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Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management

Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management
Author:
V Reid Sutton, MD
Section Editor:
Sihoun Hahn, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Apr 2022. | This topic last updated: Dec 01, 2021.

INTRODUCTION — Inborn errors of metabolism (IEM) can present as acute metabolic emergencies resulting in significant morbidity, progressive neurologic injury, or death. As a result, optimal outcomes for children with IEM depend upon recognition of the signs and symptoms of metabolic disease, prompt evaluation, and referral to a center familiar with the evaluation and management of these disorders [1]. Delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, and even death.

This topic provides an overview of the presentation, initial evaluation, and management of children with suspected IEM who present with acute metabolic decompensation. Confirmation of diagnosis for specific disorders typically requires specialized testing and should be undertaken in consultation with a specialist in genetics or metabolic diseases. Determination of the specific IEM is reviewed separately. The classification and most common chronic presentations of IEM are also discussed separately, as are individual disorders. (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Identifying the specific disorder".)

CAUSES OF ACUTE METABOLIC DECOMPENSATION — IEM that cause acute metabolic decompensation can be grouped into disorders of intermediary metabolism (classic IEM), disorders of biosynthesis and breakdown of complex molecules, and disorders of neurotransmitter metabolism (table 1). Many of the disorders of intermediary metabolism can present with acute, life-threatening illness, particularly organic acidemias, urea cycle disorders, maple syrup urine disease, and fatty acid oxidation disorders. Neurotransmitter defects and related disorders can present with severe metabolic encephalopathy. In contrast, the disorders involving complex molecules tend to progress more slowly and do not typically cause acute metabolic decompensation. (See "Inborn errors of metabolism: Classification", section on 'Classification'.)

Metabolic crises occur when there is build-up of toxic metabolites. Triggers include factors that cause increased catabolism (acute infection; surgery, trauma, or even the birthing process; fasting) or increased consumption of a food component (eg, increased protein intake when switching from breast milk to cow's milk). Acute metabolic decompensation typically occurs after a period of apparent well-being. The duration of the symptom-free period may range from hours to months and sometimes years. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Clinical evaluation' and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Age at presentation'.)

As an example, episodic metabolic decompensation with poor intake or fasting may be a feature of carbohydrate disorders, fatty acid oxidation disorders, and certain amino acid disorders. In many cases, the severity of decompensation may seem out of proportion to the precipitating condition (eg, mild gastroenteritis resulting in severe dehydration necessitating hospitalization for intravenous fluids or recurrent episodes of hypoglycemia in a school-aged child) [2,3].

Acute metabolic decompensation requires prompt recognition and intervention to prevent mortality and long-term morbidity. Disease-specific management of several IEM that can cause acute, life-threatening illness is presented separately:

(See "Organic acidemias: An overview and specific defects", section on 'Treatment of metabolic decompensation'.)

(See "Urea cycle disorders: Management".)

(See "Overview of maple syrup urine disease", section on 'Metabolic decompensation'.)

(See "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders".)

(See "Methylmalonic acidemia".)

CLINICAL PRESENTATIONS — An acute presentation with multisystem involvement is strongly suggestive of an IEM. The initial clinical manifestations of acute metabolic decompensation can include:

Vomiting and anorexia or failure to feed

Lethargy that can progress to coma

Seizures

Rapid, deep breathing that can progress to apnea (see 'Acid-base disorders' below)

Hypothermia (related to illness [eg, sepsis], not specific to a particular metabolic pathway)

Rhabdomyolysis

Unexpected infant death or a brief resolved unexplained event (BRUE)

In one review of 53 patients who presented to an emergency department and were subsequently diagnosed with an IEM, 85 percent had neurologic signs or symptoms, 58 percent had gastrointestinal signs or symptoms, and 51 percent had both neurologic and gastrointestinal signs and/or symptoms [4]. Neurologic symptoms included hypotonia, lethargy, coma, seizures, and psychomotor delay. Gastrointestinal symptoms included vomiting and hepatic dysfunction.

Other common clinical manifestations of IEM are reviewed separately. The combination of clinical and laboratory features usually seen in each specific type of IEM is also discussed in detail elsewhere. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations' and "Inborn errors of metabolism: Classification", section on 'Classification'.)

Gastrointestinal and feeding problems — Recurrent episodes of vomiting and dehydration (particularly if related to intake of protein or specific carbohydrates) are features of amino acid disorders, organic acidemias, and urea cycle disorders. Hepatomegaly with hypoglycemia or liver failure is seen in other IEM. Patients may also present with poor feeding and/or failure to thrive (FTT). FTT can range from severe to mild, depending upon the specific disorder and the severity of the defect. (See "Urea cycle disorders: Clinical features and diagnosis" and "Organic acidemias: An overview and specific defects" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Gastrointestinal'.)

Feeding problems are also variable and range from normal feeding to any of the following:

Weak suck

Infrequent feeding due to lethargy

More frequent feeding due to hypoglycemia

Shorter feeding periods with lower intake due to hypotonia

Lethargy and coma — Lethargy and coma may occur in amino acid disorders, organic acidemias, urea cycle disorders, fatty acid oxidation defects, mitochondrial disorders, and disorders of carbohydrate metabolism (usually in the context of acute or episodic decompensation as described above). Depending upon the disorder, patients may be entirely neurologically normal prior to an acute metabolic decompensation or may have a longstanding history of developmental delay.

