Testing for Inborn Errors REVIEW ARTICLE

of Metabolism

C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Jennifer M. Kwon, MD, MPH, FAAN

ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of genetic metabolic
disorders that can be identified by metabolic tests readily available to
neurologists, such as tests for ammonia, plasma amino acids, and urine
organic acids. The limitations of these tests are also discussed, as they only
screen for a subset of the many inborn errors of metabolism that exist.

RECENT FINDINGS: Advances in next-generation sequencing and the emerging

use of advanced metabolomic screening have made it possible to diagnose
treatable inborn errors of metabolism that are not included in current
newborn screening programs. Some of these inborn errors of metabolism
are especially likely to present with nonspecific neurologic phenotypes,
such as epilepsy, ataxia, or intellectual disability. However, cost may be a
barrier to obtaining these newer tests. It is important to keep in mind that
common metabolic testing may lead to treatable diagnoses. Resources are
available to guide neurologists in diagnosing genetic metabolic conditions.

SUMMARY: This article introduces the clinical presentations of treatable

CITE AS:
inborn errors of metabolism that are important for neurologists to consider
CONTINUUM (MINNEAP MINN)
in patients of all ages. Inborn errors of metabolism are rare, but they can 2018;24(1, CHILD NEUROLOGY):37–56.
present with neurologic symptoms. Newborns are now screened for many
treatable metabolic disorders, but these screening tests may miss milder Address correspondence to Dr
Jennifer M. Kwon, 601 Elmwood
presentations of treatable inborn errors of metabolism that present later in Ave, Box 631, Child Neurology,
life. These patients may present to adult neurologists who may be less Rochester, NY 14642,
likely to consider metabolic genetic testing. Jennifer_kwon@urmc.rochester.
edu.

RELATIONSHIP DISCLOSURE:
Dr Kwon has received personal
INTRODUCTION compensation for serving as a

I
nborn errors of metabolism are rare yet numerous and often present with consultant for BioMarin, the
neurologic symptoms. This article provides an overview of genetic metabolic Evidence Review Committee of
the Health Resources and
disorders that can be identified by metabolic tests readily available to Services Administration, and
neurologists, such as tests for ammonia, plasma amino acids, and urine Sanofi Genzyme and receives
research/grant support from
organic acids.
the Hunter’s Hope Foundation.
Newborns in the United States are now screened for many treatable inborn
UNLABELED USE OF
errors of metabolism, but newborn screening tests may miss milder presentations PRODUCTS/INVESTIGATIONAL
of treatable inborn errors of metabolism that can present later in life. These USE DISCLOSURE:
patients may present to adult neurologists who may be less likely to consider Dr Kwon discusses the
unlabeled/investigational use of
metabolic genetic testing. carglumic acid for the treatment
of carbamoyl phosphate
PRESENTATION OF INBORN ERRORS OF METABOLISM synthetase deficiency.

One of the challenges of testing for inborn errors of metabolism is recognizing © 2018 American Academy of
that acute, urgent, and nonspecific presenting symptoms (eg, poor oral intake, Neurology.

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INBORN ERRORS OF METABOLISM
KEY POINT
● There must be a low
threshold for considering
an inborn error of
metabolism since
presentations are
nonspecific.
CASE 2-1
COMMENT
38
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lethargy, and seizures) may warrant additional metabolic screening tests to help
identify an inborn error of metabolism with its own specific treatment (CASE 2-1).
The use of metabolic screening tests (TABLE 2-11) in addition to the standard
laboratory testing of sick patients (ie, complete blood cell count; a comprehensive
chemistry panel that includes glucose, liver transaminases, calcium, and uric
acid; ammonia; lactate; pyruvate; and urinalysis) will identify some treatable
defects of intermediary metabolism of proteins, carbohydrates, and fats.
Although inborn errors of metabolism are often seen in infants, they can
present at any age. Neurologists should consider these disorders in patients
with (1) recurrent attacks of encephalopathy, vomiting, ataxia, and metabolic
acidosis, especially when the attacks appear to be triggered by illness or changes
in diet (since both catabolism and increased protein intake can provoke
metabolic deterioration); (2) progressive or chronic symptoms of failure to
A 10-day-old infant boy was brought to the pediatric emergency
department with new-onset seizures. His prenatal course and delivery
had been normal, and he had been discharged home 24 hours after birth.
Initially, he was breast-feeding at regular intervals. After a week, he was
not feeding well and seemed to sleep more frequently. The patient’s
mother brought him to the emergency department because of an episode
in which he stiffened, arched his back, and had a series of jerks. The
event lasted seconds, and he had been lethargic since the event.
On examination, he was difficult to arouse. He was afebrile with a pulse
of 160 beats/min and a respiratory rate of 20 to 30 breaths/min, but
occasionally he had pauses in his breathing. Initial laboratory results showed
a normal complete blood cell count. A chemistry panel showed the
following abnormalities: a bicarbonate level of 16 mmol/L, glucose of
50 mg/dL, aspartate transaminase of 90 U/L, alanine transaminase of 110 U/L,
and an ammonia level of 160 µmol/L. Urinalysis showed ketones but was
otherwise normal. Plasma amino acids and urine organic acids were pending.
This is a classic presentation of an organic acid disorder, where an infant
who appears to do well shortly after birth will begin to show lethargy,
poor feeding, respiratory pauses, and seizures the week following
birth. In this setting, heightened concern for sepsis always exists,
although, in this case, the lack of fever and a normal complete blood cell
count are reassuring. The development of symptoms after a week of life
suggests that the infant may not be tolerating feeding. The abnormal
chemistry values and elevated ammonia suggest a primary metabolic
disorder, especially one of amino acid degradation, and this would
significantly alter treatment. Even without a specific diagnosis, the initial
treatment would be IV fluids with a high concentration of glucose to
maintain caloric intake and avoid further catabolism (to minimize stressing
the impaired amino acid degradation system).
FEBRUARY 2018
thrive, weakness, or developmental delay; or (3) unusual organ dysfunction such
as cardiomyopathy, hepatomegaly, skeletal findings, or lens dislocation.

