Inborn Errors of Metabolism:

From Preconception to Adulthood

Paul Kruszka, MD, MPH, National Institutes of Health, Bethesda, Maryland
Debra Regier, MD, PhD, Children’s National Rare Disease Institute, Children’s National Health System,
Washington, District of Columbia

Inborn errors of metabolism (IEM), although individually rare, occur in 1 out of every 1,500 births. The first opportunity to
detect IEM occurs during preconception counseling, when pregnant women and couples considering future pregnancies
can undergo carrier screening. For individuals of all ethnic backgrounds, the screening includes testing for a variety of IEM
and non-IEM. For individuals of Ashkenazi Jewish descent, carrier screening, per the American College of Medical Genetics
and Genomics, also includes testing for Tay-Sachs disease and four other IEM. Inborn errors of metabolism can present in
utero;​in newborns;​or in children, adolescents, and adults. Some IEM can be detected in utero with the use of ultrasonog-
raphy. Most commonly, IEM are detected at newborn screening. Expanded newborn screening, which now includes 34 core
conditions, allows for diagnosis in the newborn period and provides the opportunity for early institution of available treat-
ments. However, some newborns present with symptoms consistent with an IEM before the availability of pending newborn
screening results or present with symptoms attributable to an IEM not detectable with screening. Such situations are medical
emergencies requiring immediate consultation with a metabolic specialist. If a delay occurs in obtaining consultation, initial
treatment involves discontinuing feeding and providing high-rate glucose infusions. Some IEM present later in life. Children
may develop and present with dysmorphic facial features. In some cases, symptoms may not appear until adolescence or
adulthood when patients have residual enzyme activity that allows for slow accumulation of toxic molecules over time. Long-
term treatments are effective for some IEM. Treatments include dietary restrictions and enzyme-replacement therapies. (Am
Fam Physician. 2019;99(1):25-32. Copyright © 2019 American Academy of Family Physicians.)

Inborn errors of metabolism (IEM) are genetic con- Screening

ditions that block metabolic pathways involved in the PRECONCEPTION
breakdown of nutrients and the generation of energy. Per- The first opportunity to address IEM occurs with testing
turbation of these metabolic pathways results in a spec- of asymptomatic future parents. Certain populations have
trum of clinical findings affecting multiple organ systems. increased carrier rates for IEM, and preconception screen-
The diagnosis of IEM is challenging because the clinical ing has been shown to decrease disease prevalence.
presentation is often nonspecific;​however, more IEM are Carrier testing first began in the Ashkenazi (Eastern Euro-
now included in recommended newborn screening, which pean) Jewish population in the early 1970s with preconcep-
helps for early diagnosis. Therefore, knowledge of IEM has tion screening for carriers of Tay-Sachs disease.2,3 With the
become essential for physicians. Although individual IEM
are rare, the combined incidence is 1 out of every 1,500
births.1 This review discusses IEM disorders from precon- WHAT IS NEW ON THIS TOPIC
ception to adulthood.
Inborn Errors of Metabolism (IEM)
The American College of Obstetricians and Gynecologists
CME This clinical content conforms to AAFP criteria for has classified expanded carrier screening as an accept-
continuing medical education (CME). See CME Quiz on able pre-pregnancy and prenatal screening strategy for all
page 11. patients. Expanded screening refers to concurrently screen-
ing for as many as several hundred conditions, including both
Author disclosure:​​ No relevant financial affiliations.
IEM and non-IEM.
Patient information:​ Handouts on this topic are available at
https://​family​doctor.org/newborn-screening-tests/ (new- The initial treatment for all newborns and children with a sus-
born screening overview, including metabolic disorders) pected IEM comprises ending the buildup of toxic metabolites
and https://​family​doctor.org/condition/phenylketonuria- by discontinuing feeds and by preventing catabolism by giving
pku (PKU). glucose at a high infusion rate (5 to 10 g per kg per hour).

