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Biochemical findings in common inborn errors of metabolism.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 142C:64 –76 (2006)
A R T I C L E
Biochemical Findings in Common
Inborn Errors of Metabolism
MARZIA PASQUALI,* GAVIN MONSEN, LEAH RICHARDSON,
MARTHA ALSTON, AND NICOLA LONGO
The application of tandem mass spectrometry (MS/MS) to newborn screening has led to the detection of patients
with a wider spectrum of inborn errors of metabolism. A definitive diagnosis can often be established early
enough to start treatment before symptoms appear. Here, we review common biochemical findings in disorders
caused by deficiency of 3-methylcrotonyl-CoA carboxylase, isobutyryl-CoA dehydrogenase, 2-methyl-3hydroxybutyryl-CoA dehydrogenase, 3-ketothiolase, 2-methylbutyryl-CoA dehydrogenase, and medium chain
acyl CoA dehydrogenase. The diagnosis of these disorders requires biochemical confirmation by measurement of
plasma acylcarnitine profile, urine organic acids, and urine acylglycine profiles followed by measurement of
enzyme activity or detection of causative mutations. Early treatment can improve the outcome of these
disorders. ß 2006 Wiley-Liss, Inc.
KEY WORDS: newborn screening; tandem mass spectrometry; organic acidemias; urine acylglycine; urine acylcarnitine
How to cite this article: Pasquali M, Monsen G, Richardson L, Alston M, Longo N. 2006.
Biochemical findings in common inborn errors of metabolism.
Am J Med Genet Part C Semin Med Genet 142C:64–76.
INTRODUCTION
Inborn errors of metabolism affect the
capabilities of the organism to convert
nutrients into one another or to use
them for energy production. They are
due to impaired activity of enzymes,
Marzia Pasquali is an Associate Professor
of Pathology at the University of Utah in Salt
Lake City and Medical Director of the
Biochemical Genetics and Newborn Screening at ARUP Laboratories. She has a strong
interest in the development of new testing
for the diagnosis of inborn errors of metabolism.
Gavin Monsen is a Senior Technologist in
the Biochemical Genetics Section of ARUP
Laboratories.
Leah Richardson is a Technical Specialist
for the ARUP Laboratories Supplemental
Newborn Screening Laboratory.
Martha Alston is a Technologist in the
Biochemical Genetics Section of ARUP
Laboratories.
Nicola Longo is a Professor of Pediatrics
and Director of the Metabolic Service at the
University of Utah. His research covers
inherited disorders of fatty acid oxidation
and the development of new therapies for
metabolic disorders.
*Correspondence to: Marzia Pasquali,
Ph.D., Biochemical Genetics and Newborn
Screening Laboratories, ARUP Laboratories,
500 Chipeta Way, Salt Lake City, Utah
84108. E-mail: pasquam@aruplab.com
DOI 10.1002/ajmg.c.30086
ß 2006 Wiley-Liss, Inc.
transporters, or cofactors resulting in
accumulation of abnormal metabolites
(substrates) proximal to the metabolic
block or lack of necessary products.
Abnormal byproducts can be produced
when alternative pathways are utilized to
transform the accumulated metabolites
whose concentration renders them substrates of enzymes not usually involved in
their metabolism. The measurement of
some of these metabolites or their
byproducts after conjugation with carnitine is the basis of expanded newborn
screening by tandem mass spectrometry
(MS/MS).
Two main classes of metabolites are
currently measured by expanded newborn screening programs using MS/MS:
amino acids and acylcarnitine conjugates. The level of one or more amino
acids increases in disorders of amino acid
metabolism, when the metabolic block
is close enough to the actual amino acid,
resulting in an abnormal amino acid
profile in the newborn blood spot
(Table I). Other disorders in the intermediary metabolism of amino acids
cause organic acidemias, detected
because the abnormal metabolite is
conjugated with carnitine to facilitate
its excretion and to balance the Coen-
zyme A pool (Table II). In disorders of
fatty acid oxidation, fatty acids are
physiologically conjugated with carnitine and the acylcarnitines produced
accumulate in case of a metabolic block
(Table III). Work is in progress to allow
identification of other metabolites or to
measure the activities of individual
enzymes after the addition of suitable
substrates [Li et al., 2004]. We are only
using a small portion of the capabilities of
the instrumentation currently available
and many more diseases will become
amenable to screening as our knowledge
advances.
MS/MS allows the presymptomatic
identification of several metabolic disorders before irreversible organ damage
has occurred. The vast majority of
MS/MS allows the
presymptomatic identification
of several metabolic disorders
before irreversible organ
damage has occurred.
