Neonatal Presentations of Metabolic Disorders

Anna-Kaisa Niemi, MD, PhD*

*Division of Neonatology, Rady Children’s Hospital San Diego, University of California San Diego, San Diego, CA

Practice Gaps
1. Metabolic acidosis or primary respiratory alkalosis can be an early sign of
neonatal hyperammonemia.
2. Metabolic disorders in a neonate can involve any organ system and can be
challenging to diagnose.
3. Early detection of treatable metabolic conditions is important for
prognosis.
4. A normal newborn screening result does not exclude a metabolic disorder.

Abstract
Metabolic disorders in a neonate can present with involvement of any
organ system and can be challenging to diagnose. A newborn can
present with an acute metabolic crisis such as hyperammonemia or
seizures needing immediate management, with a more chronic clinical
picture such as cholestatic liver disease, or with structural abnormalities
such as skeletal manifestations. Early detection of treatable metabolic
AUTHOR DISCLOSURE Dr Niemi is the conditions is important to improve outcomes. Newborn screening has
recipient of the Endowed Rotating Chair in facilitated early detection and initiation of therapy for many metabolic
Clinical Excellence (ENRICH) award at
disorders. However, normal testing does not rule out a metabolic
University of California San Diego and Rady
Children’s Hospital and has provided disorder and a high index of suspicion should remain when caring for any
consulting to Horizon Pharmaceuticals. This critically ill neonate without a diagnosis. Whole exome sequencing (WES)
commentary does not contain a discussion of
an unapproved/investigative use of a or whole genome sequencing (WGS) can be powerful tools in rapid
commercial product/device. diagnosis of a potentially treatable metabolic condition in a critically ill
neonate. This review presents classic clinical presentations of neonatal
ABBREVIATIONS
FAOD fatty acid oxidation defect metabolic disorders and also highlights some uncommon neonatal
FTT failure to thrive manifestations of metabolic disorders to improve the recognition and
HFI hereditary fructose intolerance diagnosis of these conditions.
HIE hypoxic-ischemic encephalopathy
IUGR intrauterine growth restriction
LPI lysinuric protein intolerance
MMA methylmalonic acidemia
MRI magnetic resonance imaging
NBS newborn screening
PA propionic acidemia
RUSP Recommended Uniform Screening
Panel
WES whole exome sequencing
WGS whole genome sequencing

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 Objectives After completing this article, readers should be able to:

1. Recognize the need to order a serum ammonia evaluation in a neonate

with an unexplained metabolic acidosis or respiratory alkalosis.
2. Recognize that a variety of symptoms such as a history of fetal hydrops,
hypoxic-ischemic encephalopathy, cardiomyopathy, liver failure,
cholestatic liver disease, skeletal dysplasia, or Escherichia coli sepsis can be
a clue to a metabolic disorder.
3. Describe treatable metabolic disorders that present during the neonatal
period.

INTRODUCTION NEONATAL HYPERAMMONEMIA AND METABOLIC

ACIDOSIS
Inborn errors of metabolism, also known as biochemical
genetic disorders or metabolic disorders (referred to as such In neonates, classic scenarios in which a metabolic disor-
in this article), are a group of thousands of rare genetic der is more likely include those in which a neonate has
conditions that can present at any age from the fetal period severe metabolic acidosis with an anion gap, lactic acidosis,
to adulthood and can involve multiple organ systems. or hyperammonemia, which can also occur together.
(1)(2)(3) Neonatologists may only see a handful of newborns Severe metabolic acidosis with an anion gap occurs when
with metabolic disorders during their career. Although there a nonvolatile acid accumulates as a result of a block in a
is no effective treatment for some metabolic disorders and metabolic pathway. An anion gap metabolic acidosis is
the prognosis can be poor, some conditions can be effec- typical in neonates with organic acidemias such as meth-
tively managed with dietary modifications, medications, ylmalonic acidemia (MMA) and propionic acidemia (PA) as
supplements, or organ transplantation. Early detection of well as mitochondrial disorders in which lactic acid
these treatable conditions is important to improve out- accumulates.
Neonatal hyperammonemia results from either a pri-
comes. Therefore, neonatologists should have a high index
mary or secondary defect in the urea cycle, which is
of suspicion for a metabolic disorder in any critically ill
responsible for converting ammonia that is produced dur-
neonate with an unusual or unexplained presentation. New-
ing protein metabolism into blood urea nitrogen, which is
born screening (NBS) has facilitated early detection and
then excreted by the kidneys. Neonates with primary
initiation of therapy for many metabolic disorders. However,
defects in the urea cycle such as ornithine transcarbamylase
a normal test result does not rule out a metabolic disorder,
deficiency typically do not present with metabolic acidosis
and a high index of suspicion should remain when caring
but rather, have primary respiratory alkalosis resulting
for any critically ill neonate without a diagnosis.
from tachypnea. This tachypnea is thought to be caused
The purpose of this review is to summarize the classic
by stimulation of the central nervous system respiratory
clinical presentations of neonatal metabolic disorders as
center by the ammonium ion. (4)(5) In a neonate with
well as to highlight some uncommon neonatal manifesta-
hyperammonemia and a primary respiratory alkalosis (pH
tions of metabolic disorders to improve recognition of these >7.45, low partial pressure of carbon dioxide [PCO2]), urea
conditions. In this review, we focus on manifestations of cycle defects are highest on the differential. Neonatal hyper-
these disorders during the neonatal period; clinical presen- ammonemia with severe metabolic acidosis is a typical
tations after this period are beyond the scope of this review. presentation of organic acidemias such as MMA, PA,
We will discuss symptoms that can indicate a metabolic and isovaleric acidemia. (6)(7) Neonates with fatty acid
disorder rather than listing metabolic disorders and their oxidation defects (FAOD) may also present with neonatal
clinical presentations. We present several examples of met- hyperammonemia and often have a history of low/unde-
abolic disorders related to each clinical finding. For a com- tectable serum glucose. If the later is true, lipid adminis-
prehensive list of metabolic disorders associated with each tration should be avoided pending diagnosis. Mitochondrial
clinical sign, the reader is encouraged to refer to more com- disorders are a less common but possible cause of neonatal
prehensive publications, many of which are referenced here. hyperammonemia and should be considered if there is a

