Inborn errors of metabolism (IEMs) are a large group of rare genetic diseases that generally result from 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. Often the central nervous system (CNS) is affected, leading to neurological disease.[1, 2, 3, 4, 5]
The incidence of IEMs, collectively, is estimated to be as high as 1 in 800 live births,[1] but it varies greatly and depends on the population. 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 prevelant.[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 600 people of 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 adulthood. Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases. An understanding of the major clinical manifestations of inborn errors of metabolism 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. 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.
For patients with suspected or known IEMs, successful emergency treatment depends on prompt institution of therapy aimed at metabolic stabilization. Asymptomatic neonates with newborn screening results positive for an inborn error of metabolism may require emergent evaluation including confirmatory testing and, as appropriate, initiation of disease-specific management.
Provide education regarding disease and patient care (manifestations, course of disease, treatment, psychosocial support) and 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 of Rare Diseases (NORD) can direct families to resources for more than 1000 IEMs.
Single gene defects result in abnormalities in the synthesis or catabolism of proteins, carbohydrates, fats, or complex molecules. 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 inborn errors of metabolism, or IEMs, are as follows:
For more information, see the articles in the Genetic and Metabolic Disease section of the Medscape Reference Pediatrics volume.
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, whereas autosomal dominant and X-linked disorders are also present. IEMs were initially thought to be caused by single-gene mutations, but their presentation is 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 lacking and impacts the ability to predict disease course. For example, 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. Thus, environmental, epigenetic, and microbiome factors as well as additional genes are potential modifying etiologic factors in individual IEMs.[6]
United States
Individual IEMs are very rare diseases, with incidence ranging 1:10,000 (PKU) to 1:250,000 or less (GAMT deficiency).[7] 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 to 13,000 births across different studies and projected to increase as data emerging from newborn screening programs is reported.[8] The incidence of IEMs, collectively, is estimated to be as high as 1 in 800 live births.[1]
International
The overall incidence and the frequency for individual diseases varies based on racial and ethnic composition of the population and on extent of screening programs.[9] Overall rates are in a range similar to that of the United States.
The incidence within different racial and ethnic groups varies with predominance of certain inborn errors of metabolism (IEMs) within particular groups (eg, cystic fibrosis, 1 per 1600 people of European descent; sickle cell anemia, 1 per 600 people of African descent; 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 prevelance 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 .[8]
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 dominant and autosomal recessive transmission. It is also 1:1 for X-linked dominant if transmission is from mother to child.
Age for 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 tend 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 go undiagnosed until adulthood.
Prognosis varies based on the individual inborn error of metabolism and may differ for different forms of a particular IEM. A high index of suspicion is critical for early diagnosis and treatment of IEM. Rapid treatment may be lifesaving and often results in full recovery.
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. Prompt treatment of acute decompensation can be lifesaving and is critical to optimizing outcome.
IEMs can affect any organ system and usually affect multiple organ systems resulting in morbidity due to acute and/or chronic organ dysfunction. 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. Diet or stress (ie, from intercurrent illness, trauma, surgery, or immunization) may precipitate episodic decompensation.
The history varies with age at presentation and is a function of the age at which various inborn errors of metabolism (IEMs) manifest clinically.
The patient’s history may include the following:
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. In term infants without risk for sepsis who develop the symptoms of sepsis, metabolic disease may be nearly as common as sepsis. A negative newborn screen result does not exclude diagnosis of metabolic disease.
Nearly all states and many countries test newborns for a core set of 29 diseases, and many test for more than 50 diseases, most of which are IEMs using tandem mass spectrometry. Tests screened for by each state are provided by the National Newborn Screening and Genetics Resource Center (see National Newborn Screening Status Report).[2] It usually takes a few days and sometimes weeks until results are available. 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 inborn error of metabolism (IEM).[10] Cut-off values have been deliberately set to yield a low rate of false-negative results.
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.
The patients may have a history of recurrent episodes of vomiting, ataxia, seizures, lethargy, coma, or fulminant (Reye syndrome–like) hepatoencephalopathy.
Infants may appear and act normal between episodes or have a history of poor feeding, failure to thrive, fussiness, and decreased activity 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.
Undiagnosed metabolic disease should be considered in older children (>5 yr), adolescents, or even adults with subtle neurologic or psychiatric abnormalities.
Many individuals previously diagnosed as having birth injury or atypical forms of psychiatric disorders or medical diseases, such as multiple sclerosis, cerebral palsy,[7] migraines, or stroke, actually have an undiagnosed inborn error of metabolism.
The physical examination findings are nonspecific in most patients with inborn errors of metabolism (IEM), and examination findings may be normal. When present, physical findings provide important clues to the presence of an inborn error of metabolism, the category, and, occasionally, the specific metabolic disease.[11]
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; dysmorphic features; abnormalities of hair, skin, skeleton, or all three; abnormal odor; organomegaly; and abnormal muscle tone.
