Inborn Errors of Metabolism (Metabolic Disorders) : Educational Gaps

Inborn Errors of Metabolism
(Metabolic Disorders)
Gregory M. Rice, MD,* Robert D. Steiner, MD*†
*Department of Pediatrics and the Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, WI.
†
Marshfield Clinic Research Foundation, Marshfield, WI.
Educational Gaps
1. Clinicians should be able to recognize the proper metabolic
laboratory testing to evaluate for a suspected inborn error of
metabolism.
2. Clinicians should recognize the common presentations and treatments
of inborn errors of metabolism.
OBJECTIVES After completing this article, readers should be

able to:
1. Use basic and specific laboratory tests to aid in the diagnosis of

metabolic disease.
2. Understand the capabilities and limitations of modern newborn
screening approaches.
3. Recognize that urea cycle disorders can result in hyperammonemia,
which is a medical emergency that requires prompt diagnosis and
treatment.
4. Develop a basic framework for understanding inborn errors of
metabolism to aid in recognition and diagnosis of these conditions.
5. Appreciate that although most classic metabolic disorders present in
infancy, most conditions can also present with milder variants later in
life.
INTRODUCTION
Metabolic disorders can appear to be a frustratingly complex group of disorders

AUTHOR DISCLOSURE Dr Rice has disclosed to master. Many individual disorders have clinical presentations that initially
that he is a site principal investigator for
seem very similar to one another. In addition, classification systems can be
BioMarin Pharmaceutical and that he is a
collaborator on and receives support from difficult to apply because of the multitude and variety of metabolic pathways
FDA grant R01 FD003711-01A1. Dr Steiner has involved. This review serves as an update of previously published information
disclosed no financial relationships relevant to
(1)(2)(3) and attempts to impose a basic classification framework and diagnostic
this article. This commentary does contain a
discussion of an unapproved/investigative approach that can be applied by the general pediatrician or primary pediatric
use of a commercial product/device. clinician in the initial triage and identification of metabolic diseases.
Vol. 37 No. 1 JANUARY 2016 3

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The classification groups disorders into those caused by Lysosomal storage disorders are due to an inability to digest
defects in the metabolism of energy sources (lipids, proteins, or recycle large complex macromolecules and may present
or carbohydrate) and those caused by dysfunction in pathways with variable features, depending on the enzymatic block, that
within cellular organelles (mitochondria, peroxisome, lyso- may include “coarse” facial features, hepatosplenomegaly, and
some). Metabolic disorders caused by defects in protein developmental regression.
metabolism include the amino acidopathies, organic acid- Energy source problems include defects in protein, lipid,
emias, and urea cycle disorders. Disorders of lipid metab- and carbohydrate metabolism (Table). Many of these disor-
olism encompass defects in fatty acid b-oxidation and the ders can be detected in modern newborn screening (NBS)
carnitine shuttle. Carbohydrate disorders include galacto- programs. In fact, with the addition of tandem mass spec-
semia and glycogen storage disorders (GSDs) among others. trometry (which includes acylcarnitine profile and amino acid
TABLE. Summary of Clinical Features and Treatment of Disorders of

Energy Sources
FATTY ACID OXIDATION
DISORDERS ORGANIC ACIDEMIAS AMINOACIDOPATHIES UREA CYCLE DISORDERS
Metabolism Fat Protein Protein Protein

Defect in b-oxidation of fatty Defect in amino acid Defect in amino acid Defect in making urea (blood
acids. breakdown leads to breakdown leads to urea nitrogen) from
accumulation of organic accumulation of certain ammonia that results from
acid byproducts intact amino acids amino acid breakdown
Disorders Medium-chain acyl CoA Propionic Maple syrup urine Ornithine transcarbamylase
dehydrogenase (X-linked)
Long-chain 3-hydroxy acyl Methylmalonic Phenylketonuria Citrullinemia
CoA dehydrogenase
Very long-chain acyl CoA Isovaleric Homocystinuria tyrosinemia Arginosuccinic aciduria
dehydrogenase
Presentation Hypoketotic Hypoglycemia Metabolic Acidosis With No Acidosis or Hyperammonemia
Anion Gap Hyperammonemia Without Acidosis
Lethargy, vomiting Neonatal lethargy, vomiting, Elevations in specific amino Neonatal lethargy, vomiting,
Sudden infant death coma, strokes, death acids coma, death
syndrome, Reye syndrome See text for clinical features
Long-chain disorders have
cardiomyopathy and
rhabdomyolysis
Laboratory Newborn Screen Newborn Screen Newborn Screen Newborn Screen (not for
Tests ornithine
transcarbamylase)
Plasma acylcarnitines Urine organic acids Plasma amino acids Hyperammonemia
Hypoglycemia Plasma acylcarnitines Plasma amino acids
No or inappropriately low Urine orotic acid
ketones
Acute Dextrose (10% with salt) Dextrose (10% with salt) For maple syrup urine disease, Dextrose (10% with salt)
Treatment Early use of fluids to prevent Early use of fluids similar to organic acidemias Early use of fluids
hypoglycemia No protein Avoid hyponatremia Sodium benzoate/
Intravenous lipid emulsion phenylacetate
Dialysis may be needed in sick Arginine
neonate Dialysis
Chronic Low-fat diet Low-protein diet Restrict offending amino acid Low-protein diet
Management Avoid prolonged fasts Supplemental medical food Supplemental food Supplemental food
Nighttime feedings when sick Carnitine Monitor plasma amino acids Phenylbutyrate
Carnitine Liver transplantation Arginine/citrulline
Echocardiography for long- Liver transplantation
chain fatty acid oxidation
disorders
4 Pediatrics in Review
analysis), more than 40 disorders of intermediate metabo- this could indicate that the sample sat before analysis,
lism can be now be detected. Because many of these condi- which could lead to spuriously elevated values.
tions are treatable, their early detection and diagnosis can 4. Urine ketones. Ketosis/ketonuria is a prominent feature
be lifesaving. Of note, no test has perfect sensitivity, and of some metabolic disorders, such as organic acidemias.
although NBS has excellent detection rates for many condi- Fatty acid oxidation disorders (FAOD) and hyperinsu-
tions, individuals can be missed. Further, milder presenta- linism cause hypoketotic hypoglycemia.
tions of classically severe metabolic disorders can present 5. Lactate. Elevated lactate is most commonly a marker
later in life. Therefore, the clinician must continue to include of hypoxia and poor tissue perfusion. However, mito-
these disorders in the differential diagnosis of a sick child, chondrial disorders are often associated with elevated
despite advances in NBS. Many of the conditions related to blood or cerebrospinal fluid lactate in an elevated ratio to
defects in energy sources can be detected by several simple pyruvate (>20).
laboratory tests.
SPECIFIC BIOCHEMICAL LABORATORY EVALUATIONS

