SYMPOSIUM: METABOLIC MEDICINE

Metabolic screening in
children: newborn screening
for metabolic diseases past,
present and future

Why do we screen for inherited metabolic diseases?

The well-known IMDs include disorders of amino acid, organic
acid and fatty acid metabolism, urea cycle disorders and
lysosomal storage disorders (LSDs). Affected babies are usually
normal at birth. Symptoms develop after a latent period ranging
from a few hours to many years. There may be catastrophic
decompensation with encephalopathy and brain swelling or
overwhelming liver or cardiac dysfunction, or slowly progressive
cerebral or multisystem deterioration. In those who present
catastrophically in the newborn period, treatment may not
improve outcome, though knowledge of the IMD can benefit
the family. Early diagnosis and treatment may prevent encephalopathy and improve outcome. Many of those at risk of later
decompensation or progressive disease may benefit from newborn screening. There is little evidence from systematic studies of
the benefit of intervention following a diagnosis from screening.
However, it is logical that early treatment will lead to a better
outcome. There is no better example of the benefits of screening
than phenylketonuria (PKU). In contrast, the neurodevelopmental outcome of patients with galactosaemia does not seem to be
improved by newborn screening. Evidence for the effectiveness
of newborn screening is limited mainly to individual screening
programme reports comparing outcomes before and after screening, or in geographical areas that undertake or do not undertake
screening.

Mark Sharrard
Rodney Pollitt

Abstract
Newborn screening began with the diagnosis of phenylketonuria using a
simple test applicable to all newborn babies. Treatment could be given
before the onset of brain damage with near normal outcomes. Methods
became available to screen for and treat a variety of inborn errors of
metabolism, but their application was patchy. Screening for hypothyroidism is now universal in the UK, and screening for cystic fibrosis
and, more recently, haemoglobinopathies is being implemented
nationally. Tandem mass spectrometry allows detection of more than
30 metabolic disorders using the neonatal screening blood spot.
Considerable worldwide experience is now available and limited studies
have shown favourable outcomes. Following a pilot study, the UK is to
adopt tandem mass spectrometry screening for medium-chain acyl-CoA
dehydrogenase deficiency. There is the potential to develop expanded
newborn screening for aminoacidopathies, urea cycle disorders, organic
acidaemias and fatty acid oxidation defects.

Principles of screening
Wilson and Junger1 defined the 10 principles of early disease
detection, or screening, in 1968.
1. The condition sought should be an important health problem.
2. There should be an accepted treatment for patients with
recognised disease.
3. Facilities for diagnosis and treatment should be available.
4. There should be a recognised latent or early symptomatic
stage.
5. There should be a suitable test or examination.
6. The test should be acceptable to the population.
7. The natural history of the condition should be understood.
8. There should be an agreed policy on whom to treat.
9. The costs of case finding should be economically balanced in
relation to the effect of possible expenditure on medical care
as a whole.
10. Case finding should be a continuous process and not a once
and for all project.

Keywords assessment (health care); costbenefit analysis; humans;

inborn errors/diagnosis; mass spectrometry; neonatal screening/
economics; neonatal screening/organisation and administration;
newborn; predictive value of tests

What is screening?
Screening has been defined as: the systematic application of a
test or enquiry to identify individuals at sufficient risk to benefit
from further investigation or direct preventative action, amongst
persons who have not sought medical attention on account of
symptoms of the disorder. Any newborn baby is potentially at
risk of a variety of inherited metabolic diseases (IMDs) that are
amenable to treatment. A pre-symptomatic baby is a candidate
for screening for these disorders.

These principles were aimed at screening in general. The issues

in newborn screening are essentially that there should be benefit,
and this should be balanced by financial costs, costs of harm
caused by screening and the costs of false-positive and falsenegative results. Thus, for an agreed disorder causing significant
problems that can be effectively and economically treated, can
we perform a reliable, relatively inexpensive and acceptable test
to identify those to treat?
Many IMDs are attractive candidates for newborn screening.
We screen to identify infants with treatable disorders so that we
can intervene to minimise the clinical consequences. Diagnosing

Mark Sharrard MB BS FRCPCH is Consultant Paediatrician at the Sheffield

Childrens Hospital, Western Bank, Sheffield S10 2TH, UK.
Rodney Pollitt PhD FRCPath is Consultant Clinical Scientist at the Sheffield
Childrens Hospital, Western Bank, Sheffield S10 2TH, UK.