inborn errors of metabolism are inherited as
autosomal recessive traits, although there
Proline
Phenylalanine
Methionine
Leucine
Citrulline
Arginine
Abnormal
metabolite
Arginase deficiency
Liver disease
Hyperalimentation
Citrullinemia type 1
Citrullinemia type 2
Arginino succinic aciduria
Pyruvate carboxylase deficiency
(French form)
Lysinuric protein intolerance
Liver disease
Hyperalimentation
Maple syrup urine disease
Hyperalimentation
Homocystinuria
Methionine adenosyltransferase
deficiency
Glycine N-methyltransferase
deficiency
S-adenosylhomocysteine hydrolase
deficiency
Tyrosinemia type 1
Liver disease
Hyperalimentation
Prematurity
Phenylketonuria
Biopterin syntesis defects
Dihydrobiopterin reductase
Liver disease
Hyperalimentation
Prematurity
Hyperprolinemia type 2
Hyperprolinemia type 1
Lactic acidosis
Liver disease
Hyperalimentation
Possible causes
Plasma amino acids, urine organic acids
Plasma amino acids, urine neopterin
profile, blood
DHPR activity
Plasma amino acids and total plasma
homocysteine, urine organic acids
Plasma amino acids, urine organic acids
Plasma ammonia, plasma amino
acids, urine orotic acid, urine organic
acids (blood lactate and pyruvate)
Plasma ammonia, plasma amino
acids, urine orotic acid
Additional tests
Pyridoxine (for type2) (Type 1 is
considered benign)
Diet low in phenylalanine
Mental retardation, microcephaly
Febrile seizures, seizures,
developmental delays
Diet low in branched chain amino
acids, thiamine
Diet low in methionine, pyridoxine,
folic acid, betaine
Low-protein diet, benzoate,
phenylbutyrate. High-protein
(arginine), low carbohydrate diet
in citrin deficiency
Refusal to feed, lethargy progressing
to coma, hyperammonemia
Refusal to feed, lethargy progressing
to coma, brain edema
Usually asymptomatic in the neonatal
period, mental retardation,
thrombosis, cataracts
Low-protein diet, benzoate,
phenylbutyrate
Treatment
Mental retardation, spasticity,
microcephaly
Signs/symptoms
TABLE I. Amino Acid Abnormalities Identifiable by Newborn Screening
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Tyrosine
Tyrosinemia type 1
Tyrosinemia type 2
Tyrosinemia type 3
Transient tyrosinemia of the newborn
Liver disease
Prematurity
Hyperalimentation
Plasma amino acids and urine organic
acids.
Liver failure (Type 1), rickets (Type 1),
photophobia (Type 2), keratosis
(Type 2), delays (Types 2,3)
Diet low in phenylalanine and
tyrosine (Types 1–3), NTBC
(Type 1)
66
are exceptions (ornithine transcarbamylase
deficiency, 2-methyl-3-hydroxybutyrylCoA dehydrogenase deficiency, and others
that are X-linked). Parents of affected
children are usually asymptomatic, and
their child is often the first with the disease
in the family.
Symptoms of inborn errors of
metabolism usually appear early in
infancy, although several cases become
symptomatic in late childhood or
adulthood. Signs and symptoms include
failure to thrive, seizures, mental retardation, organs failure, and even death.
With the application of MS/MS for
newborn screening, the capability of
identifying simultaneously several analytes and the increased sensitivity have
led to the detection of an increased
number of patients. In asymptomatic
patients, the confirmation of diagnosis
relies on specific tests such as ionexchange chromatography for amino
acids analysis, gas-chromatography-mass
spectrometry (GC/MS) for organic
acids and acylglycines analyses, and
MS/MS with (LC-MS/MS) or without
liquid chromatographic separation for
acylcarnitines profile. The combination
of these tests, run on different specimen
types, is the key in the confirmation of
abnormal newborn screening results,
especially for patients with borderline
results. In this review, we will detail the
most common findings for selected
metabolic disorders, outlining the procedures that we follow to confirm or
exclude specific diagnoses. A number of
disorders (carnitine cycle, long-chain
fatty acid oxidation, tyrosinemias, argininemia, glutaric, propionic, methylmalonic, and isovaleric acidemias) are
covered in other chapters of this issue
and will not be repeated in this more
general review.
ORGANIC ACIDEMIAS
Organic acidemias include a large spectrum of disorders involving many metabolic pathways. A number of these
disorders are on the catabolic pathways
of branched-chain amino acids (Fig. 1),
although in most cases, they do not result
in specific abnormalities detectable by
amino acid analysis.
ARTICLE
Accumulation of specific acylcarnitine species results from a metabolic block
at any site in the pathway. Table II lists the
common abnormalities detected by newborn screening in organic acidemias.
Confirmation of screening results should
be performed, as a rule of thumb, on a
different specimen type than the screening test (e.g., urine) and possibly use a
different methodology. For confirmation
of a possible organic acidemia, usually
urine organic acids and urine acylglycine
profile are the primary and most informative tests; plasma acylcarnitine profile
is also widely used, but should be ordered
in conjunction with the urine studies,
while urine acylcarnitine profile might
give complementary information, useful
to characterize borderline patients.
For confirmation of a possible
organic acidemia, usually
urine organic acids and
urine acylglycine profile are
the primary and most
informative tests; plasma
acylcarnitine profile is also
widely used, but should be
ordered in conjunction with the
urine studies, while urine
acylcarnitine profile might give
complementary information,
useful to characterize
borderline patients.
3-Methylcrotonyl-CoA Carboxylase
Deficiency (OMIM 210200
and 210210)
3-Methylcrotonyl-CoA carboxylase is a
biotin-dependent mitochondrial enzyme
involved in the catabolism of leucine
[Baumgartner et al., 2001; Gallardo et al.,
2001], converting 3-methylcrotonylCoA to 3-methylglutaconyl-CoA (Fig. 1).