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 INBORN ERRORS OF METABOLISM
SORT:​KEY RECOMMENDATIONS FOR PRACTICE

Strength of
Clinical recommendation recommendation References Comments

The option of carrier screening for IEM should be discussed when providing C 7 Consensus
preconception counseling to women considering pregnancy.

Newborn screening is recommended for 34 disorders, including 25 IEM. C 14, 15 Consensus

An IEM disorder should always be considered in the differential diagnosis in C 24, 25 Expert opinion
infants being evaluated or treated for suspected infection, especially if the
infant does not respond to antibiotics as expected.

Physicians should consult with a metabolic specialist on an emergency basis C 16, 18 Expert opinion
upon diagnosis of IEM in a newborn.

The ACMG ACTion (ACT) sheets and algorithms should be used to further C 16, 18 Expert opinion
determine appropriate action after a positive newborn screen, particularly if
there is a delay in contacting a metabolic specialist.

ACMG = American College of Medical Genetics and Genomics;​IEM = inborn errors of metabolism.
A = consistent, good-quality patient-oriented evidence;​B = inconsistent or limited-quality patient-oriented evidence;​C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://​w ww.aafp.
org/afpsort.

advent of carrier screening, the incidence of Tay-Sachs dis- screening for inherited disorders;​however, preconception
ease decreased by 90% between 1970 and 1993 in the Jew- screening detects only the most common DNA variants
ish populations of North America.3 The American College associated with a particular IEM disorder. Thus, a normal
of Obstetricians and Gyne-
cologists (ACOG) and the
TABLE 1
American College of Medi-
cal Genetics and Genomics IEM and Non-IEM Disorder Carrier Screening Recommendations
(ACMG) have expanded the for Adults of Ashkenazi Jewish Descent from the ACMG and the ACOG
list of recommended carrier
testing for IEM beyond Tay- Carrier
Disease ACMG*† ACOG†‡§ frequency|| Sensitivity
Sachs disease in the Ash-
kenazi Jewish population Gaucher disease Recommended Consider 1/18 89% to 96%
(Table 1).4-6 Tay-Sachs disease Recommended Recommended 1/31 95% to 97%
In addition, ACOG has
Canavan disease Recommended Recommended 1/40 94% to 98%
recently classified expanded
carrier screening as an Familial hyperinsulinism — Consider 1/52 —
acceptable pre-pregnancy Glycogen storage disease type 1 — Consider 1/71 —
and prenatal screening
Maple syrup urine disease — Consider 1/81 —
strategy for all patients.7
Expanded screening refers Niemann-Pick disease type A Recommended Consider 1/90 92%
to concurrent screening Mucolipidosis IV Recommended Consider 1/127 95% to 97%
for as many as several hun-
ACMG = American College of Medical Genetics and Genomics;​ACOG = American College of Obstetri-
dred conditions—both IEM cians and Gynecologists;​IEM = inborn errors of metabolism.
and non-IEM—and is more *—ACMG recommends carrier screening in Ashkenazi Jewish individuals for these non-IEM:​cystic fibrosis,
accessible because of the familial dysautonomia, Fanconi anemia group C, and Bloom syndrome.
decreased cost of DNA †—Both ACMG and ACOG recommend carrier screening for all ethnicities for these non-IEM:​cystic fibrosis
and spinal muscular atrophy.
analysis. ‡—ACOG recommends carrier screening in Ashkenazi Jewish individuals for these non-IEM:​cystic fibrosis
Because of the previ- and familial dysautonomia;​ACOG recommends considering screening in Ashkenazi Jewish individuals for
ous recommendations and these non-IEM:​Bloom syndrome;​Fanconi anemia groups A, C, and G;​Joubert syndrome;​and Usher
syndrome.
decreased testing costs, phy- §—ACOG recommends that screening should be offered to couples of French Canadian or Cajun descent
sicians in family medicine, or with a family history of Tay-Sachs disease.
obstetrics, and maternal ||—Carrier frequency for Ashkenazi Jewish population.
fetal medicine are now Information from references 4 through 6.
able to offer preconception