BASIC LABORATORY EVALUATIONS
1. Plasma amino acids (PAA). Specific elevations or char-
1. Electrolyte panel, including bicarbonate. This simple acteristic patterns in amino acids are seen in amino
test, which is available in all hospitals and many out- acidopathies such as phenylketonuria (PKU), tyrosinemia,
patient settings, allows for the evaluation of acid-base maple syrup urine disease (MSUD), and several of the
status to determine the anion gap. Metabolic acidosis urea cycle disorders (eg, citrullinemia, argininosuccinic
with an elevated anion gap is seen in the organic acid- aciduria). Also, some organic acidemias are characterized
emias such as propionic acidemia. by elevations in the amino acid glycine.
2. Blood glucose. All children with changes in mental 2. Urine organic acids (UOA): Organic acidemias can be
status and acute illness should have blood glucose diagnosed by characteristic patterns of elevated organic
measured. Hypoketotic hypoglycemia (HKHG) is the acid metabolites in the urine, but this test can also be
primary metabolic derangement in disorders of fatty used to support the diagnosis of other types of disorders,
acid oxidation. such as FAOD and amino acidopathies. The UOA test is
3. Ammonia. Elevated ammonia concentrations can cause most sensitive when performed while the patient is in a
acute encephalopathy. In some cases, elevated plasma catabolic state, such as fasting or illness.
ammonia may be the only clue to the presence of a 3. Plasma acylcarnitine (PAC) profile: This profile can be
metabolic disorder. Hyperammonemia requires emer- helpful in the diagnosis of FAOD, and characteristic
gent intervention because a lack of treatment can result patterns are seen for most organic acidemias. The PAC
in permanent brain injury and death. Metabolically, profiles carbon chains linked (esterified) to carnitine. C2-
hyperammonemia is seen primarily with urea cycle C18 (chains with 2-18 carbon backbones) acylcarnitines
disorders and organic acidemias. In the absence of are quantified in this assay and can indicate specific
suspicion that prompts testing, hyperammonemia can conditions. For example, elevations in medium-chain
be easy to miss because ammonia testing is not part of acylcarnitines (C6-C10) are indicative of medium-chain
routine chemistry panels, often there is no acidosis, and acyl CoA dehydrogenase (MCAD) deficiency, whereas
there may be no clues other than clinical status (eg, elevations in the 3- or 5-carbon acylcarnitines (C3 or C5
lethargy, obtundation, and coma). Ammonia values may acylcarnitines) are seen in some organic acidemias. The
be spuriously elevated due to venous compression from PAC profile has allowed for detection of most FAOD and
tourniquet use or improper specimen handling. It is organic acidemias on a single plasma sample or blood
important to obtain a free-flowing sample when possible. spot, which has revolutionized metabolic disease diag-
Also, the specimen should be placed on ice at the bedside nosis and newborn screening.
and immediately transported to the laboratory. Elevated 4. Carnitine analysis: This test evaluates the concentrations
values should be rapidly confirmed by a repeat specimen. of free and total carnitine and carnitine esters (un-
Hyperammonemia is a medical emergency that requires fractionated acylcarnitines) in the plasma or urine. Mark-
the laboratory to test the sample immediately upon edly low plasma free carnitine values can be seen in primary
receipt. Whenever a result is not available within 1 hour, carnitine deficiency, a treatable disorder of carnitine
the accuracy of the result should be questioned because uptake. Elevated carnitine esters (acylcarnitines) can

occur in any metabolic disorder that results in accu- to their accumulation in the blood and urine. This is a
mulation of acylcarnitines (organic acidemias, FOADs, heterogeneous group of disorders because the various
and ketosis). Plasma carnitine values are usually more amino acids have very different toxic and pathogenic effects
helpful than urine values. on varying tissues. All can be diagnosed with the combina-
5. Newborn screening: Many disorders of intermediate tion of PAA and UOA analysis.
metabolism are detected by tandem mass spectrometry Phenylketonuria. PKU is due to a deficiency in phenyl-
(acylcarnitine profile and amino acid analysis) on new- alanine hydroxylase (PAH), the enzyme responsible for
born dried blood spots, including most FAOD, some hydroxylation of phenylalanine (phe) to tyrosine. Tetrahy-
urea cycle disorders (citrullinemia and argininosuccinic drobiopterin (BH4) is a required cofactor in this reaction.
aciduria), and the amino acidopathies. In addition, Population-based NBS for PKU is performed in all states in
enzymology or specific analyte analysis (eg, galactose the United States via tandem mass spectrometry, which
1-phosphate) allows for detection of galactosemia and shows elevated concentrations of phe and low tyrosine.
biotinidase deficiencies. As with any screening test, false- Subsequent diagnostic testing revels elevated phe on PAA
negative results can occur, and some disorders, such as analysis and elevated phenylketones on UOA. When PKU is
ornithine transcarbamylase (OTC) deficiency, are not untreated, phe and phenylketones silently accumulate, caus-
currently part of the screen. Therefore, clinicians should ing permanent brain injury. Untreated infants develop
still consider the possibility of metabolic disorders, even in microcephaly, global developmental delay, and eczematous
the context of a negative NBS result. rash. Early detection and treatment are very effective in
Some states have begun screening for lysosomal disor- preventing intellectual disability, but adults who stop the
ders, including Pompe disease, and there is ongoing dis- diet are still at risk for mood and cognitive disorders,
cussion about adding other lysosomal conditions in the including diminished executive function. (4) Therefore,
future. The National Newborn Screening & Global Resource lifelong treatment is advocated. Phe is a powerful teratogen;
