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Charles R. Roe, M.D., Institute of
Metabolic Disease, Baylor University Medical Center
Tandem mass spectrometry has been successfully developed
for the detection and quantification of acylcarnitines and amino
acids in dried bloodspots from neonates for the potential diagnosis
of 33 inherited biochemical defects, including phenylketonuria (1).
Twenty-two of these disorders are recognized by acylcarnitine analysis.
The majority of these disorders are characterized by more than one
clinical phenotype (2). This increasing phenotypic complexity is
compounded by the existence of acylcarnitine profiles that are not
necessarily specific for a single disease.
Some examples of diseases that are associated with
either identical or overlapping acylcarnitine profiles are as follows:
- It is not possible to differentiate LCHAD from
Trifunctional Protein Deficiency;
- It is not possible to distinguish between Carnitine
Palmitoyltransferase II and Carnitine Acylcarnitine Translocase
deficiencies;
- The observation of an increase in 3-hydroxy-"isovaleryl"-carnitine
raises the possibilities of 3-methylcrotonyl-CoA carboxylase,
3-methylglutaconic, hydroxymethylglutaryl-CoA lyase, and multiple
carboxylase deficiencies;
- An increase in an acylcarnitine containing 5 carbons
suggests either isovaleric acidemia or the recently identified
S-2-methylbutyryl-CoA dehydrogenase deficiency.
Actually, there are only three disorders for which
the acylcarnitine profile is completely disease-specific: MCAD,
Glutaric Aciduria type I, and Malonic Aciduria.
Although the distinction between diseases which have
similar or identical acylcarnitine profiles is often aided by knowledge
of the clinical course in that infant or child, that information
will not usually be available for the interpretation of the abnormal
newborn screening result prior to symptom onset.
The recent descriptions of newly characterized inherited
disorders that have the same blood-spot acylcarnitine profile (3,4)
emphasize the need for additional documentation to accurately diagnose
the specific disorder so that appropriate management can be implemented.
Similarly, there have been in vitro demonstrations
of distinct acylcarnitine profiles for different clinical phenotypes
of the same disease, even with the same mutation (VLCAD, LCHAD,
ETF-DH) (5, 6). The acylcarnitine profiles from neonatal blood spots
do not show any correlation with these clinical phenotypes.
Finally, not all of the diseases that are said
to be potentially detectable by tandem acylcarnitine analysis have
actually been observed in neonates. Experience now indicates
that it is also occasionally possible to have a normal newborn
screen in some cases of LCHAD and SCAD deficiencies. More information
is required to determine the extent of both false negatives and
false positives for some of these disorders. This may require a
second analysis after ~ 2 weeks of life.
Tandem mass spectrometry analysis of acylcarnitine
profiles in the neonate is a major step forward in neonatal screening.
The potential for expansion to other biochemical disorders (steroids,
bile acids, etc.) is possible and the cost should not increase significantly
with the addition of new disorders.
Tandem screening should be regarded as a more sophisticated
and comprehensive "screen" which can effectively indicate the presence
of many inherited disorders. However, the existence of several
diseases with the same neonatal acylcarnitine profile and the fact
that the neonatal blood profile can not distinguish clinical phenotypes
of the same disease emphasize the requirement for additional sophisticated
and specific testing to provide accurate diagnosis, counseling,
and appropriate treatment.
References
- Naylor EW, Chace DH. Automated tandem mass spectrometry
for mass newborn screening for disorders in fatty acid, organic
acid, and amino acid metabolism. 1999, supplement 1: S1-S4.
- Roe CR, Ding JH. Mitochondrial Fatty Acid Oxidation
Disorders. In: "The Metabolic and Molecular Bases of Inherited
Diseases", 8th edition, Chapter 101, McGraw-Hill, (In press, 2000).
- Roe CR, Cederbaum SD, Roe DS, et al. Isolated
Isobutyryl-CoA Dehydrogenase Deficiency: An Unrecognized Defect
in Human Valine Metabolism. In Press: Mol Gen and Metabol 1998,
65: 264-271.
- Gibson KM, Burlingame TG, Hogema B, et al. 2-Methylbutyryl-Coenzyme
A Dehydrogenase Deficiency: A new inborn error of L-isoleucine
Metabolism. Pediatric Research 2000.
- Roe CR, Roe DS. Recent Developments in the Investigation
of Inherited Metabolic Disorders using Cultured Human Cells. Molecular
Genetics and Metabolism. 1999, 68: 243-257.
- Roe CR, Roe DS. Detection of Gene Defects in Branched
Chain Amino Acid Catabolism. In "Methods of Enzymology", eds.
J.N. Abelson and M.I. Simon, Academic Press, 2000, In Press.
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