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Journal
of
Public Health Medicine
Vol.
20, No. 3, pp. 331-343
Printed
in
Great Britain
A systematic review
of
evidence
for the
appropriateness
of
neonatal screening
programmes
for
inborn errors
of
metabolism
Margaret J. Thomason, Joanne
Lord,
Murray D. Bain, Ronald
A.
Chalmers,
Peter Littlejohns, G. Michael Addison,
A.
Hervey Wilcox
and
Carol
A.
Seymour
Abstract
Background Developments
in
screening technology
and
increased understanding
of
the natural history and treatment
of inborn errors
of
metabolism (lEMs) have produced
pressure
to
extend neonatal screening programmes. This
review aims to assess the evidence for the appropriateness
of
such programmes.
Methods
A
formal systematic literature review
was con-
ducted.
Exclusion
and
inclusion criteria were used
to
select
papers
for
critical appraisal
by
pairs
of
reviewers. Standard
criteria were used
to
assess the appropriateness
of
neonatal
screening
for
various lEMs. Site visits were conducted
to
assess new technologies
for
newborn screening.
Results
A
total
of 1866
papers were identified
and 407
systematically selected
for
full critical appraisal. Published
evidence confirmed that universal newborn screening
for
phenylketonuria (PKU) meets all
of
the screening criteria
and
justifies
the
expense
and
infrastructure necessary
for the
collection
and
testing
of
neonatal blood spots. There
was
insufficient evidence
in the
literature
to
assess
the
cost-
effectiveness
of
screening
for any
other lEMs. There
was
reasonable evidence
to
support inclusion
in
extended
neonatal screening
of
four other lEMs: biotinidase deficiency,
congenital adrenal hyperplasia (CAH), medium-chain acyl
CoA dehydrogenase (MCAD) deficiency and glutaric aciduria
type
1
(GA1).
Conclusions Large-scale trials
of
screening
for
biotinidase,
CAH,
MCAD
and GA1
should
be
conducted, with careful
evaluation
to
establish their clinical effectiveness
and
cost-
effectiveness
in
practice. Screening
for the
latter
two
disorders would
be
dependent upon
the use of
tandem
mass spectrometry (tandem MS). The application
of
tandem
MS
to
newborn screening requires further evaluation.
The
extension
of
neonatal screening programmes
to
other lEMs
is
not
currently justified.
Keywords: neonatal screening, inborn errors
of
metabolism,
mass spectrometry, literature review
Introduction
The first population-based neonatal screening programmes for
detecting inborn errors of metabolism (lEMs) were introduced
around 30 years ago for phenylketonuria (PKU). Since that time
there has been a substantial increase in the number of identified
IEMs and although each individual disease is rare the total
incidence is significant. For example, in the United Kingdom,
with around
793
000 infants born each year, there are 60-70
affected by PKU,1 60 infants with congenital adrenal hyper-
plasia (CAH), 50-60 with medium-chain acyl CoA dehydro-
genase (MCAD) deficiency and 40-50 with disorders of organic
acid metabolism. It has been estimated that these disorders
collectively have an impact on health care comparable with that
of juvenile-onset diabetes.2
More than 99 per cent of newborns in the United Kingdom,
and infants in most other developed countries, are currently
tested for PKU and also for congenital hypothyroidism.3'4 There
is considerable pressure to expand universal newborn screening
programmes to cover a broader range of IEMs. This has been
further supported by the development of new technologies
which are applicable to multi-disease screening programmes,
for example tandem mass spectrometry (tandem MS) and
'Department
of
Child Health,
St
George's Hospital Medical School, London
SW17 ORE.
2Health Care Evaluation Unit, Department of
Public
Health Sciences, St George's
Hospital Medical School, London SW17 ORE.
3Royal Manchester Children's Hospital, Manchester M27
1HA.
4St Helier Hospital, Carshalton, Surrey SM5
1AA.
'Department
of
Cardiological Sciences,
St
George's Hospital Medical School,
London SW17 ORE.
Margaret Thomason, Health Services Research Fellow1
Joanne Lord, Lecturer
in
Health Economics2
Murray Bain, Consultant Paediatrician'
Ronald Chalmers, Professor
of
Paediatric Metabolism'
Peter Littlejohns, Professor
of
Public Health2
Michael Addison, Consultant Chemical Pathologist3
Hervey Wilcox, Consultant Chemical Pathologist4
Carol Seymour, Professor
of
Clinical Biochemistry and Metabolism5
Address correspondence
to
Dr Margaret Thomason, Health Care Evaluation
Unit, Department
of
Public Health Sciences,
St
George's Hospital Medical
School, Cranmer Terrace, London SW17 ORE.