Cerebral edema can develop in certain IEM, particularly maple syrup urine disease and disorders associated with significant hyperammonemia and severe hypoglycemia such as proximal urea cycle disorders and organic acidemias [5]. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis" and 'Hyperammonemia' below and 'Hypoglycemia' below.)

Lethargy and coma are uncommon features of lysosomal storage and peroxisomal disorders. (See "Evaluation of stupor and coma in children" and "Acute toxic-metabolic encephalopathy in children".)

Seizures — Although IEM are a rare cause of seizures in children, seizures may occur in virtually all IEM [6-8]. These seizures are typically related to the metabolic derangement but are not a generalized seizure disorder. Seizures may be the only manifestation of pyridoxine-dependent seizures that are due to alpha-aminoadipic semialdehyde (AASA) dehydrogenase deficiency [9-12]. Seizures in other IEM are usually secondary to hypoglycemia or the accumulation of toxic metabolites in disorders of intermediary metabolism. Such seizures may respond poorly to standard anticonvulsant medications, responding instead to resolution of the primary metabolic derangement. (See 'Seizures' below and "Overview of neonatal epilepsy syndromes", section on 'Severe syndromes' and "Infantile spasms: Etiology and pathogenesis", section on 'Inborn errors of metabolism' and "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures'.)

Although seizures can occur in all forms of IEM, the conditions that present most commonly with seizures include (see "Overview of neonatal epilepsy syndromes", section on 'Severe syndromes'):

Urea cycle disorders and amino acid metabolism disorders (see "Urea cycle disorders: Clinical features and diagnosis" and "Overview of phenylketonuria" and "Overview of maple syrup urine disease")

Organic acidemias (see "Organic acidemias: An overview and specific defects" and "Methylmalonic acidemia")

Gangliosidoses (see "Krabbe disease" and "Metachromatic leukodystrophy")

Disorders of pyruvate metabolism (see "Causes of hypoglycemia in infants and children", section on 'Pyruvate carboxylase deficiency' and "Overview of the hereditary ataxias", section on 'Disorders of pyruvate and lactate metabolism')

Peroxisomal disorders (see "Peroxisomal disorders")

Mitochondrial disorders (see "Approach to the metabolic myopathies", section on 'Evaluation and diagnosis' and "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Evaluation and diagnosis')

Pyridoxine and pyridoxal-5-phosphate-responsive seizures (see "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures' and "Etiology and prognosis of neonatal seizures", section on 'Cofactor and vitamin deficiencies')

Biotinidase deficiency/holocarboxylase synthetase deficiency (see "Treatment of neonatal seizures", section on 'Biotinidase deficiency' and "Overview of water-soluble vitamins", section on 'Multiple carboxylase deficiency')

Glycine encephalopathy

Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency (see "Etiology and prognosis of neonatal seizures", section on 'Cofactor and vitamin deficiencies')

Neuronal ceroid lipofuscinoses (see "Symptomatic (secondary) myoclonus", section on 'Progressive myoclonic epilepsy and progressive myoclonic ataxia' and "Overview of the hereditary ataxias", section on 'Progressive ataxias')

Disorders of creatine metabolism (see "Congenital disorders of creatine synthesis and transport")

Purine and pyrimidine metabolism disorders (see "Inborn errors of metabolism: Classification", section on 'Purine and pyrimidine disorders' and "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome')

Respiratory abnormalities — Rapid or deep breathing may be caused by the metabolic derangement. In urea cycle disorders, hyperammonemia stimulates the respiratory center, causing hyperpnea that then results in a respiratory alkalosis. In organic acidemias, the metabolic acidosis caused by the IEM leads to tachypnea (as seen in nonmetabolic causes of acidosis). As the metabolic derangement progresses, there may be significant global neurologic depression leading to apnea. (See "Urea cycle disorders: Clinical features and diagnosis", section on 'Clinical features' and "Organic acidemias: An overview and specific defects", section on 'Clinical presentation'.)

Rhabdomyolysis — Rhabdomyolysis may occur in IEM related to muscle energy metabolism, particularly those related to utilization of stored muscle glycogen and fat for energy. Rhabdomyolysis can result in acute kidney injury if not promptly treated. Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, carnitine palmitoyltransferase (CPT), and other fatty acid oxidation disorders are associated with rhabdomyolysis and may also have hypoglycemia. Certain glycogen storage diseases (GSDs), particularly McArdle disease, typically present with muscle cramping and rhabdomyolysis with exercise. (See "Clinical manifestations and diagnosis of rhabdomyolysis" and "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders".)

SIDS or BRUE — Metabolic disease plays a small but significant role in the cause of unexpected infant death [13]. Sudden infant death syndrome (SIDS) or a brief resolved unexplained event (BRUE, a subcategory of apparent life-threatening event [ALTE]) may occur in infants with amino acid disorders, organic acidemias, urea cycle disorders, fatty acid oxidation disorders, and mitochondrial disorders. (See "Acute events in infancy including brief resolved unexplained event (BRUE)" and "Sudden unexpected infant death including SIDS: Initial management", section on 'Metabolic disease' and 'SIDS and BRUE' below.)

REFERRAL — Persons who are suspected of having or are newly diagnosed with an IEM should be transferred to a center specializing in the management of these disorders as soon as they are stable enough for transport. In those unstable for transport, a clinician with experience in the management of IEM may be consulted remotely.

LABORATORY FINDINGS — Most episodes of metabolic decompensation due to IEM are associated with one or more of the following metabolic derangements (table 2) that are typically assessed in patients with one of the clinical presentations mentioned above:

Acid-base disorder (including lactic acidosis)

Hyperammonemia

Hypoglycemia

Patients may also have laboratory abnormalities related to rhabdomyolysis or bone marrow suppression with sepsis-like features.

