, and/or hormones, or progressive, with worsening over time.

While most IEMs diagnosed in this age group are not immediately life-threatening, partial ornithine transcarbamylase (OTC) deficiency, a urea cycle defect, can manifest at this time as a life-threatening metabolic catastrophe. This is observed particularly in adolescent females with a history of protein aversion, abdominal pain, and migraine-like headaches.

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Approach Considerations

With the advent of tandem mass spectrometry, expanded newborn screening has become a widely accepted global approach. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects.^[1]

For neonates with positive newborn screening results, disease-specific evaluative and confirmatory testing, which usually includes testing for metabolic derangements, repeat newborn screen and specialized testing should be performed even if the neonate appears to be asymptomatic. ACTion sheets and algorithms, developed by the American College of Medical Genetics, provide guidelines based on the specific newborn screen abnormality (see ACT Sheets and Algorithms).^[4]

Electrocardiogram (ECG), radiograph, computed tomography (CT) scan, magnetic resonance imaging (MRI) scan, ultrasonogram, and/or echocardiogram (ECHO) should be obtained as clinically indicated.

Enzyme assay or DNA analysis may be indicated in leukocytes, erythrocytes, skin fibroblasts, liver, or other tissues.

Histologic evaluation of affected tissues such as skin, liver, brain, heart, kidney, and skeletal muscle should be completed.

If a child has died, attempting to diagnose a metabolic disease is still important because of the possibility that currently asymptomatic siblings are affected or that future children will be impacted. Plasma, serum, urine, and possibly cerebral spinal fluid (CSF), skin, and selected organ specimens should be collected and frozen. If permission for autopsy is not granted, discuss with the family, as appropriate, the possibility/importance of obtaining vitreous humor, skin biopsy, and/or organ needle biopsy for evaluation. Pictures and/or radiographs may be useful in the child with dysmorphism.

A metabolic specialist may be helpful in directing the evaluation of patients with suspected or known IEMs or the neonate with positive newborn screening results.

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Laboratory Studies

Emergent Evaluation

Make every effort to collect specimens for definitive diagnosis while the child is acutely ill (particularly samples for biochemical analysis, since biochemical abnormalities may be transient).

Laboratory abnormalities can be transient; therefore, values within the reference range do not rule out an IEM.

Studies may need to be repeated during other episodes of illness.

Most IEMs with acute, life-threatening presentation can be categorized based on findings of initial laboratory evaluations with the presence of at least one of the following (see Table 1 below):

• Metabolic acidosis - Metabolic acidosis, usually with an elevated anion gap, occurs with many IEMs and is a hallmark of organic acidemias (see the Anion Gap calculator); manifestations include tachypnea, vomiting, and lethargy
• Hypoglycemia - A prospective study revealed that in the emergency department (ED), hypoglycemia (plasma glucose level < 50 mg/dL) is rare in children (0.44% of those tested), even during periods of poor enteral intake; in a study of 40 children with hypoglycemia, 32 had a metabolic workup performed on initial samples, and 28% of those had a previously undiagnosed fatty acid oxidation defect or endocrine disorder
• Hyperammonemia - Early manifestations include anorexia, abdominal pain, headache, irritability, fatigue, late tachypnea, vomiting, lethargy, seizures, coma, and death; an ammonia level greater than 100 mcg/dL in the neonate and greater than 80 mcg/dL beyond the neonatal period is considered elevated; ammonia is highest in the urea cycle defects, often exceeding 1000 mcg/dL and causing primary respiratory alkalosis, sometimes with compensatory metabolic acidosis; ammonia in organic acidemias, if elevated, rarely exceeds 500 mcg/dL, and in fatty acid oxidation defects is usually less than 250 mcg/dL
• Major exceptions include nonketotic hyperglycinemia (lethargy, coma, seizures, hypotonia, spasticity, hiccups, apnea) and pyridoxine deficiency (encephalopathy, intractable seizures)

Initial emergency laboratory evaluation

Obtain the following tests:

