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Inborn errors of metabolism: Identifying the specific disorder

Inborn errors of metabolism: Identifying the specific disorder
Author:
V Reid Sutton, MD
Section Editor:
Sihoun Hahn, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Jun 2022. | This topic last updated: Nov 22, 2021.

INTRODUCTION — Optimal outcome for children with inborn errors of metabolism (IEM) depends 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, or death.

This topic provides an overview of the evaluation for children with suspected IEM. Confirmation of diagnosis of specific disorders typically requires specialized testing and should be undertaken in consultation with a specialist in genetics or metabolic diseases. The classification, most common presentations, and initial evaluation and management of IEM, particularly those that present as metabolic emergencies, are discussed separately, as are individual disorders. (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

NEWBORN SCREENING — A newborn may present with a positive newborn screen for IEM before clinical manifestations are present or recognized. Newborn screening programs screen all newborns for a specific set of IEM [2]. The testing methods and disorders that are screened vary from state to state and country to country. (See "Newborn screening".)

Newborn screening programs increase the detection of IEM but cannot be relied upon exclusively. False-positive and false-negative screening tests occur, usually as a result of screening too early (ie, before adequate "challenge" with protein or carbohydrate), medications, and/or transfusions [3,4]. In addition, the results of the screening tests may not be available in the first few days of life, when some IEM may present. Furthermore, newborn screening programs do not screen for all IEM. As an example, the urea cycle disorders ornithine transcarbamylase deficiency and carbamoylphosphate synthetase deficiency are not detected by available newborn screening methods. Improved detection depends upon a high index of suspicion. Guidelines for evaluation following an abnormal newborn screen can be found in ACTion (ACT) sheets from the American College of Medical Genetics. These guidelines and other helpful information are also often available from the state newborn screening program (including postings on their websites). (See "Newborn screening".)

CLINICAL EVALUATION — The history should focus on previous episodes of metabolic decompensation, identification of potential triggering events, and family history of metabolic disease or members with similar presentations.

The clinician should be mindful that, while many "classic" presentations of IEM occur in infancy, almost all metabolic disorders can have later-onset presentations, including late adulthood.

History — The perinatal history for many common IEM, including urea cycle disorders, and most aminoacidopathies and organic acidemias is usually normal since impaired metabolism in the fetus is generally well compensated for by the mother.

However, in certain disorders, there may be problems with the pregnancy and abnormalities at birth. These disorders include, but are not limited to, nonketotic hyperglycinemia, peroxisomal disorders, some lysosomal storage disorders, and disorders of cholesterol biosynthesis. As examples:

Low maternal serum estriol can be found on routine maternal serum screening in pregnancies affected with Smith-Lemli-Opitz syndrome (caused by a defect in a cholesterol biosynthetic enzyme, C7-reductase), isolated steroid sulfatase deficiency (recessive X-linked ichthyosis), and multiple sulfatase deficiency (an ichthyosis with neurologic involvement). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Smith-Lemli-Opitz syndrome' and "Recessive X-linked ichthyosis" and "Overview and classification of the inherited ichthyoses", section on 'Multiple sulfatase deficiency'.)

Decreased fetal movement may be seen, particularly in Smith-Lemli-Opitz syndrome, glycogen storage disease (GSD) type IV (glycogen branching enzyme deficiency), certain lysosomal storage diseases, and peroxisomal disorders, such as Zellweger syndrome (cerebrohepatorenal syndrome). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Smith-Lemli-Opitz syndrome' and "Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease)" and "Peroxisomal disorders", section on 'Zellweger syndrome'.)

The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), acute fatty liver of pregnancy (AFLP), and hyperemesis are associated with long-chain 3-hydroxyacly-CoA dehydrogenase deficiency (albeit rarely) [5-7]. (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Acute fatty liver of pregnancy".)

Steroid sulfatase deficiency can cause prolonged labor as a result of decreased placental estrogen production [8]. (See "Recessive X-linked ichthyosis".)

Numerous IEM are associated with nonimmune hydrops (table 1). (See "Nonimmune hydrops fetalis" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Hydrops fetalis'.)