Finding may be indistinguishable from those of sepsis, respiratory illness, cardiac disease, GI obstruction, renal disease, and CNS problems. Presence of these conditions does not rule out the possibility of an inborn error of metabolism.
Symptoms for inborn errors of metabolism 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 inborn errors of metabolism (including galactosemia during the newborn period) and certain organic acidopathies may be associated with 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.
Inborn errors of metabolism most likely to cause acute decompensation in the neonate include certain forms of the tyrosinemia, organic acidemias, urea cycle defects, fatty acid oxidation defects, and galactosemia.
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.
Common findings include mild to profound mental retardation, 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 migrainelike headaches.
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 Newborn Screening ACT Sheets and Confirmatory Algorithms.[4]
ECG, radiography, CT, MRI, ultrasonography, and/or 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 affected. Plasma, serum, urine, and possibly CSF, skin, and selected organ specimens should be collected and frozen. If permission for autopsy is not granted, as appropriate, discuss with the family 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 inborn errors of metabolism or the neonate with positive newborn screening results.
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 inborn error of metabolism (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 1 of the following (see Table 1 below):
Obtain the following tests:
The table below outlines clinical and lab findings associated with various inborn errors of metabolism.
Table 1. Clinical and Laboratory Findings of Inborn Errors of Metabolism
View Table | See Table |
If initial test results are outside the reference range, consider consultation with an IEM specialist to determine which tests are appropriate, how specimens are to be collected and stored, and where they should be sent.
For patients with known IEM, studies should be disease and patient specific. Results should be compared to previous as available.
Goals of treatment for patients with an inborn error of metabolism (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 inborn error of metabolism as soon as the diagnosis is considered. Treatment of patients with a known inborn error of metabolism 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. Protocols for acute illness are available on the New England Consortium of Metabolic Programs.[2]
Strict adherence to dietary and pharmacologic regimen is recommended for patients diagnosed with an inborn error of metabolism. Early treatment 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 inborn error of metabolism diagnosed will need to be continued, usually for life.[13, 14] Long-term, routine follow-up screening should be provided for potential disease complications.
Initial ED treatment does not require knowledge of the specific metabolic disease or even disease category.[15] 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.
Initiate treatment as quickly as possible. Delay in recognition and treatment may result in long-term neurologic impairment or death. See the following steps:[15]
Further inpatient care may include the following:
Nutritional interventions for IEM 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, and rice).[5]
Emergency medications for inborn errors of metabolism (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.[16]
Helpful Web sites for finding information on orphan drug designation include the following:
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 carbamyl 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.
Treatment of hyperammonemia; enhances elimination of nitrogen. This drug is FDA approved for treatment of hyperammonemia due to urea cycle defects and is available only from a specialty wholesaler, Ucyclyd Pharma (888-829-2593). For more information, see Ammonul prescribing information.
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.
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 GABA (within the CNS) and heme. Involved in synthesis of GABA within the CNS. 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.
Enzyme cofactors are used to enhance the activity of cofactor-dependent enzymes.
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.
This agent is used for the treatment of primary and secondary carnitine deficiency.
Clinical Findings* AA OA UCD CD GSD FAD LSD PD MD Episodic decompensation X + ++ + X + - - X Poor feeding, vomiting, failure to thrive X + ++ + X X + + + Dysmorphic features and/or skeletal or organ malformations X X - - X X + X X Abnormal hair and/or dermatitis - X X - - - - - - Cardiomegaly and/or arrhythmias - X - - X X + - X Hepatosplenomegaly and/or splenomegaly X + + + + + + X X Developmental delay +/- neuroregression + + + X X X ++ + + Lethargy or coma X ++ ++ + X ++ - - X Seizures X X + X X X + + X Hypotonia or hypertonia + + + + X + X + X Ataxia - X + X - X X - - Abnormal odor X + X - - - - - - Laboratory Findings* Primary metabolic acidosis X ++ + + X + - - X Primary respiratory alkalosis - - + - - - - - - Hyperammonemia X + ++ X - + - - X Hypoglycemia X X - + X + - - X Liver dysfunction X X X + X + X X X Reducing substances X - - + - - - - - Ketones A H A A L/A L A A H/A *Within disease categories, not all diseases have all findings. For disorders with episodic decompensation, clinical and laboratory findings may be present only during acute crisis. For progressive disorders, findings may not be present early in the course of disease.
AA = Amino acidopathy
OA = Organic acidopathy
UCD = Urea cycle defect
CD = Carbohydrate disorder
GSD = Glycogen storage disorder
FAD = Fatty acid oxidation defect
LSD = Lysosomal storage disease
PD = Peroxisomal disorder
MD = Mitochondrial disorder
++ = Always present
+ = Usually present
X = Sometimes present
- = Absent
H = Inappropriately high
L = Inappropriately low
A = Appropriate