• Complete blood count (CBC) to screen for neutropenia, anemia, and thrombocytopenia
• Serum electrolytes, bicarbonate, and blood gas, to detect electrolyte imbalances and to evaluate anion gap (usually elevated) and acid/base status
• Blood urea nitrogen (BUN) and creatinine, to evaluate renal function
• Bilirubin, transaminases, prothrombin time, and activated partial thromboplastin time, to evaluate hepatic function
• Ammonia if altered level of consciousness, persistent or recurrent vomiting, primary metabolic acidosis with increased anion gap, or primary respiratory alkalosis in the absence of toxic ingestion; preferably, use an arterial sample, because skeletal muscle releases ammonia; if a venous sample is obtained, the sample must be free flow (no tourniquet); ice the sample immediately, and assay promptly; normal values are less than 100 mcg/dL in the neonate and less than 80 mcg/dL in those older than 1 month
• Obtain blood glucose and urine pH, ketones, and reducing substances, to evaluate for hypoglycemia; false-positive results for reducing substances are caused by penicillin and glucuronides (Neonates - inappropriate ketones [ie, ketonuria]; Child - ketonuria with normal glucose, low or absent ketones with hypoglycemia)
• Obtain lactate dehydrogenase, aldolase, creatinine kinase, and urine myoglobin levels in patients with evidence of neuromyopathy

The table below outlines clinical and lab findings associated with various IEMs.

Table 1. Clinical and Laboratory Findings of Inborn Errors of Metabolism

View Table

See Table

Secondary emergency studies

If initial test results are outside the reference range, consider consultation with an IEM specialist to determine which additional tests are appropriate to the acute setting, how specimens are to be collected and stored, and where they should be sent.

• Plasma quantitative amino acids and acylcarnitines (1-2 mL in ethylenediaminetetraacetic acid [EDTA] or heparin tube, on ice)
• Urine organic acids, arylglycines, and/or orotic acid (5-10 mL, freeze immediately)
• Serum lactate, pyruvate (these may be helpful but are often difficult to interpret in the critically ill child because of multiple factors that may contribute to lactic acidosis)
• Cerebrospinal fluid (CSF) lactate, pyruvate, organic acids, neurotransmitters, and/or disease-specific metabolites collected at the same time as plasma (1-2 mL)
• Electroencephalogram (EEG), nerve conduction studies, evoked potential studies, and/or electromyography may be valuable but are rarely indicated in the emergency department

For patients with known IEM, studies should be disease and patient specific. Results should be compared to previous as available

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Other Tests

The include the following:

• Disease-specific diagnosis - Disease-specific testing guided by IEM subspecialists and/or other subspecialists involved based on manifestations of disease
• Biochemical testing - Based on results of emergent initial and secondary studies that identify likely IEM or IEM category, disease-specific biochemical testing should be considered by subspecialists; many of these tests are performed by laboratories that specialize in specific metabolic diseases
• Genome testing - Targeted genome sequencing for those with suspected specific IEMs, and whole genome sequencing for those with findings concerning for possible genetic etiology that includes IEM, are increasingly being performed and have been shown to expedite diagnosis and treatment and to improve outcome

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Approach Considerations

Goals of treatment for patients with an IEM are prevention of further accumulation of harmful substances, correction of metabolic abnormalities, and elimination of toxic metabolites. Even the apparently stable patient with mild symptoms may deteriorate rapidly, with progression to death within hours. With appropriate therapy, patients may completely recover without sequelae.

Start empirical treatment for a potential IEM as soon as the diagnosis is considered. Treatment of patients with a known IEM should be disease and patient specific. Families may have treatment protocols with them developed by an IEM specialist. They may also have instructions for what resuscitation measures should be given if resuscitation is necessary.

Strict adherence to dietary and pharmacologic regimen is recommended for patients diagnosed with an IEM. Early treatment of symptoms and recognition that physiologic stressors, including intercurrent illness, trauma, surgery, and changes in diet, may precipitate symptoms is important in avoiding metabolic decompensation.

Medical therapy specific for the IEM diagnosed will need to be continued, usually for life.^{[16, 17]} Long-term, routine follow-up screening should be provided for potential disease complications.

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Medical Care

Emergent treatment

Initial ED treatment does not require knowledge of the specific metabolic disease or even disease category.^[18] In any critically ill child, airway, breathing, and circulation must be established first. Hypoglycemia, acidosis, and hyperammonemia must be corrected. Consider antibiotics in any child who may be septic.

Treatment steps

Initiate treatment as quickly as possible. Delay in recognition and treatment may result in long-term neurologic impairment or death. See the following steps.^[18]

Access and establish airway, breathing, circulation. D10 normal saline should be used as bolus fluid unless the patient is hypoglycemic, in which case, dextrose should instead be given as a bolus, as detailed below. Avoid lactated Ringer solution; avoid hypotonic fluid load because of the risk of cerebral edema, particularly if hyperammonemia is present.