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TABLE 1. Metabolic Etiologies and Laboratory Evaluation of Neonatal
Hyperammonemia
DIAGNOSTIC/HELPFUL
BIOCHEMICAL
ACIDOSIS VS ALKALOSIS ETIOLOGYa COMMENTS LABORATORY STUDIES

Neonatal Metabolic acidosis (increased Organic acidemias • Anion gap acidosis is • Urine organic acids
hyperammonemiaa anion gap) severe (diagnostic)
• MMA • MMA: often lactic acidosis • Plasma acylcarnitines
• PA • PA: at risk for • Plasma total and free
cardiomyopathy carnitine (secondary
carnitine deficiency)
• Isovaleric acidemia • Plasma amino acids
• Multiple carboxylase • Serum/plasma MMA level
deficiency
• Multiple acyl-CoA • Serum lactic acid
dehydrogenase deficiency
• 3-Hydroxymethylglutaryl- • High BUN
CoA dehydrogenase
deficiency
• 3-Methylcrotonyl-CoA • Gene sequencingb
carboxylase deficiency
Mitochondrial disorders See “Other” for features and
diagnostic studies for
mitochondrial disorders
Respiratory alkalosis (primary) Urea cycle defects • Typically very low BUN • Plasma amino acids
• NAGS deficiency • Hyperammonemia • Urine orotic acid
typically severe in NAGS,
CPS, OTC and ASS
deficiency
• CPS deficiency • Hyperammonemia not • Urine organic acids
very common in arginase (orotic)
deficiency
• OTC deficiency
• Argininosuccinate
synthetase deficiency
(citrullinemia)
• Argininosuccinate lyase
deficiency
• Arginase deficiency
Amino acid transporter • Only a minority of patients • HHH and LPI: plasma
deficiencies with HHH or LPI do not amino acids, urine amino
present during neonatal acids
period
• HHH syndrome
• LPI
• Transient • Typically <36 weeks’ • Typical diagnostic
hyperammonemia of the gestational age, metabolites of urea cycle
newborn birthweight <2.5 kg, or other disorders are not
respiratory distress, present
presents <24 hours after
birth
• May be severe and require
ammonia scavengers
and/or dialysis

Continued

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 TABLE 1. (Continued )

DIAGNOSTIC/HELPFUL
BIOCHEMICAL
ACIDOSIS VS ALKALOSIS ETIOLOGYa COMMENTS LABORATORY STUDIES

Other c
Fatty acid oxidation defects • Often severe • Plasma acylcarnitine
hypoglycemia on initial profile
presentation
• Carnitine transporter • Risk of cardiomyopathy • Plasma total and free
deficiency and cardiac arrhythmias carnitine
• Carnitine palmitoyl • Urine organic acids
transferase 2 deficiency
• Carnitine acylcarnitine • Gene sequencingb
translocase deficiency
• Long-chain 3-hydroxyacyl- • Enzyme assay from
CoA dehydrogenase fibroblastsd
deficiency
• Very-long-chain acyl-CoA
dehydrogenase deficiency
Mitochondrial disorders • Severe lactic acidosis, • There are currently no
multisystem involvement diagnostic biochemical
markers for
mitochondrial disorders
• Mitochondrial DNA • Genetic testing or
defects enzyme analysis may
lead to diagnosis
• A defect in one of the
multiple nuclear
mitochondrial genes
Pyruvate carboxylase • Lactic acidosis, ketosis, • Plasma amino acids
deficiency hypoglycemia, FTT,
seizures • Gene sequencing

