CHAPTER
92
Amino Acid Metabolism
Raymond Y Wang, William R Wilcox and Stephen D Cederbaum
Division of Metabolic Disorders, CHOC Children’s Hospital, Orange, CA, USA
This article is a revision of the previous edition article by William R Wilcox and Stephen D Cederbaum, volume 2, pp 2159–2190,
© 2007, Elsevier Ltd.
The inborn errors of amino acid metabolism are a family
of genetic conditions in which an enzyme deficiency typi-
cally results in the accumulation of a ninhydrin-positive
amino acid. They are conceptually identical to disorders
caused by enzyme defects that result in the accumulation
of the organic acid intermediates (see Chapter 97). As
our understanding of the dynamics of amino acid metab-
olism grows, simplistic notions of metabolic pathways
solely as conduits for elimination of excess substrate have
been abandoned. We now realize that most, if not all, of
these reactions are highly regulated and integrated into
the total fabric of metabolic homeostasis in which amino
acids play an important role. Nevertheless, such con-
siderations are largely beyond the scope of this concise
overview and are covered in more detail in the work by
Scriver and colleagues (1), the standard reference work
on these and other inborn errors of metabolism and one
that explores the physiologic interactions more fully.
This chapter strives to highlight the clinical, biochemi-
cal, molecular, and pathologic features of these inborn
errors of metabolism. Although approached in a reduc-
tionist manner, providing quick reference for a geneticist
with a patient carrying the diagnosis, we realize that in
practice, the undiagnosed patient presents to the physi-
cian with symptoms in search of an explanation. Based
on the clinical features described in the following sec-
tions, the physician must decide whether specific diag-
nostic tests, plasma amino acids, urine organic acids, and
ammonia for acutely ill patients, or urinary amino acids
for those with more insidious clinical symptoms, should
be performed. A deeper understanding of many amino
acid-related disorders necessitates the inclusion in this
sixth edition of a new section about serine biosynthetic
disorders as well as appreciable expansions of the sec-
tions regarding cobalamin defects, proline metabolism,
citrin deficiency, and many more.
In addition, we have updated this chapter with results
of clinical trials, as advances in therapeutics for many
© 2013, Elsevier Ltd. All rights reserved.
of the aminoacidopathies have allowed for significant
changes in patient management and outcomes. Much of
the current information on the molecular aspects of these
disorders can be accessed through the Online Mendelian
Inheritance in Man database (OMIM; http://www.ncbi.
nlm.nih.gov/omim) or the GeneTests database (http://
www.ncbi.nlm.nih.gov/sites/GeneTests/).
92.1 DISORDERS OF PHENYLALANINE
METABOLISM
92.1.1 The Hyperphenylalaninemias
Folling, a Norwegian chemist, first recognized the exis-
tence of a disorder of phenylalanine metabolism in 1934
(2). He found phenylpyruvic acid and phenylacetic acid in
the urine of mentally retarded patients in an institution for
the retarded. This condition was eventually called phenyl-
ketonuria (PKU) and is a cornerstone of research in clini-
cal and biochemical genetics. We now recognize several
genetic entities that can cause an elevation in blood phe-
nylalanine and mimic the clinical phenotype of PKU. Each
disorder interferes with the hydroxylation responsible for
the conversion of phenylalanine to tyrosine. Each disorder
causes an elevation in phenylalanine concentration in the
blood; collectively, they are referred to as the hyperphe-
nylalaninemias. These disorders are reviewed in detail by
Scriver and Kaufman (3) and Blau and colleagues (4).
92.1.2 Phenylalanine Hydroxylase
Reaction
Phenylalanine is hydroxylated to tyrosine by the enzyme
phenylalanine hydroxylase (PAH). The reaction requires
molecular oxygen, and tetrahydrobiopterin is the active
cofactor (5). The tetrahydrobiopterin is generated de
novo in humans from guanosine triphosphate (GTP) by
a complex series of enzymatic reactions (Figure 92-1).
1