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SYMPOSIUM: METABOLIC MEDICINE

and treating before symptoms develop may improve outcome and

quality of life.

dystrophy was in progress in Wales. Scotland was still screening

for galactosaemia.3

The past

The present

Phenylketonuria
PKU is a disorder of phenylalanine catabolism with an incidence
in the UK of 1/10,000 births. Untreated, it typically leads to severe
mental retardation. In the early 1950s, Bickel and colleagues2
showed that restricting dietary phenylalanine partially reversed
the behavioural effects of the disorder and allowed resumption of
mental development. They concluded that: It is reasonable to
presume that the best results of dietetic treatment of phenylketonuria will be obtained if treatment is started in infancy and
particularly in the neonatal period, a prediction that proved
correct and which provided the impetus for the development
of newborn screening. Early screening programmes used the
ferric chloride test to detect phenylpyruvate in urine obtained at
46 weeks of age (the nappy test). By 1962, almost all local
authorities in the UK had implemented screening by this method.
Quality control was difficult, however, and a significant number
of cases were missed due to genuine false-negative results or to
failure to test. In 1969, it was recommended that the screening
method be changed to measurement of phenylalanine in a dried
blood sample on filter paper obtained at 614 days of age,
following the methods pioneered in the USA by Robert Guthrie.
The assay was to be performed in designated regional or
supra-regional screening laboratories, which were to be closely
associated with diagnostic and treatment centres. Thus began the
modern era of newborn metabolic screening.
Most centres initially adopted the Guthrie microbial assay for
phenylalanine, but others chose a more accurate chemical assay
or amino acid chromatography. Amino acid chromatography can
detect a range of other metabolic disorders such as maple syrup
urine disease (MSUD) and homocystinuria. Most laboratories
have now adopted tandem mass spectrometry (MS/MS) as their
basic screening method.

Recent years have seen progressive centralisation of newborn

screening policy. A National Screening Committee under the
auspices of the four UK Chief Medical Officers was formed in
1996 with a remit to advise health departments on broad
screening policy and particularly quality issues, and to this end
it produced a set of rigorous criteria based on the Wilson and
Junger principles. The committee has relied heavily on a series
of reports commissioned through the Health Technology Programme. Early reports covered neonatal screening for inborn
errors of metabolism.4,5 A UK Newborn Screening Programme
Centre has been formed and is in the process of setting detailed
performance standards and harmonising policies and procedures
related to blood-spot screening.
A commitment to linked antenatalneonatal screening for
haemoglobinopathies appeared in the NHS Plan of July 2000. The
neonatal component has now been implemented in England,
where it is integrated with the other newborn blood-spot screens
in 12 regional laboratory centres. Antenatal screening is being
offered on a more local basis, universally in high-prevalence
areas and selectively based on an ethnic question in lowprevalence areas. Newborn screening for sickle cell diseases is
highly sensitive provided that babies who have received blood
transfusion are identified and followed-up some weeks later.
However, it generates a great deal of noise in the form of
haemoglobin variants of no known clinical significance and
unaffected carriers whose families have to be offered further
investigation and genetic counselling.
Progress in cystic fibrosis has been slower. This has been a
controversial screen and it has proved difficult to demonstrate
clear long-term benefit, though the short-term benefits are more
obvious. However, a ministerial commitment was made in 2001
to offer newborn screening throughout England (Wales and
Northern Ireland were already screening and Scotland rapidly
followed suit). Cystic fibrosis screening uses combinations of
immunoreactive trypsinogen and mutation analysis in a complex,
nationally agreed protocol.
MS/MS is a development of mass spectrometry that is used to
quantify many different metabolites within certain chemical
classes. During the early 1990s, advances in ion-source technology led to the automation of MS/MS and the development
of high-throughput methods for measuring a wide range of
metabolites in the dried blood spots obtained using the current
infrastructure. MS/MS can rapidly screen for more than 30
disorders in a single run. Measurement of excess acylcarnitines
allows the diagnosis of organic acidaemias and fat oxidation
disorders, while measurement of increased amino acids permits
the diagnosis of urea cycle disorders and aminoacidopathies,
including PKU and other disorders previously detectable by
amino acid chromatography.
Both of the 1997 Health Technology Assessment reports4,5
recognised the potential of MS/MS and recommended pilot/
research studies before its general introduction. This was
intentionally limited to a single disorder, medium-chain acylCoA dehydrogenase deficiency (MCADD), which was considered