HIHA • Fasting or protein (leucine) • High insulin

sensitive hypoglycemia • Gene sequencing

ASS¼ argininosuccinate synthetase; BUN¼blood urea nitrogen; CoA¼coenzyme A; CPS¼ carbamyl phosphate synthetase; FTT¼failure to thrive; HHH¼
Hyperornithinemia-hyperammonemia-homocitrullinemia; HIHA¼hyperinsulinism/hyperammonemia syndrome; LPI¼ lysinuric protein intolerance;
MMA¼methylmalonic acidemia; NAGS¼N-acetylglutamate synthetase; OTC¼ornithine transcarbamylase; PA¼propionic acidemia.
a
This is not a comprehensive list of all possible causes of neonatal hyperammonemia. For example, liver failure, portocaval shunt, and bacterial
colonization with urease-positive organisms may also lead to hyperammonemia. This table lists the most common metabolic causes of neonatal
hyperammonemia.
b
Gene sequencing is typically done after a diagnosis has already been made via biochemical testing for confirmation and genetic counseling.
c
These conditions can present with either metabolic acidosis or respiratory alkalosis depending on other contributing factors such as sepsis or dehydration,
but often neither metabolic acidosis nor respiratory alkalosis have the same degree of severity as do organic acidemias or urea cycle defects, respectively.
d
Skin biopsy for fibroblast culture and subsequent enzyme assay from fibroblasts may be necessary in cases in which biochemical and genetic testing do
not provide a definitive diagnosis.

concurrent severe lactic acidosis. Neonates with organic acid- • Provision of energy in the form of carbohydrate and lipids
emias, especially MMA, can also have lactic acidosis because of to promote anabolism. Unless FAOD is suspected in
secondary mitochondrial dysfunction (8)(9)(10); however, typ- which case lipids should be avoided.
ically this acidosis is not as significant as that seen in patients • Insulin administration if hyperglycemia develops
with a primary mitochondrial disorder. Table 1 provides a list of • Correction of dehydration
conditions that may present with neonatal hyperammonemia • Central catheter for high dextrose (>12.5%) concentration
and diagnostic or helpful biochemical laboratory studies that intravenous fluids and frequent blood sampling
should be performed while initiating therapy. • Administration of an intravenous ammonia scavenger
Treatment of neonatal hyperammonemia is beyond the (eg, sodium benzoate/sodium phenylacetate)
scope of this review; however, keys to management, briefly, • Hemodialysis or continuous renal replacement therapy,
are as follows: in some cases, to rapidly decrease ammonia levels

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 For further review of the management of hyperammo- NEUROLOGIC
nemia, we refer the reader to publications focused on the
Encephalopathy
management of neonatal hyperammonemia. (6)(11)(12)(13)(14) Neonatal encephalopathy is defined as abnormal brain
Hyperammonemia is one of the most common neonatal function in a newborn manifested by decreased level of
presentations of metabolic disorders that will go undetected consciousness and responsiveness, such as a poor suck.
unless the ammonia level is checked. A timely diagnosis and Hypoxic-ischemic encephalopathy (HIE) is among the most
initiation of therapy to lower ammonia levels are vital for common causes of neonatal encephalopathy. Metabolic
prognosis. disorders can manifest similarly to, and mimic, HIE. (18)
In general, neonates with HIE are symptomatic since birth
whereas newborns with metabolic disorders typically
FETAL MANIFESTATIONS OF NEONATAL METABOLIC become symptomatic after an initial normal period. How-
DISORDERS ever, some metabolic disorders, such as mitochondrial
disorders, may potentially cause a lower tolerance of stress
Nonimmune Fetal Hydrops
during labor and the affected neonate may present with a
Because of early diagnosis and treatment of rhesus (Rh)
clinical picture similar to HIE.
isoimmunization, nonimmune causes now account for the
Neonatal seizures, as a result of metabolic disorders, may
majority of fetal hydrops cases. (15)(16) Metabolic disorders also cause neonatal encephalopathy and manifest immedi-
account for about 1% to 15% of nonimmune fetal hydrops. ately at birth (see next section). Brain magnetic resonance
(15)(16)(17) In particular, patients with storage disorders imaging (MRI) may help distinguish between HIE and
such as mucopolysaccharidosis type VII (Sly syndrome), metabolic causes of encephalopathy because HIE causes
Gaucher disease, infantile galactosialidosis, and transaldo- typical radiographic patterns of brain injury. (19)(20)(21) A
metabolic cause should be considered in cases of neonatal
lase deficiency can present with fetal hydrops. In a fetus with
encephalopathy if an acute perinatal event is absent (making
hydrops or a neonate with a history of fetal hydrops, a
HIE less likely), symptoms started after an initial normal
metabolic cause should be sought if more common condi- period, or seizures persist without an intracranial abnor-
tions such as fetal anemia, an infection, a chromosomal mality. Neonatal hyperammonemia and related conditions
disorder, and cardiac abnormalities have been ruled out. A (Table 1), maple syrup urine disease, and conditions that
metabolic disorder should also be considered if nonim- cause neonatal seizures (Table 2) should be considered
mune hydrops is also associated with other features of when metabolic causes of neonatal encephalopathy are
storage disorders such as a large placenta, hepatospleno- being considered.

megaly, or coarse features.