CLASSIFICATION OF INBORN ERRORS OF METABOLISM

Metabolic disorders are often subdivided into three groups based on their
clinical and physiologic characteristics (TABLE 2-2).2 Disorders in the first group
lead to excessive accumulation of a substance or compounds with intoxicating
effects (eg, vomiting or obtundation), as seen in organic acid disorders or urea
cycle defects. The second group of disorders directly affect energy metabolism,
causing symptoms in more metabolically active organs such as the brain (eg,
coma, brain malformations), as seen in respiratory chain disorders or pyruvate
dehydrogenase complex deficiency. The third group of disorders involves defects

Common Metabolic Screening Tests Used to Identify Treatable Disorders TABLE 2-1
of Intoxication and Energy Metabolisma

Test Name Conditions Screened

Ammonia Urea cycle defects, organic acidurias

Plasma amino acids Aminoacidopathies, urea cycle disorders, some organic acidurias

Urine organic acids Organic acidurias

Plasma acylcarnitine profile Organic acidurias, fatty acid oxidation defects

a 1
Modified with permission from Kwon JM, D’Aco KE, Neurol Clin. © 2013 Elsevier.

Pathophysiologic Effects of Three Categories of Metabolic Disorders TABLE 2-2

Triggers
(Illness, Diagnosis Made by
Pathophysiologic Protein Available Metabolic
Effects Examples Appearance at Birth Load) Screening Tests Treatable
Metabolite Organic acid disorders, Usually normal Often Often Often
accumulation and urea cycle defects,
intoxication aminoacidopathies

Impairment of Mitochondrial Sometimes normal but Often Sometimes; may need Sometimes
energy metabolism disorders, fatty acid may affect metabolically enzyme or DNA testing
oxidation disorders active tissues (eg, brain
malformation)
Disruption of Peroxisomal disorders, Sometimes normal, but Rare Rarely; diagnosis usually Rare
complex molecule lysosomal disorders some present with requires specialized
metabolism dysmorphology enzyme or DNA testing
or organomegaly

DNA = deoxyribonucleic acid.

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INBORN ERRORS OF METABOLISM

KEY POINTS
● Inborn errors of
metabolism often present
with symptoms that suggest
sepsis or gastrointestinal
illness accompanied by
weakness, developmental
delay, and poor growth. If
the history suggests decline
or an attack of illness
associated with increased
catabolism or increased
protein intake, consider
testing for metabolic
disorders.
● Neurologists should
recognize the highly
specialized nature of
diagnosing and treating
metabolic disorders and
involve a metabolic
geneticist in the diagnosis
and care of patients with
inborn errors of
metabolism.
● Almost all inborn errors
of metabolism are
autosomal recessive
disorders. Genetic
counseling must be
provided to families
learning of a diagnosis of an
inborn error of metabolism.
in the catabolism of complex molecules in cell organelles, as seen in lysosomal
storage disorders or peroxisomal disorders.
This article discusses disorders in the first and second groups, which are typically
considered small molecule disorders affecting the intermediary metabolism of
proteins, fats, and sugars, while the third group includes large molecule disorders.
This article emphasizes inborn errors of metabolism with neurologic presentations
in which early diagnosis and treatments can lead to better outcomes. The following
section begins with an overview of the disorders physicians are most likely to
identify using commonly available metabolic screening tests, including urea cycle
defects, organic acidurias, and aminoacidopathies. The second section continues
with a discussion of other treatable inborn errors of metabolism that should also be
considered and that are not readily found using the tests in TABLE 2-1.
TREATABLE INBORN ERRORS OF METABOLISM IDENTIFIED BY
BIOCHEMICAL SCREENING TESTS
Abnormalities in the metabolism of amino acids can lead to urea cycle defects,
organic acid disorders, and other aminoacidopathies (FIGURE 2-1). These
disorders of protein intermediary metabolism present in infancy or childhood
and are characterized by sudden attacks, episodic relapses and remissions, and
nonspecific physical findings. Metabolic screening tests (TABLE 2-1) in blood and
urine are used to detect many of these disorders. Often, a diagnosis is
suggested by the pattern of abnormalities on screening, with more specific
diagnoses made through DNA-based or specific enzyme testing. Confirmation
of diagnoses and management requires the assistance of specialists with
expertise in metabolic disorders. Most of the disorders discussed are inherited
as autosomal recessive conditions, so carrier parents are unaffected, and

● Prior to delivery, infants

are protected from toxic
effects of metabolite
accumulation by placental
clearance, which is why a
symptom-free period often
occurs right after birth.

FIGURE 2-1
Metabolism of amino acids occurs by deamination or removal of the amino group (urea cycle
disorders), metabolism of the carboxyl skeleton of the amino acid (organic acid disorders),
or transformation into other amino acids or compounds (amino acid disorders).

40 FEBRUARY 2018

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FIGURE 2-2
Urea cycle. Pathways of the urea cycle are shown as solid (one enzymatic step)
or dashed (multiple enzymatic steps) black lines with arrows. Open, double-headed arrows
on dotted lines show amino acids that are transported between cytosol and mitochondrion.
The reactions of the urea cycle remove excess ammonia (NH4) into excretable urea and
synthesize arginine. The first two steps are intramitochondrial, and the rest occur in the
cytoplasm. The enzyme carbamoyl phosphate synthetase I (CPS) incorporates NH4 to make
carbamoyl phosphate in a reaction requiring N-acetylglutamate made from glutamate by
N-acetylglutamate synthetase (NAGS). Carbamoyl phosphate, joined with ornithine via
ornithine transcarbamylase (OTC), makes citrulline. Citrulline moves out of the mitochondria
to the cytosol where argininosuccinate synthetase (ASS) condenses it with aspartate to form
argininosuccinate. This, in turn, is cleaved by argininosuccinate lyase (ASL) to form arginine
and fumarate. As the final step in the cycle, arginine is cleaved by arginase to urea, which is
excreted, and ornithine, which is transported from the cytosol to the mitochondria, to restart
the cycle. Disorders of the urea cycle are caused by deficiencies of enzymes labeled in
hexagons and the jagged lines mark the location of the enzyme defect.