The heteromeric mitochondrial enzyme
is composed of a larger a subunit that
binds biotin, bicarbonate, and ATP
and a smaller b subunit containing the
High C5:1,
C3, C5-OH
High C6-DC,
C5-OH
High C5-OH, C5:1
High C5-OH
High C5-DC
High C4
High C5
High C3
Abnormal
acylcarnitine
3-Methylcrotonyl CoA carboxylase
(MCC) deficiency
(leucine metabolism)
Maternal MCC deficiency
Biotinidase deficiency
Prematurity
3-Ketothiolase deficiency
(isoleucine metabolism)
2-methyl-3-hydroxybutyryl-CoA
dehydrogenase deficiency
3-OH 3-CH3 glutaryl CoA
Lyase deficiency
Prematurity
Ketosis
Holocarboxylase synthase deficiency
Biotinidase deficiency
Propionic acidemia
Methylmalonic acidemia
Prematurity
Diet low in vitamin B12
Isovaleric acidemia (leucine metabolism)
2-methylbutyryl-CoA dehydrogenase
deficiency (isoleucine metabolism)
Medications (antibiotics)
Isobutyryl CoA dehydrogenase
deficiency (valine metabolism)
SCAD deficiency
Glutaric acidemia type 1
Kidney disease
Possible causes
Carnitine
Special diet, carnitine,
vigorous treatment of
fever and infections
Carnitine,
low-protein diet
Low-protein diet, fasting
avoidance, carnitine
Fasting avoidance,
carnitine, IV glucose,
vigorous treatment of
infections
Biotin
Failure to thrive, carnitine deficiency,
cardiomyopathy
Macrocephaly, brain atrophy,
hypotonia, dystonia, degeneration
of basal ganglia
Developmental delays, metabolic
acidosis, hypoglycemia
Metabolic acidosis, vomiting,
headaches, occasional
hyperammonemia
Hypoglycemia, mental retardation,
epilepsy
Plasma ammonia, basic metabolic panel,
plasma amino acids, plasma acylcarnitine
profile, urine organic acids
Comprehensive metabolic panel, plasma
ammonia, plasma amino acids, plasma
acylcarnitine profile, urine organic acids
Comprehensive metabolic panel, plasma
ammonia, plasma amino acids, plasma
acylcarnitine profile, urine organic
acids, serum biotinidase, fibroblast
studies
Vomiting, ketoacidosis, dehydration,
coma, skin rash, alopecia
Special diet, carnitine,
glycine
Plasma ammonia, basic metabolic
panel, plasma amino acids, plasma
acylcarnitine profile, urine organic
acids, serum biotinidase
Plasma ammonia, basic metabolic
panel, plasma amino acids, plasma
acylcarnitine profile, urine organic
acids and acylglycine profile
Plasma acylcarnitine profile, plasma
amino acids, urine organic acids,
acylglycine and acylcarnitine profile
Plasma acylcarnitine profile, urine
organic acids and acylcarnitine
profile
Plasma acylcarnitine profile, urine organic
acids and acylglycine profile, serum
biotinidase activity
Metabolic acidosis, hyperammonemia,
coma
Therapy
Special diet, carnitine,
vitamin B12, biotin,
other vitamins
Signs/symptoms
Metabolic acidosis, hyperammonemia,
coma, hypotonia or hypertonia
Additional tests
TABLE II. Organic Acidemias Identifiable by Newborn Screening
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High C4, C5, C5DC, C6, C8,
C10, C16
High C16, C16:1, C18, C18:1,
low free carnitine
High free
carnitine/(C16 þ C18)
Low free carnitine (C0)
and C2
High C16-OH,
C16:1-OH, C18-OH,
C18:1-OH
High C4
High C14:1, C14
High C6, C8, C10:1
Abnormal acylcarnitine
Medium chain acyl CoA
dehydrogenase (MCAD)
deficiency
Diet (special care formulas)
Medications
Very long chain acyl CoA
dehydrogenase (VLCAD)
deficiency
Ketosis
Short chain acyl CoA
dehydrogenase (SCAD)
deficiency
Isobutyryl CoA dehydrogenase
deficiency
Long chain 3-OH acyl CoA
dehydrogenase deficiency
Sepsis
Ketosis
Primary carnitine deficiency
Maternal primary carnitine deficiency
Prematurity
Infant of vegan mother
Medications
Carnitine palmitoyl
transferase I deficiency
Sepsis
Carnitine supplementation
Carnitine palmitoyl
transferase 2 (CPT2)
deficiency
Carnitine acylcarnitine
translocase (CACT)
deficiency
Medications
Multiple acyl CoA
dehydrogenase (MADD)
deficiency
Toxins
Possible causes
Frequent feedings,
low-fat diet with MCT
oil, low-dose carnitine
Frequent feedings,
low-fat diet with MCToil
Frequent feedings,
low-fat diet with MCT
oil, carnitine
Hypoglycemia, cardiomyopathy,
sudden death
Hypoglycemia, cardiomyopathy,
hypotonia, sudden death
Hypoglycemia
Hypoglycemia, cardiac arrest,
cardiomyopathy, dysmorphism
Plasma carnitine, plasma acylcarnitine profile, urine organic acids,
3-OH-fatty acids, DNA testing
Plasma carnitine levels, carnitine
transport in fibroblasts
Plasma carnitine, plasma acylcarnitine profile, urine organic acids
Plasma carnitine, plasma acylcarnitine profile, urine organic acids, DNA testing,
enzyme/transporter assay
in fibroblasts
Plasma carnitine, plasma acylcarnitine profile, urine organic acids, fibroblast studies
Hypoglycemia, metabolic acidosis, recurrent vomiting, hepatomegaly
Frequent feedings,
low-fat diet, carnitine
Hypotonia (?)