Seizures
Most neonatal seizures are caused by acute brain injury, and
Intrauterine Growth Restriction
brain MRIs can often determine the cause (eg, structural
Intrauterine growth restriction (IUGR) has multiple etiologic
brain abnormality, intracranial bleeding, HIE). (22)(23)
factors, ranging from placental insufficiency to chromosomal/
However, brain MRI findings in some metabolic disorders,
genetic and infectious causes. Metabolic disorders that can such as molybdenum cofactor deficiency, can mimic that of
lead to IUGR include mitochondrial disorders (energy HIE. (24)(25) Table 2 lists metabolic causes of neonatal
deficiency), peroxisomal disorders, disorders of cobalamin seizures with treatable or potentially treatable conditions
metabolism, and cholesterol biosynthesis defects. Typically, marked with an asterisk. Most of the time, however, therapy
however, IUGR is not the only clinical manifestation of should be initiated before the onset of symptoms or very
early in the course of symptoms (preferably before brain
these conditions.
MRI findings are apparent) such as in molybdenum cofactor
In the following sections, several clinical findings are
deficiency and serine biosynthesis defects. (26)(27)(28)
presented based on organ systems; if the reason for these
Treatment before the onset of symptoms can be possible
findings is unknown, the clinician should consider a met-
for disorders detected on NBS or if a diagnosis has been
abolic disorder. Some of the clinical findings presented made prenatally (eg, because of a history of metabolic
often have a fetal origin and may be detected prenatally, disorder in a previous child). Metabolic disorders should
especially those that involve structural changes. be strongly considered if the brain MRI in a neonate with

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 TABLE 2. Metabolic Causes of Neonatal Seizures
Neonatal seizures Typically present with isolated Cerebral folate deficiency (cerebral folate receptor gene FOLR1)*
neonatal seizures Creatine metabolism disorders (various genes)*
Folinic acid responsive seizures*
Glycine Encephalopathy (also known as non-ketotic hyperglycinemia)a,*
Glucose Transporter (GLUT1) deficiency*
Molybdenum cofactor deficiency (3 genes)b,*
Pyridoxal (activated B6) responsive seizures (pyridoxal phosphate-binding
protein gene PLBP, pyridoxamine 5-prime-phosphate oxidase gene PNPO)*
Pyridoxine (B6) responsive seizures (ALDH7A1 gene)*
Serine biosynthesis defectc,*
Sulfite oxidase deficiency
Typically present with other Biotinidase deficiency (though does not typically present in neonatal period)*
systemic symptoms (such as Fatty acid oxidation defects (if severe hypoglycemia)*
metabolic acidosis, lactic Maple syrup urine disease*
acidosis, hyperammonemia)
Mitochondrial disorders (severe lactic acidosis, often multisystem involvement)
Organic acidemias (eg, methylmalonic acidemia, propionic acidemia, multiple
carboxylase deficiency)d,*
Peroxisomal disorders (eg, Zellweger syndrome)
Urea cycle defects (if severe hyperammonemia)*

Conditions for which a treatment may be available are marked with an asterisk.
a
No effective therapy available but glycine reduction may relieve symptoms in some cases.
b
Treatment available only for 1 type of molybdenum cofactor deficiency and should be started before the onset, or early (within days of onset of
symptoms).
c
No effective therapy available but serine supplementation may relieve symptoms if started early.
d
Treatment is available for some organic acidemias. Seizures, if they do occur, mostly occur during an acute metabolic crisis (eg, hyperammonemia).
Therefore, the most important approach to treatment and prevention of seizures is management and prevention of an acute metabolic crisis.

seizures does not demonstrate a structural anomaly or acute metabolic, possible disorders include mitochondrial disor-
injury, if the perinatal history is normal, and especially if ders, peroxisomal disorders, and Pompe disease.
electroencephalography shows burst suppression. Identify-
ing treatable conditions early is important for prognosis.
Hydrocephalus
Diagnosis often requires sampling of cerebrospinal fluid for
Hydrocephalus is not a common presentation of a metabolic
neurotransmitters or amino acids and/or genetic testing
disorder in a neonate but has been described in patients
(gene panels for neonatal seizures, whole exome sequenc-
ing [WES], whole genome sequencing [WGS]). with cobalamin C and cobalamin D disorders. (30)(31)(32)