© Oxford University Press 1998
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332JOURNAL OF PUBLIC HEALTH MEDICINE
automated immunoassay. Before the introduction of any such
screening programme there should be good evidence that the
additional screening and consequent treatment costs, and the
potential anxiety to parents, are outweighed by the benefits of
health improvements and savings in health care. The fact that a
wide range of metabolic disorders can be detected by using new
technologies does not necessarily mean that screening for these
disorders should be undertaken. The longer-term implications
for individuals, the health service and society should also be
considered. For some IEM disorders it is not even clear that
early detection offers any benefit to the child.5
A health technology assessment project was undertaken in
the United Kingdom to assess current newborn screening
programmes, to evaluate the available evidence for their
expansion and to make recommendations for future develop-
ments. Two fundamental questions were addressed: (1) Which
IEMs should be screened for? (2) What technologies should be
used for screening?
A consortium was established to review the technical,
clinical and economic implications of screening. The project
team consisted of a combination of the disciplines of clinical
biochemistry, metabolic medicine (both adult and paediatric),
public health and health economics. Two members of this team
were also experts on the automation of technologies and on
mass spectrometry. Although the aim was to provide advice to
the National Health Service the literature review was interna-
tional and the results are pertinent to those countries with
comparable incidence rates of IEMs to those in the United
Kingdom. To avoid compromising the high rate of coverage of
current newborn screening programmes the assumption was
made that the infrastructures for sample collection would not be
substantially altered.
Methods
Three methods of data collection were used: a formal
systematic review of the literature was conducted, a ques-
tionnaire was sent to all newborn screening laboratories in the
United Kingdom to enquire about current practice and grey
literature, and visits were made in the United Kingdom, United
States and Finland to assess potential new technologies for
newborn screening.
For the purpose of the systematic review a classical
definition of an IEM was taken, i.e. a monogenic disease
resulting in deficient activity in a single enzyme in a pathway of
intermediary metabolism. Disorders thus considered were the
catabolic and synthetic pathways of carbohydrates, amino acids,
organic acids, fatty acids, purines, pyrimidines, porphyrins,
steroids, lipids and bile acids, and secondly of the processes
involved in the uptake, synthesis and utilization of
the
essential
cofactors for enzymes in these pathways, including trace metals
and vitamins; also included were disorders of lyosomal enzymes.
The categories of IEM included in the review were:
(1) phenylketonuria;
(2) amino acidopathies;
(3) disorders of carbohydrate metabolism;
(4) disorders of organic acid metabolism;
(5) fatty acid oxidation defects;
(6) disorders of adrenal steroidogenesis;
(7) lipoprotein disorders;
(8) peroxisomal disorders;
(9) disorders of the urea cycle;
(10) respiratory chain/tricarboxylic acid cycle disorders;
(11) trace metal disorders;
(12) purine-pyrimidine disorders;
(13) lysosomal disorders.
Other inherited disorders, for example of membrane transport,
of connective tissue, of blood and of blood-forming tissues, of
the defence and immune systems, and of muscle and skin were
excluded. Congenital hypothyroidism, which can be caused by
metabolic defects of thyroxine synthesis, was not considered.
The search methods and selection criteria are shown in Fig.
1.
A total of
407
papers were selected for critical appraisal. For
each of the 13 categories of IEM at least two subject experts
read and critically appraised all of the selected papers using an
agreed checklist, which included study population, screening
method, incidence, clinical follow-up procedure, outcomes and
costs.
Conclusions regarding each disorder were drawn in
relation to the fulfilment of seven criteria based on the Wilson
and Jungner screening criteria:
(1) the disorder should be clinically and biochemically well
defined;
(2) there should be a known incidence of the disease in
populations relevant to the United Kingdom;
(3) the disorder should be associated with significant
morbidity or mortality;
(4) effective treatment should be available;
(5) there should be a period before the onset of the disease
during which intervention improves outcome;
(6) there should be an ethical safe, simple and robust
screening test for the disease;
(7) the screening should be cost effective.