Center website (http://genes-r-us.uthscsa.edu) provides a fetal exposure to increased concentrations in utero may
complete list of conditions screened in each state, and the result in “maternal PKU syndrome,” which consists of
Screening, Technology and Research in Genetics (STAR-G) dysmorphic facial characteristics, microcephaly, intrauter-
Project (http://www.newbornscreening.info) offers detailed ine growth restriction, and congenital heart disease.
clinician and parental handouts on each condition. Exposed children may have intellectual disability or learn-
ing disabilities. Therefore, women who have PKU should
attempt to have their phe concentrations well-controlled
PROTEIN METABOLISM DISORDERS
before pregnancy and must maintain strict control of such
These disorders include amino acidopathies, organic acid- concentrations throughout the duration of pregnancy. This
emias, and urea cycle disorders. When most amino acids are can be difficult to achieve if the pregnancy is unexpected or
metabolized, the initial step is deamination, which removes the prospective mother has been off the PKU diet. Accord-
the amine group and leaves ammonia and an organic acid. If ingly, preconception counseling is imperative.
an enzymatic block occurs in this initial step, that particular Treatment of PKU requires strict lifelong restriction of
amino acid accumulates in the blood and urine. PKU is one phe via dietary protein restriction and supplementation
example of such a block in which phenylalanine accumu- with phe-free protein-containing medical foods/beverages
lates. If the block is in metabolism of the residual organic to prevent protein deficiency. Blood phe concentrations
acid, the offending organic acid accumulates and an organic must be monitored regularly and dietary protein intake
acidemia ensues. Finally, if the block is in the urea cycle, adjusted accordingly. BH4 supplementation is a relatively
ammonia cannot be metabolized to urea and excreted, result- new therapy that has variable efficacy; it helps to lower
ing in hyperammonemia. Laboratory diagnosis of these con- plasma phe concentrations in some patients but usually
ditions relies primarily on three tests: plasma ammonia does not replace the low-phe diet.
(NH4), PAA, analysis, and UOA analysis. Urine amino acids A small number of patients who have abnormal NBS
(UAA) analysis is sometimes useful as an ancillary test. results indicating elevated phe have a more severe disorder
that is due to a defect in BH4 metabolism rather than PAH
Amino Acidopathies deficiency. Phe is only mildly elevated in these patients, but
Amino acidopathies are autosomal recessive genetic condi- they develop dystonia due to central dopamine deficiency.
tions resulting from an enzymatic block that prevents Treatment consists of dopamine and biopterin supplemen-
metabolism of specific amino acids (Figure), which leads tation as well as more complex therapeutic strategies.
Figure. Simplified metabolism of protein to
ammonia and organic acids. PAA¼plasma
amino acids, NH4¼ammonia, UOA¼urine
organic acids
Maple Syrup Urine Disease. MSUD is due to a deficiency without treatment. Acute metabolic decompensation is
in the enzyme branched-chain a-ketoacid dehydrogenase, related to the neurotoxic and osmotic effects of hyper-
which catalyzes the second step in metabolism of the leucinemia; interestingly, valine and isoleucine are not
branched-chain amino acids (BCAAs) isoleucine, valine, neurotoxic.
and leucine. The condition affects all ethnic groups but is Management during an episode of decompensation
most common among the Old Order Mennonites. In the includes: stopping all leucine intake, administering high-
United States, all states screen for MSUD by tandem mass dextrose content isotonic intravenous fluids and intravenous
spectrometry. Diagnostic testing shows elevated valine, iso- lipid emulsion, and providing leucine-free nasogastric/gastro-
leucine, leucine, and allo-isoleucine on PAA analysis and stomy feedings. (5) BCAA-free parenteral nutrition can be
characteristic organic acids on UOA analysis. The severe ordered from specialty pharmacies and allows for the delivery
form of MSUD often presents within the first postnatal of protein without leucine. Patients with MSUD should never
week. The neonate frequently has diminished arousal and receive hypotonic fluids because cerebral edema in these
feeds poorly; if treatment is not initiated quickly, hyperto- patients can be fatal. Rapid reductions in serum osmolality
nicity, coma, and death occur within hours. High leucine must be strictly avoided, and serum sodium concentrations
concentrations cause these effects. should be maintained in the high-normal range. In some
Patients with MSUD may have little evidence of meta- cases, hypertonic saline and mannitol are indicated to prevent
bolic acidosis or ketosis during an acute episode. Cerumen hyponatremia and resultant cerebral edema. Dialysis has been
and urine may smell like maple syrup, but only when employed as an emergency rescue therapy, but proper and
leucine is markedly elevated. Therefore, this finding should aggressive metabolic therapy can obviate the need for dialysis.
not be relied on for screening. Affected patients develop Management of hyperleucinemia is complex and requires
acute episodes of metabolic decompensation associated admission to the pediatric intensive care unit and the involve-
with high leucine intake or catabolic stressors (febrile ment of a metabolic expert familiar with the acute manage-
illness, prolonged fasting) throughout life. Affected patients ment of MSUD. Chronic management involves strict dietary
are well between episodes, but when leucine concentrations restriction of leucine. Early identification via NBS before the
rise, they develop headache, confusion, hallucinations, leth- initial episode and tight lifelong metabolic control result in
argy, and vomiting, which progress to coma and death good outcomes, although unexpected late and devastating