Discontinue oral intake in patients with decreased level of consciousness and patients who are vomiting.

Eliminate intake or administration of potentially harmful protein or sugars, especially galactose and fructose. Disease-specific offending agents should be eliminated for those with a known IEM and those with positive newborn screen results.

Correct hypoglycemia, prevent catabolism, and promote urinary excretion of toxic metabolites. Correct hypoglycemia, if present, with an intravenous (IV) dextrose bolus, as D10 for neonates and D10 or D25 beyond the neonatal period, 0.25-1 g/kg/dose, not to exceed 25 g/dose, and followed by continuous IV administration of dextrose. For all patients in whom IEM cannot be ruled out, give dextrose 10% IV at 1-1.5 maintenance (7-8 mg/kg/min) to keep the glucose level at 120-150 mg/dL, which should prevent catabolism. High-volume maintenance fluid will also promote urinary excretion of some toxic metabolites. Add insulin, 0.2-0.3 IU/kg, as needed to maintain the glucose level in the desired range.

Correct metabolic acidosis and electrolyte abnormalities. Sodium bicarbonate or, if the patient is hypokalemic, potassium acetate should be administered to correct acidosis. The pH (< 7.0-7.2) and dose of 0.25-0.5 mEq/kg/hr (up to 1-2 mEq/kg/hr) IV at which sodium bicarbonate or potassium acetate should be administered are controversial because data are lacking. Rapid correction or overcorrection may have paradoxic effects on the CNS. For intractable acidosis, consider hemodialysis. Add electrolytes at maintenance concentrations, with appropriate adjustments to correct electrolyte disturbances if present.

Correct hyperammonemia. Significant hyperammonemia is life-threatening and must be treated immediately upon diagnosis. To reduce ammonia, sodium phenylacetate and sodium benzoate (Ammonul; US Food and Drug Administration [FDA] approved for hyperammonemia due to urea cycle defects and neonatal hyperammonemic coma) can be administered to augment nitrogen excretion. If less than 20 kg, administer a loading dose of 250 mg/kg (2.5 mL/kg) in 10% glucose via central line over 90-120 minutes, then 250 mg/kg/day (2.5 mL/kg/day) in 10% glucose via central continuous infusion; if greater than 20 kg, administer 5.5 g/m² (55 mL/m²) over 90-120 minutes, then 5.5 g/m²/day (55 mL/m²/day). Ammonul must be given by central line.

Arginine is an essential amino acid in patients with urea cycle defects and should be administered as arginine HCL (600 mg/kg, ie, 6 mL/kg, IV in 10% glucose over 90-120 minutes, then 600 mg/kg/day IV continuous infusion) unless the patient has arginase deficiency, in which case it should not be given. Arginine dose should be decreased to 200 mg/kg for known carbamoyl phosphate synthetase (CPS) or ornithine transcarbamylase (OTC) deficiency. Arginine can be mixed with Ammonul.

For an ammonia level greater than 500-600 mg/dL before Ammonul or greater than 300 mg/dL and rising after Ammonul, hemodialysis should likely be initiated. If hemodialysis is not readily available, peritoneal dialysis (< 10% as effective as hemodialysis) or double volume exchange transfusion (even less effective) can be performed while arrangements are made to transport the patient to a center where hemodialysis is possible, as long as this does not delay transfer. Two to three days of therapy is usually necessary.

Administer cofactors if indicated. L-carnitine (25-50 mg/kg IV over 2-3 minutes or as infusion, followed by 25-50 mg/kg/day, maximum 3 g/day) may be administered empirically in life-threatening situations associated with primary carnitine deficiency. Administration of L-carnitine to patients with secondary carnitine deficiency is controversial. Consultation with an IEM specialist is recommended.^[18] Carnitine cannot be given with Ammonul. Pyridoxine (B6) (100 mg IV) should be given to neonates with seizures unresponsive to conventional anticonvulsants. Patients may require transfer to a tertiary care facility for further evaluation and treatment.

Treatment to stabilize the patient should be initiated prior to transfer. Do not delay treatment to arrange transfer.

When selecting the mode of transport and transport team, keep in mind that patients may deteriorate rapidly.