Microcephaly OPHTHALMOLOGIC
Although many metabolic disorders cause microcephaly Patients with metabolic diseases often need to be followed
postnatally, microcephaly at birth can be found in neonates for ophthalmologic manifestations. Furthermore, the oph-
with mitochondrial disorders, pyruvate metabolism disor-
thalmologic evaluation in a sick neonate may lead to a
ders, cobalamin synthesis defects, serine synthesis defects
diagnosis of a metabolic disorder. Neonates with metabolic
(also a cause of neonatal seizures), and sterol synthesis
disease can have eye abnormalities because of an accumu-
defects. (29) For additional information, refer to the section
on maternal conditions affecting a neonate. lation of an abnormal metabolic product (eg, galactosemia,
mucopolysaccharidoses) or a deficient energy metabolism
(mitochondrial diseases). Ocular manifestations of meta-
Hypotonia
Neonatal hypotonia is a nonspecific symptom that can arise bolic disorders include corneal clouding (mucopolysacchar-
from an abnormality in the central nervous system, periph- idoses, mucolipidoses), congenital cataract (see next
eral nervous system, neuromuscular junction, muscle itself, section), and cherry red spot (Niemann-Pick A and B,
or a metabolic or electrolyte abnormality. If the cause is galactosialidoses, gangliosidoses). (2)(33)

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Cataract including central nervous system disorders, primary pul-
Although many metabolic manifestations in the eye present monary processes, or physiologic disturbances such as
later in infancy or childhood, in the neonatal period, the hypoxemia or hypercapnia. A metabolic cause for neonatal
finding of a cataract in a neonate with multisystem disease tachypnea should be sought in cases of anion gap metabolic
can be an indication of galactosemia, a peroxisomal disor- acidosis, because the tachypnea could be the result of
der, Lowe syndrome, or multiple acyl-coenzyme A (CoA) accumulating organic acid (organic acidemias) or lactic acid
dehydrogenase deficiency. (33) (mitochondrial diseases). These infants typically have a
secondary respiratory alkalosis in an attempt to compensate
for their metabolic acidosis. Tachypnea associated with a
CARDIAC
primary respiratory alkalosis (pH >7.45, no anion gap)
Cardiomyopathies should prompt a clinician to consider hyperammonemia
A cardiomyopathy diagnosis can reveal an undetected met- as a result of a urea cycle defect, especially if there is any level
abolic disorder or a diagnosis of a metabolic disorder can of encephalopathy.
reveal an undetected cardiomyopathy or risk for it in future Pulmonary alveolar proteinosis can occur in patients with
years. Metabolic disorders can cause a dilated, hypertrophic lysinuric protein intolerance (LPI), (39) and pulmonary
or left ventricular noncompaction type of cardiomyopathy. arterial hypertension can be seen in some neonates with
(34)(35) Metabolic disorders in which cardiomyopathy can glycogen storage disorders, such as type I glycogen storage
be the presenting symptom include primary carnitine defi- disease (von Gierke), (40) but these typically do not manifest
ciency (typically associated with a dilated cardiomyopathy, during the neonatal period.
though cardiac presentation is more common later in child-
hood), very-long-chain acyl-CoA-dehydrogenase deficiency
GASTROINTESTINAL/NUTRITIONAL
and other long-chain FAODs (typically dilated cardiomyop-
athy), Pompe disease (hypertrophic cardiomyopathy), mito- Liver Failure
chondrial disorders (fatal infantile hypertrophic obstructive Metabolic disorders account for 13% to 54% of cases of
cardiomyopathy, also dilated cardiomyopathy), or Barth neonatal liver failure. (41)(42) Galactosemia, tyrosinemia,
syndrome (X-linked, more common in males, associated mitochondrial disorders (especially mitochondrial DNA
with left ventricular noncompaction type). Neonates with PA depletion syndromes), and congenital disorders of glycosyl-
are at risk for either dilated or hypertrophic cardiomyopathy. ation are common metabolic causes of liver failure in
Furthermore, although a neonate with cardiomyopathy neonates, though tyrosinemia typically presents after the
often has lactic acidosis because of poor perfusion second- neonatal period. Galactosemia can present within days of
ary to cardiac dysfunction, severe intractable lactic acidosis consuming galactose-containing milk (breast milk or lactose-
in a neonate should prompt an evaluation for a mitochon- containing formula) with signs of hepatocellular damage
drial disorder. such as jaundice, hepatomegaly, elevated transaminases,
and coagulopathy. Escherichia coli sepsis is relatively com-
Arrhythmias mon in symptomatic neonates with galactosemia. Positive
Accumulation of storage material in cardiomyocytes lead- urine-reducing substances without the presence of glucose
ing to cardiac conduction defects and arrhythmias may in the urine can be a sign of galactosemia. All galactose
occur in storage disorders. Though this typically does not (lactose)–containing products must be immediately stopped
occur in neonates, newborns with Pompe disease can if galactosemia is being considered, and soy-based formula
exhibit a shortened PR interval on electrocardiography. used until a diagnosis is either confirmed or ruled out. (43)
(36) Arrhythmias may also be caused by the accumulation Neonatal acute liver failure with elevated transaminases,
of toxic metabolites as occurs during a metabolic crisis in coagulopathy, and severe lactic acidosis can be seen in
patients with an FAOD. (37)(38) neonates with mitochondrial DNA depletion syndromes
(typically, multiple genes involved). (44)(45) The diagnosis
of hereditary fructose intolerance (HFI) should be consid-
RESPIRATORY
ered in a neonate who presents with recurrent episodes of
Tachypnea liver dysfunction (elevated transaminases, even coagulop-
Tachypnea is a common nonspecific symptom in both athy) with hypoglycemia, lactic acidosis, and hyperuricemia
term and preterm infants that can have multiple causes, that rapidly corrects with stopping formula and provision of