attacks may occur throughout life. Liver transplantation has cleavage that results in elevated cerebrospinal fluid glycine
been an effective option for some patients and can help to leading to neonatal seizures, hiccups, and apnea.
prevent recurrent metabolic decompensations. (6)
A milder, intermittent form of MSUD exists in which Organic Acidemias
patients have recurrent episodes of altered mental status Organic acids are the deaminated remains of amino acids.
due to hyperleucinemia associated with illness or excessive Defects in their degradation result in their massive accu-
protein intake. Between episodes they are well and may have mulation in the blood and urine, leading to metabolic
normal PAA analysis results. acidosis. Affected infants develop poor feeding, tachypnea,
Homocystinuria. Classic homocystinuria is caused by a vomiting, and lethargy in the first few days after birth. NBS
deficiency in cystathionine b-synthetase. Laboratory testing is helpful in identifying some neonates before the initial
shows marked elevations of homocystine in the blood and episode, but others may present in crisis before NBS results
urine and methionine elevations on NBS and PAA. The become available. NBS identifies elevated odd-chain acyl-
condition is not associated with acute metabolic decompen- carnitine (C3 or C5 acylcarnitines) species by tandem mass
sation but may result in intellectual disability, tall stature, spectrometry. An organic acidemia is clinically suggested by
osteoporosis, recurrent thrombosis, and ectopia lentis (lens metabolic acidosis with an elevated anion gap. Confirma-
dislocation). Homocystinuria may be considered in the tion of disease is based on UOA analysis, which reveals a
differential diagnosis of Marfan syndrome. A minority of characteristic pattern of abnormal organic acids, and acyl-
patients responds to pyridoxine (vitamin B6), and a trial of carnitine profile and carnitine analysis are helpful. All of
high-dose vitamin B6 should be given if this is a possibility. the common organic acidemias are inherited in an autosomal
Management includes betaine, which helps to decrease recessive pattern.
plasma homocystine concentrations, and aspirin to prevent Treatment during an episode includes stopping all pro-
stroke. Dietary methionine restriction and B vitamin sup- tein intake, administering high-dose carnitine supplements,
plements are also used. and promoting an anabolic state with dextrose-containing
Tyrosinemia. Hepatorenal tyrosinemia (also known fluids (10% dextrose in normal saline), intravenous lipid
as tyrosinemia type 1) is due to a defect in the enzyme emulsions, and in some cases, insulin. Intravenous bicar-
fumarylacetoacetase (FAH). This deficiency results in accu- bonate to correct the acidosis is often necessary. Some
mulation of blood tyrosine and urine succinylacetone, elevation defects are partially or completely amenable to cofactor
of which is pathognomonic for the condition. NBS involves therapy with vitamins (eg, biotin for biotinidase deficiency
the detection of succinylacetone by tandem mass spectrom- and vitamin B12 for some forms of methylmalonic acid-
etry. Blood tyrosine may also be elevated on NBS dried blood emia). The profoundly ill child with an organic acidemia
spots, but this test lacks sensitivity and specificity for the may require hemodialysis, which can be lifesaving, partic-
condition because infants may have elevated tyrosine con- ularly to correct profound metabolic acidosis or hyperam-
centrations related to hepatic immaturity or other milder monemia. Long-term treatment requires restriction of the
forms of tyrosinemia. In addition, normal tyrosine values offending amino acids via protein restriction and supple-
can be seen in infants who have hepatorenal tyrosinemia in mentation with metabolic formulas. Carnitine and cofactor
the newborn period. Plasma methionine is often more supplementation are also given. Some minor illness can be
dramatically elevated than tyrosine, and elevations in both managed at home with use of a sick day protocol, which
are likely due to secondary liver disease rather than the often includes monitoring of urine ketones, decreased
specific enzyme deficiency. Confirmation of the condition dietary protein intake, increased dietary calorie intake,
relies on UOA with a specific request for succinylacetone and a local emergency department triage plan.
and PAA for elevated tyrosine and methionine. DNA testing Propionic Acidemia. Propionic acidemia is caused by a
of the FAH gene can be helpful in confirmation. defect in the enzyme propionyl CoA carboxylase, which
When untreated, hepatorenal tyrosinemia typically leads to abnormal metabolism of isoleucine, valine, methi-
results in liver failure during infancy or early childhood. onine, and threonine. UOA analysis shows elevated 3-OH
Renal tubular acidosis and recurrent episodes of neuro- propionic acid and methylcitrate, plasma acylcarnitines and
pathic pain can also occur. Nitisinone, along with dietary NBS show an elevated C3 acylcarnitine, and PAA analysis
tyrosine restriction, is an effective treatment and may obvi- may show elevated glycine. Classically, patients present in
ate the need for liver transplantation. the newborn period with overwhelming metabolic acidosis
Hyperglycinemia. Another amino acidopathy is nonketo- with a high anion gap. The newborn may have prominent
tic hyperglycinemia, a typically lethal deficiency in glycine ketosis, which is an otherwise rare feature in the first
postnatal weeks. Ammonia concentrations may be markedly severe “cerebral” organic acidemia, and in contrast to other
elevated, but the presence of profound metabolic acidosis organic acidemias, metabolic acidosis, ketosis, and hyper-
makes this condition easy to distinguish from urea cycle ammonemia may not be present during an acute episode.
disorders. Low blood pH can lead to multiorgan dysfunc- Unfortunately, there is no easily obtainable marker of met-
tion, including cardiac and respiratory failure. Pancytopenia abolic decompensation in this condition; initiation of met-
and pancreatitis can occur during an episode. Brain injury, abolic care is based on results of the child’s physical
including stroke, often accompanies severe metabolic de- examination and history. Patients have been known to
compensations, which can lead to permanent intellectual develop permanent basal ganglia injury and resulting move-
disability or movement disorders. Recurrent episodes of ment disorder following a fever associated with a mild ill-
metabolic acidosis and decompensation can occur with ness. Therefore, the aggressive use of dextrose-containing
illness, fasting, or excessive protein intake. Elevated urine fluids is indicated for any febrile illness.
ketones are an early sign of metabolic crisis. Liver trans- GA1 is a target of NBS, which shows elevated plasma C5
plantation may decrease the frequency of recurrent metabolic dicarboxylic (C5DC) acylcarnitine in most affected individuals.
crisis. Late-onset cardiomyopathy and cardiac dysrhythmia Diagnostic testing may show elevated urine glutaric and 3-OH
are being increasingly recognized. (7) glutaric acid on UOA analysis, and C5DC acylcarnitine may
Methylmalonic Acidemia. Classically, methylmalonic acid- be elevated on plasma or urine acylcarnitine analysis. Some
emia is due to a deficiency in the enzyme methylmalonyl affected patients, known as “low excretors,” have normal blood
CoA mutase, which is the step immediately following and urine metabolite testing results, which can make diagnosis
propionyl CoA carboxylase in the metabolism of isoleucine, challenging. DNA testing of the GCDH gene can be helpful in
valine, methionine, and threonine. Methylmalonic acide- establishing a diagnosis in these patients.
mias can also be due to several defects in cobalamin (vitamin Clinically, affected children often exhibit macrocephaly
B12) metabolism, some of which also cause elevations in but are well until a catabolic crisis occurs. A febrile illness
homocysteine. In the classic form, this condition presents in can be neurologically devastating, resulting in dystonia and
the newborn period similarly to propionic acidemia, with movement disorders. Neuroimaging may reveal basal gan-
acidosis, ketosis, and hyperammonemia. UOA analysis glia injury in the survivors of a crisis. Subdural hematomas
shows elevated methylmalonic acid (MMA) and methylcitrate; can occur and have been mistaken for child abuse.
plasma acylcarnitines and NBS show elevated C3 acylcarnitine. Chronic management consists of carnitine supplemen-
Plasma alanine and glycine values are often elevated on PAA tation and dietary lysine and tryptophan restriction, but
testing, and a specific, widely available test is plasma MMA, perhaps most important is avoidance of catabolism during
which shows marked elevations. routine illnesses by administration of glucose-containing
Metabolic crisis can cause stroke, resultant intellectual fluids. Aggressive sick day management with dextrose-
disability, and movement disorder. Many patients have recur- containing fluids can prevent the neurologic sequelae. The
rent episodes of metabolic acidosis due to illness, catabolic prognosis is excellent for children who avoid brain injury
stress, or excessive protein intake throughout life. Late-onset until age 6 years because GA1 is unlikely to result in
complications include renal disease, which often necessitates permanent brain injury after this age. (8)(9)
transplantation in adolescence or adulthood. Milder variants of Other Organic Acidemias. Other organic acidemias
methylmalonic acidemia also exist, some of which may present screened for on NBS and diagnosable on UOA analysis
in adulthood. Specifics of management depend on the enzyme include isovaleric acidemia and biotinidase deficiency.
defect. They generally include dietary restriction of the offend-
ing amino acids; administration of vitamin B12 with specific Urea Cycle Disorders
form, dosing, and route of administration; and administration Hyperammonemia. The urea cycle disposes of toxic ammo-
of carnitine. Organ transplantation can be very effective, as in nia from the deamination of amino acids by converting it to
many other inborn errors of metabolism. In this case, liver or nontoxic urea for renal excretion. If the urea cycle is dys-
combined liver and kidney transplantation is undertaken. functional, ammonia accumulates in the blood, leading to
Glutaric Acidemia. Glutaric acidemia type 1 (GA1) is due altered mental status, lethargy, vomiting, cerebral edema,
to a defect in enzyme glutaryl CoA dehydrogenase, which is and ultimately coma and death. Hyperammonemic enceph-
involved in the metabolism of the amino acids tryptophan alopathy can be rapidly fatal and is a medical emergency.
and lysine. The condition is more common in Amish Unlike the organic acidemias, severe metabolic acidosis is
individuals but can occur in any ethnic group. GA1 is a not is a prominent finding; some ill patients have mild