Quantitative plasma acylcarnitine
profile, urine organic acids, enzyme assay
in fibroblasts, DNA testing
Plasma acylcarnitine profile, urine organic
acids, enzyme assay in
fibroblasts, DNA testing
Frequent feedings,
low-fat diet with MCT
oil, carnitine,
riboflavin
Carnitine
Frequent feedings,
low-fat diet with MCT
oil, carnitine
Therapy
Hypoglycemia, cardiomyopathy,
sudden death
Signs/symptoms
Frequent feedings,
low-fat diet, carnitine
Plasma acylcarnitine profile, urine organic
acids and acylglycine
profile, DNA testing
Hypoglycemia, sudden death
Additional tests
TABLE III. Abnormalities of Fatty Acid Oxidation and the Carnitine Cycle Identifiable by Newborn Screening
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ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Valine
Leucine
Isoleucine
Cytosol
69
Mitochondrial matrix
α-Ketoisovaleric acid
α-Ketoisocaproic acid
α-Keto-β-methylvaleric
acid
Branched Chain KetoacidDehydrogenase (BCKD) (Thiamine)
Isobutyryl-CoA
2-Methylbutyryl-CoA
Isobutyryl-CoA
Dehydrogenase
Metacrylyl-CoA
2-Methylbutyryl-CoA
Dehydrogenase
Tiglyl-CoA
Hydratase (Crotonase)
3-OH-Isobutyryl-CoA
3-OH-Isobutyryl-CoA
Deacylase
3-OH-Isobutyric Acid
3-OH-Isobutyric acid
Dehydrogenase
Methylmalonic acid
semialdehyde
Methylmalonic semialdehyde Dehydrogenase
Propionyl-CoA
Hydratase (Crotonase)
2-Methyl-3-OHbutyryl-CoA
3-Methyl-3-OH-ButyrylCoA Dehydrogenase
2-Methylacetoacetyl-CoA
Isovaleryl-CoA
IsovalerylCoA
Dehydrogenase
3-Methylcrotonyl-CoA
CO2
MethylcrotonylCoA
Carboxylase (Biotin)
3-Methylglutaconyl-CoA
3-MethylglutaconlylCoA Hydratase
3-OH-3-Methylglutaryl-CoA
3-OH 3-methyl
glutaryl-CoA lyase
3-Ketothiolase
Acetyl-CoA
Mevalonic acid
Cholesterol
Acetoacetic acid +
Acetyl-CoA
Figure 1. Catabolic pathways of branched chain amino acids. Intermediate metabolites feed into the citric cycle or into the respiratory
chain. Enzymatic blocks can occur at any point in these pathways.
binding site for 3-methylcrotonyl-CoA
[Holzinger et al., 2001; Sweetman and
Williams, 2001]. The two subunits are
encoded by two different genes, MCCA
(3q25-q27) and MCCB (5q12-q13.1),
respectively. Deficiency of 3-methylcrotonyl-CoA carboxylase is inherited as an
autosomal recessive trait and heterogeneous mutations in the MCCA and
MCCB genes have been reported in
affected patients [Dantas et al., 2005].
The phenotype is extremely variable
with patients presenting in infancy with
severe neurological involvement and
developmental delays, to patients with
recurrent attacks of metabolic decompensation followed by complete recovery to asymptomatic adults [Bartlett
et al., 1984; Bannwart et al., 1992; Visser
et al., 2000; Koeberl et al., 2003a; Baykal
et al., 2005; Dantas et al., 2005]. Signs
and symptoms include ketoacidosis,
hypoglycemia, seizures, hyperammonemia, and coma. In other patients, failure
to thrive is the predominant sign. There
is no clear correlation between genotype
and phenotype and modifying genes and
environmental factors must have a major
influence on the phenotype of 3methylcrotonyl-CoA carboxylase deficiency [Dantas et al., 2005].
Patients with 3-methylcrotonylCoA carboxylase deficiency can be
identified through newborn screening
by MS/MS because of an increased
concentration of a hydroxylated five
carbon atoms species (C5-OH) corresponding to 3-hydroxyisovaleryl-carnitine [Roschinger et al., 1995; van Hove
Patients with 3-methylcrotonyl-CoA carboxylase deficiency
can be identified through
newborn screening by MS/MS
because of an increased concentration of a hydroxylated five
carbon atoms species (C5-OH)
corresponding to 3-hydroxyisovaleryl-carnitine.
et al., 1995; Koeberl et al., 2003a].
Newborn screening has also identified
asymptomatic affected mothers of heterozygous babies [Koeberl et al., 2003a].