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 a dextrose infusion. Although an infant with HFI typically Diarrhea
presents with the classic clinical symptoms when the child Diarrhea resulting from metabolic disorders can be related
starts consuming vegetables and fruit (important sources of to deficient absorption such as rare intestinal disacchari-
fructose), some infant formulas may contain fructose, dase deficiencies (congenital lactase deficiency or sucrase
sucrose, or sorbitol (the latter 2 can be metabolized to isomaltase deficiency). (51)(52) Protein-losing enteropathy
fructose) and symptoms can occur earlier. (46) in an infant with multisystem involvement (eg, cardiac,
liver) can be a clue to congenital disorders of glycosylation.
(53)(54)
Cholestatic Liver Disease
Cholestatic liver disease is common in sick neonates, and
parenteral nutrition–induced cholestasis is common in RENAL
patients in the NICU. Peroxisomal disorders, mevalonic
Hemolytic Uremic Syndrome
aciduria, and congenital disorders of glycosylation are also A metabolic etiology is not typically considered in cases of
possible causes of neonatal cholestatic liver disease, espe- hemolytic uremic syndrome, which is well-described in
cially in a neonate with multisystem involvement. Bile acid patients with cobalamin synthesis pathway defects espe-
synthesis defects typically present with isolated cholestatic cially in cobalamin C defect. (55)(56)
liver disease. (47)(48) In adults, citrin deficiency typically
manifests with recurrent hyperammonemia, but neonates
Renal Fanconi Syndrome
often present with intrahepatic cholestasis. (49)
Generalized aminoaciduria, glucosuria, and renal tubular
acidosis can be seen in neonates with galactosemia,
Pancreatitis hereditary cystinosis, hereditary fructose intolerance,
Neonates with PA, MMA, isovaleric acidemia, and other mitochondrial disorders, and Fanconi-Bickel syndrome
organic acidemias are at risk for pancreatitis, especially (hepatorenal glycogenosis, glycogen storage disease type
during a metabolic crisis. Therefore, amylase and lipase XI). (2)(57)
should be checked in these patients with symptoms of
pancreatitis such as vomiting. (6)(7)(50) Renal Cysts
Multiple renal cysts or polycystic kidneys can be seen, even
Hepatosplenomegaly prenatally, in patients with peroxisomal disorders (eg, Zell-
Neonates with various storage disorders (eg, GM1 ganglio- weger syndrome), congenital disorders of glycosylation,
carnitine palmitoyl transferase II deficiency, and some
sidosis, I-cell disease, mucopolysaccharidosis type VII (Sly),
congenital disorders of glycosylation. (2)(58)(59)
or Niemann-Pick type A and C) can present with hepato-
splenomegaly or splenomegaly. A storage disorder is more
likely if there are additional findings such as fetal hydrops, SKELETAL
ascites, coarse facial features, and skeletal abnormalities
Stippled Epiphyses
such as dysostosis multiplex. (2)
Peroxisomal disorders are classic metabolic disorders asso-
ciated with stippled epiphyses (chondrodysplasia punctata).
Failure to Thrive These include peroxisomal biogenesis defects such as Zell-
Failure to thrive (FTT) is a nonspecific finding that can be weger syndrome as well as defects in peroxisomal enzymes
present in multiple metabolic diseases as a result of differ- such as rhizomelic chondrodysplasia punctata. (58)(60)(61)
ent causes such as malabsorption (associated with exocrine Of note, warfarin embryopathy can mimic some features of
pancreatic insufficiency, intestinal disaccharidase deficien- peroxisomal disorders, particularly structural defects such
cies), aminoaciduria (associated with renal Fanconi as stippled epiphyses. (62)
syndrome), or energy failure (found in mitochondrial
diseases). Metabolic causes of FTT should be sought, espe- Orthopedic/Skeletal
cially if the patient has already been evaluated for more Rhizomelic (proximal) shortening of limbs is typical of
common causes or if there are other signs of a metabolic peroxisomal disorders. Multiple skeletal abnormalities (ie,
disorder (eg, acidosis, dysmorphic features, multisystem dysostosis multiplex) such as thoracic deformity, kyphosis,
involvement). hip dislocation, clubfeet, and deformed long bones can be