acidosis related to dehydration and shock. Prolonged fast- acid, although this test result may be negative in well-
ing and moderate illness with poor oral intake or fever can compensated males and many female heterozygotes. When
provoke a hyperammonemic crisis due to catabolism and ordering UOA for patients in whom OTC deficiency is
increased proteolysis. Similarly, excessive protein intake suspected, clinicians should specify that orotic acid identi-
results in increased production of ammonia and resultant fication is desired. DNA testing of the OTC gene confirms
encephalopathy. Severe forms may present in the first the diagnosis. Even though this is an X-linked condition,
hours after birth. Recurrent unrecognized episodes can females can be affected, with a range from severe disease
lead to global developmental delay, spasticity, and intellec- to asymptomatic. Some female heterozygotes and mildly
tual disability. Milder forms may present later in life with affected males choose to avoid high-protein foods, likely
failure to thrive, developmental delay, and recurrent vom- due to the accumulation of toxic ammonia, which may result
iting or protein aversion. Any child with unexplained acute in failure to thrive during childhood. Female heterozygotes
encephalopathy, recurrent episodes of lethargy and vomit- may also present with hyperammonemia during the imme-
ing, or failure to thrive with protein aversion should have diate postpartum period when the protein turnover from
ammonia measured. This might be the only marker of the involution of the uterus and the catabolic stress of delivery is
disease. Evaluation for hyperammonemia includes liver high.
function tests, electrolytes, UOA analysis (for orotic acid), Long-term treatment typically includes citrulline supple-
and PAA analysis. Hyperammonemia can also result from mentation, dietary protein restriction, and oral sodium or
valproic acid administration or liver dysfunction, so pa- glycerol phenylbutyrate. Liver transplant is effective in pre-
tients should be evaluated for these conditions as well. venting recurrent episodes of hyperammonemia. (8)
Treatment of hyperammonemic encephalopathy must be Other Urea Cycle Disorders. Other urea cycle disorders
implemented immediately and includes cessation of protein include citrullinemia, argininosuccinic aciduria, and car-
intake and reduction of catabolic stress. Intravenous 10% bamyl phosphate synthetase 1 (CPS 1) deficiencies, all of
dextrose in normal saline and an intravenous lipid emulsion which are autosomal recessive and present with recurrent
infusion should be started to provide protein-free energy. episodes of hyperammonemia. CPS 1 is not associated with
Central venous access should be established for the delivery elevated urine orotic acid. All United States states perform
of arginine hydrochloride with sodium phenylacetate and NBS for citrullinemia and argininosuccinic aciduria.
sodium benzoate once hyperammonemia is confirmed.
This treatment should always be supervised by a metabolic
LIPID METABOLISM DISORDERS
disease specialist. Care should be taken to avoid hypona-
tremia, which can increase the risk of developing cerebral Fatty Acid Oxidation Disorders
edema. Infants whose initial presentation is severe hyper- FAOD are caused by defects in the b-oxidation of fatty acids
ammonemia may require hemodialysis, and the time spent or derangement of carnitine metabolism. The key clinical
in coma correlates with outcome, so preparation for dialysis feature of these disorders is a propensity to HKHG with
should begin immediately upon diagnosis in infants. Long- prolonged fasting. During fasting, blood glucose from a
term treatment includes dietary protein restriction, arginine recent meal is used, followed by breakdown of hepatic
or citrulline supplementation (depending on the defi- glycogen stores to maintain normal blood glucose concen-
ciency), sodium or glycerol phenylbutyrate, and sick day trations. As glycogen becomes depleted, gluconeogenesis
management with an emergency department protocol. (GNG) is initiated to maintain normal blood glucose con-
Liver transplantation reduces episodes of recurrent centrations. GNG receives the energy for glucose biosyn-
hyperammonemia. (10) thesis from oxidation of fatty acids. Patients with FAOD
Ornithine Transcarbamylase Deficiency. OTC deficiency cannot fully metabolize fatty acids and, therefore, cannot
results in recurrent episodes of hyperammonemia associ- release their stored energy. Further, production of free acetyl
ated with catabolic stress (illness, fasting, labor and delivery) CoA required for manufacture of ketone bodies is dimin-
or excessive protein intake. This condition is not universally ished, which leads to HKHG.
screened for in newborns; a negative NBS result in most If FAOD are undiagnosed, the first hypoglycemic episode
states does not rule out this condition. Testing during a may occur in infancy or early childhood when the child has a
catabolic episode reveals elevated plasma ammonia, and prolonged fast in the context of an intercurrent illness. The
PAA analysis often shows elevated glutamine (a storage presenting sign may be sudden death or severe HKHG,
form of ammonia) with decreased citrulline and arginine. resulting in brain injury and seizure. The brain is particu-
UOA analysis in affected males documents elevated orotic larly sensitive to HKHG because it relies on ketone body
utilization for energy during times of hypoglycemia. NBS may also result in retinopathy and peripheral neuropathy.
has allowed for diagnosis before the initial episode in most Both conditions are screened for in NBS, but the sensitivity of
cases, thereby prompting treatment and parental education, this screening test is not 100%. Therefore, clinicians should
with the goal of preventing brain injury and disability. remain vigilant for these disorders in children who have
The treatment of FAOD includes parental education to suggestive clinical histories, even if NBS results are normal.
avoid prolonged fasting, particularly during an illness, and Diagnosis is by PAC profile, which shows elevated unsatu-
the use of intravenous dextrose-containing fluids to prevent rated long-chain acylcarnitines (C14:1) in VLCAD deficiency
hypoglycemia if the child cannot feed well due to illness or and 3-hydroxy-acylcarnitines (C16-OH) in LCHAD deficiency.
injury. An emergency department protocol outlining the Because biochemical abnormalities in these disorders (par-
condition and treatment should be given to all families of ticularly VLCAD) can be minimal or nonexistent when a
affected children. Supplemental carnitine may be pre- child is well, DNA testing or enzymology is often required
scribed. Long-chain FAOD (LCFAOD) are also associated to confirm the diagnosis.
with cardiomyopathy and recurrent rhabdomyolysis. All Treatment involves dietary fat restriction and supplemen-
forms of FAOD have an autosomal recessive inheritance. tation with medium-chain triglyceride oil to provide the
Medium-chain Acyl CoA Dehydrogenase (MCAD) muscle with a usable source of energy from fat. To prevent
Deficiency. The MCAD enzyme breaks down medium-chain HKHG, patients must avoid fasting during intercurrent
fatty acids to short-chain fatty acids and acetyl CoA, which illnesses, similar to MCAD deficiency. Thus, parental edu-
can be used to provide energy for GNG and ketone body cation is vital. If a patient is unable to take sufficient energy
formation. Prolonged fasting during an intercurrent illness by mouth, intravenous administration of dextrose-containing
triggers hypoglycemic episodes. During an illness with poor fluids should be initiated. Carnitine supplementation is
oral intake, a child’s liver glycogen is depleted. When a controversial. Regular cardiac evaluations are indicated and
prolonged fast is superimposed on this state, GNG cannot creatine kinase (CK) should be followed during illness.
maintain adequate blood glucose concentrations due to Competitive and isometric sports must be restricted
defective b-oxidation of fatty acids. Children develop nor- for many patients due to recurrent exercise-induced
mally, but an unprevented initial episode of HKHG may rhabdomyolysis.
result in sudden death or permanent brain injury. The Primary Carnitine Deficiency. Primary carnitine defi-
clinical presentation of MCAD deficiency is related to the ciency is a rare autosomal disorder caused by a defect in
effects of HKHG and includes altered mental status, the OCTN2 carnitine transporter, which leads to systemic
lethargy, and ultimately seizure and death. depletion of carnitine due to both diminished intestinal
MCAD deficiency is the most common of the FAOD and absorption and renal reabsorption. The condition is
is typically found on NBS by blood spot acylcarnitine anal- screened for on NBS, and the diagnosis is based on the
ysis, a diagnosis that occurs before the onset of the first finding of markedly low blood free carnitine concentrations
episode. However, some infants present on the second or with elevated urine carnitine excretion. DNA testing can be
third postnatal day, which is too early for NBS to be helpful. used to confirm the diagnosis. Untreated patients develop
NBS and confirmatory diagnostic PAC profile shows ele- cardiomyopathy and recurrent episodes of HKHG. Reye-
vated C6, C8, and C10 acylcarnitines. UOA testing may like encephalopathy can occur. Treatment with high-
show elevated hexanoylglycine and suberylglycine. dose oral carnitine supplementation appears to prevent
Parental education about avoiding fasting during inter- cardiomyopathy.
current illness is the most important intervention. Many Other Fatty Acid Oxidation Disorders. Other FAOD that
children receive carnitine supplementation. Patients are are screened for by NBS and can be diagnosed on PAC
given emergency department protocols that explain the analysis include carnitine palmitoyltransferase 2 and mul-
condition and treatment. If children avoid HKHG episodes tiple acyl-CoA dehydrogenase (also known as glutaric acid-
during the first several years after birth, normal develop- emia type 2) deficiencies.
ment is expected and the prognosis is excellent.
Long-chain Fatty Acid Oxidation Disorders. LCFAOD
CARBOHYDRATE DISORDERS
include very-long-chain acyl CoA dehydrogenase (VLCAD)
and long-chain 3-hydroxy acyl CoA dehydrogenase (LCHAD) Classic galactosemia is due to a deficiency in the enzyme
deficiencies. LCFAOD are severe conditions that may result galactose-1-phosphate uridyltransferase (GALT), which leads
in rhabdomyolysis, cardiomyopathy, liver dysfunction, and to accumulation of galactose and galactose-1-phosphate.
recurrent HKHG, even with appropriate treatment. LCHAD The initiation of lactose (glucose and galactose)-based