An abnormal laboratory value may be the first finding noted that suggests an IEM. In some disorders, these laboratory abnormalities are only present during the episode of metabolic decompensation. Thus, blood and urine samples should be obtained for both the initial and specialized tests (table 3) at the time of presentation if possible. Samples for specialized tests should be processed and stored appropriately for further testing if indicated. (See 'Evaluation of specific critical presentations' below.)

Other common laboratory findings in patients with IEM are reviewed separately. The combination of clinical and laboratory features usually seen in each specific type of IEM is also discussed in detail elsewhere. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Classification", section on 'Classification' and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Laboratory findings'.)

Acid-base disorders — Acid-base disorders may occur in many disorders of intermediary metabolism (table 2). (See 'Acid-base disorder' below.)

Metabolic acidosis (low serum bicarbonate [HCO3] and low arterial pH) is usually present in organic acidemias. Metabolic acidosis also may be present in amino acid disorders, disorders of pyruvate metabolism, mitochondrial disorders, and disorders of carbohydrate metabolism [14,15]. The metabolic acidosis in these disorders is usually accompanied by an increased anion gap. The anion gap results from the presence of abnormal metabolites, such as ketoacids, lactic acid, or the organic acid that is unable to be metabolized. Lactic acidosis caused by abnormal oxidative metabolism is a frequent finding in mitochondrial disorders, glycogen storage disorders (GSDs), and disorders of gluconeogenesis. (See "Approach to the child with metabolic acidosis" and "Approach to the adult with metabolic acidosis" and "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis".)

Metabolic acidosis is uncommon in lysosomal storage and peroxisomal disorders and is not seen in urea cycle disorders.

A respiratory alkalosis (low arterial partial pressure of carbon dioxide [PCO2] and elevated arterial pH) is suggestive of hyperammonemia, which is a characteristic feature of urea cycle disorders [16]. The respiratory alkalosis is caused by hyperpnea, which is induced by hyperammonemia. Respiratory alkalosis also may occur in Leigh syndrome (a mitochondrial disorder) and other disorders associated with hyperammonemia. (See "Simple and mixed acid-base disorders".)

Hyperammonemia — Hyperammonemia is a characteristic feature of the urea cycle defects and organic acidemias, particularly propionic and methylmalonic acidemias (table 2) [17]. It also may occur in other amino acid disorders (such as lysinuric protein intolerance) and fatty acid oxidation defects. Modest elevations of ammonia occur rarely in mitochondrial disorders or with hepatic dysfunction. (See 'Hyperammonemia' below.)

Ammonia concentrations tend to be highest in urea cycle disorders (300 to 1000 micromol/L [5.1 to 17 mcg/mL]). However, ammonia can be normal in urea cycle disorders when the patient is not acutely ill and can sometimes be over 1000 micromol/L (17 mcg/mL) in organic acidemias. Of note, there is variability in the normal range of serum ammonia reported due to differences in units used and methodology employed by each laboratory.

Modest elevations of ammonia occur rarely in mitochondrial disorders or with hepatic dysfunction. The ammonia concentration is usually normal in disorders of carbohydrate metabolism, lysosomal storage disorders, and peroxisomal disorders [14].

Hypoglycemia — Hypoglycemia typically occurs in disorders of ketogenesis, fatty acid oxidation disorders (such as medium-chain acyl-CoA dehydrogenase deficiency), some GSDs, disorders of gluconeogenesis, and hereditary fructose intolerance (HFI) (table 2). It also may occur in amino acid disorders, organic acidemias, and mitochondrial disorders. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Causes of hypoglycemia in infants and children" and "Overview of inherited disorders of glucose and glycogen metabolism".)

The hypoglycemia in GSD and organic acidemias usually is accompanied by ketosis, whereas no ketosis or inappropriately low ketone body production is more typical of disorders of ketogenesis and fatty acid oxidation disorders in which fatty acids cannot be converted to ketoacids in the liver. Patients with GSD may also have increased plasma concentrations of lactate, pyruvate, triglycerides, and uric acid. (See 'Hypoglycemia' below.)

Bone marrow suppression — Bone marrow suppression can occur in organic acidemias, such as propionic and methylmalonic acidemias, and may manifest as neutropenia, anemia, or pancytopenia. In various lysosomal storage disorders, such as Gaucher disease, engorged macrophages may crowd out normal marrow cells and lead to anemia and thrombocytopenia. Disorders of vitamin B12 transport and biosynthesis, such as cobalamin C disease, may cause anemia due to functional vitamin B12 deficiency.

Elevated serum muscle enzymes — The hallmark of rhabdomyolysis is an elevation in creatine kinase (CK) and other serum muscle enzymes. Laboratory findings in patients with rhabdomyolysis are reviewed in greater detail separately. (See "Clinical manifestations and diagnosis of rhabdomyolysis", section on 'Laboratory findings'.)

INITIAL EVALUATION — The detection of IEM depends upon a high index of suspicion. Patients with certain critical presentations, such as hypoglycemia or hyperammonemia, in particular should be evaluated for IEM. Patients with life-threatening illness should undergo concurrent evaluation for other conditions in the differential diagnosis (eg, sepsis, cardiac disease) [18-20]. We suggest a stepwise approach to evaluation, beginning with basic tests that are routinely available [2,4,9,18,21,22] before completing specialized metabolic investigations. These basic tests are prompted in any infant or child who presents with the neurologic and/or gastrointestinal symptoms described above. (See 'Evaluation of specific critical presentations' below and 'Differential diagnosis' below and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Identifying the specific disorder" and "Inborn errors of metabolism: Classification", section on 'Classification'.)