Some of these mothers had a history of
recurrent vomiting requiring IV fluids
after minor illnesses or high-protein
meals [Koeberl et al., 2003a].
Urine organic acid analysis is the
most informative test to confirm 3methylcrotonylglycinuria.
Affected
patients show a markedly increased
excretion of 3-hydroxyisovaleric acid
and the presence of 3-methylcrotonylglycine (Fig. 2A) that increases during
episodes of acute decompensation.
Urine acylglycine analysis might
help in cases where 3-methylcrotonylglycine is only mildly elevated (Fig. 2B).
Quantitative analysis of acylcarnitine
profiles in plasma and urine provides
further supporting evidence, showing a
marked increase in C5OH carnitine
and the absence of other acylcarnitine
species seen in other disorders such as
3-ketothiolase deficiency, 3-hydroxy-3methylglutaryl-CoA lyase deficiency, or
multiple carboxylase deficiency (Fig. 3).
An isolated increase in C5OH carnitine
can be seen with biotinidase deficiency
that can be easily excluded by measurement of serum enzyme activity. The
diagnosis is confirmed by measuring
enzyme activity in cultured fibroblasts.
Holocarboxylase synthase deficiency
can also cause 3-methylcrotonylglycinuria and is excluded by measuring
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ARTICLE
organic acids and urine acylglycine
profiles and normal levels of ethylmalonic acid [Sass et al., 2004]. Therapy
with carnitine supplements has reversed
clinical symptoms in the first patient
reported.
2-Methyl-3-hydroxybutyryl-CoA
Dehydrogenase Deficiency
(OMIM 300438)
Figure 2. Urine organic acid profiles from patients with 3-methylcrotonyl-CoA
carboxylase deficiency. 3-Hydroxyisovaleric acid and 3-methylcrotonylglycine are the
key metabolites in urine. Note variable excretion of 3-methylcrotonylglycine (compare
3A and 3B) and consistently elevated excretion of 3-hydroxyisovaleric acid. Isolated
elevations of 3-hydroxyisovaleric acid can also be seen in patients with biotinidase
deficiency that should be excluded in all patients with 3-methylcrotonyl-CoA
carboxylase deficiency. IS, internal standard.
activity of another carboxylase in the
same cells.
Although the clinical presentation
of 3-methylcrotonylglycinuria is variable and several patients have been
asymptomatic, all patients should be
considered at risk for developing life
threatening Reye-like episodes in case of
metabolic stress, such as protein load,
infections, or prolonged fasting [Nyhan
et al., 2005].
Isobutyryl-CoA Dehydrogenase
Deficiency
Isobutyryl-CoA dehydrogenase catalyzes the conversion of isobutyryl-CoA
to methylacrylyl-CoA (Fig. 1) in the
metabolism of valine. Its deficiency has
been reported only recently in a patient
presenting with failure to thrive, anemia,
and dilated cardiomyopathy [Roe et al.,
1998]. This patient had profound carnitine deficiency and responded well to
carnitine supplements with reversal of
cardiomyopathy and normalization of
growth parameters [Roe et al., 1998].
All subsequent patients were prospectively identified by newborn screening
and the clinical significance of this
disease is still uncertain [Sass et al.,
2004]. Heterogeneous mutations in the
ACAD8 (OMIM 604773) gene on
11q25 have been identified in patients
with isobutyryl-CoA dehydrogenase
deficiency [Nguyen et al., 2002; Sass
et al., 2004].
Increased concentrations of isobutyryl (C4)-carnitine in blood and urine
and of isobutyrylglycine in urine are
the biochemical findings characteristics
of this disease. Newborn screening by
MS/MS may identify newborn with
isobutyryl-CoA dehydrogenase deficiency by their increased C4-carnitine
level [Koeberl et al., 2003b] as in the
more common Short chain acyl-CoA
dehydrogenase (SCAD) deficiency.
The presumptive diagnosis relies on
detection of isobutyrylglycine in urine
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD, OMIM 300256)
deficiency is an X-linked disorder of
isoleucine degradation [Zschocke et al.,
2000; Ensenauer et al., 2002; Sutton et al.,
2003; Garcia-Villoria et al., 2005] characterized by a progressive loss of mental
and motor skills with developmental
regression, seizures, and rigidity sometimes triggered by illnesses. The metabolic
block occurs in the conversion of
2-methyl-3-hydroxybutyryl-CoA to 2methylacetoacetyl-CoA (Fig. 1), one step
before the last enzyme (3-ketothiolase)
of the isoleucine degradation pathway.
Different missense mutations in the
HADH2 gene, located on Xp11.2, have
been identified in a series of five patients
with this disease [Ofman et al., 2003].
Females can be affected by this disorder
due to skewed X-inactivation, although
their phenotype is usually milder of that
seen in males [Perez-Cerda et al., 2005].