feedings in the newborn who has galactosemia leads rapidly and fatigue develop within a few minutes of starting to
to metabolic decompensation, with liver dysfunction, jaun- exercise, followed by a “second wind” phenomenon in
dice, and coagulopathy. Escherichia coli sepsis and cataracts which the patient briefly feels better. Patients have markedly
can occur. Because initial symptoms may begin in the first elevated CK concentrations following exercise. Diagnosis is
few postnatal days, treatment must begin without delay. often by muscle biopsy, which demonstrates deficient myo-
Late-diagnosed infants who survive the initial episode of phosphorylase activity on enzymatic analysis and glycogen
metabolic decomposition often develop intellectual disabil- accumulation within the myocytes. DNA analysis of the
ity. Due to NBS, the natural course of classic galactosemia is PYGM gene may be the best method for diagnosis and
rarely observed today, but even with early detection, appro- obviates the need for biopsy. Avoidance of strenuous aero-
priate treatment, and excellent control, many still develop bic and isometric exercise is recommended. However, the
tremor, specific learning disabilities, and speech/language patient should also avoid deconditioning by participating
deficits. Even with early and optimal treatment, most af- in light aerobic activity as tolerated.
fected females develop ovarian failure, often requiring Among the several other important carbohydrate disor-
estrogen replacement in adolescence. ders are other GSDs; hereditary fructose intolerance, a
All states currently screen for galactosemia on NBS. condition that results in vomiting and liver dysfunction
Confirmation is via GALT enzyme activity and blood galactose- following ingestion of sucrose or fructose (children often
1-phosphate values. DNA testing can be helpful to look for avoid sweets and classically have an absence of dental
milder mutations, which are associated with an excellent caries); and glycogen synthase deficiency (GSD 0), a con-
prognosis, such as the Duarte variant. dition that results from the inability to form hepatic glyco-
Chronic management is based on lifelong dietary restric- gen and leads to recurrent ketotic hypoglycemia without
tion of galactose. Such restriction should be initiated imme- hepatomegaly.
diately upon receipt of abnormal NBS results because
treatment delays result in clinical morbidity. Affected
LYSOSOMAL STORAGE DISORDERS
school-age children should be screened for speech and
learning disabilities. The lysosome is a cellular organelle that digests large
complex macromolecules for recycling or degradation. Lyso-
somal storage disorders are progressive conditions related
GLYCOGEN STORAGE DISORDERS
to the accumulation of these large macromolecules (muco-
Glycogen storage disorders (GSDs) result from the inability polysaccharides, sphingolipids, oligosaccharides) within
to degrade stored glycogen in the liver and muscle. Hepatic vulnerable tissues. The lysosome can be thought of as a
(GSD 1) forms primarily cause fasting hypoglycemia, whereas bag of individual enzymes, each dedicated to degradation of
muscular (GSD V) forms result in recurrent rhabdomyolysis. a particular macromolecule. When a lysosomal enzyme is
GSD type 1a (also known as von Gierke disease) is due to deficient, the macromolecule that it normally digests accu-
deficiency in the enzyme glucose-6-phosphatase, which mulates within the cell, leading to space occupation and
results in massive hepatomegaly, growth failure, and recur- cellular dysfunction. Many of these disorders are character-
rent episodes of ketotic hypoglycemia, often presenting in ized by progressive involvement of the liver, spleen, brain, or
infancy. Patients have elevated lactic and uric acids and bones related to accumulation of the undigested materials in
triglycerides. Frequent doses of cornstarch or continuous these tissues. Clinical features are specific to the particular
gastrostomy feedings are required to prevent recurrent disorder but may include hepatosplenomegaly, bony defor-
hypoglycemia. Late complications include malignant trans- mity, developmental regression, sensory loss (hearing and
formation of hepatic adenomas, hypertension, and renal vison), and coarse facial characteristics. Most of these con-
insufficiency. GSD type 1b is additionally associated with ditions have an autosomal recessive inheritance, except
neutropenia, frequent infections, and inflammatory bowel Fabry disease and mucopolysaccharidosis type II (Hunter
disease. Treatment can be very successful but requires disease), which are X-linked. Because the conditions can
careful follow-up. have significant phenotypic overlap, urine metabolite
GSD type V (also known as McArdle disease) results screening tests can be helpful in the initial evaluation.
from a defect in the enzyme myophosphorylase. Onset is Specifically, urine glycosaminoglycan (GAG) analysis for
usually in adolescence and is characterized by exercise- mucopolysaccharidoses and urine oligosaccharides are use-
induced muscle pain, fatigue, and rhabdomyolysis. Myo- ful screening tests for lysosomal disorders. Ultimately, the
globinuria and resultant renal injury can occur. Muscle pain laboratory diagnosis involves demonstration of enzymatic
deficiency in lymphocytes or fibroblasts and, more recently, funduscopic examination reveals cherry red spots on the
DNA testing. maculae of most infants. The disorder progresses quickly,
Mucopolysaccharidoses (MPSs) result from the accumu- with vision loss, progressive macrocephaly, seizures, spas-
lation of polysaccharide-based macromolecules (GAGs) in ticity, and unresponsiveness to the environment. Viscero-
tissues. Classically, children appear normal at birth and megaly does not occur. There is no effective treatment and
develop progressive symptomology over subsequent years. Tay-Sachs disease is usually fatal by age 4 years. Carrier
Coarsened facial features, bony deformity, developmental screening programs have reduced the incidence among
regression, and visceromegaly are typical. Diagnosis is Ashkenazi Jews.
initially by urinary GAG analysis and confirmed by enzyme Fabry disease is due to a-galactosidase deficiency. In
analysis or DNA. Skeletal radiographs may show the char- males, the condition presents in late childhood or early
acteristic dysostosis multiplex appearance. Several of the adolescence with episodes of acroparesthesias (painful
disorders now have treatments available, including enzyme hands and feet) or recurrent abdominal pain. Female het-
replacement therapy (ERT) (MPS I, II, IV, VI), and hema- erozygotes may also present with abdominal pain in ado-
topoietic stem cell transplantation may be therapeutic for lescence or early adulthood. Untreated patients develop
some of the disorders that have central nervous system proteinuria and resultant renal insufficiency, often requir-
involvement and are not currently amenable to treatment ing dialysis and ultimately renal transplantation. Females
with ERT. may develop renal insufficiency on average about 10 years
MPS I (Hurler syndrome) involves progressive coarsen- later than males, although some females have few symp-
ing of facial features, hepatosplenomegaly, corneal cloud- toms and may not develop kidney disease. Other associated
ing, bony deformity, and developmental regression. Without features include reduced sweating, angiokeratomas of the
treatment, the condition is fatal. Due to the efficacy of ERT skin, early arthrosclerosis and stroke, and cardiac hyper-
and hematopoietic stem cell transplantation (HSCT), some trophy. Diagnosis can be made by demonstration of low a-
have argued for inclusion of this condition on the expanded galactosidase enzyme activity in males. DNA testing can
NBS. MPS II (Hunter syndrome) is similar to MPS I but also be helpful, particularly in females in whom enzyme
without corneal clouding. MPS I and II both have milder testing is not useful because they may show near-normal
forms without developmental regression that are amenable enzyme activity. ERT is available for treatment.
to ERT, which does not cross the blood-brain barrier. How- Gaucher disease type 1 is due to lysosomal b-glucocer-
ever, ERT is sometimes used in the severe forms with brain ebrosidase deficiency. The condition results in massive
involvement to temporize progression and potentially accumulation of glucocerebroside in the liver, spleen, and
improve the quality of life. MPS III (Sanfilippo syndrome) bone marrow. Gaucher is more common in individuals of
is primarily a neurodegenerative condition that results in Ashkenazi Jewish decent. Features include anemia and
slow developmental regression, with death often in the thrombocytopenia due to marrow obliteration and splenic
second decade of life. The visceral and bony manifestations sequestration, hepatosplenomegaly, and bone pain. The
are less prominent than in other MPS disorders. Children brain is not affected, although Parkinsonism has been
often present with behavioral and attention issues before the recently shown to be associated with Gaucher disease.
onset of motor and cognitive regression. MPS IV differs (11) ERT and substrate inhibitors are available for treatment.
from the other conditions, with characteristic and often Neuropathic variants (types 2 and 3) also exist. Type 2 is
severe bony involvement and short stature. Finally, MPS associated with early onset, rapid, and severe neurodegen-
VI is very similar to MPS I but never has developmental eration in childhood, and type 3 is associated with ocular
regression. and neuromotor dysfunction, often with severe visceral signs
Tay-Sachs disease is caused by a deficiency in the enzyme of Gaucher disease in childhood.
b-hexosaminidase A. The enzymatic block results in accu- Krabbe disease is due to deficiency in the lysosomal
mulation of the sphingolipid GM2 ganglioside in vulnerable enzyme galactosylceramidase. The condition results in infan-
tissues. Diagnosis is by DNA analysis of the HEXA gene tile neurodegeneration. Infants present in the first few post-
or enzyme assay of b-hexosaminidase A in leukocytes. natal months with increasing muscle tone and profound
Tay-Sachs disease is more common in people of Ashkenazi irritability. Recurrent fevers without source can been seen.
Jewish descent, but it can be seen in any ethnic group. The infant develops seizures, vision loss, and developmen-
Symptoms usually begin in early infancy with weakness and tal regression, with death often occurring before 12
an exaggerated startle reflex. Myoclonic jerks and develop- months of age. Diagnosis is by enzyme assay or DNA
mental regression also occur early in the course of disease. A analysis. Cerebrospinal fluid protein is often markedly

