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Metabolic Screening in Childre PDF
Metabolic Screening in Childre PDF
Keywords assessment (health care); costbenefit analysis; humans; 1. The condition sought should be an important health problem.
inborn errors/diagnosis; mass spectrometry; neonatal screening/
2. There should be an accepted treatment for patients with
recognised disease.
economics; neonatal screening/organisation and administration;
3. Facilities for diagnosis and treatment should be available.
newborn; predictive value of tests
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.
What is screening?
9. The costs of case finding should be economically balanced in
Screening has been defined as: the systematic application of a relation to the effect of possible expenditure on medical care
test or enquiry to identify individuals at sufficient risk to benefit as a whole.
from further investigation or direct preventative action, amongst 10. Case finding should be a continuous process and not a once
persons who have not sought medical attention on account of and for all project.
symptoms of the disorder. Any newborn baby is potentially at
risk of a variety of inherited metabolic diseases (IMDs) that are These principles were aimed at screening in general. The issues
amenable to treatment. A pre-symptomatic baby is a candidate in newborn screening are essentially that there should be benefit,
for screening for these disorders. and this should be balanced by financial costs, costs of harm
caused by screening and the costs of false-positive and false-
negative results. Thus, for an agreed disorder causing significant
problems that can be effectively and economically treated, can
Mark Sharrard MB BS FRCPCH is Consultant Paediatrician at the Sheffield we perform a reliable, relatively inexpensive and acceptable test
Childrens Hospital, Western Bank, Sheffield S10 2TH, UK. to identify those to treat?
Many IMDs are attractive candidates for newborn screening.
Rodney Pollitt PhD FRCPath is Consultant Clinical Scientist at the Sheffield We screen to identify infants with treatable disorders so that we
Childrens Hospital, Western Bank, Sheffield S10 2TH, UK. can intervene to minimise the clinical consequences. Diagnosing
PAEDIATRICS AND CHILD HEALTH 17:7 273 r 2007 Elsevier Ltd. All rights reserved.
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and treating before symptoms develop may improve outcome and dystrophy was in progress in Wales. Scotland was still screening
quality of life. for galactosaemia.3
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SYMPOSIUM: METABOLIC MEDICINE
to be the only condition sufficiently common to give useful The sensitivity of MS/MS screening is generally high and
results within a reasonable time frame. The plan was for a 2-year approaches 100% for most disorders including MCADD and
screening phase with a further 2 years of clinical follow-up; any PKU.9 However, it is difficult to determine how many cases have
resulting policy decision would be made after this. Overall, been missed. Several studies have reported missed cases of
approximately 700,000 babies were to be screened, representing glutaric aciduria type I, cobalamin metabolism defects, tyrosi-
one-half of UK births during the 2-year period; the remainder naemia type I and 3-ketothiolase deficiency. Also, pyridoxine-
from the non-screened areas acted as controls, to be captured responsive homocystinuria appears to be not detected using MS/
through the British Paediatric Surveillance Scheme. The screen- MS identification of raised methionine.
ing arm of the study confirmed expectations in that sensitivity Before the results of screening became available, 312% of
and specificity were high but a significant proportion of screen- affected infants died or become symptomatic. Typically, these
ing-detected cases had relatively mild forms of the biochemical babies had severe variants, or untreatable disorders such as non-
defect. Based on the preliminary findings, the Minister for Public ketotic hyperglycinaemia. Five such cases were reported from
Health announced in February 2007 that screening for MCADD Australia8 (of 48 diagnosed infants), six from North Carolina11
would be introduced throughout England within the next 2 years. (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
The future
be appropriate.
Expanded MS/MS screening Some of the individual MS/MS screens, notably those for the
There are an increasing number of reports of disease detection tyrosinaemias, homocystinuria and propionic and methylmalonic
rates from expanded screening programmes around the world acidaemia, consistently lack specificity. These tests generate
(Table 1). Excluding the Australian data, as PKU was not repeat requests and their PPVs are lower than those for other
included, the frequency of IMDs detected by newborn screening disorders. The specificity of MS/MS screening may be improved
ranges between 1/2400 and 1/4300. The frequency of fatty acid by screening on day 57, as in the German study,9 rather than
oxidation disorders is 1/10,000 to 1/16,000, with MCADD being on day 2 as in the USA.6,7,11 Second-tier tests may improve
the most common in this group. PKU and hyperphenylalaninae- specificity, particularly for type I tyrosinaemia9 and homocysti-
mia are the most common aminoacidopathies. nuria. In the UK MCADD screening pilot study,13 the specificity
was greater than 99.997% with a PPV of 85%. False-positives
Overall positive predictive value from neonatal intensive care babies were not a problem, and the
The positive predictive value (PPV) is the fraction of all screening excellent specificity may be due to the age of screening in the UK
positive results that are found to be true positives. With MS/MS, (58 days).