Congenital hypothyroidism
Initially, screening for congenital hypothyroidism used a radioimmunoassay for thyroxine in dried blood spot samples. This
method lacked specificity, and a blood-spot assay for thyrotropin
was developed. Although the thyrotropin-based screen fails to
detect secondary hypothyroidism, its practical advantage was the
deciding factor and this method was adopted in the UK.
Other screens
By 1980, Guthrie was able to list more than 20 disorders that
could be detected by blood-spot screening. The Scottish
programme was particularly active, using specific microbial
assays to screen for MSUD, homocystinuria, tyrosinaemia and
galactosaemia and also performing large-scale pilot studies on
congenital adrenal hyperplasia and biotinidase deficiency. However, few of these additional tests entered long-term use, either
because of the rarity of the disorder or because of problems with
the assay. A survey conducted in 1993 found that 12% of
UK babies were being screened for homocystinuria, 3% for
tyrosinaemia, 16% for cystic fibrosis and 9% for haemoglobinopathies, and a pilot study of screening for Duchenne muscular

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The sensitivity of MS/MS screening is generally high and

approaches 100% for most disorders including MCADD and
PKU.9 However, it is difficult to determine how many cases have
been missed. Several studies have reported missed cases of
glutaric aciduria type I, cobalamin metabolism defects, tyrosinaemia type I and 3-ketothiolase deficiency. Also, pyridoxineresponsive homocystinuria appears to be not detected using MS/
MS identification of raised methionine.
Before the results of screening became available, 312% of
affected infants died or become symptomatic. Typically, these
babies had severe variants, or untreatable disorders such as nonketotic hyperglycinaemia. Five such cases were reported from
Australia8 (of 48 diagnosed infants), six from North Carolina11
(of 49 diagnosed) and three from Germany9 (of 106 diagnosed).
As non-ketotic hyperglycinaemia is poorly detected by MS/MS
screening and is untreatable, screening for this disorder may not
be appropriate.
Some of the individual MS/MS screens, notably those for the
tyrosinaemias, homocystinuria and propionic and methylmalonic
acidaemia, consistently lack specificity. These tests generate
repeat requests and their PPVs are lower than those for other
disorders. The specificity of MS/MS screening may be improved
by screening on day 57, as in the German study,9 rather than
on day 2 as in the USA.6,7,11 Second-tier tests may improve
specificity, particularly for type I tyrosinaemia9 and homocystinuria. In the UK MCADD screening pilot study,13 the specificity
was greater than 99.997% with a PPV of 85%. False-positives
from neonatal intensive care babies were not a problem, and the
excellent specificity may be due to the age of screening in the UK
(58 days).
MS/MS screening detects some disorders at a much higher
frequency than that expected from observation of those presenting clinically. In Australia,14 the incidence of MCADD diagnosed
by screening was more than double that in children under 4 years
of age diagnosed clinically. While the allele frequency of the
common 985A-G missense mutation in the ACADM gene
responsible for MCADD was 89% in those diagnosed clinically,
it was only 76% in the screened population. Similar observations
have been made in other populations, including in the UK,13
suggesting that milder mutations, though causing the MCADD

to be the only condition sufficiently common to give useful

results within a reasonable time frame. The plan was for a 2-year
screening phase with a further 2 years of clinical follow-up; any
resulting policy decision would be made after this. Overall,
approximately 700,000 babies were to be screened, representing
one-half of UK births during the 2-year period; the remainder
from the non-screened areas acted as controls, to be captured
through the British Paediatric Surveillance Scheme. The screening arm of the study confirmed expectations in that sensitivity
and specificity were high but a significant proportion of screening-detected cases had relatively mild forms of the biochemical
defect. Based on the preliminary findings, the Minister for Public
Health announced in February 2007 that screening for MCADD
would be introduced throughout England within the next 2 years.