26 American Family Physician www.aafp.org/afp Volume 99, Number 1 ◆ January 1, 2019

 TABLE 2

Inborn Errors of Metabolism for Which Newborn Screening

Is Recommended by the Secretary of Health and Human
Services Advisory Committee on Heritable Disorders in
screening test does not always elimi-
Newborns and Children
nate the possibility of an IEM disorder.
Condition listed by category Clinical presentation
NEWBORN Amino acid disorder
IEM disorder screening began in Classic phenylketonuria Cognitive impairment, seizures, spasticity
the 1960s with Dr. Robert Guthrie’s Homocystinuria Marfan-like appearance, lens dislocation, cogni-
development of a screening test for tive impairment, thromboembolism
phenylketonuria (PKU) from a blood Maple syrup urine disease Progressive encephalopathy
spot8; early knowledge of the disorder Tyrosinemia, type I Liver failure, septicemia, hypoglycemia, Fanconi
allowed for treatment of PKU with diet syndrome (renal tubulopathy)
restriction of the amino acid phenylal- Fatty acid oxidation disorder
anine.9 Expanded newborn screening Carnitine uptake defect/ Hypoketotic hypoglycemia, cardiomyopathy,
beyond PKU has occurred largely as carnitine transport defect liver disease
a result of the introduction of tandem Long-chain L-3 hydroxyacyl-CoA Hypoketotic hypoglycemia, cardiomyopathy,
mass spectrometry, which allows for dehydrogenase deficiency liver disease, recurrent rhabdomyolysis
testing of multiple metabolic condi- Medium-chain Acyl-CoA Reye-like syndrome, metabolic crisis after fasting
tions from a single blood spot.10,11 dehydrogenase deficiency with lethargy, nausea, vomiting, coma
Sensitivity for newborn screening Trifunctional protein deficiency Hypoketotic hypoglycemia, cardiomyopathy,
liver disease, recurrent rhabdomyolysis
using tandem mass spectrometry is
99.9%, and specificities range from Very long-chain Acyl-CoA dehy- Hypoketotic hypoglycemia, cardiomyopathy,
drogenase deficiency liver disease, recurrent rhabdomyolysis
99.9% to 99.99%.12,13 Because of the low
prevalence of these conditions, how- Organic acidemia
ever, positive predictive values range 3-hydroxy-3-methylglutaric Metabolic decompensation triggered by periods
from 26% to 37%.12,13 aciduria of fasting or infections

The Secretary of Health and Human 3-methylcrotonyl-CoA Encephalopathy, ketoacidosis, hyperammonemia

carboxylase deficiency
Services Advisory Committee on Her-
ß-ketothiolase deficiency Ketoacidotic attacks, sometimes leading to coma
itable Disorders in Newborns and
Glutaric acidemia type I Macrocephaly, encephalopathy
Children created the Recommended
Uniform Screening Panel14 to indicate Holocarboxylase synthetase Metabolic acidosis, neurologic defects, skin rash
deficiency
the conditions for which screening
Isovaleric acidemia Encephalopathy, ketoacidosis, hyperammonemia
should occur.15 The panel lists 34 core
Methylmalonic acidemia Encephalopathy, ketoacidosis, hyperammonemia
conditions, 25 of which are IEM15 (Table (cobalamin disorders)
215,16). The Recommended Uniform
Methylmalonic acidemia Encephalopathy, ketoacidosis, hyperammonemia
Screening Panel also lists 26 secondary (methylmalonyl-CoA mutase)
conditions that can be detected on tan- Propionic acidemia Encephalopathy, ketoacidosis, hyperammonemia
dem mass spectrometry that are in the
differential diagnosis of the core dis- Urea cycle disorders

orders.14 A number of criteria must be Argininosuccinic aciduria Neurologic and liver abnormalities

