Newborn screening for inborn errors of
metabolism has been in place in many countries for many years. Strong
arguments have been made for screening not only for improving care of
patients identified through screening, but also for reducing the cost of
this care. Indeed, there are numerous examples, PKU most notably, of how
early diagnosis and treatment have prevented serious illness or death from
these disorders. However, as Wilcken and colleagues point out, formal
evidence for the clinical effectiveness of screening is lacking,
especially for rarer diseases, such as inborn errors of metabolism.
Randomized, controlled trials of screening have been very limited because
of the rarity of these disorders and also because of the strong conviction
based on clinical experience that there is a benefit from early diagnosis.
Against this backdrop Wilcken et al compared the effectiveness
screening for inborn errors of metabolism in all newborns with tandem mass
spectrometry from 1998 to 2002 to conventional biochemical screening
performed because of clinical suspicion from 1974 to 1998. The study
population lived in New South Wales (Australia) and the Australian Capital
Territory and totaled six million. Thirty-one disorders were selected for
study. PKU and pterin disorders were excluded because effective screening
by other methods had been in place for many years; also excluded were
disorders known to be benign or of maternal origin.
The diagnosis rates were reported in four-year brackets, i.e.,
1974-1978, 1978-1982 … 1998-2002, etc. During the six four-year periods
preceding the implementation of tandem mass spectrometry screening, 22-34
cases were diagnosed per period giving rates from 6.6 to 9.0 cases per
100,000 births. Diagnoses were made at different ages depending on the age
of clinical presentation. There were no trends toward increased overall
rates of diagnosis between 1982 and 1998 even though some of the 31
disorders were first recognized during these periods.
Between 1998 and 2002, when all infants were tested between 48 and 72
hours after birth, 57 infants were diagnosed with one of the 31 inborn
errors or 15.7 diagnoses per 100,000 births. Of these, 48 infants were
diagnosed by screening, while six were diagnosed clinically before or at
the same time as the screening result became available, usually within 24
hours of testing. Two patients, siblings with ornithine transcarbamylase
deficiency born to a mother with known risk, did not undergo screening.
Seven patients whose diagnoses were made later on clinical grounds had
negative results on newborn screening.
Although results showed an increase in the rate of diagnosis following
the introduction mass spectrometry screening in newborns, most of the
increase could be accounted for by the diagnosis of medium-chain acyl-CoA
dehydrogenase deficiency and to a lesser extent by the diagnosis of other
disorders of fatty acid oxidation.
The authors calculated the cost of establishing a diagnosis. The
incremental cost of the tandem mass spectrometry screening was $0.70 (USD)
per newborn. The cost of confirmatory testing was $217 and the cost per
relevant disorder detected was $3,939 if PKU was excluded or $2,519 if it
was included. They concluded that their approach provides a rapid and
inexpensive way to screen for a wide range of very rare metabolic diseases
and that it identifies more cases than are diagnosed clinically. However
they caution that it is not yet clear which patients identified through
newborn screening would have become symptomatic if screening had not been
performed.
Wilcken B et al. New Eng J Med 2003;348:2304-2312.
Editor’s Comment: This paper brings to the fore the debate over the
extent to which tandem mass spectrometry technology should be used to
screen for a growing number of inborn errors of metabolism. As noted in a
recent article by Marshall,1 the debate pits parents and often
physicians who advocate the application of this technology against
ethicists with concerns over costs and public health officials with
concerns over how the potentially large amount of genetic data will be
managed. The Wilcken study demonstrates the successful implementation of
the technology in a public health setting. It documents that the
technology leads to an increased rate of diagnosis at low cost, especially
for disorders of fatty acid oxidation, although acknowledges the
possibility that some patients diagnosed as newborns may not have become
symptomatic if screening had not been performed. Readers should note that
metabolic screening by tandem mass spectrometry was highlighted by a
recent lead article in GGH.2 This article explains how
technology works, provides guidelines for its use and describes its
successful application in North Carolina. Together, these articles provide
support for advocates of wider use of tandem mass spectrometry for newborn
screening.
References
1.
Marshall E.
Science 2001;294:2272-2274.
2.
Millington D, Koeberl D. GGH 2003;19:32-38.
William A. Horton, MD