The past medical history [9-12] and review of systems [11,13-16] should include questions regarding (see "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Clinical presentations' and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Laboratory findings'):

Hospitalization for lethargy and/or dehydration with rapid response to infusion of intravenous (IV) fluid or glucose

Recurrent hypoglycemia

Metabolic decompensation out of proportion to duration or severity of acute illness

A personal or family history of thrombotic events (suggestive of homocystinuria)

Recurrent vomiting (in some cases, the child may have been diagnosed with formula intolerance or pyloric stenosis during infancy, so it is important to ask about these entities specifically)

Diarrhea, which may be a feature of carbohydrate intolerance or mitochondrial disorders

Episodic abdominal pain, which may occur in Fabry disease and the hepatic porphyrias [13,14,16] (see "Fabry disease: Clinical features and diagnosis" and "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis")

Photophobia, an indication of corneal involvement that may occur in cystinosis and tyrosinemia type II [15] (see "Cystinosis" and "Disorders of tyrosine metabolism")

Muscle cramping after exercise, suggesting fatty acid oxidation defects, muscle glycogenoses and other GSDs, or myoadenylate deaminase deficiency [16]

Developmental delay, with or without loss of milestones

Lethargy in the morning (after an overnight fast) or with delayed feeding

Poor feeding

Poor growth/failure to thrive

Protein or carbohydrate aversion

Several IEM are triggered by specific circumstances. It is important to ask about the following triggers in the evaluation of a child with suspected IEM [11,17]:

Ingestion of certain sugars may trigger disorders of carbohydrate intolerance (ie, galactosemia, hereditary fructose intolerance). (See "Galactosemia: Clinical features and diagnosis" and "Causes of hypoglycemia in infants and children", section on 'Disorders of gluconeogenesis'.)

Ingestion of protein may trigger urea cycle defects, organic acidemias, amino acid disorders, and hyperinsulinism with hyperammonemia. (See "Urea cycle disorders: Clinical features and diagnosis" and "Organic acidemias: An overview and specific defects" and "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)

Ingestion of carbohydrate may trigger pyruvate dehydrogenase deficiency, mitochondrial respiratory chain disorders, or hyperinsulinism.

The introduction of complementary foods (eg, infant cereals, fruit juice, and pureed fruits, vegetables, or meats) to the infant diet may trigger disorders of carbohydrate metabolism, urea cycle defects, and organic acidemias.

Infection, fever, fasting, or catabolism may trigger amino acid disorders, organic acidemias, fatty acid oxidation disorders, urea cycle defects, and disorders of gluconeogenesis and glycogenolysis.

Anesthesia or surgery may trigger thromboembolic events in homocystinuria in addition to the disorders triggered by fasting described above.

Certain drugs may trigger porphyria (table 2) and glucose-6-phosphate dehydrogenase deficiency (table 3).

The family history should include a three-generation pedigree and questions regarding [5,12,16,18]:

Consanguinity (most of the disorders have autosomal-recessive inheritance, although some, such as ornithine transcarbamylase deficiency, Hunter syndrome, X-linked adrenoleukodystrophy, and creatine transporter deficiency, are X linked (figure 1) and some, such as MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], MERFF [myoclonic epilepsy with ragged red fibers], and NARP [neuropathy, ataxia, and retinitis pigmentosa], have a mitochondrial [maternal] inheritance pattern (figure 2)).

Similarly affected individuals (the absence of such a history does not exclude IEM, since most are autosomal recessive and only affected siblings would be likely).

Early childhood deaths due to neurologic, cardiac, and/or hepatic dysfunction. Sepsis or unexplained deaths in siblings or maternal male relatives (the absence of such a history does not exclude IEM, since most are autosomal recessive and the recurrence risk is 25 percent).

Examination — The physical examination of infants and children with IEM may be normal [12], demonstrate nonspecific findings, or provide clues to specific disorders. The disorders associated with selected examination findings are listed in the table (table 4). (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations'.)