The future
Expanded MS/MS screening
There are an increasing number of reports of disease detection
rates from expanded screening programmes around the world
(Table 1). Excluding the Australian data, as PKU was not
included, the frequency of IMDs detected by newborn screening
ranges between 1/2400 and 1/4300. The frequency of fatty acid
oxidation disorders is 1/10,000 to 1/16,000, with MCADD being
the most common in this group. PKU and hyperphenylalaninaemia are the most common aminoacidopathies.
Overall positive predictive value
The positive predictive value (PPV) is the fraction of all screening
positive results that are found to be true positives. With MS/MS,
the overall PPV for detection of IMDs from the first blood spot
sample ranges from 5% to 11%. False-positives are an inevitable
part of any screening programme, and may be over-represented
in very low birthweight and neonatal intensive care babies.7 In
non-MS/MS screens used in US screening programmes, Kwon
and Farrell12 reported PPVs for screening for galactosaemia
(0.53%), biotinidase deficiency (5.90%), congenital hypothyroidism (1.91%) and congenital adrenal hyperplasia (0.54%).
These low PPVs may reflect the early screening times adopted in
the USA.

Inherited metabolic disease detection rate for tandem mass spectrometry screening programmes.
Study

Number
screened

Number of
disorders

Screening
positives

Number
diagnosed

Frequency of detected
inherited metabolic
diseases

Positive
predictive
value (%)

USA, Pittsburgh6
USA, New England7
Australia8
Germany, BadenWurttemberg9
South Korea10
USA, North Carolina11

700,000
164,000
362,000
250,000

23
31
23

633
560
950

163
42
48
106

1/4300
1/3900
1/7500
1/2400

8
10
11

79,179
239,415

35
31

1166

28
49

1/2800
1/4100

6
5

Not including PKU.

 Including 1084 borderline positives, 27 of these screening positive on repeat. Positive predictive value using borderline repeat positives was 33%.

Table 1

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biochemical phenotype, result in a mild disorder that may never

present clinically. Similarly, 3-methylcrotonyl CoA carboxylase
(3-MCC) deficiency rarely presents clinically but has been
detected by screening with a frequency of up to 1/12,000.
Affected individuals may be at risk of catastrophic decompensation,15 but it is not possible to predict who will be affected. While
MS/MS screening may identify some individuals who may never
need treatment, not screening puts others at risk of avoidable
adverse outcomes.
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is
relatively frequently diagnosed by MS/MS screening (up to
1/32,000 births). Symptomatic SCADD is less frequently found
and the clinical features are variable and sometimes transient.16
SCADD diagnosed by newborn screening must be treated
cautiously, along with other disorders that are not clearly defined.

diseases are not generally seen as important public health

problems, and screening for rare disorders is not an effective
use of resources. MS/MS screening can be viewed as a single test
for MS/MS-detectable disease. The more genuine disorders that
are included in the MS/MS screen, the more important the health
problem being addressed.
The second principle concerns treatment. Many individuals
with MS/MS-detectable diseases are treated effectively. Some
inevitably die in the neonatal period, and MS/MS screening
provides a diagnosis. This does not benefit that individual baby,
but parents can find comfort in knowing why their baby died.
Furthermore, knowledge of the diagnosis allows future prenatal
diagnosis and family studies, and may enable diagnosis of
previous unexplained deaths. The benefit of screening is therefore to the family rather than to the individual. The fourth
principle concerning latency can be incorporated into this
argument.
MS/MS screening identifies a risk for those with milder
conditions or milder variants of recognised disorders. This is
exemplified by 3-MCC deficiency and may be applied especially
to those with MCADD. While individuals may not appear to have
a disorder, they can be managed in such a way as to minimise
their risk of an adverse outcome.
The seventh principle supports MS/MS screening. The
example of SCADD shows it is inappropriate to screen for
disorders that are undefined and have no clear natural history.
The fourth principle relates to test performance. The data
summarised here show that MS/MS screening performs well, and
when screening is conducted at a carefully selected age, around
day 58, the specificity is high and the sensitivity appears to be
close to 100% for many disorders.
Acceptability, which is addressed in the eighth principle,
should be no different for the blood test than for PKU and
hypothyroid screening. Parents must be informed about the tests
that are performed on their baby, and data from other screening
programmes suggest that parents accept screening if they are
provided with adequate information.
The cost of adding extra tests to MS/MS screening is negligible
in itself. Although confirmatory tests generate costs, these must
be weighed against the costs that would have been incurred had
the child presented clinically, which are likely to be considerable
greater.