met for a disease to be added to the Rec- Citrullinemia type I Mild hyperammonemia, failure to thrive
ommended Uniform Screening Panel, Other
including the ability of U.S. states to Biotinidase deficiency Metabolic acidosis, neurologic defects, skin rash
conduct the screening, evidence of a net Classic galactosemia Liver and renal failure after start of milk feeds in
benefit from screening, and availability first week of life
of effective treatments.17 Individual Glycogen storage disease type II Failure to thrive, cardiomyopathy, hypotonia
U.S. states control newborn screening;​ (Pompe disease)
not all U.S. states screen for all core and Mucopolysaccharidosis I Hydrocephalus, cognitive impairment, coarse
facies
secondary conditions.14,15
Many IEM in newborns are med- X-linked adrenoleukodystrophy Intellectual regression, leukodystrophy, adrenal
insufficiency
ical emergencies, and physicians
should take immediate action if a pos- Information from references 15 and 16.
itive newborn screen is received. The

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 INBORN ERRORS OF METABOLISM
TABLE 3

Inborn Error of Metabolism Disorders Found in Second Trimester Prenatal Ultrasonography

Ultrasound findings

Brain Hydrops Renal Hyperecho- Liver Left ventricular

Condition IUGR anomalies fetalis anomaly genic colon Polyhydramnios steatosis noncompaction

Lysosomal storage diseases X

Cholesterol synthesis X
disorders (Antley-Bixler
syndrome, Greenberg dys-
plasia, CHILD syndrome)

Glycogen storage disease X X

type IV

Peroxisomal disorders X X

Fatty acid oxidation X X X

disorders

Organic acidemia (Barth X X X X

syndrome, methylmalonic
acidemia, holocarboxylase
synthetase deficiency,
mevalonic aciduria)

Amino acidopathies X X X

Congenital disorders of X X
glycosylation

CHILD syndrome = congenital hemidysplasia with ichthyosiform erythroderma and limb defects;​IUGR = intrauterine growth restriction.
Information from references 19 and 20.

following actions should be taken:​(1) contact the parents of are mucopolysaccharidosis VII, Gaucher disease, and GM1
the newborn to inform them of the situation;​(2) assess the gangliosidosis.19 Other IEM presenting in utero on ultraso-
newborn’s clinical condition;​and (3) provide prompt refer- nograpy during the second trimester are shown in Table 3.19,20
ral to a metabolic specialist.16,18 The ACMG provides ACTion Maternal history, examination, and laboratory findings
(ACT) sheet resources that describe the short-term actions a may be used in addition to fetal ultrasonography for indi-
health professional should follow in communicating with the cators of IEM for two particular conditions. In ornithine
family and in determining the appropriate steps for an infant transcarbamylase, the pregnant mother may be symptomatic
who has screened positive for an IEM disorder (see Medical with hyperammonemia, coma, and psychiatric symptoms.21
Genetic Practice Resources at http://​w ww.acmg.net). In long-chain hydroxyacyl dehydrogenase deficiency, the
mother can present with an acute fatty liver;​hyperemesis;​
Clinical Presentation and a syndrome with symptoms of hemolysis, elevated liver
Various IEM can present throughout a patient’s life span, enzymes, and low platelet count.22
from the prenatal period through adulthood. For all prenatal genetic diseases, whether detected with
ultrasonography or suspected from clinical findings, a
PRENATAL definitive diagnosis can be accomplished with chorionic
Some IEM present in pregnancy, with abnormalities villi sampling or amniocentesis.23
detected on ultrasound. For example, hydrops fetalis (fluid
accumulation in multiple body areas, such as ascites, pleu- NEWBORN
ral or pericardial effusions, or skin edema) may be seen on Many IEM present in the first month of life. Often, the new-
prenatal ultrasonography after 26 weeks’ gestation in lyso- born will initially appear healthy because metabolites occur-
somal storage diseases. Lysosomal storage diseases are a ring in the IEM disorder have been cleared via placental
group of disorders that result from an enzyme deficiency circulation during the intrauterine period. Those metabolites
that blocks the ability of lysosomes to digest large cellular accumulate only after birth;​thus, a symptom-free period
molecules. The most common lysosomal storage diseases after birth is a vital component of the medical history.16