LABORATORY EVALUATION — We suggest a stepwise approach to evaluation, beginning with basic tests that are routinely available [9-12,15,17], before completing specialized metabolic investigations (table 5). The confirmatory diagnosis of most IEM requires specialized testing that may include detection of abnormal metabolites in the plasma, urine, and/or cerebrospinal fluid (CSF); assay of enzyme activity in skin, red blood cells, white blood cells, skeletal muscle, or liver; and/or chromosome or DNA analysis [11]. Decisions regarding specialized testing are best undertaken in consultation with a specialist in genetics or metabolic disorders and laboratory personnel to make sure that specimens are obtained, processed, and analyzed appropriately [11].

The ordering clinician should know the method used to perform the analyses so that the results can be correctly interpreted. As an example, quantitative amino acid analysis is more reliable than is qualitative analysis using paper chromatography to identify specific disorders, as discussed below. Results of all specialized metabolic testing should be reviewed by a specialist in IEM (usually the medical director of the laboratory) to assist with interpretation.

Laboratory findings in IEM are discussed in detail separately. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Laboratory findings'.)

Initial evaluation — The initial evaluation of IEM is discussed in detail separately (table 5 and table 6). (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Initial evaluation'.)

Specialized tests — The most common specialized tests for IEM include quantitative plasma amino acids, qualitative urine organic acids, serum lactate, and acylcarnitine profile. These tests should only be performed as indicated by the clinical presentation and initial laboratory evaluation, although the samples should be obtained at the time of acute presentation, if possible.

Plasma amino acids — Quantitative amino acid analysis in plasma or serum is used to confirm the diagnosis of urea cycle disorders (figure 3) and other disorders of amino acid metabolism (table 7). Quantitative plasma amino acid analysis is typically performed by high pressure liquid chromatography (HPLC), although tandem mass spectroscopy (MS/MS) can also be used to measure amino acids. Amino acid analysis must be performed quantitatively rather than qualitatively. When a qualitative amino acid screen is performed by two-dimensional paper chromatography, elevations are reported only in groups of amino acids, and specific disorders cannot be identified reliably.

Most amino acids (except argininosuccinic acid and alloisoleucine) are present in the plasma within a normal range in healthy individuals. Mild elevations of 5 to 10 percent above normal usually are not significant. Fasting or a recent meal can affect plasma levels of some amino acids. The significance of elevated or reduced levels of specific amino acids is indicated in the table (table 7).

Urine organic acids — Analysis of organic acids in urine is performed by gas chromatography/mass spectrometry (GC/MS). A qualitative assay of these compounds is adequate because pathogenic organic acids (eg, methylmalonic or propionic acid) are not present in significant amounts in the urine of normal individuals (table 8).

Lactate and pyruvate — Lactate and pyruvate should be measured in arterial blood (tourniquet pressure and/or hemolysis may increase the lactate level erroneously [18,19]) and transported on ice [11]. For accurate measurement of pyruvate, the sample must be collected in perchlorate (or a similar media) to inactivate enzymes that degrade pyruvate.

Lactic acidosis caused by abnormal oxidative metabolism is a frequent finding in mitochondrial disorders (eg, disorders of oxidative phosphorylation), glycogen storage diseases (GSDs), disorders of gluconeogenesis, and disorders of pyruvate metabolism. The ratio of lactate to pyruvate (normal value 10:1 to 20:1) may be helpful in differentiating among these conditions. The lactate-to-pyruvate ratio typically is high in mitochondrial disorders and in pyruvate carboxylase deficiency and normal or low in GSDs and pyruvate dehydrogenase deficiency. However, exceptions occur, and the lactate-to-pyruvate ratio sometimes is normal in mitochondrial disorders. Elevated lactic acid also may be present in disorders of amino acid metabolism, organic acidemias, and fatty acid oxidation disorders (table 6).