The abnormal metabolites in urine or
whole blood and plasma of patients with
MHBD deficiency are essentially the
same as those observed in patients with
3-ketothiolase deficiency: 2-methyl-3hydroxybutyrate and tiglylglycine in urine,
C5:1 (tiglyl) carnitine and C5-OH (2methyl-3-hydroxybutyryl) carnitine in
whole blood and plasma. Newborn screening by MS/MS can identify the two
characteristic acylcarnitine species (C5:1,
C5-OH). The diagnosis must be confirmed with urine organic acids and
enzyme assay in cultured fibroblasts,
since in some cases, urine organic acids
are indistinguishable from those of a
patient with 3-ketothiolase deficiency,
although the clinical presentation is different. Dietary treatment with an
isoleucine restricted, high-carbohydrate
diet may improve the condition and,
if initiated early, may prevent neuro-
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Figure 3. Plasma acylcarnitine profiles obtained by MS/MS in patients with 3methylcrotonyl-CoA carboxylase deficiency. Note the great variability in C5OH
(3-hydroxyisovaleryl-) carnitine. * ¼ Internal standards (m/z 311 ¼ d9-C5; m/z
347 ¼ d3-C8; m/z 375 ¼ d3-C10; m/z 403 ¼ d3-C12; m/z 437 ¼ d9-C14; m/z
459 ¼ d3-C16; m/z 487 ¼ d3-C18).
degeneration [Zschocke et al., 2000;
Olpin et al., 2002; Sutton et al., 2003].
3-Ketothiolase Deficiency
(OMIM 203750)
3-Ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) is an enzyme
3-Ketothiolase (mitochondrial
acetoacetyl-CoA thiolase,
T2) is an enzyme involved
in isoleucine catabolism and
ketone bodies metabolism. Its
deficiency is characterized by
intermittent episodes of
severe ketoacidosis, usually
with normoglycemia or
hyperglycemia (for which
they can be confused with
diabetes mellitus) that can
result in hyperventilation,
dehydration, lethargy,
coma, and death.
involved in isoleucine catabolism and
ketone bodies metabolism. Its deficiency
is characterized by intermittent episodes
of severe ketoacidosis, usually with
normoglycemia or hyperglycemia (for
which they can be confused with
diabetes mellitus) that can result in
hyperventilation, dehydration, lethargy,
coma, and death. Episodes are usually
71
associated with severe vomiting and are
triggered by infections or other illnesses.
Analysis of urine organic acids by GC/
MS during acute episodes reveals high
excretion of 2-methyl-3-hydroxybutyrate, 2-methylacetoacetate, and tiglylglycine with large amounts of 3hydroxy-butyrate and acetoacetate.
Analysis of acylcarnitines by MS/MS in
whole blood or in plasma shows
increased concentrations of C5OH (2methyl-3-hydroxybutyryl) carnitine,
and C5:1 (tiglyl) carnitine (Fig. 4). The
diagnosis is confirmed by enzyme assay
in cultured fibroblasts. Therapy consists
in mild protein restriction to limit the
intake of isoleucine, avoidance of fasting,
supplementation with carnitine, avoidance of prolonged fasting, and prompt
treatment of illnesses that can precipitate
acute attacks.
The gene coding for this enzyme,
ACAT1, maps to 11q22.3-23.1 and
heterogenous mutations have been
reported in patients with 3-ketothiolase
deficiency [Fukao et al., 2001, 2002;
Fukao and Yamaguchi, 2002; Mrazova
et al., 2005]. Two groups of patients have
been identified based on the presence of
null mutations in both alleles or of
mutations leaving some residual activity
in at least one of the mutant alleles
[Fukao et al., 2003; Zhang et al.,
2004]. Although there is no correlation
between phenotype and genotype, there
are differences in the biochemical profiles under stable conditions between
the two groups [Fukao et al., 2001].
In the group of patients with two null
alleles the typical organic acids and
acylcarnitine profile persists even in
stable conditions. By contrast, tiglylglycine, 2-methyl-3-hydroxybutyrate, and
2-methyl-3-hydroxybutyrylcarnitine
are not always detected in the group of
patients with residual 3-ketothiolase
activity [Fukao et al., 2003]. Newborn
screening by MS/MS can identify
infants with 3-ketothiolase deficiency
with severe mutations, but it might fail to
detect infants with the ‘‘milder’’ mutation(s). The outcome of 3-ketothiolase
deficiency is favorable with early diagnosis, dietary therapy, and appropriate
treatment of ketoacidosis [Fukao et al.,
2001].
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Figure 4. MS/MS plasma acylcarnitine profile in a patient with b-ketothiolase
deficiency. Note the simultaneous elevation of C5:1 and C5OH carnitine. * ¼ Internal
Standards (m/z 311 ¼ d9-C5; m/z 347 ¼ d3-C8; m/z 375 ¼ d3-C10; m/z 403 ¼ d3C12; m/z 437 ¼ d9-C14; m/z 459 ¼ d3-C16; m/z 487 ¼ d3-C18).
ARTICLE
Chinese origin [Matern et al., 2003], we
have identified patients of different ethnicity. The gene (ACADSB) is located on
chromosome 10q25-26 and mutations
have been reported in affected patients
[Andresen et al., 2000; Matern et al.,
2003]. Homozygosity for a methionine
to valine change at position 356 of the
mature protein (M356V) has been found
in several of the Hmong patients studied,
suggesting a founder effect [Matern et al.,
2003]. A newborn screening result with
elevated C5-carnitine could indicate also
isovaleric acidemia (isovalerylcarnitine is
a 5-carbon atom species) and should be
followed up with urine organic acids
and urine acylglycine analyses in order
to identify the specific metabolic defect.