Evidence on the last criterion (cost-effectiveness) was available
only in very few studies and was reviewed separately, as were
papers relating to multi-disease screening technologies. No
published controlled intervention studies were identified; the
literature consisted of uncontrolled trials of screening and
observational studies.7 There were no data suitable for meta-
analysis. As all the literature was grade III or less,8 inclusion
criteria were content based only.
Results
Disease-based appraisals
The fulfilment of the screening criteria for those IEMs which
are either currently screened for, or for which newborn
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SYSTEMATIC REVIEW OF NEONATAL SCREENING333
Strategy
On-line
Manual
Organic
Grey
Medline
BIDS(Embase, Science Citation
Index to Scientific & Technical
Textbooks
Conference proceedings
Index Medicus
Current Contents
References of references
Theses, laboratory reports
Literature
Index,
Proceedings)
Search
Criteria
Keywords/Textwords
inborn error of metabolism plus one of
+ mass screening
+ outcome
+ incidence
+ false positive reactions
+ false negative reactions
+ costs and cost analysis
+ sensitivity and specificity
Citations andAbstracts
1866 references
Review by
and by a fco-ordinator
subject expert
Exclusion Criteria
Not neonatal screening (unless long-term incidence or outcome data)
Not well baby screening (unless long-term incidence or outcome data)
Pure laboratory-based studies pre-1980
Methodology unsuitable for mass population screening
f
Inclusion Criteria
Inborn errors of metabolism + defined screening test + data on at least one of
• population incidence
• effectiveness of screening
• health outcomes with or without screening
• screening and/or treatment costs
• defined screening technologies suitable for blood samples
407 references
Figure
1
Methods of identification and selection of papers.
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334JOURNAL OF PUBLIC HEALTH MEDICINE
screening has been suggested in the literature, are listed in Tables
1-4. Ideally, for
a
disease
to be
identified
as
suitable for inclusion
in a neonatal screening programme, all the criteria should be
fulfilled. (Because of the lack of cost-effectiveness data for any
disorders other
than PKU this
criterion
is
omitted from
the
tables.)
Table 1 shows that PKU fulfils all the criteria and may
therefore be taken as the standard against which to compare
other disorders. Non-PKU aminoacidopathies, because of their
uncertain incidence and a lack of evidence of effective
treatment, do not fulfil all the criteria. Among the disorders
of fatty acid ^-oxidation (Table 2) medium-chain acyl CoA
dehydrogenase (MCAD) deficiency shows greatest fulfilment
of the criteria, because of its high incidence and the potential
large health benefits from treatment, although the natural
history of this disorder is not yet fully known and it has been
suggested that many individuals may remain asymptomatic.9
Other disorders of fatty acid /3-oxidation fail significantly to
fulfil the screening criteria. Screening for MCAD deficiency is
dependent upon the use of tandem MS. None of the 'common'
organic acid disorders (Table 3) show even moderately good
fulfilment of the screening criteria, many presenting acutely in
the newborn period and most showing relatively poor long-term
outcome despite improvements in therapy. There is additionally
no evidence to suggest that early detection and treatment
improve outcome. Glutaric aciduria type 1 (GA1) may be an
exception, as this disorder has a significant asymptomatic
period and is associated with severe neurological sequelae that
may be totally preventable by simple treatment. Similar factors
relate to biotinidase deficiency (Table 4) despite the relatively
low incidence of
the
complete deficiency.10 In both cases (GA1
and biotinidase) therapy is simple, effective and cheap.
Screening for GA1 is dependent upon the use of tandem MS
whereas screening for biotinidase deficiency utilizes a simple
assay of enzyme activity.
Congenital adrenal hyperplasia (CAH) caused by deficiency
of the enzyme 21-hydroxylase (Table 4) would completely
fulfil the screening criteria except that for most females there is
essentially no asymptomatic period; these infants should be
identified clinically at birth or at the post-natal examination.
However, there is still benefit from early detection and diagnosis
from newborn screening by avoiding diagnostic uncertainty and
preventing gender mis-assignment. Newborn screening pro-
grammes for CAH have recently been introduced in both
France" and Sweden.12
Previous justification for neonatal screening programmes for
galactosaemia (Table 4) has been based on prevention of
morbidity; however, published evidence suggests that, despite
early treatment, long-term outcome is poor, with a continuing
degree of neurological handicap.13 Screening for heterozygous
familial hypercholesterolaemia (Table 4) has been proposed to
allow treatment for this condition to be started before the
development of symptomatic disease. However, measurement
of total cholesterol or apolipoproteins in the neonatal period is
poorly predictive of later values and no proven benefits have yet
been shown to arise from treatment of children very early in
life.