The following additional tests should be obtained in patients with abnormal arterial lactate and pyruvate values:

Triglycerides and uric acid to detect elevations seen in some GSD (see "Overview of inherited disorders of glucose and glycogen metabolism")

Brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to detect basal ganglia abnormalities associated with mitochondrial disorders and to measure the level of intracellular lactate and other metabolites

Muscle biopsy for routine staining, electron microscopy, and special stains for mitochondrial enzymes, with tissue frozen for pyruvate enzyme studies and electron transport chain studies to diagnose deficiencies of the mitochondrial respiratory chain

Echocardiogram to identify the cardiac dysfunction seen in some mitochondrial disorders

Muscle and/or skin biopsy to test enzymes involved in pyruvate metabolism (note that, while these studies can be done on skin, they are more reliable when performed on muscle tissue due to higher levels of enzyme expression in muscle)

Acylcarnitine profile — Analysis of acylcarnitine conjugates is performed by MS/MS and can be measured in a plasma sample or a filter-paper bloodspot. This test is used for the diagnosis of fatty acid oxidation disorders. It also may detect organic acidemias in which the acylcarnitine profile is abnormal (eg, propionic acidemia, isovaleric acidemia). (See "Organic acidemias: An overview and specific defects" and "Metabolic myopathies caused by disorders of lipid and purine metabolism".)

Molecular genetic testing — The cost of genetic testing has dropped dramatically with the development of next-generation sequencing (NGS) methods, including whole-exome sequencing (WES), and further refinement for clinical diagnostic use. Access to this testing has significantly improved the diagnostic rate for all genetic conditions, including IEM [20]. Many of the more recently discovered IEM, particularly the congenital disorders of protein glycosylation [21] and mitochondrial/energy disorders [22], do not have biochemical markers or enzymatic deficiencies available as clinical tests. As such, the only way to diagnose certain disorders such as these is through genetic testing. In addition, molecular testing will probably play a significant role in assessing eligibility for novel therapies as they are developed [23]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications" and "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Molecular genetic studies'.)

Biochemical testing is still generally considered the first-line diagnostic test for common IEM with acute presentations due to a more rapid turnaround time for test results. Another limiting factor for genetic testing is that genetic variants are not always identifiable in individuals with an IEM diagnosis or variants of uncertain pathogenicity are identified that require some functional (biochemical or enzymatic) confirmation [24]. However, comprehensive genetic tests such as WES may someday supplant biochemical or enzyme testing for many IEM as the turnaround time continues to decrease due to improvements in testing, bioinformatics, and analytic methods.

Other — Other specialized tests are obtained in the evaluation of IEM based upon the suspected diagnosis, with the aim of confirming the diagnosis and guiding management. These may include [9,11,18,19]:

Eye examination by an ophthalmologist to detect characteristic features of specific IEM (table 9).

Echocardiogram to evaluate the presence of cardiomyopathy if a disorder of long-chain fatty acid metabolism, mitochondrial disorder, or other energy disorders is suspected.

Skin, skeletal muscle, or liver biopsy for enzyme assay, histology, or electron microscopy if these tissues are affected.

Lumbar puncture for measurement of glucose, protein, lactate, pyruvate, glycine, serine, alanine, organic acids, neurotransmitters, pterins, or other disease-specific metabolites.

Serum ketones (beta-hydroxybutyrate, acetoacetate) and/or free fatty acids in children with hypoglycemia.

Quantitative plasma carnitine levels (free, total, and acylcarnitine) if fatty acid oxidation disorders are suspected.

Urine sulfocysteine for sulfite oxidase and molybdenum cofactor deficiencies for those with early-onset seizures.

Urine purine/pyrimidine panel analysis to assess for disorders of purine and pyrimidine metabolism for those with early-onset seizures and developmental disabilities.

Urine polyol analysis to assess disorders of polyol metabolism that include both leukodystrophy and liver phenotypes.

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. (See "Congenital disorders of creatine synthesis and transport", section on 'Diagnosis'.)

Urinary glycosaminoglycans and oligosaccharides to evaluate the possibility of lysosomal storage disorders.

Carbohydrate-deficient transferrin (abnormally glycosylated transferrin isoforms) for congenital disorders of glycosylation.

Very-long-chain fatty acid analysis for peroxisomal disorders. (See "Peroxisomal disorders".)

Uric acid (elevated in patients with GSD and Lesch-Nyhan disease and decreased in patients with defects of purine metabolism or molybdenum cofactor deficiency).