Outcome of MS/MS screening

The few reports on the outcome of MS/MS-screened infants have
necessarily looked only at the short-term outcome.
The German study9 concluded that 70 of the 106 infants
diagnosed by screening needed treatment; 61 of these (87%) were
asymptomatic at diagnosis and remained asymptomatic, thereby
having benefited from screening. In the German population,
1/4100 infants would benefit from treatment. A substantial
proportion of these would have PKU.
Waisbren et al.17 compared the outcomes of 50 children
diagnosed by MS/MS newborn screening with 33 children
diagnosed clinically with similar disorders and 94 children with
false-positive screening results. Children diagnosed by screening
required less hospitalisation under the age of 6 years and were
less likely to have learning difficulties. They had a higher median
developmental quotient, and unlike the clinically diagnosed
group had no significant deficits in communication, daily living
skills, socialisation or motor skills. In families that received a
false-positive screening diagnosis, there was a higher rate of
hospital admission, and higher levels of parental stress and
parentchild dysfunction.
In children with propionic, methylmalonic or isovaleric
acidaemia, those diagnosed by MS/MS screening exhibited less
early mortality and less severe symptoms at diagnosis. Their
short-term neurodevelopmental outcome was more favourable.
However, screening may have diagnosed some milder cases of
isovaleric acidaemia that may have never developed abnormalities.18
Wilcken et al.14 assessed the outcome of MCADD patients
diagnosed by screening or clinically. The risk of a severe adverse
event was significantly higher in those diagnosed clinically
(57%) than in those diagnosed by screening (8%). One patient in
each group had an intellectual outcome more than one standard
deviation below the mean. In other studies, the outcome in those
who present clinically has been less good. Despite early
detection, several programmes have found MCADD to be
associated with subsequent death, though, overall, screening is
of benefit.

The way forward

The introduction of whole population screening by MS/MS for
MCADD in England has come after one of the few screening
evaluation exercises to be conducted anywhere in the world.
MCADD screening requires laboratories to use MS/MS, with the
potential to undertake expanded MS/MS screening. Wilson and
Jungers third principle may be an obstacle for universal MCADD
screening, and hence expanded screening; a recent review of
services for IMDs has highlighted great inequalities of service
provision across the UK.
Evidence from overseas supports the introduction of expanded
MS/MS screening for some of the detectable disorders. By
learning from those programmes with the best performance we
can adopt the optimal criteria for extended MS/MS screening.
Such screening would have to be initiated on a pilot basis and
would represent a substantial undertaking. Specific centres could

Wilson and Junger in the era of MS/MS screening

The first principle states the disorder sought should be an
important health problem. To those with a disorder detected by
MS/MS screening, their disorder is an important problem. Rare

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normal outcome or a reduction in disability. Experience with PKU

has clearly demonstrated the benefits of screening, and a number
of additional screening tests have been highly effective on a
smaller scale.
Worldwide experience has shown that MS/MS screening is
highly effective in detecting more than 30 IMDs, with evidence of
improved outcomes. MS/MS screening is being universally
adopted in the UK for MCADD, and there is an opportunity to
take advantage of the MCADD screening infrastructure to expand
it to include urea cycle disorders, aminoacidpathies, fat oxidation
defects and organic acidaemias. There is also the potential to
develop MS/MS screening for LSDs, especially as effective
therapies are becoming available.
~