2-Methylbutyryl-CoA
Dehydrogenase Deficiency
2-Methylbutyryl-CoA dehydrogenase
(SBCAD, short branched chain acylCoA dehydrogenase, OMIM No. 600301)
catalyzes the conversion of 2-methylbutyryl-CoA to tiglyl-Coa in the catabolic
pathway of isoleucine (Fig. 1). The
deficiency of this enzyme has been
described only recently [Andresen et al.,
2000; Gibson et al., 2000] and the
phenotype is not yet well defined,
ranging from completely asymptomatic
patients to muscle weakness, cerebral
palsy, developmental delays, lethargy,
hypoglycemia, and metabolic acidosis.
Biochemically, 2-methylbutyryl-CoA
dehydrogenase deficiency is characterized by increased urinary excretion of 2methylbutyrylglycine (Fig. 5B), without
an increase in isovalerylglycine, and
increased whole blood and plasma concentrations of 2-methylbutyryl(C5) carnitine (Fig. 5A). Diagnosis can be
confirmed by enzyme assay in fibroblasts
or DNA studies. Therapy consists of
protein restriction and carnitine supplements.
Newborn screening by MS/MS can
identify patients with 2-methylbutyrylCoA dehydrogenase deficiency by elevated C5-carnitine. Although the majority of patients described belong to the
Hmong population, an ethnic group of
Figure 5. Urine acylcarnitine profile (A) and urine acylglycine profile (B) from a
patient with 2-methylbutyryl-CoA dehydrogenase deficiency. A: Note the extreme
elevation of C5 carnitine.* ¼ Internal standards (m/z 311 ¼ d9-C5; m/z 403 ¼ d3-C12;
m/z 459 ¼ d3-C16; m/z 487 ¼ d3-C18). B: PG ¼ propionylglycine; IBG, isobutyrylglycine; BG, butyrylglycine; 2MBG, 2-methylbutyrylglycine; IVG, isovalerylglycine.
The internal standards are deuterated glycine conjugates (d3-PG; d7-IBG; d3-BG; d92MBG; d9-IVG).
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
FATTY ACID OXIDATION
DISORDERS
Fatty acid oxidation plays a major role
in energy production in conditions of
increased demand, such as during a
prolonged fasting, illness, and/or muscular exertion. In these cases, the depletion of glycogen stores and the falling
glucose levels activate lipid mobilization
from fat stores and its utilization by the
liver, the heart, and the muscle. Fatty
acid b-oxidation occurs in mitochondria
and it involves at least 20 steps, some of
which catalyzed by enzymes with overlapping chain length specificity (Fig. 6).
While short and medium chain fatty
acids are believed to freely cross the
mitochondrial membrane, long chain
fatty acids (C16 and C18) enter the
mitochondrial matrix after conjugation
with carnitine. Measurement of these
Fatty acid b-oxidation occurs in
mitochondria and it involves at
least 20 steps, some of which
catalyzed by enzymes with
overlapping chain length
specificity. While short and
medium chain fatty acids are
believed to freely cross the
mitochondrial membrane,
long chain fatty acids (C16 and
C18) enter the mitochondrial
matrix after conjugation
with carnitine.
acylcarnitine conjugates allows newborn
screening for several of these disorders.
Abnormalities in beta-oxidation
can result in hypoketotic hypoglycemia,
myopathy, cardiomyopathy, sudden
infant death syndrome (SIDS). Analysis
of urine organic acids and plasma
acylcarnitine is part of the routine
evaluation of a patient presenting with
hypoglycemia. In urine organic acids,
excess excretion of dicarboxylic acids,
especially unsaturated, deriving from
microsomal o-oxidation of fatty acids
not metabolized by mitochondria,
C16:0 palmitoylCoA
without excess 3-hydroxybutyrate is a
nonspecific sign of defective b-oxidation. Other abnormal organic acids and
acylcarnitine species allow the identification of the specific defect in the boxidation cascade. Many disorders of
fatty acid oxidation are episodic, not
only clinically but also biochemically.
This means that a normal organic acid or
acylcarnitine result obtained from an
asymptomatic patient does not necessarily exclude a fatty acid oxidation
disorder. Newborn screening by MS/
MS allows the identification of patients
with fatty acid oxidation disorders,
often before symptoms occur. Often,
the newborn screening blood spot
is the most informative sample for
detecting these disorders.