Testing in patients with history and physical exam findings suggestive of an IEM should be performed at the time of presentation or when symptoms are most pronounced because laboratory values may be normal when the patient is well. Blood and urine samples (and cerebrospinal fluid [CSF] in patients with persistent seizures, dystonia, or focal neurologic signs) should be obtained at the time of the initial evaluation (to the extent possible) for both basic tests and selected specialized tests (table 3), even though the specialized tests may not be necessary [4,21]. This is because medical interventions may affect certain laboratory results that are necessary to establish the diagnosis (eg, administration of glucose-containing intravenous [IV] fluids will affect the ability to detect hypoglycemia) [2].

The initial laboratory evaluation of a patient with suspected IEM includes (table 3) [2,9,18]:

Complete blood count (CBC) with differential – Hematologic manifestations of IEM may involve any or all of the cell lines. The CBC also may provide a clue to sepsis, which may be the trigger for a metabolic crisis. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Hematologic abnormalities'.)

Arterial blood gas – An arterial blood gas (or venous blood gas if unable to obtain arterial access) is used to detect acid-base disturbances. Metabolic acidosis with an increased anion gap is commonly associated with organic acidemias. Respiratory alkalosis is commonly seen in urea cycle disorders as a result of hyperammonemia (table 2). (See 'Acid-base disorder' below.)

Blood glucose – Hypoglycemia is typical of disorders of ketogenesis (eg, fatty acid oxidation disorders), glycogen storage disorders (GSDs), and disorders of carbohydrate metabolism (eg, disorders of fructose metabolism). (See 'Hypoglycemia' below.)

Serum ammonia – The blood sample to measure ammonia concentration should be obtained from an artery or vein without using a tourniquet, placed on ice for transport to the laboratory, and analyzed immediately. If the plasma ammonia concentration is >100 micromol/L (1.7 microgram/mL), the measurement should be repeated immediately. Significant elevations in ammonia (≥300 micromol/L [5.1 microgram/mL]) are most commonly associated with urea cycle disorders and certain organic acidemias (particularly propionic and methylmalonic acidemias). An elevated ammonia concentration (≥120 micromol/L [2.0 microgram/mL] in the newborn and ≥80 micromol/L [1.4 microgram/mL] in older infants and children) is neurotoxic and must be treated immediately. The duration of hyperammonemia, rather than the peak level, is predictive of poor developmental outcome in newborns. (See 'Hyperammonemia' below and 'Immediate management' below.)

Electrolytes, blood urea nitrogen (BUN), creatinine – Measurement of serum electrolytes is necessary to calculate the anion gap. A metabolic acidosis with an increased anion gap is commonly seen in organic acidemias. In addition, the finding of hyponatremia and hyperkalemia may provide a clue to salt-wasting. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Kidney disease' and "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis".)

Uric acid – Uric acid may be high in patients with GSD. These patients usually present with fasting hypoglycemia, ketosis, and muscle symptoms. Uric acid can also be abnormal in patients with more chronic forms of IEM, with decreased levels seen in patients with defects of purine metabolism or molybdenum cofactor deficiency and increased levels in patients with Lesch-Nyhan disease. (See "Urate balance" and "Overview of inherited disorders of glucose and glycogen metabolism", section on 'Clinical and laboratory features'.)

Examination of the urine, including color, odor, dipstick, and presence of ketones – Several components of the urinalysis are helpful in the evaluation of the child with potential IEM:

The presence or absence of ketones in the urine is helpful in determining the etiology of hypoglycemia. (See 'Hypoglycemia' below.)

The urine pH is helpful in determining the cause of metabolic acidosis, if metabolic acidosis is present. (See 'Acid-base disorder' below.)

Decreased urine specific gravity in a patient who is vomiting is suggestive of impaired ability to concentrate the urine, which is suggestive of renal tubular dysfunction (particularly when it occurs in conjunction with glucosuria and proteinuria). Renal tubular dysfunction occurs in a number of IEM. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Kidney disease'.)

The presence of leukocyte esterase or nitrites on dipstick analysis is suggestive of urinary tract infection, which may be the precipitant for metabolic crisis, or the presenting manifestation of an IEM that has an associated increased risk of sepsis (eg, galactosemia, GSD type Ib [glucose-6-phosphatase deficiency, von Gierke disease]). (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Rapidly available tests'.)

The presence of reducing substances in the urine is a clue to certain IEM if the urine dipstick is negative for glucose (table 2). Children who have non-glucose-reducing substances in the urine may have a carbohydrate intolerance disorder (eg, galactosemia, hereditary fructose intolerance [HFI]) or an amino acid disorder. However, the absence of reducing substances in the urine does not exclude these disorders. False-positive tests for urine-reducing substances in children may occur in children who have taken penicillins, salicylates, ascorbic acid, or drugs excreted as glucuronides [2]. (See "Galactosemia: Clinical features and diagnosis" and "Causes of hypoglycemia in infants and children", section on 'Hereditary fructose intolerance' and "Inborn errors of metabolism: Classification", section on 'Amino acid disorders'.)