Similarly, screening for Wilson disease (Table 4) by the
measurement of caeruloplasmin, the copper transporting
protein of plasma, has been proposed but its concentration in
neonates with Wilson disease is not yet known. Thus newborn
screening programmes are not currently recommended for any
of these three IEMs.
Review of screening technologies
Several different techniques including bacterial inhibition
assays (Guthrie), chromatography and
fluorimetry
are currently
used to screen for PKU. Dried blood spots are generally used
but some centres use liquid blood samples. A laboratory
screening for more than one disorder will normally use more
than one technique and the methods used vary from manual to
partly automated. Full automation of neonatal screening,
whatever technique is used, will require the development of
an automated punch capable of assessing the quality and
position of blood spots on the filter paper.
The technology already exists which could lead to the
development of
a
fully automated system capable of performing
several tests. By the use of different labels, time-resolved
fluorescence, currently used for congenital hypothyroidism
screening, can measure up to four analytes simultaneously. This
number of
tests
can be further widened by the use of
a
detector
with photometric and luminometric capabilities in addition to
fluorimetry; such an instrument can combine immunoassay
with enzymatic and chemical methods. Such machines will be
expensive (more than £100000) and would only be likely to be
cost effective in large-scale screening laboratories.
Molecular (DNA) techniques appear generally unsuitable
for universal neonatal screening for IEMs, as these disorders
are almost all caused by a very large number of different
individual mutations, sometimes specific to families, and
genotype-phenotype correlations are not clear. The ideal role
of molecular testing in newborn screening may be for
confirmation in cases identified from more conventional
methods, especially where the latter are less specific (e.g. for
cystic fibrosis).14
Tandem MS has the potential for simultaneous multi-disease
screening, including PKU, using a single analytical technique
and would be complementary to immunoassay-based methods
required for congenital hypothyroidism, cystic fibrosis and
CAH screening.15 Evidence on the current status and future of
potential neonatal screening by tandem MS was obtained both
from the literature review and from visits to four laboratories,
two in the United Kingdom and two in the United States,
currently utilizing or developing the technique. The procedure
used was similar in all the laboratories and all use a punched
sample from the dried blood spot
card.
The technology has been
demonstrated to be robust (i.e. sensitive and specific) and
suitable for the reliable detection of PKU and certain other
IEMs.16
However, concrete data from prospective newborn
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Table 1 Fulfilment of screening criteria for selected amino acid disorders
Amino acid
disorder
Clinically and
biochemically
well-defined
disorder
Known incidence
in populations
relevant to UK
Associated with
significant morbidity
or mortalityEffective treatment
available
Period before onset
during which
intervention improves
outcome
Ethical,
safe, simple
and robust screening
test
PKU
Maple syrup urine
disease (MSUD)
Homocystinuria
Tyrosinaemia type 1
• Clinical and
biochemical
spectrum of disease
well known31
• Clinical and
biochemical
phenotypes well
described33
• 1:12 000 (average
UK figure)1
?
Average
1:185000
world-wide;33
0:467448
screened
in Scotland34
• Natural history
now well
delineated37
• Spectrum of
clinical presentations
well characterized38
together with
associated biochemical
phenotype
?
Average
1:291000
world-wide37
Estimated 1 234 000
in UK, but significant
regional variation
?1:10500039
• Severe neurological
damage impairing
cognitive development;
early death
• Developmental delay,
seizures and
encephalopathy.
Presentation in neonatal
period usually fatal
without treatment and
later in life death may
occur during episodes
of metabolic
development
• Neurological
dysfunction,
thrombo-embolic
events, impaired
vision and ectopia
lentis
• Liver failure, renal
tubular dysfunction,
neuropathic crises
and hepatocellular
carcinoma during and
after second decade
of life
• Dietary therapy3
? Dietary therapy,
but does not
completely prevent
metabolic crises35
or prevent
developmental
delay
? Pyridoxine and
dietary therapy with
methionine restriction
and
L-cysteine
supplementation
• Early diagnosis and
treatment reduce
incidence of neurological
handicap from 80-90%
to 6-8%32
? Neonatal onset usually
at 4-7 days (possible before
result of screening
available)
• Early diagnosis and
treatment improves
IQ by some 35
points.37
? Dietary therapy
effective in short term,
but alternative
treatments eventually
needed,
e.g liver
transplant. Long-term
efficacy of NTBC
treatment still under
investigation
?