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INBORN ERRORS OF METABOLISM
KEY POINTS
● In the setting of acute
encephalopathy (eg,
where a lumbar puncture
would be considered an
appropriate test),
remember to check an
ammonia level.
● Elevated ammonia levels
can cause vomiting,
encephalopathy, cerebral
edema, and
hyperventilation.
● Urea cycle defects can
present as a catastrophic
neonatal illness or during
childhood or teenage years,
often after significant
stress (eg, pregnancy,
steroids, excessive protein
ingestion.)
● Although ornithine
transcarbamoylase
deficiency is X-linked, men
may present later in life.
CASE 2-2
COMMENT
42
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siblings are at risk. For this reason, if these diagnoses are considered, genetic
counseling should be sought.
Urea Cycle Defects
Excess amino acids are metabolically consumed via the urea cycle (FIGURE 2-2),
which serves to convert ammonia into excretable urea and synthesize arginine,
which is essential for nitric oxide and creatine production.3,4 Neonates with
urea cycle defects generally appear normal for their first 24 hours of life (as
they benefit from the placental clearance of ammonia) and afterward become
lethargic and have difficulty feeding (CASE 2-2).4 Vomiting, hypothermia,
hyperventilation, and cerebral edema with bulging fontanelle can develop early
in the course of disease and are the result of ammonia intoxication. Respiratory
alkalosis results from this hyperventilation, and, if acidosis develops, it is a late effect
from respiratory depression and tissue damage. Routine chemistries are often
unremarkable or may only show a low blood urea nitrogen (as low as 1 mg/dL).
TABLE 2-3 outlines some of the clinical characteristics of the urea cycle
disorders as well as the plasma citrulline and urine orotic acid profiles that can
help distinguish them. Except for arginase deficiency, the other urea cycle
defects have similar clinical presentations in the neonatal period: infants may be
asymptomatic in the first 24 to 48 hours and then develop progressive lethargy,
poor feeding, vomiting, hypothermia, seizures, and hyperventilation. Arginase
deficiency has classically been thought to present with a more slowly progressive
course, resulting in spastic quadriparesis, intellectual disability, and less
abnormal hyperammonemia. Later-onset urea cycle defects may present with
episodic ataxia, progressive cognitive and physical disabilities, or fulminant
progressive encephalopathy. All urea cycle defects are inherited as autosomal
A 3-day-old infant girl was brought to the emergency department with a
1-day history of poor feeding and decreased activity. On presentation, she
was lethargic and tachypneic and had developed abnormal movements of
her right arm and leg, which were worrisome for seizures. A sepsis workup
and metabolic tests were performed, and antibiotics and antiepileptic
medications were initiated. Initial investigations showed a high ammonia
(440 μmol/L) level and respiratory alkalosis. She was started on sodium
phenylacetate and sodium benzoate, IV arginine, IV high dextrose, and
continuous insulin infusion, and when her ammonia level continued to rise
to 890 μmol/L, she was prepared for dialysis. Her plasma amino acids
showed elevated glutamine and glycine and undetectable citrulline.
The high ammonia and plasma amino acid profile suggest a proximal urea
cycle defect, possibly carbamoyl phosphate synthetase, ornithine
transcarbamylase, or N-acetylglutamate synthase deficiency (FIGURE 2-2).
Subsequent genetic testing confirmed N-acetylglutamate synthase deficiency,
which is the rarest of the urea cycle defects but has a specific treatment
(carglumic acid).
FEBRUARY 2018
recessive disorders except for ornithine transcarbamoylase deficiency, which is
X-linked. While this suggests that males are likely to have a more severe
presentation of ornithine transcarbamoylase deficiency, many reports exist of
males who present in adulthood (CASE 2-3).
The principles of treatment3,4 in urea cycle defects, particularly in the acute
state, are to (1) rapidly lower plasma ammonia to normal levels; (2) employ
pharmacologic interventions to enhance nitrogen excretion; and (3) use
nutritional strategies to address the catabolic state by providing essential amino
acids, glucose, and fats.
The long-term management of these disorders requires dietary restriction of
protein, use of nitrogen scavengers such as sodium phenylbutyrate and sodium
benzoate, and replacement of citrulline and arginine as needed. Liver
transplantation can also be used to treat urea cycle defects.

Organic Acid Disorders (Organic Acidemias, Organic Acidurias)

Organic acid disorders are caused by deficiencies of enzymes (often located
in the mitochondria) needed for the metabolism of the activated carbon skeleton
of amino acids (FIGURE 2-1).2 They are characterized by an accumulation of
organic acids proximal to the defective enzyme in the metabolic pathway.

Distinguishing Biochemical Findings and Selected Clinical Characteristics TABLE 2-3

of Urea Cycle Disordersa

Enzyme Deficiency Urine Orotic Acid Plasma Citrulline Selected Clinical Characteristics
N-acetylglutamate synthase Low Low Rarest of the urea cycle disorders; N-
(CASE 2–2) acetylglutamate synthase deficiency also has a
specific and effective treatment, carglumic acid

Carbamoyl phosphate Low Low Some patients with carbamoyl phosphate

synthetase synthetase deficiency may also respond to
carglumic acid

Ornithine transcarbamoylase
(CASE 2–3)
High Low Most common urea cycle defects; X-linked; while
often lethal in boys, girls who present in the
neonatal period may do poorly as well; both
men and women may present later in life with
an episodic ataxia or encephalopathy, often
associated with illness, high protein load, or
steroid-triggered catabolism

Argininosuccinate synthetase High Very high Presentation and management similar to ornithine
transcarbamoylase deficiency

Argininosuccinate lyase High High, with high Episodic hyperammonemia; unique symptoms
argininosuccinate including hypertension, liver fibrosis, and
developmental delay; plasma and CSF show
elevated argininosuccinate

Arginase High Normal Progressive spastic quadriplegia and mental

retardation

CSF = cerebrospinal fluid.

