Inborn Errors of Metabolism

Foreword
N e w U n d e r s t a n d i n g of
Mechanisms and New Hope for
Tr e a t m e n t s

Bonita F. Stanton, MD
Consulting Editor

Inborn errors of metabolism (IEM) are defined by the National Institutes of Health as “a
group of disorders that causes a block in a metabolic pathway leading to clinically sig-
nificant consequences.”1 The 5001 IEMs identified to date are generally classified into
six groups: urea cycle disorders, organic acidemias, fatty acid oxidation defects,
amino acidopathies, carbohydrate disorders, and mitochondrial disorders. As also
noted by Ayman W. El-Hattab, MD and V. Reid Sutton, MD, the Guest Editors of this
issue of Pediatric Clinics of North America, while individually most IEM are rare, in
aggregate, an estimated 1/1000 persons have an IEM.2 Therefore, it is important for
child health providers to remain informed about the many advances in the field of
IEM in recent years.
The manifestations of an IEM result from a range of mechanisms typically resulting in
either the production of excessive amounts of toxic substances or the inadequate pro-
duction of critical substances. Disease manifestations, once viewed as resulting from
single gene defects, are now understood to result from a host of factors, including in-
teractions with other genes, interactions between the impacted gene and the environ-
ment, epigenetic factors, and the hosts’ microbiome. Recognition of the contribution of
these multiple ramifications and interactions beyond the impact of the genetic muta-
tion itself has greatly increased our understanding of the mechanisms of the gene mu-
tation and possible treatment approaches.3 Indeed, our growing recognition that the
interactions within a cell or organ and between the impacted individual and his/her
environment produce results far greater than would be expected from a simple additive
process has led to a new appreciation of the manifestations of IEM.4,5
This greater appreciation of the complexity of IEMs has led to the development
of many new ways to diagnose, evaluate, and approach the mutations and the

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deliberating disease effects. These advances have been accompanied by substantial

improvements in survival, resulting in new challenges and opportunities for treatment
approaches.2 In this issue of Pediatric Clinics of North America, Professors El-Hattab
and Sutton and the distinguished clinicians and scientists they have assembled sum-
marize and explain advances made in the field as a whole as well as those specific to
individual categories of disorders. The multiple manifestations and the speed at which
diagnostic and treatment advances have been made over the last decade for the IEM
assure the relevance of this issue for all pediatric care providers regardless of spe-
cialties or areas of focus.

Bonita F. Stanton, MD
Seton Hall-Hackensack Meridian School of Medicine
Seton Hall University
400 South Orange Street
South Orange, NJ 07079, USA
E-mail address:
bonita.stanton@shu.edu

REFERENCES

1. National Institutes of Health (NIH). Available at: https://www.genome.gov/27551373/

the-nih-mini-study-general-information-about-inborn-errors-of-metabolism/. Ac-
cessed December 24, 2017.
2. Alfadhel M, Al-Thihli K, Moubayed H, et al. Drug treatment of inborn errors of meta-
bolism: a systematic review. Arch Dis Child 2013;98(6):454–61.
3. Argmann CA, Houten SM, Zhu J, et al. A next generation multiscale view of inborn
errors of metabolism. Cell Metab 2016;23(1):13–26.
4. Scriver CR, Waters PJ. Monogenic traits are not simple: lessons from phenylketon-
uria. Trends Genet 1999;15:267–72.
5. Dipple KM, McCabe ER. Modifier genes convert “simple” Mendelian disorders to
complex traits. Mol Genet Metab 2000;71:43–50.