Acute onset within
weeks of birth or delayed
into infancy and childhood
• Dried blood spots tested
with bacterial inhibition
test, chromatography or
fluorometry. Tandem MS16
can also be used
• Dried blood spots tested
with bacterial inhibition
test.34 Tandem MS36 can
also be used
•Dried blood spots for
associated
hyper-
methioninemia; bacterial
inhibition assay40 or
chromatography unreliable
but tandem MS much
more robust41
• Dried blood spots by
fluorometry.42
Also tandem MS16
in
H
JO
m
m
O
TI
m
O
n
m
m
z
z
o
• Criteria fulfilled.
?
More data required.
X Criteria not fulfilled.
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Table 2 Fulfilment of screening criteria for selected disorders of fatty acid /3-oxidation
Fatty acid
disorder
Clinically and
biochemically
well-defined
disorder
Known incidence
in populations
relevant to UK
Associated with
significant morbidity
or mortalityEffective treatment
available
Period before onset
during which
intervention improves
outcome
Ethical,
safe, simple
and robust screening
test
Medium-chain acyl
CoA dehydrogenase
(MCAD) deficiency
Mitochondrial
long-
chain fatty acid
oxidation disorders
Multiple acyl CoA
dehydrogenase
deficiency (MACDD)
• Genetically and
clinically fairly well
characterized.
Incidence and
long-term outcome
unknown for
asymptomatic
individuals
X Clinical and
biochemical features
variable and diverse.
Outcome poor to
unknown
X Presentation highly
variable and natural
history unknown
71:6500 to 1:20 000
(estimated)43
X Unknown but
appears rare
X Unknown but
appears rare
• Life-threatening
hypoglycaemic
encephalopathy from
neonatal period. Acute
rhabdomyolosis in
adults now also
recognized
? Hypoglycaemia,
encephalopathy, early
death in some cases.
Cardiomyopathy in older
patients; others less
severe disease
? Presentation ranges
from death in infancy
with acidosis,
hypoglycaemia,
hyperammonaemia,
convulsions and
neurological symptoms
to much milder disease
in later childhood/adult
life
• Regular
high-
carbohydrate intake,
emergency dietary
regimen for illness,
L-carnitine
therapy
?
Treatment of milder
cases may be
effective but outcome
in severe cases is
poor
? Milder cases may
respond to an
increased carbohydrate
and reduced fat and
protein intake,
riboflavm and
L-carnitine.
Severe
infantile disease
often refractory to
therapy
• Although presentation in
newborn period now
described,
large majority
are asymptomatic during
the period of newborn
screening
X Not known for all
conditions and
presentations
X Severe neonatal
disease often presents
before screening result
would be available.
Associated dysmorphic
features and polycystic
kidneys in some cases
imply intrauterine
damage
• Dried blood spots;
determination of
octanoylcarnitine using
tandem MS43
? Dried blood spots;
determination of long-chain
acylcarnitmes (C,,»-C18)
using tandem MS but
these are currently
difficult to detect and not
all cases may be identified
• Dried blood spots;
determination of relevant
acylcarnitines using
tandem MS possible but
not yet proven
o
c
50
Z
>
r
o
c
r
o
x
m
r
X
2
m
a
n
z
rn
MJ>S References throughout.
• Criteria fulfilled.
?
More data required.
X
Criteria not fulfilled.
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Table 3 Fulfilment of screening criteria for selected organic acid disorders
Organic acid
disorder
Methylmalonic
aciduria
Propionic acidaemia
Isovaleric acidaemia
Glutaric aciduria
type 1
3-hydroxy-3-methyl-
glutaric aciduria
Clinically and
biochemically
well-defined
disorder
?
Generally well
characterized and
defined although
long-term outcome
still unclear
? Reasonably well
characterized and
defined.