Metabolomic profiling is an emerging clinical diagnostic test that can screen for hundreds of small molecules in a single test. This may be done in place of other small molecule testing (eg, plasma amino acid, urine organic acid, acylcarnitine analyses, etc) in individuals with chronic symptoms and an undifferentiated phenotype suspected to be due to perturbation in a biochemical pathway (eg, a child with developmental delay, seizures, autism, etc) or in a patient with an equivocal molecular test result in a gene known to cause a small molecule IEM [25,26]. Metabolomic profiling may be most effective in pinpointing the diagnosis when it is combined with exome analysis.

EVALUATION OF SPECIFIC PRESENTATIONS — The diagnostic approach to the child with suspected IEM depends to some extent upon the clinical presentation. In some cases, the clinical presentation suggests a particular disorder, and the diagnostic evaluation can be streamlined. In other cases, the clinical presentation may be associated with certain groups of metabolic disorders, and narrowing the differential diagnosis requires additional testing. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Classification" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Evaluation of specific critical presentations'.)

The diagnostic approaches for the most common chronic clinical presentations of IEM are presented below. These presentations are associated with certain groups of metabolic disorders, and narrowing the differential diagnosis requires additional testing. Diagnostic confirmation for specific disorders is discussed in the individual topic reviews related to the disorder (eg, (see "Overview of maple syrup urine disease")).

Metabolic emergencies — The evaluation of critical presentations is discussed separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Evaluation of specific critical presentations'.)

Developmental delay — The initial evaluation for IEM in children with developmental delay or regression should be individually tailored based upon the clinical history and physical examination [18]. The possibility of an IEM in a child with developmental delay or intellectual disability of unknown etiology should be reviewed periodically since signs and symptoms of some IEM may become more apparent over time (eg, hepatomegaly in lysosomal storage disorders) [27]. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Developmental delay' and "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis" and "Intellectual disability in children: Evaluation for a cause".)

Studies to consider include:

Quantitative plasma amino acid analysis. (See 'Plasma amino acids' above.)

Qualitative urine organic acid analysis. (See 'Urine organic acids' above.)

Serum lactate (preferably arterial). (See 'Lactate and pyruvate' above.)

Metabolomic profiling of small molecules may replace many laboratory tests. (See 'Other' above.)

Serum uric acid and creatine kinase to screen for glycogen storage disease (GSD). (See "Overview of inherited disorders of glucose and glycogen metabolism".)

Quantitative urine mucopolysaccharides and oligosaccharides to detect lysosomal storage disorders [18].

Plasma and urine creatine and guanidinoacetate levels to detect disorders of creatine metabolism, such as guanidinoacetate methyltransferase deficiency. Plasma analysis alone cannot reliably detect X-linked creatine transporter deficiency. (See "Congenital disorders of creatine synthesis and transport", section on 'Diagnosis'.)

Serum phytanic acid and very-long-chain fatty acids to diagnose peroxisomal disorders.

Dilated ophthalmologic exam to detect optic atrophy or retinal findings seen in peroxisomal, lysosomal storage, and mitochondrial disorders (table 9).

Brain magnetic resonance imaging (MRI) to assess for leukodystrophy or basal ganglia changes found in lysosomal storage or mitochondrial disorders, respectively.

Hepatosplenomegaly — Associated findings that suggest a particular IEM and help direct the diagnostic evaluation are discussed in detail separately. The etiology of acute liver failure is also reviewed elsewhere. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Organomegaly' and "Acute liver failure in children: Etiology and evaluation".)

We suggest the following studies if the hepatomegaly and/or splenomegaly are isolated or if no associated clinical or laboratory features are present:

Plasma lactate, triglycerides, uric acid, and creatine kinase to screen for GSD (see "Overview of inherited disorders of glucose and glycogen metabolism")

Quantitative urine mucopolysaccharides and oligosaccharides to screen for lysosomal storage disorders

Red blood cell galactose-1-phosphate (if patient has not received a blood transfusion) and/or urine galactitol level to assess for galactosemia (see "Galactosemia: Clinical features and diagnosis")

Serum very-long-chain fatty acids to detect peroxisomal disorders (see "Peroxisomal disorders")

Quantitative plasma amino acid analysis and urine organic acid analysis for tyrosinemia type 1 (see "Disorders of tyrosine metabolism")

Liver biopsy to evaluate the type and location of abnormal storage material with a frozen sample of unfixed liver saved for further diagnostic studies

If the diagnosis is not established after the above evaluation, further testing may include enzyme assays on white blood cells (eg, Gaucher, Niemann-Pick, or sialidosis), urine bile acid analysis (disorders of bile acid metabolism), transferrin isoelectric focusing (congenital disorders of glycosylation), and acid lipase.