a
Data from Ah Mew N, et al, GeneReviews.3

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INBORN ERRORS OF METABOLISM
KEY POINTS
● Hyperammonemia is
seen in organic acid
disorders because the
accumulating acids inhibit
the urea cycle.
● Treatable cobalamin
defects may present in
adulthood with brain and
spinal cord abnormalities
suggestive of myelin
disorders.
CASE 2-3
COMMENT
44
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Accumulation of organic acids leads to metabolic acidosis with an anion gap and
hyperammonemia, which occurs because excess organic acids deplete coenzyme
A (CoA) and impair urea cycle reactions, which, in turn, leads to encephalopathy
and seizures. Accumulating organic acids also have toxic effects on other organs,
leading to bone marrow suppression, cardiomyopathy, renal dysfunction, and
pancreatitis. FIGURE 2-3 contains some of the more important organic acid
disorders likely to present to neurologists.
METHYLMALONIC ACIDEMIA. Methylmalonic acidemia is relatively common
compared to other organic acid disorders, with an estimated prevalence of 1 per
48,000,6 and is likely to present with neurologic symptoms at all ages, often
without clear metabolic crises. Several genetic defects can result in the increased
production and therefore excretion of methylmalonic acid. The classic and severe
form is due to an absence of methylmalonyl-CoA mutase activity (FIGURE 2-3),
and young infants present with acute encephalopathy including coma, lethargy,
hypotonia, vomiting, and respiratory distress. Later, neurologic sequelae include
A 17-year-old boy was brought to the emergency department after a
new-onset generalized convulsion that lasted 6 minutes and was
associated with urinary incontinence. Prior to this, he had been healthy
but had begun experiencing intermittent nausea and vomiting for 1 week
without diarrhea or fever, coincident with starting a new fitness program
and the intake of high-protein supplements. On arrival in the emergency
department, he was afebrile with normal vital signs. He was lethargic but
arousable to pain.
Initial laboratory results were notable for an elevated alanine
aminotransferase level of 166 U/L (normal range less than 42 U/L) and an
ammonia level of 787 μmol/L (normal range 16 μmol/L to 60 μmol/L). The
rest of his comprehensive chemistry panel (including bicarbonate level),
coagulation profile, and complete blood cell count were normal.
Ultrasound of his abdomen was normal. He was started on lactulose, but
after 24 hours his ammonia level did not improve, and he became less
responsive. He was intubated, and a head CT showed diffuse cerebral
edema. Prior to being started on dialysis, plasma amino acids and
quantitative urine organic acids were obtained, which showed a low
plasma citrulline level of 7 μmol/L (normal range 19 μmol/L to 62 μmol/L),
and his urine orotic acid was elevated at 27.7 mmol/mol creatinine
(normal range 0 mmol/mol to 1.3 mmol/mol creatinine).
Neurologists should consider obtaining an ammonia level when faced with
acute encephalopathy.3 The history of taking in a high protein load just prior
to decompensation is suggestive of a disorder of amino acid metabolism,
and the very high ammonia level with no metabolic acidosis (based on
normal bicarbonate level) suggests a urea cycle defect.5 The additional
finding of low citrulline and elevated urine orotic acid suggests that the
defect is in ornithine transcarbamoylase (FIGURE 2-2).
FEBRUARY 2018
FIGURE 2-3
Intermediary metabolism of amino acids leads to adenosine triphosphate production via the
Krebs cycle. Pathways of intermediary metabolism of glucose and selected amino acids are
shown with one or two arrowheads to indicate one or multiple enzymatic steps. All pathways
lead to the Krebs cycle, which, in turn, drives oxidative phosphorylation to make adenosine
triphosphate. Disorders are labeled in parallel lines, which are placed to mark the enzymatic
block. Vitamin cofactors are shown as ovals and include biotin, pyridoxine, folate,
adenosylcobalamin (Ado-Cbl), and methylcobalamin (Me-Cbl). Cobalamin, or vitamin B12,
is transported across the cell membrane and metabolized to Ado-Cbl. Methylmalonic
acidemia is therefore caused by defects in the pathway making cobalamin or by
methylmalonyl-CoA mutase deficiency.
ATP = adenosine triphosphate; CoA = coenzyme A; PC = pyruvate carboxylase complex deficiency;
PDHD = pyruvate dehydrogenase deficiency.

extrapyramidal symptoms, such as dystonia, associated with basal ganglia

(globus pallidus or putamen) injury. Chronic renal dysfunction is another late
complication. The laboratory findings show severe metabolic acidosis, ketonuria,
hyperammonemia, neutropenia, and thrombocytopenia. Urine organic acids
include marked accumulation of methylmalonic acid, 3-hydroxypriopionate,
2-methylcitrate, and tiglylglycine.
Abnormalities of intracellular cobalamin processing can also present with
methylmalonic acidemia and may respond to cobalamin supplementation
(FIGURE 2-3 and CASE 2-4). These disorders may present in adulthood with
mental status changes, dementia, and myelopathy. Imaging may show
demyelinating lesions in the brain and spinal cord.

PROPIONIC ACIDEMIA AND ISOVALERIC ACIDEMIA. Propionic acidemia and isovaleric

acidemia have similar presentations to methylmalonic acidemia in infants
(TABLE 2-48–13). Of the three, propionic acidemia tends to be associated
with more long-term neurologic sequelae, including basal ganglia and white

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INBORN ERRORS OF METABOLISM
KEY POINT
● Serum methylmalonic
acid and homocysteine,
commonly used to identify
vitamin B12 and folate
deficiency, will also help
screen for treatable
cobalamin defects.
CASE 2-4
COMMENT
46
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matter lesions. Isovaleric acidemia is generally less severe in presentation
and outcome.
Acute management of methylmalonic acidemia, propionic acidemia, and
isovaleric acidemia includes correcting the acidosis, hypoglycemia, and
hyperammonemia.6,8–10 In methylmalonic acidemia, parenteral cobalamin
may help nonclassic presentations of disease. In propionic acidemia, biotin
administration may enhance the defective enzyme function. Chronic
management of methylmalonic acidemia, propionic acidemia, and isovaleric
An 8-year-old boy was brought to the emergency department for a
new-onset seizure and a 3-month history of behavior changes. His seizure
was a generalized convulsion lasting 1 minute that had begun while he was
eating breakfast. A few weeks prior to this event, he had become
increasingly irritable, with aggressive outbursts, agitation, and visual
hallucinations, but he had been healthy previous to these symptoms. He
had been started on risperidone a week before presentation to the
emergency department. In the emergency department, about an hour
after his seizure, he seemed tired but could talk and walk.
His physical examination was unremarkable. His neurologic examination
was notable for limited cooperation, slow responses, increased tone of his
arms and legs, stiff gait, and brisk reflexes. He had no dysmetria.
His initial laboratory evaluation showed a normal comprehensive
chemistry panel, ammonia level, and complete blood count. His CSF
showed normal protein and glucose and no evidence of infection. His
EEG (awake) showed a slow background and no epileptiform discharges.
Brain MRI showed scattered small patches of periventricular signal
abnormalities on T2-weighted images (that were nonenhancing on
postcontrast T1-weighted images), prominent in the centrum semiovale
and basal ganglia.
The radiologic findings prompted admission for observation and
additional testing. Thyroid, cortisol, lysosomal storage enzymes,
very-long-chain fatty acids, and vitamin E, vitamin B12, and folate levels
were normal. Plasma homocysteine was 200 μmol/L (normal less than
20 μmol/L), plasma methylmalonic acid was 1013 μmol/L (normal less than
30 μmol/L), and his plasma amino acid studies confirmed elevations in
homocystine as well as a low methionine. Urine organic acids also showed
excretion of high amounts of methylmalonic acid.
Based on the MRI, neurologists would consider a diagnosis of an acquired
white matter disorder or an early presentation of hereditary disorders of
white matter such as metachromatic leukodystrophy or X-linked
adrenoleukodystrophy. Small molecule disorders such as organic acidurias
may also present in this way, and prompt specific treatment may be
lifesaving. This boy’s metabolic profile was consistent with a cobalamin
processing defect that results in elevated levels of methylmalonic acid
and homocysteine.7 He showed improvement once he began receiving
cobalamin injections.
FEBRUARY 2018
acidemia includes protein restriction, and some have benefited from
liver/kidney transplantation.
TABLE 2-4 also mentions two other organic acid disorders. Multiple
carboxylase deficiency caused by either biotinidase deficiency or
holocarboxylase synthetase deficiency can be treated with biotin. Multiple
carboxylase deficiencies should therefore be considered in any young child with
nonspecific neurologic findings, such as spasticity or myelopathy with upper
motor neuron findings, especially if skin abnormalities are present.11,12 Children
with glutaric aciduria type I may be seen by neurologists for their macrocephaly.
Their imaging, which shows widened sylvian fissures and prominent
subarachnoid spaces, may be misinterpreted as showing cortical atrophy.13
Prompt recognition of this disorder can prevent progressive brain (especially,
basal ganglia) injury. Management protocols for glutaric aciduria type I,