Long-term
outcome in
'milder'
cases unknown
•
Well
characterized
? Becoming better
characterized but
complete natural
history unknown
? Long-term outcome
with therapy unknown
Known incidence
in populations
relevant to UK
7 Not known with
certainty but probably
<1:80000
7 Probably
<1:100000
?Very low in UK,
probably <1:200000
? Unclear but may be
as high as
1:50000
? Not known,
probably
<
1.80 000
Associated with
significant morbidity
or mortality
• Life-threatening
episodes of acute
illness with
longer-
term problems of
neurological handicap
and renal damage
• Life-threatening
episodes of acute
illness with
longer-
term problems of
neurological handicap
• Presents with
acidosis, vomiting,
tremors, coma and
death in the neonatal
period and beyond
• Severe crippling
choreoathetoid cerebral
palsy of postnatal onset
• Episodic hypokekotic
hypoglycaemia causing
coma and death and
possible long-term
neurological sequelae
into at least teenage
years
Effective treatment
available
7 Improving with diet,
antibiotics,
L-carnitine,
somatotrophin, organ
transplantation, and
B12 in vitamin
responsive cases
? Improving with diet,
antibiotics,
L-carnitine,
somatotrophin, liver
transplantation, B12
in vitamin responsive
cases
• Diet plus glycine
and
L-carnitine
therapy
?
Current opinion
suggests
L-carnitine
therapy pre-
symptomatically may
prevent onset of
neurological damage
• Moderate dietary
modification,
emergency regimen
for illness, and
L-carnitine
therapy.
Need for lifelong
therapy unknown
Period before onset
during which
intervention improves
outcome
?
Many cases present in
neonatal period, others
later in infancy and
childhood.
No evidence
early intervention
improves outcome
7 Many cases present in
neonatal period. Evidence
of improved outcome
following early
intervention not
available
7 Many cases present
acutely in neonatal period.
No evidence early
intervention improves
outcome but will prevent
acute episodes
• All patients seem to
have an asymptomatic
period of a month or
more
7
Generally there is
asymptomatic period
though neonatal
presentation is
recognized
Ethical,
safe, simple
and robust screening
test
• Dried blood spots;
determination of
propionylcarnitines using
tandem MS but levels may
be very low in some cases
• Dried blood spots;
determination of
propionylcarnitines using
tandem MS
• Dried blood spots;
determination of
isovalerylcarnitines using
tandem MS
• Dried blood spots;
determination of
glutarylcarnitines by
tandem MS
• Dried blood spots;
determination of
3-methyl
glutarylcarnitines using
tandem MS
«<
H
m
2
>
(-}
J0
m
<
o
m
o
2
>
>
r-
on
n
pa
tn
rn
Z
Z
O
29.44.46.47
References throughout.
• Criteria fulfilled.
7
More data required.
X
Criteria not fulfilled.
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Table 4 Fulfilment of screening criteria for other metabolic disorders
Metabolic
disorder
Clinically and
biochemically
well-defined
disorder
Known incidence
in populations
relevant to UK
Associated with
significant morbidity
or mortalityEffective treatment
available
Period before onset
during which
intervention improves
outcome
Ethical,
safe, simple
and robust screening
test
Biotinidase deficiency •Causes multiple ?Estimated in UK
carboxylase deficiency, about
IIIIOOOO48
Long-term outcome
of therapy to be fully
evaluated
Congenital adrenal
hyperplasia (CAH)
Familial
hypercholesterolaemia
(FH)
•
Well
defined.
Refers to
21-hydroxylase
deficiency
• Well-characterized
cause of
hyper-
cholesterolaemia
Galactosaemia • Very well-defined
defect
Wilson disease• Well-characterized
defect in copper
transport
• Estimated
1.6000
to1:2100049-50
• Homozygotes
1:100000052
Heterozygotes 1:200
to
1:1000
1:4400013
•
1:50000
to
1:10000055
• Progressive
neurological disease
which may be fatal
in many cases
• Hyponatraemic
dehydration,
vinhzation
• Heterozygotes:
vascular damage
(atherosclerosis)
estimated to cause 5%
of premature coronary
heart disease (CHD)53
Approx. 50% men with
FH develop CHD by age
50,
50% women by 60
Homozygotes: fatal
• Liver and renal
damage, cataract
formation,
immunodeficiency,
neurological damage
• Liver failure
neurological damage
• Oral biotm.
Requirements for
life-long therapy
not known
• Steroid replacement
? Benefit from
intervention
(heterozygotes) during
childhood yet to be
demonstrated
X Dietary therapy
reverses
hepatotoxicity and
prevents cataract
development but not
progressive neuro-
degenerative disorder56
or ovarian failure
• Penicillamine.