If possible, at the time of the initial evaluation, samples also should be obtained for the specialized tests that may be necessary depending upon the results of the initial evaluation [2,4,21]:

Quantitative plasma amino acids

Acylcarnitine profile

Serum lactate

Qualitative urine organic acids

These samples should be placed in the appropriate tubes or containers, processed, and stored according to the requirements of individual clinical laboratories. Important aspects of the handling and/or processing of specimens and pertinent findings of specific tests as related to IEM are discussed separately. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Specialized tests'.)

EVALUATION OF SPECIFIC CRITICAL PRESENTATIONS — IEM may present as a critical illness with acute metabolic decompensation associated with metabolic derangement in individuals of any age. The particular combination of metabolic derangements can help to distinguish among the various categories of IEM (table 2), guiding decisions regarding additional evaluation, as discussed below and elsewhere. These findings also are used to guide immediate management [2]. (See 'Clinical presentations' above and 'Laboratory findings' above and 'Initial evaluation' above and 'Immediate management' below and "Inborn errors of metabolism: Identifying the specific disorder", section on 'Specialized tests'.)

Evaluation of patients who present with other clinical manifestations suggestive of an IEM is presented separately. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Evaluation of specific presentations'.)

Hypoglycemia — Hypoglycemia in infants and children requires prompt recognition and treatment to prevent severe and potentially permanent neurologic sequelae. The treatment of hypoglycemia, discussed in detail separately, should be initiated as soon as possible after critical samples are obtained. (See "Approach to hypoglycemia in infants and children", section on 'Immediate management'.)

The presence or absence of ketosis helps to distinguish among the different types of IEM that can cause hypoglycemia (table 2) (see 'Hypoglycemia' above). As examples:

Ketosis is usually present in patients with hypoglycemia and glycogen storage disease (GSD) except GSD I; these patients also typically have increased plasma concentrations of lactate, pyruvate, triglycerides, and uric acid. (See "Overview of inherited disorders of glucose and glycogen metabolism" and "Causes of hypoglycemia in infants and children" and "Metabolic myopathies caused by disorders of lipid and purine metabolism".)

Ketosis is also usually present in patients with hypoglycemia and organic acidemia or maple syrup urine disease. (See "Organic acidemias: An overview and specific defects" and "Overview of maple syrup urine disease".)

Ketosis is usually inappropriately low to absent in patients with fatty acid oxidation disorders and disorders of ketogenesis (such as 3-hydroxy-3-methylglutaryl [HMG] CoA lyase and 3-ketothiolase deficiency) because fatty acids cannot be converted to ketoacids in the liver. (See "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders".)

Additional evaluation for metabolic causes of hypoglycemia should be performed while the patient is hypoglycemic (or on samples that were obtained at the time of presentation and appropriately stored). Additional evaluation includes:

Plasma acylcarnitine profile and quantitative plasma carnitine levels (free, total, and acyl). Low carnitine levels are seen in primary carnitine deficiency or in secondary carnitine deficiency associated with organic acidemias or mitochondrial disorders. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Specialized tests'.)

Measurements of lactate, triglycerides, uric acid, and creatine kinase (CK) may assist in the diagnosis of certain GSD. Lactate, triglycerides, and uric acid typically are elevated in glucose-6-phosphatase deficiency (GSD Ia, von Gierke disease), the most common GSD. CK concentration is increased in glycogen debrancher deficiency (GSD III, Forbes disease). (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)" and "Glycogen debrancher deficiency (glycogen storage disease III)".)

The approach to the neonate, infant, or child with hypoglycemia is discussed in greater detail separately. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia" and "Approach to hypoglycemia in infants and children".)

Hyperammonemia — An elevated ammonia concentration is neurotoxic and must be treated. Treatment, described below, should be initiated pending confirmation of a specific diagnosis. (See 'Immediate management' below.)

Additional tests should be ordered if the plasma ammonia is elevated and the tests have not been obtained previously (algorithm 1). These include (table 3):

Quantitative plasma amino acid analysis. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Plasma amino acids'.)

Qualitative urine organic acid analysis. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Urine organic acids'.)

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and measures of liver synthetic function should be checked since liver dysfunction/liver failure can result in hyperammonemia, independent of an IEM. (See "Acute liver failure in children: Etiology and evaluation".)

Acid-base disorder — The most common acid-base disorders seen in IEM are metabolic acidosis and respiratory alkalosis.

Metabolic acidosis — Metabolic acidosis due to an IEM is usually associated with an increased anion gap (table 2). The anion gap results from the presence of abnormal metabolites, such as ketoacids, lactic acid, or methylmalonic acid. The evaluation of metabolic acidosis is discussed in detail separately. (See "Approach to the child with metabolic acidosis" and "Approach to the adult with metabolic acidosis" and "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis".)

The urine pH is helpful in determining the cause of metabolic acidosis. The appropriate physiologic response to metabolic acidosis is increased urinary acid excretion, with the urine pH usually falling below 5. A urine pH >5 is more suggestive of metabolic acidosis due to renal tubular acidosis rather than an IEM. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance" and 'Acid-base disorders' above.)

Respiratory alkalosis — Respiratory alkalosis usually accompanies hyperammonemia in urea cycle disorders, unless shock or secondary infection is present. The respiratory alkalosis is caused by hyperpnea that is induced by the elevated ammonia level. The evaluation of respiratory alkalosis and other acid-base disorders are discussed in greater detail separately. (See "Simple and mixed acid-base disorders".)

