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Newborn screening and inborn errors of metabolism.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 157:1 –2 (2011)
Newborn Screening and Inborn Errors of
How to cite this article: Pasquali M, Longo N. 2011. Newborn screening and inborn errors of
metabolism. Am J Med Genet Part C Semin Med Genet 157:1–2.
After a rapid expansion due to the
introduction of tandem mass spectrometry (MS/MS), newborn screening programs in the United States are evaluating
[Mudd, 2011] which disorders should be
added to current panels. Recently,
screening for severe combined immunodeficiency has been recommended for
addition to the existing core panel in
part as a result of a successful pilot
project [Baker et al. 2010]. In the field
of metabolic disorders (which actually
includes some of the immunodeficiencies
caused by defective purine metabolism),
other disorders could be considered for
inclusion in newborn screening panels.
This issue of the Journal includes new
views on classic metabolic disorders
affecting amino acid metabolism (homocystinuria, disorders of methionine metabolism, vitamin B12 metabolism, and
urea cycle defects – lysinuric protein
intolerance (LPI) and argininosuccinic
aciduria) and new metabolic disorders
that could be considered for inclusion in
newborn screening programs (disorders
of creatine synthesis and lysosomal storage disorders).
An elevation of methionine is a frequent
finding in newborn screening. The
*Correspondence to: Pasquali Marzia,
PhD, Biochemical Genetics and Newborn
Screening Laboratories, ARUP Laboratories,
500 Chipeta Way, Salt Lake City, UT 84108.
DOI 10.1002/ajmg.c.30290
Published online 10 February 2011 in Wiley
Online Library (
ß 2011 Wiley-Liss, Inc.
reason for which methionine is measured by newborn screening programs is
mostly for the identification of classic
homocystinuria due to cystathionine
b-synthase deficiency. Mudd provides
a comprehensive review of this topic in
his paper. Affected patients present
with dislocation of the optic lenses,
mental retardation, early thromboembolic events, and skeletal abnormalities.
Although the pathophysiology is not
completely clear, homocysteine can
interfere with formation of disulfide
bonds in critical domains leading to
misfunction of the zonular fibers that
suspend the lens and in fibrillin, leading
to the classically described marfanoid
habitus. In this case, hypermethioninemia is due chiefly to remethylation of
the accumulated homocysteine. Other
causes of elevated methionine are:
(i) Deficient activity of methionine
adenosyltransferases I and III (MAT I/
III) that impairs conversion to S-adenosylmethionine (AdoMet) and is usually
clinically benign as long as methionine
levels are maintained below a certain
threshold; (ii) glycine N-methyltrasferase (GNMT) deficiency, a very rare
condition characterized by hepatomegaly and elevated transaminases; (iii)
hydrolase deficiency, that can cause a
spectrum of diseases from neonatal
hydrops, mental retardation with leukoencephalopathy to muscle weakness
and developmental delays; (iv) citrin
deficiency, in which the lack of
the mitochondrial aspartate–glutamate
exchanger impairs the urea cycle by
limiting the supply of aspartate that can
conjugate with citrulline to form argininosuccinic acid; (v) tyrosinemia type I
caused by fumarylacetoacetate hydrolase
deficiency in which both liver damage
and the abnormal metabolites can impair
function of methionine adenosyltransferases. These metabolic disorders
should be differentiated from common,
non-genetic conditions causing elevated
methionine such as liver disease, lowbirth-weight and/or prematurity, and
high protein diets.
Vitamin B12 as methylcobalamin
plays an essential role in methionine
metabolism, being essential for the
remethylation of homocysteine to
methionine Watkins and Rosenblatt
thoroughly review the inborn errors of
cobalamin in their article in the issue
[Watkins and Rosenblatt, 2011]. Deficiency of vitamin B12 or disorders of
vitamin B12 metabolism can result in the
accumulation of homocysteine, and
low methionine levels. In addition,
vitamin B12 as adenosylcobalamin is
required for activity of mitochondrial
methylmalonylCoA mutase, and its
deficiency can result in methylmalonic
acidemia. The genes for a series of
inborn errors of intracellular cobalamin
metabolism, designated cblA–cblG
by complementation analysis, were
recently identified. These conditions
can cause isolated methylmalonic acidemia (cblA, cblB, and cblD variant 2),
isolated hyperhomocysteinemia (cblD
variant 1, cblE, and cblG) or combined
methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, and
cblF). Currently, patients with conditions resulting in elevated methylmalonic acid are identified by newborn
screening by an elevated C3(propionyl)carnitine. In addition, some laboratories
are starting to monitor low levels of
methionine and its ratio to other metabolites to identify isolated defects of
methionine synthesis [Tortorelli et al.,
The urea cycle converts waste nitrogen
into urea. Proper functioning of this
cycle requires the coordinated action of
several enzymes and transporters and an
adequate supply of intermediate metabolites. While the hyperammonemia is
common to all urea cycle defects with
similar clinical consequences, some
enzyme or transporter deficiencies have
distinctive clinical presentations probably
reflecting other mechanisms of toxicity.