Pre-symptomatic
treatment with zinc
may be possible57
• Presentation generally
in early infancy and
childhood
?
Clinically present at 3
days to 8 weeks, most
commonly at 3 weeks
?
Coronary heart
disease only
angiographically
detectable in young
adult life
(heterozygotes)
? Present typically in
second week of life
• Most cases present
in late childhood,
adolescence and early
adulthood58-59
• Dried blood spots;
colorimetric assay of
enzyme activity.51 Need to
distinguish subjects with
partial deficiency
• Determination of 17a-
hydroxy progesterone
from dried blood spots11
XTotal or LDL
cholesterol or
apolipoprotem B can be
measured from blood
spots54
but are poorly
predictive of later
values
? Colorimetric enzyme
assay on dried blood
spots.60
False positive
rate 0.03%, false negative
rate 0-7%. Beutler
fluorescent assay61
? Enzymatic assay of
caeruloplasmin62 or
ELISA method63 but not
yet validated for use in
newborns
O
a
2
o
-a
C
CO
r
X
m
>
r
x
2
m
D
n
z
m
• Criteria fulfilled.
?
More data required.
X Criteria not fulfilled.
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Table 5 Collective fulfilment of criteria and recommendations for newborn screening
Inborn error of metabolismFulfilment of screening criteria and recommendation for newborn screening
PKU
Maple syrup urine disease (MSUD)
Homocystinuria
Tyrosinaemia type 1
Medium-chain acyl CoA dehydrogenase
(MCAD) deficiency
Mitochondrial long-chain fatty acid oxidation
disorders
Multiple acyl CoA dehydrogenase deficiency
(MACDD)
Methylmalonic aciduria 1
Propionic acidaemia J
Isovaleric acidaemia
Glutaric aciduria type
1
*
3-hydroxy-3-methyl-glutanc aciduria
Biotinidase deficiency*
Congenital adrenal hyperplasia (CAH)*
Familial hypercholesterolaemia (FH)
Galactosaemia
Wilson disease
(1) Fulfils all screening criteria (including cost-effectiveness)
(3) Low incidence, neonatal onset often pre-dates availability of screening result, long-term outcome of treatment variable.
(3) Low incidence and effectiveness of treatment over a lifetime unproven
(3) Low incidence, no evidence of improved outcome from early, pre-symptomatic treatment
(2) High frequency, morbidity and mortality largely preventable by simple, cheap and effective treatment, simple screening test
requires tandem MS. Screening research programme required to assess exact incidence, long-term outcomes and cost-effectiveness
(4) Unknown natural history, low incidence, ineffective treatments in many cases and possible ambiguous screening results with
possible false negatives using tandem MS
(4) Widely variable clinical presentation, some cases with intrauterine damage, dysmorphology, acute neonatal presentation,
ineffective treatment, low unknown incidence and unproven screening test (although possible with tandem MS)
(3) Highly variable outcome, many cases present in newborns before screening result available, treatment efficacy variable. At best,
potential candidates for newborn screening. Incidence has to be considered collectively with other similar disorders detectable using
tandem MS. Tandem MS does not distinguish these two organic acid disorders
(3) Very low incidence offset by collective incidence of other disorders; early treatment may prevent acute episodes and prevent
neurological damage Potential candidate for newborn screening, requires tandem MS
(3) Potentially preventable severe neurological and disabling disorder, thus a candidate for newborn screening despite probable low
incidence. Assessment of screening research programme required to ascertain exact incidence in UK population and evaluate
prevention of neurological disease in screened and treated individuals. Requires tandem MS
(3) Fairly low incidence but simple treatment with prevention of neurological damage makes this a potential candidate for newborn
screening.
Incidence must be considered collectively as above; requires tandem MS
(2) Preventable severe neurological disorder, thus a candidate for newborn screening despite estimated low incidence. Screening
research programme required to assess exact incidence in UK, long-term outcomes and cost-effectiveness
(2) To fully meet all criteria may need screening at an earlier age (e.g. day 3) to allow availability of results by 10-12 days of age
(4) No suitable validated neonatal screening test Benefit of intervention in neonatal period not determined
(4) Therapy does not prevent neurological or ovarian toxicity; long-term outcome does not benefit from early intervention through
neonatal screening
(3) Low incidence No suitable validated neonatal screening test
H
m
>
H
o
m
<
m
o
z
m
o
z
n
73
tn
m
z
z
o
(1) Evidence that
all
criteria
are met.