Unexplained acid-base disorder — Among patients with an otherwise unexplained acid-base disorder, additional evaluation should include:

Plasma lactate and pyruvate levels (the latter is only accurate when obtained in a specimen container with perchlorate) (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Lactate and pyruvate')

Quantitative plasma amino acid analysis (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Plasma amino acids')

Quantitative urine organic analysis (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Urine organic acids')

SIDS and BRUE — The following are the most common IEM that can cause sudden infant death syndrome (SIDS) or a brief resolved unexplained event (BRUE, a subcategory of apparent life-threatening events [ALTEs]) (see "Acute events in infancy including brief resolved unexplained event (BRUE)" and "Sudden unexpected infant death including SIDS: Initial management", section on 'Metabolic disease'):

Fatty acid oxidation defects, the most common of which is medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (see "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders")

Disorders of amino acid metabolism and urea cycle disorders (see "Inborn errors of metabolism: Classification", section on 'Amino acid disorders' and "Overview of phenylketonuria" and "Overview of maple syrup urine disease" and "Urea cycle disorders: Clinical features and diagnosis")

Organic acidemias (see "Organic acidemias: An overview and specific defects")

Laboratory evaluation for these disorders is recommended for all cases of SIDS and selected cases of ALTE (eg, event is truly life threatening and other findings suggest an IEM). The best source of blood for testing in cases of SIDS is usually the newborn screening card. This evaluation includes:

Plasma acylcarnitine profile (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Acylcarnitine profile')

Quantitative plasma carnitine levels to test for primary (eg, defect in the sodium-dependent carnitine transporter) or secondary carnitine deficiency (eg, loss of carnitine caused by disorders such as fatty acid oxidation disorders or organic acidemias) (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Other')

Quantitative plasma amino acid analysis (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Plasma amino acids')

Qualitative urine organic acid analysis (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Urine organic acids')

Plasma lactate and pyruvate (the latter is only accurate when obtained in a specimen container with perchlorate) (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Lactate and pyruvate')

Postmortem evaluation is discussed separately. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Postmortem'.)

Seizures — Metabolic disorders are rare causes of seizures in children. Seizures caused by IEM usually present early and may not be responsive to standard antiseizure medications [7]. In patients with persistent seizures, dystonia, or focal neurologic signs, cerebrospinal fluid (CSF) should be obtained for glucose (along with contemporaneous blood glucose) and protein. An additional 1 mL of CSF should be reserved for potential future studies.

The likelihood of an IEM causing seizures is highest in individuals with infantile-onset seizures or persistent seizures with developmental delay/hypotonia/hypertonia or developmental regression. In such individuals, the evaluation for these IEM may include (see "Inborn errors of metabolism: Identifying the specific disorder", section on 'Specialized tests'):

A trial of pyridoxine (100 mg intravenously) or pyridoxal phosphate (the active form of pyridoxine) under electroencephalographic observation in neonates with frequent or persistent seizures [23-25]; if there is no response, a trial of leucovorin (folinic acid) and biotin should be considered (algorithm 2). Alpha-aminoadipic semialdehyde (AASA), a biomarker for pyridoxine-dependent seizure or leucovorin-responsive seizure, can be clinically measured both in plasma and urine.

Qualitative urine organic acid analysis. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Urine organic acids'.)

Quantitative plasma amino acid analysis. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Plasma amino acids'.)

Arterial lactate and pyruvate concentrations. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Lactate and pyruvate'.)

Quantitative CSF amino acid analysis performed at the same time the sample is obtained for plasma amino acid analysis. A CSF:plasma glycine ratio >0.08 is abnormal and consistent with glycine encephalopathy, also known as nonketotic hyperglycinemia.

Quantitative CSF lactate; individuals with disorders of mitochondrial energy metabolism may have normal plasma lactate levels but elevated CSF levels; therefore, measuring lactate either by direct analysis of the CSF or by measuring brain lactate by magnetic resonance (MR) spectroscopy is recommended.

Plasma and urine creatine and guanidinoacetate levels to assess for abnormalities of creatine metabolism, such as guanidinoacetate methyltransferase deficiency. Plasma analysis alone cannot reliably detect X-linked creatine transporter deficiency.

Dilated ophthalmologic examination to detect the cherry-red spot associated with gangliosidoses (picture 1) or retinal findings of mitochondrial diseases.

Cranial magnetic resonance imaging (MRI) to evaluate for leukodystrophy or basal ganglia changes associated with gangliosidoses or mitochondrial disorders, respectively; MR spectroscopy is indicated if an inborn error of small molecule metabolism (a neurometabolic disorder) is suspected.

If the MRI and/or ophthalmologic examination suggest a particular disorder, further studies are done to confirm the diagnosis. If no diagnosis is established, secondary studies are needed to detect disorders of purine and pyrimidine metabolism (urine purines and pyrimidines), fatty acid oxidation (plasma acylcarnitine profile), neurotransmitter metabolism (CSF neurotransmitter metabolites), copper metabolism (serum copper, ceruloplasmin for Menkes disease), or peroxisomes (very-long-chain fatty acid, phytanic acid, pipecolic acid).

Rhabdomyolysis — Lactate dehydrogenase, aldolase, CK, and urine myoglobin in patients who have complaints of muscle weakness, tenderness, cramping, atrophy, or exercise intolerance may indicate the presence of rhabdomyolysis (eg, McArdle disease, very-long-chain acyl-CoA dehydrogenase [VLCAD], carnitine palmitoyltransferase [CPT] II). (See "Specific fatty acid oxidation disorders" and "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)" and "Clinical manifestations and diagnosis of rhabdomyolysis", section on 'Evaluation and diagnosis'.)