Medium Chain Acyl-CoA
Dehydrogenase (MCAD)
Deficiency (OMIM 201450)
Medium chain acyl-CoA dehydrogenase
deficiency (MCAD) is the most common
disorder of fatty acid oxidation, with an
estimated frequency of 1:6,000 to 1:10,000
Caucasian births [Roe and Ding, 2001;
S-CoA
VLCAD: C14-C20
Acyl-CoA
LCAD: C12-C18
FAD
Acyl-CoA dehydrogenases
FADH2 MCAD: C4-C12
O
SCoA
2,3-Enoyl-CoA
O
H2O
Hydratases
S-CoA
SCAD: C4-C6
TFP: C12-C18
Crotonase: C4>C14
L-3-hydroxyacyl-CoA
NAD+
LCHAD (TFP): C12-C18
Hydroxyacyl-CoA dehydrogenases
NADH+H+ SCHAD: C4>C16
S-CoA
3-Ketoacyl-CoA
TFP: C6-C16
O O
HS-CoA
MKAT: C4-C12
Thiolases
OH O
C14:0 myristoyl-CoA
O
β-ketothiolase: C4
S-CoA
Acyl-CoA + Acetyl-CoA
TCA cycle
muscle
(n-2) S-CoA
O
73
li v er
Ketogenesis
New Cycle
Figure 6. Mitochondrial b-oxidation of fatty acids. Fatty acids are progressively shortened by two carbon units at each cycle by a series
of enzymes with overlapping specificity. At the end of each cycle, the residual fatty acyl chain (two carbon atoms shorter) enters another cycle
for further shortening. The relative specificity of each enzyme toward a carbon length chain is indicated. VLCAD, very long chain acyl CoA
dehydrogenase; LCAD, long chain acyl CoA dehydrogenase; MCAD, medium chain acyl CoA dehydrogenase; SCAD, short chain acyl
CoA dehydrogenase; TFP, tri functional protein; LCHAD, long chain 3-hydroxy acyl CoA dehydrogenase; SCHAD, short chain
3-hydroxy acyl CoA dehydrogenase; MKAT, medium chain 3-keto acyl CoA thiolase; TCA, tri-carboxylic acid (Krebs).
74
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Medium chain acyl-CoA
dehydrogenase deficiency is
the most common disorder
of fatty acid oxidation,
with an estimated frequency
of 1:6,000 to 1:10,000
Caucasian births.
Nyhan et al., 2005]. The symptoms of
the disease are variable, from completely
The symptoms of the disease are
variable, from completely
asymptomatic patients to
hypoglycemia, lethargy, coma,
sudden death and they are
usually triggered by prolonged
fasting or illness.
The gene encoding medium chain
acyl-CoA dehydrogenase, ACADM,
maps to 1p21 and is composed of 12
exons [Zhang et al., 1992]. Among
patients presenting with clinical symptoms, 98% carry at least one copy of the
common mutation K304E, with 80%
being homozygous for this mutation
[Gregersen et al., 1991; Yokota et al.,
1991; Andresen et al., 1997, 2001; Pollitt
and Leonard, 1998]. There is a wide
spectrum of the second causative mutation in these patients [McKinney et al.,
2004]. In newborns detected prospectively by newborn screening, the Y42H
mutation has been found frequently in
association with the common mutation
K304E [Andresen et al., 2001; Zschocke
ARTICLE
et al., 2001; O’Reilly et al., 2004]. This
mutation (Y42H) has not yet been
reported in patients with clinical symptoms [Andresen et al., 2001; Zschocke
et al., 2001] and is associated with lower
levels of diagnostic metabolites in blood
and urine [Waddell et al., 2006].
Patients with MCAD deficiency are
identified by MS/MS newborn screening
because of the characteristic acylcarnitine
profile, with increased concentration
of C6-(hexanoyl), C8-(octanoyl), and
C10:1-(decenoyl) carnitine and elevated
C8/C2 and C8/C10 ratios (Fig. 7).
Urine organic acids and urine acylglycines analyses during metabolic crisis,
show increased excretion of dicarboxylic
acids (adipic, suberic, sebacic) saturated
asymptomatic patients to hypoglycemia,
lethargy, coma, sudden death and they
are usually triggered by prolonged fasting or illness [Roe and Ding, 2001].
Although the majority of patients present in the first year of life, clinical
symptoms can occur at any time and as
many as 20% of patients die prior to
diagnosis [Iafolla et al., 1994]. The
treatment consists in avoidance of fasting, low-fat diet, carnitine supplementation, and institution of an emergency
plan in case of intercurrent illness
or other metabolic stress. Early diagnosis
through newborn screening and
early initiation of treatment leads to
Early diagnosis through
newborn screening and early
initiation of treatment leads to
improved outcome.
improved outcome [Wilson et al., 1999;
Carpenter et al., 2001].
Figure 7. Plasma acylcarnitine profiles in patients with MCAD deficiency. Note the
consistent pattern with elevation of C6, C8, and C10:1 carnitines, although the C8
concentration is much higher in 7B. * ¼ Internal Standards (m/z 311 ¼ d9-C5; m/z
347 ¼ d3-C8; m/z 375 ¼ d3-C10; m/z 403 ¼ d3-C12; m/z 437 ¼ d9-C14; m/z
459 ¼ d3-C16; m/z 487 ¼ d3-C18).
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
and unsaturated, little or absent ketones,
and increased excretion of hexanoylglycine and suberylglycine [Rinaldo et al.,
1988; Gregersen et al., 1994; Roe and
Ding, 2001]. Phenylpropionylglycine is
usually present in older patients. When
patients are metabolically stable, the
urinary concentration of these analytes
is greatly reduced, although hexanoylglycine and suberylglycine remain
detectable. The abnormal plasma acylcarnitine profile is always present. Follow
up of an abnormal newborn screening for
MCAD deficiency should include analysis of urine organic acids, urine acylglycines, and plasma acylcarnitine profile.
The diagnosis can be confirmed by DNA
analysis.
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