Cardiomyopathy — Cardiomyopathy due to IEM can be hypertropic or dilated. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Cardiomyopathy' and "Causes of dilated cardiomyopathy" and "Hypertrophic cardiomyopathy in children: Clinical manifestations and diagnosis".)

Hypertrophic cardiomyopathy may occur in lysosomal acid maltase deficiency (GSD type II, Pompe disease), mucopolysaccharidoses, and other IEM. The diagnosis of these conditions is established by alpha glucosidase (acid maltase) enzyme assay or quantitative urine mucopolysaccharide measurement, respectively. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)" and "Mucopolysaccharidoses: Clinical features and diagnosis".)

Dilated cardiomyopathy can occur in fatty acid oxidation disorders, organic acidemias, and mitochondrial disorders (eg, disorders of oxidative phosphorylation). The initial evaluation includes:

Plasma acylcarnitine profile. (See 'Acylcarnitine profile' above.)

Quantitative plasma carnitine levels. (See 'Other' above.)

Qualitative urine organic acid analysis. (See 'Urine organic acids' above.)

Serum lactate and pyruvate levels. (See 'Lactate and pyruvate' above.)

Skeletal muscle biopsy for routine examination, electron microscopy, and mitochondrial enzyme stains. A frozen tissue sample should be kept for electron transport chain studies to be used in the diagnosis of mitochondrial disorders.

Skeletal myopathy — Myopathy (muscle weakness, tenderness, cramping, atrophy, or exercise intolerance) can occur in lysosomal and nonlysosomal GSD, disorders of fatty acid oxidation, and mitochondrial disorders. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Myopathy' and "Approach to the metabolic myopathies" and "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Approach to the patient with muscle weakness".)

Additional evaluation of patients with myopathy includes:

Creatine kinase, aldolase, triglycerides, and uric acid to detect GSD. (See "Overview of inherited disorders of glucose and glycogen metabolism" and "Muscle enzymes in the evaluation of neuromuscular diseases", section on 'Metabolic myopathies'.)

Plasma acylcarnitine profile. (See 'Acylcarnitine profile' above.)

Quantitative plasma carnitine levels. (See 'Other' above.)

Serum lactate (preferably arterial). (See 'Lactate and pyruvate' above.)

Skeletal muscle biopsy for routine examination, electron microscopy, and mitochondrial enzyme stains. A frozen tissue sample should be kept for electron transport chain studies to be used in the diagnosis of mitochondrial disorders.

The approach to the metabolic myopathies is discussed in detail separately. (See "Approach to the metabolic myopathies".)

Postmortem — Postmortem evaluation of children with suspected, but undiagnosed, IEM at the time of death is essential to determine the cause of death and to permit accurate counseling regarding the cause of death, the recurrence risk for the family, and prenatal diagnosis of future pregnancies [9,11,19]. In one review of all metabolic autopsies performed at a tertiary care children's hospital over a five-year period, metabolic autopsy successfully identified an undiagnosed metabolic disease in 18 percent of 23 cases [28]. Such identification was less likely in patients who had undergone extensive premorbid clinical evaluation without diagnosis.

Autopsy is typically performed in cases of unexpected death. However, routine autopsy may not provide information related to IEM [11,19]. If adequate information is to be obtained, it is essential to collect relevant blood, urine, and tissue specimens before or shortly after death (ie, within one to two hours, if possible) [5,9,19]. Plasma amino acids, lactate, pyruvate, and total and free carnitine are not accurate when postmortem specimens are analyzed [11].