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seen at birth in neonates with mucolipidosis type II (I-cell infiltration and hypersplenism leading to anemia and often
disease), GM1 gangliosidosis, or multiple sulfatase defi- pancytopenia can occur in storage disorders such as
ciency. (63)(64) A storage disorder should be considered Gaucher disease. Pancytopenia (often relatively mild and
in an infant with skeletal involvement, coarse features, and/ transient lasting a few weeks) can be found, especially in
or multisystem disease. Arthrogryposis multiplex congenita neonates with organic acidemias during and after an acute
(ie, multiple congenital contractures) have been described in metabolic crisis and is well described in patients with MMA
neonates with mitochondrial disorders (65) and storage and PA. (6)(69)
disorders such as perinatal-lethal Gaucher disease. (66)
Vacuolated Lymphocytes
Patients with diseases such as Pompe disease, mucolipido-
DERMATOLOGIC
sis type II, mucopolysaccharidoses, and Niemann-Pick dis-
Jaundice ease type I often have vacuolated lymphocytes that are seen
Cholestatic liver disease can lead to jaundice (see gastroin- on a blood smear. (2)
testinal section).
Coagulopathy
Ichthyosis Any metabolic disorder that presents with liver failure
Ichthyosiform or collodion skin changes are typical of the typically also has an associated coagulopathy and can be
perinatal lethal form of Gaucher disease. A history of fetal caused by galactosemia and mitochondrial DNA depletion
hydrops, ascites, and hepatosplenomegaly in a critically ill defects.
newborn further supports this diagnosis. Congenital ich-
thyosis (often with congenital erythroderma) can also be Hemophagocytic Lymphohistiocytosis
seen in neonates with peroxisomal disorders, X-linked Several metabolic disorders have been described to cause a
chondrodysplasia punctata, serine synthesis defects, steroid hemophagocytic lymphohistiocytosis/macrophage activa-
sulfatase deficiency, and multiple sulfatase deficiency. Of tion syndrome; these include LPI, multiple sulfatase defi-
note, low maternal serum unconjugated estriol in prenatal ciency, Gaucher disease, and galactosialidosis as well as
screening can be an indication of X-linked ichthyosis in a some organic acidemias. (70)
male fetus. (67)(68)

ODORS
DYSMORPHIC FEATURES
Some metabolic disorders have a classic distinctive odor in
Dysmorphic facial features are common in many chromo- sweat, urine, or other body secretions because of the accu-
somal and genetic syndromes. Neonates with metabolic mulating metabolite. The odor is typically stronger during a
disease can have coarse facial features, especially in severe metabolic crisis or when a metabolic disorder is poorly
forms of storage disorders such as multiple sulfatase defi- controlled. Table 3 includes examples of typical odors that
ciency, mucolipidosis type II (I-cell disease), infantile gal- have been typically associated with metabolic disorders.
actosialidosis, infantile sialidosis, GM1 gangliosidosis, and
peroxisomal disorders (especially Zellweger syndrome). (2)
NEWBORN SCREENING
Multisystem involvement is, again, typical of these conditions.
NBS, especially expanded NBS with tandem mass spectrom-
etry, has made it possible to analyze multiple analytes
HEMATOLOGIC
simultaneously and detect several inborn errors of metab-
Cytopenias olism. Most organic acidemias, FAODs, and amino acid-
Anemia, thrombocytopenia, and neutropenia, in isolation or emias can be detected via NBS. To promote uniform and
in combination (including pancytopenia), can occur in comprehensive NBS, the Department of Health and Human
neonates with metabolic disorders. Cytopenia can be caused Services has a list of w40 conditions called the Recom-
by a deficiency of a metabolite essential for cytopoiesis, bone mended Uniform Screening Panel (RUSP), which is peri-
marrow infiltration by storage material, hypersplenism, or odically updated with new disorders. (3)(71)(72) It is
bone marrow suppression during a metabolic crisis. Mac- recommended that all states screen for the conditions listed
rocytic anemia can be seen in inborn errors of cobalamin in the RUSP. However, although this list offers guidance,
(B12) or folate (folic acid) metabolism. Bone marrow it is not enforced by law. Some states adopt new