Inpatient care

Further inpatient care may include the following:

• Once toxic metabolites have been normalized, protein can be reintroduced using an essential amino acid solution, initially at 0.5-0.75 g/kg/day and gradually increased; for amino and organic acid disorders and urea cycle defects, protein intake should be restricted to 40-50% of recommended daily allowance (RDA); lipids, 2-3 g/kg/day as 20% intralipid, can be given to increase caloric intake, but they are contraindicated for certain fatty acid oxidation defects; for patients able to tolerate enteral feeding, protein-restricted preparations (eg, Mead Johnson 80056) may be given; with definitive diagnosis, specific dietary regimens, available for most IEMs, should be initiated
• Pharmacologic therapy to increase activity of abnormal cofactor-dependent enzymes (eg, thiamine [B-1] 5-20 mg/day PO up to 500 mg/day, biotin 5-20 mg/day PO, riboflavin [B-2] 200-300 mg PO tid, cobalamin [B-12] 1-2 mg/day IM) may be given; vitamins may be given empirically
• Transplantation (organ or bone marrow)
• Enzyme replacement therapy
• Gene therapy

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Diet

Nutritional interventions for IEMs include medical foods and dietary supplements along with dietary modifications to exclude nutrients that cannot be metabolized due to the specific IEM. The use of medical foods and/or dietary supplements prevent death, intellectual disability, or other adverse health outcomes.^[5]

Two types of medical foods are used in the treatment of IEMs. One type meets the majority of nutritional requirements while excluding the IEM-specific nutrient that cannot be metabolized. The second type includes products modified to be low in protein and are used in natural protein-restricted diets to provide energy and variety in the diet (eg, specially modified flour, cereals, and baked goods, meat and cheese substitutes, pasta, rice).^[5]

Odimet is a free online tool that helps patients adhere to dietary restrictions and requirements in the management of congenital metabolic diseases.^[19] The interactive and personalized tool facilitates dietary compliance and allows individualized modifications that best suit the patient's needs.

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Medication Summary

Emergency medications for IEMs in infants and children include drugs to eliminate toxic metabolites and/or amino acids and enzyme cofactors to compensate for metabolic deficiencies. These and other drugs may be required to maintain and treat the underlying IEM. Some IEMs are treated with replacement enzymes that are FDA approved, designated as orphan drugs, or investigational.^[20]

The National Organization for Rare Disorders (NORD) is a helpful Web site for finding information on orphan drug designation.

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Levocarnitine (Carnitine, Carnitor)

• Dosing, Interactions, etc.

Clinical Context:  An amino acid derivative, synthesized from methionine and lysine, required in energy metabolism. Can promote excretion of excess fatty acids in patients with defects that bioaccumulate acyl-CoA esters. Carnitine is indicated for most organic acidemias and is controversial for fatty acid oxidation defects.

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Class Summary

This agent is used for the treatment of primary and secondary carnitine deficiency.

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Arginine (L-arginine, RGene-10)

• Dosing, Interactions, etc.

Clinical Context:  Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate. Provides 1 mol of urea plus 1 mol ornithine per mol of arginine when cleaved by arginase. Preparation is 10% arginine hydrochloride. Can be mixed with sodium phenylacetate and sodium benzoate. If administering separately, mix with sodium bicarbonate.

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Pyridoxine (Nestrex, Vitamin B6)

• Dosing, Interactions, etc.

Clinical Context:  Precursor of pyridoxal, which functions in the metabolism of proteins, carbohydrates, and fats. Also aids in the release of liver- and muscle-stored glycogen and in the synthesis of gamma-aminobutyric acid (GABA) (within the CNS) and heme. Indicated for seizures of unknown etiology unresponsive to conventional anticonvulsants and for seizures in patients with known pyridoxine-dependent IEM. Give undiluted or mix with other solutions. Incompatible with alkaline or oxidizing solutions and iron salts. Not to be mixed with sodium bicarbonate.

• References

Sodium benzoate/sodium phenylacetate (Ammonul)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for acute hyperammonemic and associated encephalopathy due to urea cycle defects. For ammonia levels >500-600 mcg/dL, hemodialysis is the preferred treatment; however, sodium phenylacetate and sodium benzoate should be considered if dialysis cannot be initiated immediately. Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mole is identical to that of urea (2 mol of nitrogen). Ammonul should be administered with arginine-HCL for carbamoyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiencies and should not be given for arginase deficiency.

Approved as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Preparation contains 100 mg/mL each of sodium phenylacetate and sodium benzoate and comes in 50-mL vials. Must dilute IV dose in at least 25 mL/kg of dextrose 10% up to 600 mL. Do not mix directly with other medications, but it may be piggybacked. Give in addition to daily fluid requirement but decrease maintenance fluid by volume of Ammonul given.

• References