28 American Family Physician www.aafp.org/afp Volume 99, Number 1 ◆ January 1, 2019

 INBORN ERRORS OF METABOLISM

Symptoms of IEM in newborns are typically nonspecific, all variations of metabolic diseases are covered in newborn
such as lethargy, poor feeding, vomiting, abnormal breath- screening tests.
ing, seizures, and/or hypotonia. Although these signs also
signal infection (including sepsis), which is more com- CHILDREN
mon, IEM must be considered in the differential diagnosis. Most conditions that present in the newborn period can
Additional findings that should raise concern about the present during childhood in a similar or less severe man-
possibility of an IEM disorder are metabolic acidosis, un- ner and in some cases are linked with dysmorphic physical
explained hypoglycemia,
constitutional liver dysfunc-
tion, and encephalopathy.16 TABLE 4
All newborns being
Metabolic Laboratory Testing when Inborn Errors of
evaluated for these pre-
Metabolism Are Suspected
sentations should have an
ammonia level and urine Examples of inborn errors of metabolism
Test Significance associated with abnormal values
ketone tests performed in
addition to the evaluation Urine
for possible infection or Ketones Sign of ketosis Ketouria found in organic acidemias, hypo-
sepsis. If acidosis is a con- ketotic hypoglycemia in fatty acid oxidation
disorders
cern (i.e., urine pH is low,
respiratory rate is abnor- Organic acids Elevated organic acids Amino acidopathies, organic acidemias,
mal), a confirmation blood in urine especially when fatty acid oxidation disorders
patient is in a fasting or
gas measurement should
catabolic state
be performed, even if the
pulse oximetry is normal. Blood
If any one of these tests is Electrolytes, creatine Acid-base analysis Anion gap in organic acidemias (i.e.,
abnormal or if the new- kinase, creatinine methylmalonic acidemia and propionic
acidemia)
born does not respond to
antibiotics as expected, 24,25
Creatine kinase Cardiomyopathy Fatty acid oxidation disorders, organic aci-
an IEM disorder should demias, mitochondrial disorders, glycogen
storage disorders
be considered, and a met-
abolic specialist should Coagulation studies, Liver disease Fatty acid oxidation disorders, tyrosinemia
be consulted. If obtaining alanine aminotrans- type I, mitochondrial defects, hereditary
ferase, aspartate fructose intolerance
support from a metabolic
aminotransferase
specialist is delayed, plasma
amino acids, acylcarnitine Glucose Hypoglycemia Glycogen storage diseases and fatty acid
oxidation disorders
profile, and urine organic
acids should be measured Ammonia Elevated levels cause Urea cycle disorders, organic acidemias
(Table 416). encephalopathy
Whereas many IEM pres- Arterial/venous gas pH, acid base analysis Acidosis (organic acidemias), elevated pH
ent after a period during (pH, bicarbonate, CO 2) (occasionally in urea cycle disorders)
which the newborn appears
Acylcarnitines Quantifies carbon chains Organic acidemias and fatty acid oxidation
healthy, some IEM may
esterified to carnitine disorders
clinically present before
the physician has received Amino acids Elevated amino acid Maple syrup urine disease, phenylketonuria,
the IEM disorder screening levels tyrosinemia type 1, some urea cycle disor-
ders, elevated glycine in organic acidemias
test results. Additionally, a
normal newborn metabolic Lactate Hypoxia and tissue per- Mitochondrial disorders, pyruvate dehydro-
screen should not deter fusion problems genase or carboxylase deficiency, organic
acidemias, glycogen storage diseases
physicians from perform-
ing a metabolic workup in Information from reference 16.
a sick newborn because not

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 INBORN ERRORS OF METABOLISM
FIGURE 1

A B C

Recognizable dysmorphic features associated with inborn errors of metabolism disorders.