elevated. HSCT has been used in Krabbe disease with genome or nuclear genes required for mitochondrial func-
mixed results. Milder, late-onset forms of Krabbe disease tion (13). Point mutations in the mitochondrial genome are
also exist. transmitted via maternal inheritance, deletions or dupli-
Pompe disease (GSD II) is due to a deficiency in the cations in the mitochondrial genome are usually sporadic,
enzyme acid a-glucosidase (GAA) that results in accumu- and mutations in nuclear genes required for mitochon-
lation of glycogen in the lysosome of muscle cells. Classi- drial function are inherited in a mendelian pattern, usually
cally, this condition presents in early infancy with autosomal recessive. The mitochondria have several
hypertrophic cardiomyopathy, shortened P-R interval on important functions but most important is the production
electrocardiography, and skeletal and respiratory muscle of cellular energy in the form of adenosine triphosphate via
weakness. CK values are elevated. Heart failure, respiratory the respiratory chain. Genetic alterations that diminish the
insufficiency, and death occur without treatment. ERT is mitochondria’s ability to produce energy result in dys-
available and is most efficacious if started before cardiac function in tissues with the highest energy demands.
function deteriorates. Therefore, Pompe disease is being Therefore, mitochondrial disorders preferentially affect
added to NBS. Milder forms of the condition may present the brain, skeletal and cardiac muscles, and the eye.
with muscle weakness and elevated CK values later in Muscle biopsy may show ragged red fibers on light micros-
childhood or adulthood. Diagnosis is by demonstration of copy. Strategies for diagnosing mitochondrial diseases
GAA enzyme deficiency on blood spot or fibroblasts or by vary and are beyond the scope of this review, but they
DNA analysis. include next-generation DNA sequencing of multigene
panels for nuclear gene mutations, sequencing of the mito-
chondrial genome, and specific assays of muscle respiratory
PEROXISOMAL DISORDERS
chain activity. Because plasma lactate is neither a sensi-
The peroxisome is a cellular organelle with disparate func- tive nor specific marker of mitochondrial disease, the
tions, including oxidation of very long-chain fatty acids decision to evaluate a patient for mitochondrial disease
(VLCFAs). Defects in peroxisomal function or assembly should rely on the clinical phenotype.
can result in several severe neurodegenerative disorders. MELAS (mitochondrial encephalomyopathy, lactic acid,
These conditions are not included in NBS and may present and strokelike episodes) is one common mitochondrial
with severe infantile hypotonia, skeletal dysplasia, sensory disorder that is usually due to a maternally inherited muta-
deficits (hearing and vision loss), hepatomegaly, or neuro- tion in the mitochondrial tRNA for leucine. Symptoms often
logic regression in childhood. Zellweger syndrome results present in adolescence with diabetes mellitus, recurrent
from near or complete absence of peroxisomes. Affected strokelike episodes, migraine headaches, and hearing loss.
infants present with dysmorphic facial characteristics, sei- Kearns-Sayre syndrome usually results from sporadic (non-
zures, liver disease, characteristic bone involvement, pro- inherited) partial deletions of the mitochondrial genome.
found hypotonia, and hearing and vision deficits. Magnetic Common features include cardiac conduction abnormali-
resonance imaging of the brain shows a leukodystrophy ties, cardiomyopathy, lactic acidosis, and progressive exter-
(abnormal myelination). The condition is usually fatal in nal ophthalmoplegia. Respiratory chain disorders are
infancy. usually inherited in an autosomal recessive pattern and
Adrenoleukodystrophy is an X-linked condition that are related to mutations in nuclear genes important for
results from a deficiency in peroxisomal oxidation of assembly, maintenance, or production of the respiratory
VLCFAs. It presents with developmental regression, white chain (but may also be maternally inherited due to mito-
matter disease, new-onset spasticity, and adrenal failure chondrial point mutations). These conditions usually pre-
typically in school-age boys, although there is a broad sent in infancy with hypotonia, muscle weakness, global
spectrum of phenotypes. Onset occurs after a period of developmental delays, lactic acidosis, and seizures. Neuro-
normal growth and development. Initial screening for both imaging may show basal ganglia lesions consistent with
of these conditions is by plasma VLCFA analysis. HSCT Leigh syndrome.
may halt progression in some patients (12).
CONCLUSION
MITOCHONDRIAL DISORDERS
Metabolic disorders can be difficult to understand due to
Mitochondrial disorders are complex multisystemic con- their rarity and the multiplicity of conditions. Applying
ditions that result from mutations in the mitochondrial context to this group of conditions can aid in the initial
evaluation. Disorders of energy sources can largely be
screened for by a few simple tests. Amino acidopathies deficiency, and glutaric acidemia type I, may improve long-term
can be evaluated via PAA and UOA analysis; organic outcomes for affected children. (4)(8)(9)
acidemias via electrolytes, urine ketones, UOA analysis, • On the basis of primarily consensus, due to lack of relevant clinical
and PAC profile; urea cycle disorders via UOA and PAA studies, inborn errors due to defects in the metabolism of energy
sources (protein, fatty acids, and carbohydrates) may present in
analysis and ammonia; and FAOD via UOA, PAC profile,
infancy with overwhelming metabolic decompensation, and
urine ketones, blood glucose, and plasma carnitine. In initial laboratory evaluations may reveal hyperammonemia,
addition, NBS allows for the early recognition of many, but nonketotic hypoglycemia, or a metabolic acidosis with an
not all of these disorders. Therefore, clinicians should elevated anion gap, depending on the disorder.
consider these conditions in the differential diagnosis, • On the basis of primarily consensus, due to lack of relevant clinical
even for a child who has a negative NBS result. The studies, specific laboratory testing for inborn errors of
lysosomal disorders are more difficult to diagnosis via metabolism should include plasma amino acids, urine organic
acids, plasma carnitine, and plasma acylcarnitine profile.
routine screening tests, but the clinical features (eg, vis-
• On the basis of primarily consensus, due to lack of relevant clinical
ceromegaly, developmental regression, coarse facial fea-
studies, disorders of cellular organelles, such as lysosomal and
tures) should alert the clinician to the possibility.
peroxisomal disorders, may present with progressive
organomegaly, developmental regression, dysmorphic facial
characteristics. or sensory loss.
Summary
By their very nature, rare inborn errors of metabolism challenge the
generation and application of evidence-based medicine.
CME quiz and references for this article are at http://pedsinreview.
• On the basis of limited research evidence as well as consensus,
newborn screening for select metabolic disorders, including aappublications.org/content/37/1/3. Access this and all other PIR
phenylketonuria, medium-chain acyl CoA dehydrogenase CME quizzes available for credit at: http://www.aappublications.
org/content/pediatrics-review-quizzes.
Parent Resources from the AAP at HealthyChildren.org