Selected Organic Acid Disorders TABLE 2-4

Organic Acid Urine Organic Acid

Disorders Defective Enzyme (Cofactor) Findings Selected Clinical Findings

Propionic Propionyl-CoA carboxylase 3-Hydroxypropionate, Classic presentation in infancy with

acidemia8 (biotin) methylcitrate, tiglylglycine, encephalopathy, severe metabolic acidosis,
and propionylglycine hyperammonemia, and neutropenia; central
nervous system white matter and basal
ganglia abnormalities may develop

Isovaleric Isovaleryl-CoA dehydrogenase Isovaleryl glycine and Like methylmalonic acidemia and propionic
acidemia9,10 isovaleric acid acidemia, presents with encephalopathy
and metabolic acidosis; urine has a “sweaty
feet” odor; about one-half of patients
have a later-onset, more chronic form of
the disease

Multiple Four biotin-requiring 3-Hydroxypropionate, Biotinidase and holocarboxylase synthetase

carboxylase carboxylase enzymes, including
deficiency11,12,a propionyl CoA carboxylase and
pyruvate carboxylase
3-hydroxyisovalerate, and
3-methylcrotonylglycine
deficiency are associated with hypotonia,
seizures, lethargy, irritability, alopecia, rash,
and laryngeal stridor,11 but biotinidase
deficiency is milder and presents later;
urine may have a strong (“tomcat”) odor;
myelopathy with or without vision loss is
one presentation of biotinidase deficiency;12
treatment with biotin is effective for both
disorders

Glutaric Glutaryl-CoA dehydrogenase Glutaric acid and After a period of normal development,
aciduria type I13 3-hydroxyglutarate infants present with metabolic crises
associated with dystonia, opisthotonus,
and seizures; may have macrocephaly and
involuntary movements; central nervous
system imaging shows widened sylvian
fissures and increased subarachnoid
spaces

CoA = coenzyme A.
a
Multiple carboxylase deficiency is due to biotinidase deficiency and holocarboxylase synthetase deficiency.

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INBORN ERRORS OF METABOLISM
KEY POINTS
● The organic acid
disorders methylmalonic
acidemia and propionic
acidemia can selectively
damage basal ganglia and
white matter.
● Late-onset organic acid
disorders may be treatable
and are relatively easy to
screen for with urine
studies; their identification
may prevent permanent
brain injury.
● Elevated phenylalanine
acts as a neurotoxin, which
is why the phenylalanine-
restricted diet for
phenylketonuria is a diet
for life.
● Untreated
homocystinuria is
associated with strokes,
lens dislocation, and
skeletal abnormalities.
● The clinical presentation
of maple syrup urine
disease, with metabolic
crisis and coma, is similar to
the organic acid disorders,
but there may be no
metabolic acidosis or
hypoglycemia.
48
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
including supportive care during illness and infection, will prevent catabolism
and the onset of metabolic crises.
Amino Acid Disorders (Aminoacidopathies)
Amino acid disorders are due to enzyme defects in amino acid metabolism and
are identified with plasma amino acid assays.2 (Urine amino acid assays are not
usually indicated and should only be ordered by a metabolic specialist.) Amino
acid disorders are often characterized by early encephalopathy, usually without
metabolic acidosis, but the nature of the encephalopathy and clinical
presentation vary. Some of the better-known aminoacidopathies are discussed in
this article. All are inherited as autosomal recessive traits.
PHENYLKETONURIA. Phenylketonuria is caused by defects in phenylalanine
hydroxylase (FIGURE 2-3), which converts phenylalanine to tyrosine in the
presence of the cofactor tetrahydrobiopterin. Elevated phenylalanine interferes
with transport of tryptophan and tyrosine into the brain and also has direct toxic
effects on the brain. During early development, high levels of phenylalanine
cause severe irreversible mental retardation. The devastating effects of
phenylketonuria can be prevented by initiation of a phenylalanine restricted
diet within the first weeks of life. Thanks to newborn screening, infants with
phenylketonuria can be identified shortly after birth and treated early, thereby
avoiding permanent cognitive impairment. However, because phenylalanine has
toxic effects even in the adult brain, patients with phenylketonuria are advised to
stay on their diet for life. Phenylketonuria is the most common treatable
aminoacidopathy, with an incidence of approximately 1 per 11,000.14
HOMOCYSTINURIA. Homocystinuria is caused by a deficiency in cystathionine
$-synthase, which catalyzes the metabolism of homocysteine to cystathionine.
Some patients with homocystinuria respond to pharmacologic doses of
pyridoxine. The reason for this is not quite clear since pyridoxine is not a
cofactor, although pyridoxal 50 -phosphate is a ligand for cystathionine
$-synthase. Since pyridoxine responsiveness only occurs when residual
cystathionine $-synthase activity is present, it is not surprising that those who are
unresponsive to pyridoxine have more severe presentations.15 Homocystinuria is
associated with the childhood onset of cognitive impairment, skeletal
abnormalities including lens dislocation, marked myopia, and vascular disease
with strokes and pulmonary embolism.
Other signs include bony abnormalities including scoliosis, anterior chest
deformities, and disproportionately long legs that are similar to those seen in Marfan
syndrome. Diagnosis is suggested by elevated plasma levels of homocysteine,
homocystine (measured in plasma amino acid assays), and methionine. Those who
do not respond to pyridoxine are placed on a methionine-restricted and cysteine-
supplemented diet and may also receive pyridoxine and betaine, a methyl donor
that remethylates homocysteine to methionine. These treatments appear to lower
the risk of intravascular thrombosis.16
MAPLE SYRUP URINE DISEASE. Maple syrup urine disease is a rare disorder
(incidence of approximately 1 per 185,000) caused by defects in the enzyme
branched chain a-keto acid dehydrogenase.17 Patients typically present in the
first 1 to 2 weeks of life when infants develop feeding difficulties and decreased
FEBRUARY 2018
responsiveness, after which stupor, respiratory abnormalities, myoclonus,
posturing, and spasms may occur. The characteristic odor of burnt sugar may
be detected at this time. The fontanelle may be full or bulging, and imaging studies
may show cerebral edema. Routine laboratory evaluation may show ketonemia/
ketonuria, metabolic acidosis, and hypoglycemia, or these findings may be absent,
requiring a high index of suspicion to make this diagnosis. Plasma amino acids (as
well as urine and CSF) will show elevations in leucine, isoleucine, valine, and their
keto acid derivatives; some of these compounds appear to be highly neurotoxic.
Less common presentations of maple syrup urine disease include neonatal
ophthalmoplegia (with or without other cranial nerve palsies), hypotonia,
episodic decompensations (CASE 2-5) (including coma and signs of raised
intracranial pressure), or more chronic failure to thrive and slowed development.17
The acute effects of maple syrup urine disease need to be treated with
aggressive supportive measures, including IV fluid hydration, dextrose
administration, and branched-chain amino acid–free total parenteral nutrition.9
Chronic maintenance treatment includes use of branched-chain amino acid–free
formulas and low-protein diets. Thiamine, a cofactor for branched-chain a-keto
acid dehydrogenase, may be used as an additional treatment in some cases. These
measures can significantly improve neurologic outcome when instituted promptly.