(A) Six-month-old girl with Zellweger syndrome,26 which is a leukodystrophy caused by a peroxisome biogenesis
defect. Clinical features include epicanthal folds, high forehead, broad nasal bridge, hypoplastic supraorbital ridges,
and enlarged anterior fontanel.
Reprinted with permission from Klouwer FC, Berendse K, Ferdinandusse S, et al. Zellweger spectrum disorders. Orphanet J Rare Dis. 2015;10:151.

(B) A 21-month-old child with mevalonic aciduria displaying typical dysmorphic features to include down-slanting
eyes, blue sclerae, low set ears, and long face. 27 Mevalonic aciduria presents with developmental delay, progressive
ataxia, failure to thrive, visual defects, and periodic fevers.
Reprinted with permission from Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmoglobulinemia D
syndrome. Orphanet J Rare Dis. 2006;1:13.

(C) Congenital disorders of glycosylation are a group of disorders with a disturbed ability to glycosylate certain tissue
proteins and/or lipids, resulting in myriad presentations including seizures, ataxia, failure to thrive, liver disease, and
brain anomalies. Lipodystrophy in a congenital disorder of glycosylation syndrome type 1a is shown. 28
Reprinted with permission from Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. Lancet Neurol.
2012;11(5):453-466.

examination findings (Figure 1).26-28 Two of the most well- most important intervention is arranging urgent transfer
known examples are lysosomal storage disorders, Hunter to a center with a metabolic specialist.16,18 While awaiting
syndrome and Hurler syndrome.29,30 The dysmorphic transfer, the initial treatment is the same for all newborns
features may not present at birth, but they become more and children with a suspected IEM disorder:​stopping the
pronounced over time as the storage molecule accumulates. buildup of toxic metabolites by discontinuing feedings and
preventing catabolism by providing glucose at a high infu-
ADOLESCENTS AND ADULTS sion rate (5 to 10 g per kg per hour).33,34 This is the equivalent
Primary care physicians occasionally encounter IEM in ado- of 10% dextrose in an electrolyte solution at 1.5 times main-
lescents and adults (Table 531). Some children with IEM are tenance rate or 5% dextrose at twice the maintenance rate.
living longer because of new treatments and a better under- If this infusion leads to an elevation of serum lactate levels,
standing of how to avoid metabolic decompensation (e.g., it suggests the possibility of a mitochondrial disorder. If this
avoiding high-protein diets in organic acidemia and urea occurs, the 10% dextrose fluid should be replaced with a
cycle disorders). Also, some IEM have their onset in adults, lower glucose load, such as 5% dextrose.16
for example, adult-onset lysosomal storage disorders. Patients Although long-term treatment of IEM is beyond the
with these IEM have residual enzyme activity that allows scope of this review, note that chronic therapy is available
for slow accumulation of toxic molecules over time, and for many IEM. The best known examples that respond to
symptoms may not appear until adulthood. Some of these long-term management are the prototypical IEM disor-
disorders (e.g., Gaucher disease) can be treated with enzyme der, PKU, and Gaucher disease. PKU can be treated with a
replacement therapy.32 restricted phenylalanine diet, and Gaucher disease can be
treated with enzyme replacement. This demonstrates why
Treatment accurate diagnosis is important.
When physicians encounter a newborn or infant with acute This article updates a previous article on this topic by Raghu-
decompensation that is attributable to an IEM disorder, the veer, et al. 35

30 American Family Physician www.aafp.org/afp Volume 99, Number 1 ◆ January 1, 2019

 TABLE 5

Inborn Errors of Metabolism Presenting in Adolescents and Adults

Condition Incidence Pathophysiology Child presentation Adult/adolescent presentation

Hemochromatosis 1:​200 to High absorption of iron Rare before age 40 Liver disease, diabetes melli-
1:​400 in tus, renal failure, arthritis
Caucasians