(2) Evidence that
all
criteria except known natural history
of
disorder are
met.
(3) Evidence that most criteria
are met, but
lack
of
evidence
for
some criteria.
(4) Evidence that some criteria
are not met.
"Trials
of
neonatal screening recommended.
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340JOURNAL OF PUBLIC HEALTH MEDICINE
screening using tandem MS is lacking or unsubstantiated, and
further research through large-scale, well-conducted and exter-
nally assessed trials is required before this technology can be
universally introduced into newborn screening programmes.
Economic evidence
There was insufficient evidence in the literature to assess the
economic value of screening for any disorder other than PKU.
Twelve economic evaluations of neonatal screening for inborn
errors of metabolism were identified.17"28 The literature
covered a range of disorders, but only PKU was included in
more than one study. There were eight cost-benefit studies of
neonatal screening for PKU,17"21'23'25'27 all of which concluded
that PKU screening is worth while in monetary terms
alone.
Not
all of the papers included sample collection costs, but where
they did these were outweighed by the net benefits of screening.
This suggests that PKU screening alone justifies the collection
of blood samples from neonates.
Discussion
The striking finding of this review was the lack of robust
evaluation data. The absence of controlled trials meant reliance
had to be put on observational studies. As it is difficult to
quantify the rigour of this type of research, all being grade
HI
or
less,8
all studies were included if they fulfilled the content
criteria. Agreement on the Wilson and Jungner6 criteria was
then achieved by paired reviewers and eventually with the
whole group. As there remains a subjective element because of
the types of study used, underlying references have been
provided so that readers can refer to the specific papers.
Nevertheless, some evidence has been obtained for the
appropriateness or otherwise of screening for a wide range of
IEMs.
There is clear evidence that all of
the
criteria are met for
PKU screening, which provides a positive net benefit to the
individual and to society. In addition, PKU screening by itself
justifies the infrastructure of sample collection and testing of
newborn blood spots.29
Table 5 summarizes the results and recommendations for
each disorder. Only four disorders showed adequate fulfilment
of the screening criteria to be considered for inclusion in
expanded newborn screening programmes. These were biotini-
dase deficiency, CAH, MCAD deficiency and, possibly, GAL
For these disorders structured, co-ordinated and continuing
evaluation, including economic analysis, will be necessary to
provide evidence which would justify the long-term continua-
tion of these programmes. A number of other disorders,
including some of the more common disorders of organic acid
metabolism, require further basic research before widespread
trials of neonatal screening could be advocated.
Concern has also been expressed about the lack of
consideration of the infrastructure required to deal with the
infants identified by newborn IEM screening. In many areas of
the United Kingdom, for example, there appears to be relatively
poor liaison between the screening laboratories, midwives and
other health-care personnel, and no provision is made for the
co-ordinated follow-up or management of identified patients.30
Thus there is a need for a better infrastructure for notification
and continued care, including parental counselling, of patients
with IEMs identified through newborn screening. Few areas
provide adequate information to parents about newborn
screening or the IEMs screened for, nor do they currently
require informed consent from the parents;5 issues which will
need to be addressed if expanded screening programmes are
introduced.
Newborn screening for MCAD and GA1 depends upon the
use of tandem MS technology. Pressure to develop and
introduce this technology is particularly acute in countries
such as the United States where blood spots are taken within the
first 24-48 hours after birth. However, the utility and
application of tandem MS for prospective newborn screening
has been demonstrated in only one centre (in the United States),
with only a limited number of newborns screened.29 The
technology therefore requires further assessment through
primary research before it can be considered for universal
introduction. The size of screening laboratories varies widely;
for tandem MS technologies to be cost-effective each
laboratory would need to perform a minimum number of tests
per year, necessitating rationalization of current screening
laboratories. There is a need for co-ordinated national policies
for newborn screening that ensures the appropriate dissemina-
tion of new screening technologies and the expansion of the
routine screening programme where there is good evidence of
the efficacy of early detection and treatment. Any such changes
must be accompanied by careful evaluation to ensure their
effectiveness and cost-effectiveness in practice.
Acknowledgement
This work was funded by the NHS Health Technology
Assessment Programme.
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