Liver dysfunction/failure — Liver function tests (aminotransferases, bilirubin, prothrombin time) in patients with coagulopathy, jaundice, or other evidence of liver dysfunction/failure. Hereditary fructose intolerance (HFI) and galactosemia typically present with liver dysfunction and coagulopathy. Citrin deficiency, transaldolase deficiency, tyrosinemia type I, and disorders of bile acid biosynthesis may present with cholestatic jaundice and acute liver failure. (See "Galactosemia: Clinical features and diagnosis" and "Causes of hypoglycemia in infants and children", section on 'Hereditary fructose intolerance' and "Causes of cholestasis in neonates and young infants", section on 'Genetic/metabolic disorders'.)

DIFFERENTIAL DIAGNOSIS — In neonates, the differential diagnosis includes sepsis, congenital viral infection [26], duct-dependent heart disease, drug withdrawal, congenital adrenal hyperplasia, and congenital hyperinsulinism [2,10,18]. In older children, the differential diagnosis includes diabetes, ingestion or intoxication, encephalitis, and adrenal insufficiency [9]. Most of these are distinguished from IEM by laboratory findings specific to each disorder. Evaluation and/or empiric therapy, if indicated, for these conditions should be undertaken concurrently with the evaluation for IEM since early initiation of supportive measures and definitive therapy is critical for both IEM and the other diagnoses. (See appropriate topic reviews.)

IMMEDIATE MANAGEMENT — Infants and children with critical metabolic illness require immediate management to prevent further acute deterioration and long-term sequelae. Appropriate and aggressive treatment before confirmation of the diagnosis may be lifesaving or prevent or reduce the long-term neurologic sequelae of some of these conditions [10,18,21].

Pending confirmation of the diagnosis, supportive interventions are undertaken. These include provision of ventilatory support and fluid resuscitation, removal of accumulating metabolites, and prevention of catabolism (by promoting anabolism). In addition, selected cofactors may be administered, if indicated, before confirmation of the diagnosis and in some cases to support the diagnosis (eg, pyridoxine) [2,27].

Specific therapy is usually initiated after confirmation of the diagnosis. Treatment should be planned in consultation with a geneticist or specialist in metabolic disease [18].

Stabilize circulation, airway, and breathing

Fluid resuscitation with saline (usually normal saline, but electrolyte composition should be based upon clinical status and serum electrolyte concentrations) should be provided as necessary to maintain adequate circulation. Lactate (ie, lactated Ringer's solution) should be avoided because of the potential to exacerbate lactic acidosis [2]. The administration of hypotonic fluids may cause cerebral edema [28,29].

Ventilatory support should be provided as necessary when direct toxic effects of metabolites cause respiratory depression or cerebral edema.

Treat hypoglycemia to prevent catabolism

Treatment of hypoglycemia should be initiated as soon as possible. Administration of intravenous (IV) dextrose (with electrolytes) provides energy and prevents catabolism. An infusion rate of 8 to 10 mg of dextrose per kilogram body weight per minute should be adequate to suppress catabolism. Dextrose solutions containing up to 10 percent dextrose can be infused through a peripheral IV catheter. Central IV access may be necessary to administer higher concentrations of dextrose if initiation of oral intake will be delayed for more than 24 hours. Critical blood samples for evaluation of metabolic causes of hypoglycemia should be obtained before treatment, if possible (see 'Hypoglycemia' above). The treatment of hypoglycemia is discussed in detail separately. (See "Management and outcome of neonatal hypoglycemia" and "Approach to hypoglycemia in infants and children", section on 'Immediate management'.)

Insulin as a continuous IV infusion may be administered if necessary to promote anabolism and maintain serum glucose between 100 and 120 mg/dL (5.56 mmol/L to 6.67 mmol/L). A typical dose for insulin in these situations is 0.05 units per kilogram body weight per hour as a continuous IV infusion. The rate should be adjusted based upon blood sugar levels [2].

Remove toxic metabolites

Enteral or parenteral nutrition should be withheld pending a specific diagnosis. Continued IV administration or oral intake of amino acids or specific carbohydrates that rely upon a defective pathway for metabolism can increase toxic metabolite concentrations and worsen the clinical condition [2,10,18,30].

Additional measures to decrease toxic metabolites (eg, dialysis or medications to divert amino acids away from a defective metabolic pathway) may be necessary depending upon the disease and severity of intoxication. Significant hyperammonemia is life threatening and must be treated immediately by hemodialysis and/or medications, such as sodium phenylacetate-sodium benzoate (Ammonul) in patients with urea cycle disorders. The acute management of hyperammonemia in patients with urea cycle defects is discussed separately. (See "Urea cycle disorders: Management", section on 'Initial management of metabolic decompensation'.)

Correct metabolic acidosis

Bicarbonate may be necessary to correct metabolic acidosis in some circumstances. However, if the acidosis is the result of an untreated organic acidemia, it is unlikely that bicarbonate administration alone will be of any significant benefit. Bicarbonate should be administered with caution since rapid or overcorrection of acidosis may have adverse effects on the central nervous system [2]. Administration of bicarbonate to hyperammonemic patients should be avoided since it may cause cerebral edema and decrease the urinary excretion of ammonia [2]. (See "Approach to the adult with metabolic acidosis", section on 'Overview of therapy' and "Approach to the child with metabolic acidosis", section on 'Intravenous bicarbonate therapy'.)