Gaucher disease 1:​855 Deficiency of lysosomal Bone disease, hepato- Similar to early presentation
type 1 (Ashkenazi enzyme glucocerebrosidase splenomegaly, anemia, with the addition of osteopo-
Jewish) thrombocytopenia rosis and Parkinson disease

X-linked adrenoleu- 1:​20,000 to Peroxisomal disorder; Visual and hearing impair- Males:​onset 20 to 30 years
kodystrophy 1:​50,000 very long-chain fatty acid ment, leukodystrophy, of age with gait distur-
accumulation resulting in cerebellar ataxia, dementia bance, spastic paraparesis,
destruction of myelin and dementia, psychosis, adrenal
adrenal cortex insufficiency
Females:​onset after 30 years
of age, spastic paraparesis,
peripheral neuropathy

Wilson disease 1:​30,000 Copper accumulation Liver failure Tremor, Parkinson-like symp-
disorder toms, dysarthria, renal failure,
dementia

3-methylcrotonyl 1:​36,000 Leucine metabolism disorder Infants present with Asymptomatic mother iden-
CoA carboxylase seizures and feeding tified after her newborn has
deficiency difficulties abnormal newborn screening
test because of mother’s
metabolites in infant’s blood

Fabry disease 1:​50,000 to X-linked lysosomal storage Males with less than 1% Heterozygous females typi-
1:​1 17,000 disease from deficiency of the α-Gal A present in child- cally present later in life than
males enzyme alpha-galactosidase hood or adolescence with males with milder symptoms
A (α-Gal A) acroparesthesia, angio-
keratoma, renal and heart
disease

Ornithine transcarba- 1:​70,000 Most common urea cycle dis- Often fatal in newborn Adolescent females with
mylase deficiency order;​X-linked inheritance males dietary protein aversion,
abdominal pain, and
headaches

Homocystinuria 1:​200,000 Reduced activity of the cysta- Developmental delay Osteoporosis, dislocated
thionine ß-synthase enzyme, ocular lenses, thrombophilia
which is involved in the con-
version of the essential amino
acid methionine to another
amino acid (cysteine)

Carnitine palmi- Rare Fatty acid metabolism Newborns present with Rhabdomyolysis, muscle
toyltransferase II disorder cardiomyopathy and liver weakness, and myopathy in
deficiency failure adolescents and adults after
physical activity

GM2 gangliosidosis Rare Lysosomal storage disease Progressive weakness, Motor neuron disease, dysto-
(Tay-Sachs disease decreased attentiveness, nia, cerebellar degeneration,
and Sandhoff disease) blindness, and death in bipolar disease, psychosis
year 2 or 3 of life

Porphyria Rare Abnormally high levels of Rare before puberty Seizures, extremity pain,
porphyrins and porphyrin pre- chest pain, abdominal pain,
cursors because of deficiency photosensitivity
of the enzyme hydroxymeth-
ylbilane synthase

Information from reference 31.

January 1, 2019 ◆ Volume 99, Number 1 www.aafp.org/afp American Family Physician 31

 INBORN ERRORS OF METABOLISM

Data Sources:​ A PubMed search was completed in Clinical Que- 12. Lund AM, Hougaard DM, Simonsen H, et al. Biochemical screening of
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Dis. 2010;​33(suppl 3):​S133-S138.
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inghouse, Bandolier, and Essential Evidence Plus. Search date:​
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15. Advisory Committee on Heritable Disorders in Newborns and Chil-
The opinions and assertions contained herein are the private dren. Recommended Uniform Screening Panel. https://​w ww.
views of the authors and are not to be construed as official or hrsa.gov/advisor ycommittees/mchbadvisor y/heritabledisorders/
as reflecting the views of the U.S. Department of Health and recommendedpanel/index.html. Accessed July 1, 2017.
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17. Perrin JM, Knapp AA, Browning MF, et al. An evidence development
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32 American Family Physician www.aafp.org/afp Volume 99, Number 1 ◆ January 1, 2019