Summary and the Role of Newborn Screening

Defects of intermediary protein metabolism (urea cycle disorders, organic acid
disorders, and aminoacidopathies) are relatively easy to diagnose using the
metabolic tests described in TABLE 2-1, and they have serious neurologic sequelae

A 5-year-old girl was admitted with a high fever, vomiting, and worsening CASE 2-5
somnolence. Her developmental history was normal. Encephalitis or
meningitis was suspected, and she was given acyclovir and cefotaxime.
A full septic evaluation was performed. Her lumbar puncture was normal,
and her other laboratory tests were remarkable only for mild hyponatremia
with a sodium level of 130 mmol/L and a low bicarbonate level of
11 mmol/L. Her plasma ammonia, glucose, and lactate were normal. The
patient’s head CT and later MRI were normal.
She had experienced a similar episode, also with a febrile illness,
2 years previously, also with similarly inconclusive screening tests.
However, during the current admission, she had more metabolic testing,
and her plasma amino acids showed elevations of leucine, isoleucine,
and valine, consistent with maple syrup urine disease. She was treated with
protein restriction and received parenteral glucose, nonbranched-chain
amino acids, and lipids to lower her branched-chain amino acid levels.
Clinical recovery followed.

This is a case of intermittent maple syrup urine disease, which can present COMMENT
18
with intermittent attacks of lethargy and ataxia, especially during illness.
Prevention of these attacks allows children with the intermittent form of
maple syrup urine disease to have normal development.

CONTINUUMJOURNAL.COM 49

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INBORN ERRORS OF METABOLISM

if unrecognized and untreated. Disorders of fatty acid and carbohydrate

metabolism (eg, medium-chain acyl-CoA dehydrogenase deficiency,
galactosemia) will not receive similar attention in this article, and the reader is
directed to other excellent resources.2,19 The disorders described above as well as
other important and treatable conditions arising from defects in the intermediary
metabolism are currently screened for in newborns in the United States so
that affected infants can be promptly recognized and receive appropriate
treatment.20 Still, it is important for the neurologist to keep in mind that
screening programs may still miss milder presentations of these disorders, so the
metabolic tests outlined in TABLE 2-1 remain important to consider. The next
section describes treatable inborn errors of metabolism seen by neurologists that
require additional tests to identify.

TREATABLE INBORN ERRORS OF METABOLISM NOT DETECTED ON COMMON

METABOLIC SCREENING
Many treatable inborn errors of metabolism that present to neurologists are
not readily identified by common metabolic screening tests nor do they
reliably present with metabolic acidosis or hyperammonemia. In the case of
pyridoxine-dependent seizures and glucose-transporter deficiency syndrome,
these diagnoses are generally considered in the evaluation of a neonate with
refractory seizures, and it is in this setting that the additional tests, such as the
pyridoxine challenge or CSF glucose, are obtained. These diagnoses are less
frequently considered after early infancy, so a high index of suspicion is needed
to embark on screening and diagnostic testing. TABLE 2-5 lists some inborn errors

TABLE 2-5 Additional Metabolic Tests to Consider When Screening for

Treatable Inborn Errors of Metabolism

Treatable Inborn Errors Of Metabolism

Biochemical Assay/Test Identified Treatment
Blood and CSF lactate, Pyruvate dehydrogenase complex Ketogenic diet, thiamine
pyruvate deficiency
Few treatments; some may respond to biotin21
Pyruvate carboxylase deficiency

Blood copper, Wilson disease Chelation

ceruloplasmin
Menkes syndrome (X-linked) No treatment except in presymptomatic boys22,23

CSF glucose (compared Glucose transporter 1 deficiency Ketogenic diet

with serum glucose)

CSF amino acids Nonketotic hyperglycinemia No treatment for severe, early-onset form; in late-onset
disease, treatment includes glycine restriction, sodium
benzoate, N-methyl-D-aspartate (NMDA) receptor
antagonists24
Urine creatine Creatine deficiency syndromes (including Creatine, possibly with ornithine supplementation and
metabolites guanidinoacetate methyltransferase arginine restriction
deficiency)

CSF = cerebrospinal fluid.