• Organic Causes of Weight Gain and Obesity: https://www.healthychildren.org/English/health-issues/conditions/obesity/Pages/Organic-
Causes-of-Weight-Gain-and-Obesity.aspx

PIR Quiz
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1. Individual CME quizzes are available via a handy blue CME link under the article title in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.
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1. You are working in the pediatric emergency department when parents bring in their REQUIREMENTS: Learners
12-day-old male infant. They assert he has not been waking to feed over the past 24 hours. can take Pediatrics in
He normally breastfeeds every 3 hours for 20 minutes and now he sleeps almost Review quizzes and claim
continuously. They state he has had a cough and runny nose for the past few days with a credit online only at:
temperature of 38.1°C (100.5°F) and has been “floppy” for the past several hours. http://pedsinreview.org.
On physical examination, he is difficult to wake. His respiratory rate is 36 breaths/min, heart
rate is 120 beats/min, blood pressure is 57/35 mm Hg, and temperature is 38.0°C (100.4°F).
To successfully complete
His lungs are clear and cardiac examination reveals regular rate and rhythm without
murmur. His abdomen is soft. He has poor capillary refill (4-5 sec) and markedly decreased
articles for AMA PRA
tone. You suspect infection or a metabolic disorder. Which of the following is the initial
Category 1 CreditTM,
laboratory test in the evaluation of a metabolic disorder?
learners must
A. Blood glucose. demonstrate a minimum
B. Liver panel. performance level of 60%
C. Plasma amino acids. or higher on this
D. Serum ketones. assessment, which
E. Urine organic acids. measures achievement of
2. An 8-day-old female infant is admitted to the general pediatric ward with a 2-day history of the educational purpose
lethargy and vomiting. She was born at 38 weeks’ gestation via repeat cesarean section and/or objectives of this
and did well. She was discharged home on postnatal day 3. She has been breastfeeding activity. If you score less
every 3 hours with supplemental 20-cal/oz formula. Since last evening, she has become than 60% on the
difficult to arouse and has had multiple episodes of vomiting. She is not febrile and does assessment, you will be
not have cough, rhinorrhea, diarrhea, or a rash. There have been no ill contacts. given additional
She is started on ampicillin and gentamicin after obtaining blood, urine, and cerebrospinal opportunities to answer
fluid for culture. The third-year medical student on the service raises his hand and says he questions until an overall
has been researching a differential diagnosis. He states that urea cycle defects can present 60% or greater score is
in this manner and perhaps plasma ammonia should be assessed. Which of the following is achieved.
true when evaluating plasma ammonia?
A. A capillary specimen is more reliable than a venous specimen. This journal-based CME
B. Elevated results require a repeat specimen sent the following day, after initiation of activity is available
therapy. through Dec. 31, 2018,
C. The specimen should be placed on ice at bedside and immediately sent to the however, credit will be
laboratory. recorded in the year in
D. The specimen should be tested within 3 hours. which the learner
E. Venous compression from tourniquet use may cause a falsely low result. completes the quiz.
3. You are seeing a 17-year-old girl in the adolescent medicine clinic for the first time. She
states that she was diagnosed with phenylketonuria as an infant. She also mentions she
has been sexually active for the past 3 years and believes she is currently pregnant.
Although her primary physician has repeatedly counseled her to maintain a strict
phenylalanine-free diet, she has been noncompliant. You explain to her the risks to the
fetus associated with elevated phenylalanine levels, which includes which of the
following?
A. Craniosynostosis.
B. Hepatoblastoma.
C. Intellectual disability.
D. Renal insufficiency.
E. Skeletal dysplasia.
4. As the intern covering the pediatric ward, you check on a 5-day-old infant who was
recently admitted for a sepsis evaluation. His babysitter felt he had been lethargic, with
three episodes of emesis over the previous 12 hours. You note he has been started on
antibiotics, but you decide to obtain an ammonia assessment, which is reported as
1,742.3 mg/dL (1,244 µmol/L) 20 minutes later. You review the initial management of urea
cycle defects. Which of the following is most accurate in the treatment of a urea cycle
defect?
A. All US states screen for ornithine transcarbamylase deficiency.
B. Fever and common childhood illnesses do not play a role in exacerbations in
infants with urea cycle disorders.
C. Hemodialysis is commonly required to lower plasma ammonia concentrations and
nephrology should be consulted upon diagnosis.
D. Liver transplantation does not improve the long-term management of hyper-
ammonemia due to urea cycle defects.
E. Other dietary strategies, rather than removing protein from the diet, are recom-
mended by experts to avoid hyperammonemic crises.
5. You are preparing a lecture for pediatric residents on inborn errors of metabolism. Your
goal is to provide the information they need to immediately identify infants who may
present with a metabolic disorder and to begin management of these infants. Which of the
following acute treatments is most useful in the emergent management of suspected
metabolic disorders?
A. Dextrose-containing fluids with salt.
B. Dextrose-containing fluids without salt.
C. Hypertonic saline bolus (3 mL/kg).
D. Hypertonic saline bolus (10 mL/kg).
E. Normal saline bolus (10 mL/kg).

Inborn Errors of Metabolism (Metabolic Disorders)
Gregory M. Rice and Robert D. Steiner
Pediatrics in Review 2016;37;3
DOI: 10.1542/pir.2014-0122
Updated Information & including high resolution figures, can be found at:
Services http://pedsinreview.aappublications.org/content/37/1/3
References This article cites 13 articles, 2 of which you can access for free at:
http://pedsinreview.aappublications.org/content/37/1/3.full#ref-list-1
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Inborn Errors of Metabolism (Metabolic Disorders)
Gregory M. Rice and Robert D. Steiner
Pediatrics in Review 2016;37;3
DOI: 10.1542/pir.2014-0122
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/37/1/3
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca,
Illinois, 60143. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved.
Print ISSN: 0191-9601.

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Inborn Errors of Metabolism

OBJECTIVES After completing this article, readers should be

1. Use basic and speciﬁc laboratory tests to aid in the diagnosis of

Metabolic disorders can appear to be a frustratingly complex group of disorders

Vol. 37 No. 1 JANUARY 2016 3

TABLE. Summary of Clinical Features and Treatment of Disorders of

Metabolism Fat Protein Protein Protein

SPECIFIC BIOCHEMICAL LABORATORY EVALUATIONS

Vol. 37 No. 1 JANUARY 2016 5

Vol. 37 No. 1 JANUARY 2016 7

Vol. 37 No. 1 JANUARY 2016 9

Vol. 37 No. 1 JANUARY 2016 11

Vol. 37 No. 1 JANUARY 2016 13

Parent Resources from the AAP at HealthyChildren.org

Vol. 37 No. 1 JANUARY 2016 15

Vol. 37 No. 1 JANUARY 2016 17

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