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 Teratogenic Effect
TABLE 3. Typical or Distinctive Odors Described Maternal uncontrolled phenylketonuria is a well-known
in Metabolic Disorders cause of a metabolic disorder with adverse fetal effects.
High maternal phenylalanine levels during pregnancy can
ODOR METABOLIC DISEASE
lead to microcephaly, intellectual disability, congenital heart
Maple syrup Maple syrup urine disease defects, esophageal atresia, and IUGR. The specific effects
Boiled cabbage Tyrosinemia and extent of the impact depend on the magnitude and
Hypermethioninemia timing of high phenylalanine levels with the period of
Mousy, musty Phenylketonuria organogenesis (ie, first trimester) being the most sensitive
Sweaty feet Isovaleric acidemia for structural anomalies.
Glutaric acidemia type II
Rotting fish Trimethylaminuria (odor only manifestation)
False-positive NBS Result
Cat urine 3-hydroxy-3-methylglutaric aciduria Two well-described maternal conditions that can cause a
Tomcat urine Multiple carboxylase deficiency false-positive NBS result in a neonate are primary carnitine
deficiency (carnitine transporter deficiency, low C0 on NBS)
and 3-methylcrotonyl-coA-carboxylase deficiency (high C5-
recommendations early whereas others are still in the pro- OH). If an infant has a positive NBS result for these
conditions, it could be the result of a maternal condition.
cess of adopting them. Some states also screen for additional
disorders not listed in the RUSP. This leads to slight
heterogeneity of disorders screened for by each state. (73) WHOLE EXOME/GENOME SEQUENCING
The most recent additions to the RUSP (and adopted by
A comprehensive review of WES and WGS is beyond the
many states) include Pompe disease, mucopolysaccharido- scope of this review; however, these diagnostic modalities
sis type I (ie, Hurler syndrome), and X-linked adrenoleu- have proven to be powerful tools in the rapid diagnosis of
kodystrophy. Disorders are typically detected with either an genetic and metabolic disorders in critically ill neonates and
elevated (upstream from the metabolic defect) or low (down- can provide a diagnosis in up to 30% to 50% of critically ill
stream from the metabolic defect) amount of analyte, or via infants in the NICU. (74)(75)(76)(77)(78)(79)(80) Early diag-
enzyme activity. It is important to recognize that a normal nosis can guide clinical management and improve progno-
NBS does not rule out a metabolic disorder because an sis in cases for which a therapy is available or help direct care
infant’s metabolite may have been above or below a cutoff toward palliative care in cases with a poor prognosis.
value at the time the NBS was performed. Also, most
metabolic disorders are not detected on NBS. Examples SUMMARY
of disorders not detected via NBS include mitochondrial
Metabolic disorders can present in various ways in a neo-
disorders, disorders of pyruvate metabolism, congenital
nate, ranging from a subtle symptom or finding in 1 organ
disorders of glycosylation, and most storage diseases, as
system to a severe multisystem presentation requiring
well as most conditions that cause neonatal seizures (Table
immediate management. Early recognition of treatable con-
2), with some exceptions. Therefore, maintaining a high
ditions can improve mortality and morbidity in neonates
index of suspicion of an inborn error of metabolism is vital affected by these conditions. Furthermore, a definitive diag-
in any critically ill neonate. nosis allows for genetic counseling about recurrence risk,
which is important for early recognition of these conditions
MATERNAL METABOLIC DISORDERS AFFECTING THE in future pregnancies or early in the neonatal period. Pre-
FETUS OR NEONATE natal diagnosis can help plan for a delivery at a tertiary care
center with expertise in metabolic disorders. Expanded NBS
Maternal metabolic disorders can affect the neonate because with more conditions added periodically, as well as WES and
the maternal metabolite can be toxic and thus, teratogenic. WGS, will continue to lead to earlier diagnoses of metabolic
Alternatively, high maternal amounts of the metabolite can disorders in a neonate. A high index of suspicion and
be transferred across the placenta to the fetus and post- continuous medical education about the advancing knowl-
natally lead to a false-positive NBS. edge of these conditions will help neonatologists detect

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metabolic conditions early and initiate treatment in those methylmalonic acidemia. Proc Natl Acad Sci USA.
2013;110(33):13552–13557
conditions for which an effective therapy is available.
10. Wilnai Y, Enns GM, Niemi AK, Higgins J, Vogel H. Abnormal
hepatocellular mitochondria in methylmalonic acidemia.
Ultrastruct Pathol. 2014;38(5):309–314
11. Niemi AK, Enns GM. Pharmacology review: sodium phenylacetate
American Board of Pediatrics and sodium benzoate in the treatment of neonatal
Neonatal-Perinatal Content hyperammonemia. Neoreviews. 2006;7(9):e486–e495 doi: 10.1542/
neo.7-9-e486
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• Know the etiology, clinical manifestations, laboratory features, therapy for urea cycle disorders: twenty years later. J Pediatr.
and management of infants with lysosomal, peroxisomal, and 2001;138(1 suppl):S46–S55
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14. Ah Mew N, Simpson KL, Gropman AL, Lanpher PBC, Chapman
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KA, Summar ML. Urea cycle disorders overview. GeneReviews.
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17. Sudrié-Arnaud B, Marguet F, Patrier S, et al. Metabolic causes of
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 Neonatal Presentations of Metabolic Disorders
Anna-Kaisa Niemi MD
NeoReviews 2020;21;e649
DOI: 10.1542/neo.21-10-e649

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 Neonatal Presentations of Metabolic Disorders
Anna-Kaisa Niemi MD
NeoReviews 2020;21;e649
DOI: 10.1542/neo.21-10-e649

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http://neoreviews.aappublications.org/content/21/10/e649

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 2000. Neoreviews is owned, published, and trademarked
by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,
Illinois, 60007. Copyright © 2020 by the American Academy of Pediatrics. All rights reserved.
Online ISSN: 1526-9906.

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