50 FEBRUARY 2018

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of metabolism in which additional biochemical assays may lead to KEY POINTS
treatable diagnoses.21–24
● Pyridoxine-dependent
epilepsy used to be a
Pyridoxine-Dependent Epilepsy clinical diagnosis but now
The classic presentation of pyridoxine-dependent epilepsy is an infant with biochemical (plasma and
severe neonatal seizures refractory to standard anticonvulsant therapy in urine α-aminoadipic
semialdehyde) and
whom the seizures respond both clinically and electrographically to large daily
molecular (ALDH7A1 gene)
supplements of pyridoxine (vitamin B6). Although neurologists have been aware tests are available.
of this disorder for some time, only recently has the exact defect been shown to
be mutations in the ALDH7A1 gene.25 Prior to having a true biochemical or ● Diagnosis of glucose
genetic test for the condition, the diagnosis had traditionally been a clinical one, transporter type 1 deficiency
requires documentation of
made by administering 100 mg to 500 mg of IV pyridoxine (pyridoxine low CSF glucose values in
challenge) while monitoring the EEG and looking for significant improvement the setting of normal blood
and cessation of seizures. Now, direct DNA testing is available, and the diagnosis glucose. Mutational testing
can also be confirmed by finding elevations in plasma and urine a-aminoadipic of the SLC2A1 gene can also
be performed.
semialdehyde. Later-onset forms or atypical cases include late-onset seizures (up
to 2 years of age); seizures that initially respond to anticonvulsants and then ● Patients with glucose
become intractable; seizures during early life that do not respond to pyridoxine transporter type 1 deficiency
but that are then controlled with pyridoxine several months later; and prolonged can be treated with the
ketogenic diet.
seizure-free intervals (up to 5.5 months) that occur after pyridoxine
discontinuation. Cognitive impairment is common.
Pyridoxine-dependent seizures are treated with high doses of daily
pyridoxine. In the past, before specific testing was available, many children with
intractable early-onset epilepsy were continued on empiric pyridoxine treatment
for at least several months. It is also known that another form of neonatal
encephalopathy and seizures is caused by abnormalities in the pyridoxal
pathway. The related disorder is caused by recessive mutations in pyridoxal 50 -
phosphate oxidase,26 and this condition is treated with pyridoxal phosphate,
although some cases are responsive to pyridoxine.27

Glucose Transporter Type 1 Deficiency Syndrome

Glucose transporter type 1 deficiency syndrome is caused by impaired transport
of glucose across the blood-brain barrier, which causes a wide range of clinical
phenotypes, the most typical of which are early-onset seizures, developmental
delay, and movement disorders.28 This condition can also present with cognitive
impairment with fluctuating ataxia, motor incoordination, or altered
consciousness. Other children may have more normal developmental trajectories
but may have early-onset generalized epilepsy. The diagnosis is made by
documenting a low CSF glucose in the setting of normal blood glucose levels.
Mutation analysis of the SLC2A1 gene can also be performed. The evaluation of
the CSF glucose should be accompanied by a CSF lactate evaluation. In glucose
transporter type 1 deficiency syndrome, CSF lactate is low to normal, while it is
often elevated in other inborn errors of metabolism or infections.29 Without
glucose, the only other source for brain energy is through ketones, so treatment
with the ketogenic diet is recommended as it will likely stop the seizures and may
prevent other neurologic sequelae.

Creatine Deficiency Syndromes

Creatine deficiency syndromes are composed of three disorders that lead to
low creatine levels in the brain.30,31 They are caused by defects in creatine

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INBORN ERRORS OF METABOLISM

biosynthesis due to a deficiency of either the enzyme arginine:glycine

amidinotransferase deficiency or guanidinoacetate methyltransferase deficiency
or caused by creatine transport defects due to mutations in the X-linked
transporter gene SLC6A8. In all cases, a nonspecific syndrome of developmental
and cognitive impairment, global delays, and epilepsy may occur. In
guanidinoacetate methyltransferase deficiency due to mutations in GAMT
(CASE 2-6), the epilepsy may be intractable, and patients may also develop a

CASE 2-6 A 30-month-old boy with a history of developmental delay presented

with a several-week history of brief eye-rolling episodes. In the past
week, the episodes had become more frequent and had been occurring
throughout the day, often lasting minutes at a time. His prior history was
notable for developmental delay after an unremarkable pregnancy and
birth. He began rolling at age 5 months, sitting at age 8 months, and taking
independent steps at 15 months of age. He was a quiet and content infant
who did not start using syllables or babbling until he was 10 months of age,
and currently, at age 2 years, only said “uh oh” and “mo.” He repeated
other words when prompted but had limited spontaneous speech, did not
follow simple commands, and tended to get objects he wanted rather
than point to them. The patient had no history of regression and was
otherwise healthy. His growth parameters (stature, weight, and head
circumference) had been proceeding along the 50th to 60th percentiles.
His family history was unremarkable for developmental delays,
intellectual disabilities, autism, or seizures.
Video-EEG monitoring over 2 days showed a slow-waking background
and frequent epileptiform discharges with complex morphology lasting 1
to 5 seconds. Discharges lasting more than 3 seconds had clear clinical
correlates, including eye rolling and, occasionally, myoclonic jerks of his
head and shoulders. His head MRI with contrast was normal. He was
started on clobazam, then levetiracetam was added, but after several
months, his seizures continued. Metabolic testing, including all tests listed
in TABLE 2-2 (performed for ketogenic diet initiation), was normal. Because of
his history of delays and his refractory epilepsy, chromosomal microarray
testing and a next-generation sequencing epilepsy panel were ordered.
The microarray was normal, but the next-generation sequencing
epilepsy panel showed two pathogenic variants in the guanidinoacetate
N-methyltransferase (GAMT) gene, predicted to cause a creatine deficiency
syndrome. When appropriate treatment was instituted, his seizures resolved
within days, and within weeks he began speaking.

COMMENT This boy’s impressive recovery after diagnosis and initiation of disease-
specific treatment shows the value of thinking about treatable causes of
neurologic presentations such as developmental delay and epilepsy. The
use of next-generation sequencing epilepsy panels or the newer
metabolomics panel offers hope that these potentially treatable diagnoses
will not be missed.