take responsibility for collating data for certain groups of

disorders and share the burden of analysing test performance
and outcomes. Expanded MS/MS screening in the UK seems
feasible.
Other screens
Newborn screening is undertaken for various other metabolic
disorders around the world. In certain circumstances, the high
local prevalence of a disorder may render it attractive for
screening. Glucose-6-phosphate dehydrogenase deficiency, a
treatable enzyme deficiency resulting in severe haemolytic
anaemia, is especially prevalent in the Far East and Mediterranean areas, where screening programmes are highly effective.
Individual non-MS/MS screens for homocystinuria, galactosaemia, MSUD and biotinidase deficiency have been included
in screening programmes either singularly or collectively in
various locations, and all four have been included in programmes
in some states in the USA. Data from the USA have shown
better outcomes in children with these four disorders collectively
when diagnosed by screening in terms of neurodevelopment,
ability of parents to meet health-care needs and parental stress.19
The outcome in infants with homocystinuria detected by screening is almost normal.20 However, the neurodevelopmental
outcome in galactosaemia is not positively influenced by
treatment.
The LSDs are a group of individually rare metabolic diseases
with a combined prevalence, in one Australian study, of 1/7700.
LSDs may cause neurodegeneration, and progressive abnormalities of connective tissue, skeleton or viscera. A pre-symptomatic
phase and the development of effective treatments (enzyme
replacement therapy, bone marrow transplantation or substrate
reduction drug therapy) make LSDs attractive for screening.
Treatable disorders include Fabrys, Gauchers, Hurlers,
Krabbes, NiemannPick A/B and Pompe diseases. Newborn
screening using the neonatal blood spot is being developed. One
method uses immunochemistry to demonstrate absent enzyme
protein. Alternatively, substrate is added to an extract of the
blood spot and MS/MS detects the product, diagnosing many
disorders from a single sample. Sample processing is more
complex and more expensive than for amino acid and acylcarnitine analysis, and the treatment of these disorders can be
extremely expensive. An MS/MS method for screening for Krabbe
disease is being used in New York State.
Wilsons disease is characterised by storage of copper in the
brain, liver and other organs and may cause progressive liver
disease and neurodegeneration. It is treatable if detected early or
pre-symptomatically. The serum protein caeruloplasmin, which
is detectable by immunochemistry, is deficient in most patients.
Studies using blood or urine have been used to screen children
and have shown that Wilsons disease can be detected.
Population screening demanding further samples beyond the
neonatal period would require an entirely new infrastructure and
may not be acceptable to the population. Wilsons disease is rare
in the UK and screening would be unlikely to be cost-effective.

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2 Bickel HJ, Gerrard J, Hickmans EM. The influence of phenylalanine
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3 Streetly A, Grant C, Pollitt RJ, Addison GM. Survey of scope of
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4 Pollitt RJ, Green A, McCabe CJ et al. Neonatal screening for inborn
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5 Seymour CA, Thomason MJ, Chalmers RA et al. Newborn screening for
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7 Zytkovicz TH, Fitzgerald EF, Marsden D et al. Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in
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10 Yoon HR, Lee KR, Kang S et al. Screening of newborns and high-risk
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spectrometry in South Korea: a three-year report. Clin Chim Acta
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11 Frazier DM, Millington DS, McCandless SE et al. The tandem mass
spectrometry newborn screening experience in North Carolina:
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Conclusion
The principles of screening are applicable to IMDs, especially as
many IMDs have a latent phase and are now treatable with a

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Oude Luttikhuis HG, Touati G, Rabier D et al. Severe hypoglycaemia
in isolated -methylcrotonyl-CoA carboxylase deficiency; a rare, severe
clinical presentation. J Inherit Metab Dis 2005; 28: 11368.
van Maldegem BT, Duran M, Wanders RJ et al. Clinical, biochemical,
and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. JAMA 2006; 296: 94352.
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Dionisi-Vici C, Deodato F, Roschinger W et al. Classical organic
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Waisbren SE, Read CY, Ampola M et al. Newborn screening compared
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Practice points










278

Screening aims to identify treatable disorders before symptoms develop to improve outcome and quality of life
Many IMDs have a presymtomatic phase and are treatable with
improved outcomes, making them attractive for screening
Currently in the UK, the screening programme includes
phenylketonuria, hypothyroidism, cystic fibrosis and sickle
cell disease; MCADD will be included from 2009
Individual add-on screening programmes in the UK and
overseas have benefited patients with IMDs
MS/MS can detect over 30 IMDs, including disorders of amino
and organic acids, the urea cycle and fat oxidation, in a single
test using the newborn blood spot
Studies from around the world have shown that MS/MS can
detect selected IMDs with high sensitivity and specificity, and
suggest that screening has a positive effect on outcome
The outcome for those with MCADD detected by MS/MS
screening in the UK and overseas has been good
There will be the potential to introduce expanded MS/MS
screening in the UK using the infrastructure of the MCADD
screening programme
There is the potential to develop MS/MS screening for
treatable LSDs

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