If the parents/caregivers grant permission, appropriate samples should be obtained in consultation with a specialist in genetic or metabolic disease and may include [5,9,11,19]:

Several blood spots (four to six) on a newborn screening card or filter paper for acylcarnitine analysis or other studies.

Plasma (3 to 5 mL) in lithium heparin tube, separated and frozen at -70ºC.

White blood (5 to 10 mL) in ethylenediaminetetraacetic acid (EDTA) tube for DNA analysis. The sample should be refrigerated, not frozen. Other whole blood samples may be used, if necessary.

Urine (5 to 10 mL, or more, if possible, in 1 to 2 mL aliquots) frozen in plain sterile containers.

Cerebrospinal fluid (CSF; 3 to 5 mL, in 1 mL aliquots) frozen and stored at -70ºC.

Vitreous humor for organic acid analysis if urine is not available (collected by intraocular puncture at autopsy, frozen at -20 or -70ºC) [29].

Skin biopsy for fibroblast culture. Specimens, 3 mm in diameter, should be obtained by punch or incisional biopsy from the flexor surface of the forearm and anterior thigh using sterile technique. The specimens should be refrigerated (not frozen) in tissue culture medium, if available, or viral culture medium or normal saline if tissue culture medium is not available.

Two fresh (unfixed) samples of liver (1 cm3). One sample frozen in liquid nitrogen or dry ice for enzyme analysis, histology, and DNA analysis. The other sample stored in appropriate medium (eg, glutaraldehyde) for electron microscopy. If autopsy is not performed, it may be possible to obtain permission for postmortem needle biopsy of the liver for histologic studies (if indicated).

If specimens are otherwise unavailable, it may be possible to retrieve archived newborn screening blood spots on filter paper for analysis by tandem mass spectrometry (MS/MS) or other methodology.

Additional postmortem evaluation may include photographs of dysmorphic features, and/or radiographic studies to evaluate neurologic, cardiac, or skeletal abnormalities.

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 AND RECOMMENDATIONS

Optimal outcome for children with inborn errors of metabolism (IEM) (table 10) depends upon early recognition. Delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, or death. (See 'Introduction' above.)

Although newborn screening programs increase the detection of IEM, they cannot be relied upon exclusively. Improved detection depends upon a high index of suspicion. (See 'Newborn screening' above.)

The history in a patient with IEM should focus on previous episodes of metabolic decompensation, identification of potential triggering events, and family history of metabolic disease or members with similar presentations. (See 'History' above.)

The examination is often normal but may provide clues to specific disorders (table 4). (See 'Examination' above.)

Laboratory evaluation for IEM should be undertaken in all patients with suggestive history, examination, and/or abnormalities of routine laboratory tests. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Clinical presentations' and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Laboratory findings' and 'Clinical evaluation' above and 'Laboratory evaluation' above.)

Testing should be performed at the time of presentation or when symptoms are most pronounced. Patients with life-threatening illness should undergo concurrent evaluation for other conditions in the differential diagnosis. (See 'Laboratory evaluation' above and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Differential diagnosis'.)

We suggest a stepwise approach to the laboratory evaluation, beginning with basic tests that are routinely available, before obtaining specialized metabolic investigations (table 5 and table 6). Decisions regarding specialized testing are best undertaken in consultation with a specialist in genetics or metabolic disorders and laboratory personnel to make sure that specimens are obtained, processed, and analyzed appropriately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Initial evaluation' and 'Specialized tests' above.)

The diagnostic approach to the child with suspected IEM depends upon the clinical presentation. When the clinical presentation suggests a particular disorder, the evaluation can be streamlined. When the clinical presentation is associated with certain groups of disorders, additional testing is needed to narrow the differential diagnosis. Additional evaluation for developmental delay or regression, hepatomegaly, cardiomyopathy, and skeletal myopathy are discussed above. Critical presentations are discussed separately. (See 'Evaluation of specific presentations' above and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Evaluation of specific critical presentations'.)

Postmortem evaluation of children with suspected, but undiagnosed, IEM at the time of death is essential to determine the cause of death and to permit subsequent genetic counseling and/or prenatal diagnosis. (See 'Postmortem' above.)

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