52 FEBRUARY 2018

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movement disorder with basal ganglia abnormalities on MRI. Magnetic
resonance spectroscopy will demonstrate a deficient creatine peak. However,
this testing is not always feasible in routine clinical practice. Diagnosis is
generally made by measurement of guanidinoacetate, creatine, and creatinine
in urine and plasma, but these tests may not be straightforward to obtain. The
creatine depletion and clinical effects of guanidinoacetate methyltransferase
and arginine:glycine amidinotransferase deficiency (but not the X-linked
transporter defect) may be partially reversed with creatine supplementation.
Guanidinoacetate methyltransferase deficiency is also treated with ornithine
supplementation and dietary arginine restriction.

Pyruvate Dehydrogenase Complex Deficiency

The pyruvate dehydrogenase complex converts pyruvate into acetyl-CoA, one
of the first crucial steps of the tricarboxylic acid cycle. The excess pyruvate is
converted to lactate, and pyruvate dehydrogenase complex deficiency is the most
common disorder leading to lactic acidemia.32 This complex consists of three
enzymes, the complicated reactions of which depend on a number of coenzymes,
including thiamine. Defects in pyruvate dehydrogenase complex limit
carbohydrate metabolism and decrease energy production. Most cases of
pyruvate dehydrogenase complex deficiency are caused by defects in the E1
a-subunit gene PDHA1 on Xp22. Although X-linked, both males and females
with mutations in PDHA1 can present with severe or milder symptoms. The most
severe presentation includes brain malformation with neonatal lactic acidosis.
Seizures, apnea, worsening weakness, and ataxia are also reported. MRI findings
with basal ganglia and brainstem abnormalities are common. While the diagnosis
is suggested by elevated lactate in blood and CSF, mutational analysis (eg, genetic
mitochondrial next-generation sequencing panel) is useful. Some, but not all,
patients benefit from a ketogenic diet33 and thiamine supplementation.

Wilson Disease
Wilson disease is a disorder of copper transport caused by mutations in a
copper-transporting ATPase gene (ATP7B) that causes gradual copper
accumulation in the liver, brain, kidney, and cornea.34 The presentation may be
with hepatic disease (jaundice, hepatitis, rapidly progressive liver failure) or a
neuropsychiatric disorder (tremor, dysarthria, irritability, psychosis). The
diagnosis is suggested by low serum copper and ceruloplasmin with increased
urinary copper excretion. Treatment consists of copper chelation with
penicillamine or trientine, zinc to interfere with copper absorption, and avoidance
of high copper-containing foods. Liver transplant may also be indicated. For more
information on Wilson disease, refer to the article “Wilson Disease” by Ronald F.
Pfeiffer, MD, FAAN,35 in the August 2016 issue of Continuum.

APPROACHES TO TESTING FOR INBORN ERRORS OF METABOLISM

The treatable disorders of metabolism described in this article are individually
rare but, as a group, are likely to be seen in neurology practices. While readily
available and relatively inexpensive screening tests such as those listed in TABLE 2-1
may be useful in some cases, this approach will identify only a small portion
of the inborn errors of metabolism likely to present to neurologists. TABLE 2-5
lists a few more tests that may be useful in metabolic screening. However,
metabolic assays can be challenging to interpret with their own false positives

CONTINUUMJOURNAL.COM 53

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INBORN ERRORS OF METABOLISM

and risks for missed diagnoses. Often, these assays are repeated multiple times
when results are ambiguous, which increases the costs of screening.
A more comprehensive approach to metabolic testing might involve
whole-exome sequencing or phenotype-driven next-generation sequencing
panels (eg, comprehensive epilepsy panels, ataxia panels). The yield of
next-generation sequencing epilepsy panels in epileptic encephalopathy is
relatively high,36,37 and they not only help make diagnoses but provide assurance
that a treatable inborn error of metabolism has not been missed. The cost of this
technology is a barrier to widespread use, but this may change as the costs go
down and as the burdens of repeated metabolic (especially CSF) testing are
recognized. Metabolomics profiling is a small molecule screening approach that
promises to provide a much more comprehensive survey of metabolic
derangements than can currently be assessed using other available metabolic
tests.38,39 While these platforms are cheaper than next-generation sequencing
panels, they still require additional confirmatory biochemical and molecular
diagnostic testing. If metabolomics profiling detects two or three potential
targets, then the costs of following up with additional testing may begin to
approach that of whole-exome sequencing.
Several of the small molecule disorders discussed in this article are screened in
newborns to ensure that treatment is provided promptly. It should also be kept in
mind that newborn screening programs in the United States are regulated and
managed by each state, leading to regional variations in clinical follow-up and
care. Furthermore, some forms may present later in life, and some older children
and adults will not have had an opportunity to be screened for these disorders.
For these reasons, it is preferable to repeat metabolic screening tests, even if the
newborn screen was known to be normal, if testing appears clinically indicated.
The best strategies for performing an extended metabolic screening
evaluation will vary with clinical presentation. While this article is meant
to serve as an introduction to more familiar treatable inborn errors of
metabolism, additional resources can help clinicians interested in refining
their metabolic screening strategy for particular patients (refer to the
section on useful websites).

CONCLUSION
This article discusses testing for inborn errors of metabolism, specifically those
disorders of small molecules that are relatively easy to screen for, are treatable,
and for which effective treatment leads to improved neurologic outcomes.
Yet, many of these defects in intermediary metabolism, so readily screened for
using plasma amino acids, urine organic acids, and acylcarnitine profiling, are
not ones that practicing neurologists are likely to diagnose in practice. In fact,
many of the more important and treatable conditions are already screened for in
newborns in the United States.20 The list of other inborn errors of metabolism
that cause epilepsy,40 weakness,41 or leukodystrophies,42 for example, is
extensive and should be considered by the clinician in the appropriate clinical
scenario. Newer technologies such as metabolomics screening improve the
sensitivity of existing biochemical assays, but whole-exome sequencing remains
a powerful, although still expensive, tool for diagnosing rare but potentially
treatable inborn errors of metabolism.

54 FEBRUARY 2018

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USEFUL WEBSITES
TREATABLE INTELLECTUAL DISABILITY: AN INTERACTIVE
TOOL FOR THE CLINICIAN
This website summarizes more than 80 treatable
inborn errors of metabolism that are related to
intellectual disability.
treatable-id.org
GENETIC METABOLIC CENTER FOR EDUCATION
This website provides a four-part tutorial video
series, Metabolism 101, that reviews basic
information about metabolic disease identification
and management.
geneticmetabolic.com
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