Provide cofactors — Administration of cofactors is pending confirmation of diagnosis and may be indicated in select circumstances, as outlined below [2,23]:

Cobalamin (vitamin B12, 1 mg subcutaneously or intramuscularly [IM]) may be administered to patients with metabolic acidosis and suspected organic acidemia (in case the patient has a form of methylmalonic acidemia that is responsive to vitamin B12). (See "Organic acidemias: An overview and specific defects", section on 'Methylmalonic acidemia'.)

Pyridoxine (100 mg IV) or pyridoxal phosphate (the active form of pyridoxine [vitamin B6], 10 mg/kg IV [24]) should be given to neonates with seizures unresponsive to conventional antiseizure medications; if there is no response to pyridoxine, leucovorin (folinic acid, 2.5 mg IV) should be administered for possible leucovorin-responsive seizures (algorithm 2) [31]. (See "Treatment of neonatal seizures", section on 'Pyridoxine or PLP responsive seizures'.)

Biotin (10 mg orally or via nasogastric tube) should be administered to neonates with recurrent seizures for possible biotin-responsive multiple carboxylase deficiency. (See "Overview of water-soluble vitamins", section on 'Multiple carboxylase deficiency'.)

Riboflavin (50 mg IV three times daily) should be considered in multiple acyl-CoA dehydrogenase deficiency and in disorders of riboflavin transport (Brown-Vialetto-Van Laere syndrome). (See "Specific fatty acid oxidation disorders", section on 'Multiple acyl-CoA dehydrogenase deficiency'.)

Carnitine supplementation (100 mg/kg per day in three divided doses either orally or IV) may be useful in patients with organic acidemias, fatty acid oxidation disorders, and primary or secondary carnitine deficiency [32]. A higher dose (200 mg/kg per day IV or 300 mg/kg per day orally) may be used to promote excretion of organic acids (eg, excretion of propionylcarnitine in propionic acidemia) in critically ill patients with one of these disorders. (See "Organic acidemias: An overview and specific defects", section on 'Management' and "Specific fatty acid oxidation disorders", section on 'Carnitine cycle defects'.)

Additional therapies in select patients

Empiric administration of antibiotic therapy is indicated for patients with possible sepsis or serious bacterial infection [2]. There is a risk of sepsis in untreated galactosemia, and certain organic acidemias when untreated may present with neutropenia and infection. Thus, the diagnosis of an IEM does not exclude the possibility of a concomitant serious infection. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants" and "Management and outcome of sepsis in term and late preterm infants" and "Septic shock in children: Rapid recognition and initial resuscitation (first hour)".)

Fresh-frozen plasma may be necessary for patients with coagulopathy related to hepatic dysfunction [2]. (See "Hemostatic abnormalities in patients with liver disease".)

In cases of cerebral edema due to maple syrup urine disease or hyperammonemia, hemofiltration should be employed to remove the offending agents (leucine and ammonia, respectively) in addition to routine measures used to treat cerebral edema. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis" and "Elevated intracranial pressure (ICP) in children: Management".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of metabolism".)

SUMMARY

Optimal outcome for children with inborn errors of metabolism (IEM) (table 1) depends upon early recognition. Delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, or death. (See 'Introduction' above.)

The most important clue to an IEM in the neonate is deterioration after an initial period of well-being. Infants with IEM are not typically sick immediately at delivery. Older infants and children may present with recurrent episodes of metabolic decompensation. (See 'Causes of acute metabolic decompensation' above.)

The initial clinical manifestations of acute metabolic decompensation can include (see 'Clinical presentations' above):

Vomiting and anorexia or failure to feed

Lethargy that can progress to coma

Seizures

Rapid, deep breathing that can progress to apnea

Hypothermia

An acute life-threatening event (ALTE) or sudden infant death syndrome (SIDS)

Rhabdomyolysis

Patients can also present with an acid-base disorder, hyperammonemia, or hypoglycemia. (See 'Laboratory findings' above.)

The initial evaluation of IEM includes (see 'Initial evaluation' above and 'Evaluation of specific critical presentations' above):

Complete blood count (CBC) with differential

Arterial blood gas

Blood glucose

Serum ammonia

Electrolytes, blood urea nitrogen (BUN), creatinine, uric acid

Liver function tests – Aminotransferases, bilirubin, prothrombin time

Examination of the urine, including color, odor, dipstick, and presence of ketones

Testing should be performed at the time of presentation or when symptoms are most pronounced. Both basic tests and selected specialized tests (table 3) should be obtained at the time of the initial evaluation (to the extent possible), even though the specialized tests may not be necessary, because medical interventions may affect certain laboratory results that are necessary to establish the diagnosis. Patients with life-threatening illness should undergo concurrent evaluation for other conditions in the differential diagnosis. (See 'Initial evaluation' above and 'Differential diagnosis' above and 'Evaluation of specific critical presentations' above.)

Most episodes of critical illness are associated with one or more metabolic derangements (table 2) that can help to distinguish among the various categories of IEM and guide decisions regarding additional evaluation and immediate management. (See 'Evaluation of specific critical presentations' above.)

Management of hypoglycemia, hyperammonemia, and seizures must be initiated promptly to prevent long-term sequelae. Supportive interventions include provision of ventilatory support and fluid resuscitation, removal of accumulating metabolites, and prevention of catabolism. In addition, selected cofactors may be administered, if indicated, before confirmation of the diagnosis and in some cases to support the diagnosis. (See 'Immediate management' above.)

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