In argininosuccinic aciduria, patients can
show mental retardation even in the
absence of hyperammonemia. In addition, these patients can have severe liver
disease despite good metabolic control.
Erez and colleagues review this urea cycle
disorder in their article in the issue [Erez
et al., 2011]. These chronic complications are most probably caused by a
combination of tissue-specific deficiency
of arginine and/or elevation of argininosuccinic acid.
LPI is an inherited aminoaciduria
caused by defective cationic amino acids
transport at the basolateral membrane of
epithelial cells. Sebastio and coauthors
cover this unique condition in their
contribution to the issue [Sebastio et al.,
2011]. LPI is caused by mutations in the
SLC7A7 gene, which encodes the
yþLAT-1 protein, part of an heterodimeric amino acid transporter. This
condition is not well known in the
USA, although it has worldwide
distribution. Patients typically present
symptoms after weaning with refusal
of feeding, vomiting, and failure to
thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma,
are recurrent clinical features. These
patients are at high risk for pulmonary
alveolar proteinosis and renal disease. This
condition is diagnosed by urine amino
acids, showing markedly elevated excretion of lysine and other dibasic amino
acids. This condition has features of a urea
cycle, that respond to standard therapy,
and other elements of toxicity that the
authors relate to possible intracellular
arginine trapping with activation of
inflammation and other processes.
The past several years have seen a rapid
increase in the number of therapies
available for patients with lysosomal
storage disorders. The availability of
therapy renders some of these conditions
less severe, but are dependent upon a
timely diagnosis so that irreversible organ
damage can be prevented as discussed by
Nakamura et al. in their paper on newborn screening for lysosomal disorders
[Nakamura et al., 2011]. The disorders
screened differ widely among them, but
many can be screened measuring enzyme
activity of the respective lysosomal
enzyme in blood spots. The past methods
relied on fluorometric assays for the
detection of enzyme activity. These are
difficult to multiplex since all reactions
produce the same type of signal. Measurement of enzyme activity using artificial substrates that can be assayed by MS/
MS allows multiplexing and screening for
multiple disorders at once.
Disorders of creatine metabolism
and transport have only been recently
described, but appear as excellent candidates for inclusion in newborn screening
programs. Longo and colleagues discuss
these disorders in their article [Longo et
al., 2011]. All of them cause mental
retardation that in the case of biosynthetic
defects (deficiency of arginine: glycine
amidinotransferase deficiency or guanidinoacetate methyltransferase) can be
prevented by early therapy. Unlike lysosomal storage disorders, therapy is relatively simple and inexpensive.
The field of metabolic disorders continues to expand identifying their
pathophysiology and providing the
opportunity of novel therapies. Early
diagnosis remains essential to prevent
organ damage or death and newborn
screening programs provide the opportunity for universal identification of
these conditions. The practicing physician needs to be aware of new metabolic
disorders that could be amenable to
screening because of emerging therapeutic options.
Baker MW, Laessig RH, Katcher ML, Routes JM,
Grossman WJ, Verbsky J, Kurtycz DF,
Brokopp CD. 2010. Implementing routine
testing for severe combined immunodeficiency within Wisconsin’s newborn screening program. Public Health Rep 125 (Suppl.
2): 88–95.
Erez A, Nagamani SCS, Lee B. 2011. Argininosuccinate Lyase Deficiency -Argininosuccinic Aciduria and Beyond. Am J Mad
Genet C (in press).
Longo N, Ardon O, Vanzo R, Schwartz E,
Pasquali M. 2011. Disorders of Creatine
Transport and Metabolism. Am J Med
Genet C (in press).
Mudd SH. 2011. Hypermethioninemias of
Genetic and Non-genetic Origin: a Review.
Am J Med Genet C (in press).
Nakamura K, Hattori K, Endo F. 2011. Newborn
screening for lysosornal storage disorders.
Am J Med Genet C (in press).
Sebastio G, Sperandeo MP, Andria G. 2011.
Lysinuric protein intolerance; reviewing
concepts on a multisystem disease. Am J
Med Genet C (in press).
Tortorelli S, Turgeon CT, Lim JS, Baumgart S,
Day-Saivatore DL, Abdenur J, Bernstein JA,
Lorey F, Lichter-Konecki U, Oglesbee D,
Raymond K, Matern D, Schimmenti L,
Rinaldo P, Gavrilov DK. 2010. Two-tier
approach to the newborn screening of
methylenetetrahydrofolate reductase deficiency and other remethylation disorders
with tandem mass spectrometry. J Pediatr
Watkins D, Rosenblatt DS. 2011. Inborn Errors of
Cobalamin Absorption and Metabolism.
Am J Med Genet C (in press).
Marzia Pasquali*
Nicola Longo
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inborn, errors, metabolico, screening, newborn
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