the overall PPV for detection of IMDs from the first blood spot MS/MS screening detects some disorders at a much higher
sample ranges from 5% to 11%. False-positives are an inevitable frequency than that expected from observation of those present-
part of any screening programme, and may be over-represented ing clinically. In Australia,14 the incidence of MCADD diagnosed
in very low birthweight and neonatal intensive care babies.7 In by screening was more than double that in children under 4 years
non-MS/MS screens used in US screening programmes, Kwon of age diagnosed clinically. While the allele frequency of the
and Farrell12 reported PPVs for screening for galactosaemia common 985A-G missense mutation in the ACADM gene
(0.53%), biotinidase deficiency (5.90%), congenital hypothyr- responsible for MCADD was 89% in those diagnosed clinically,
oidism (1.91%) and congenital adrenal hyperplasia (0.54%). it was only 76% in the screened population. Similar observations
These low PPVs may reflect the early screening times adopted in have been made in other populations, including in the UK,13
the USA. suggesting that milder mutations, though causing the MCADD
Inherited metabolic disease detection rate for tandem mass spectrometry screening programmes.
Table 1
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SYMPOSIUM: METABOLIC MEDICINE
biochemical phenotype, result in a mild disorder that may never diseases are not generally seen as important public health
present clinically. Similarly, 3-methylcrotonyl CoA carboxylase problems, and screening for rare disorders is not an effective
(3-MCC) deficiency rarely presents clinically but has been use of resources. MS/MS screening can be viewed as a single test
detected by screening with a frequency of up to 1/12,000. for MS/MS-detectable disease. The more genuine disorders that
Affected individuals may be at risk of catastrophic decompensa- are included in the MS/MS screen, the more important the health
tion,15 but it is not possible to predict who will be affected. While problem being addressed.
MS/MS screening may identify some individuals who may never The second principle concerns treatment. Many individuals
need treatment, not screening puts others at risk of avoidable with MS/MS-detectable diseases are treated effectively. Some
adverse outcomes. inevitably die in the neonatal period, and MS/MS screening
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is provides a diagnosis. This does not benefit that individual baby,
relatively frequently diagnosed by MS/MS screening (up to but parents can find comfort in knowing why their baby died.
1/32,000 births). Symptomatic SCADD is less frequently found Furthermore, knowledge of the diagnosis allows future prenatal
and the clinical features are variable and sometimes transient.16 diagnosis and family studies, and may enable diagnosis of
SCADD diagnosed by newborn screening must be treated previous unexplained deaths. The benefit of screening is there-
cautiously, along with other disorders that are not clearly defined. fore to the family rather than to the individual. The fourth
principle concerning latency can be incorporated into this
Outcome of MS/MS screening argument.
The few reports on the outcome of MS/MS-screened infants have MS/MS screening identifies a risk for those with milder
necessarily looked only at the short-term outcome. conditions or milder variants of recognised disorders. This is
The German study9 concluded that 70 of the 106 infants exemplified by 3-MCC deficiency and may be applied especially
diagnosed by screening needed treatment; 61 of these (87%) were to those with MCADD. While individuals may not appear to have
asymptomatic at diagnosis and remained asymptomatic, thereby a disorder, they can be managed in such a way as to minimise
having benefited from screening. In the German population, their risk of an adverse outcome.
1/4100 infants would benefit from treatment. A substantial The seventh principle supports MS/MS screening. The
proportion of these would have PKU. example of SCADD shows it is inappropriate to screen for
Waisbren et al.17 compared the outcomes of 50 children disorders that are undefined and have no clear natural history.
diagnosed by MS/MS newborn screening with 33 children The fourth principle relates to test performance. The data
diagnosed clinically with similar disorders and 94 children with summarised here show that MS/MS screening performs well, and
false-positive screening results. Children diagnosed by screening when screening is conducted at a carefully selected age, around
required less hospitalisation under the age of 6 years and were day 58, the specificity is high and the sensitivity appears to be
less likely to have learning difficulties. They had a higher median close to 100% for many disorders.
developmental quotient, and unlike the clinically diagnosed Acceptability, which is addressed in the eighth principle,
group had no significant deficits in communication, daily living should be no different for the blood test than for PKU and
skills, socialisation or motor skills. In families that received a hypothyroid screening. Parents must be informed about the tests
false-positive screening diagnosis, there was a higher rate of that are performed on their baby, and data from other screening
hospital admission, and higher levels of parental stress and programmes suggest that parents accept screening if they are
parentchild dysfunction. provided with adequate information.
In children with propionic, methylmalonic or isovaleric The cost of adding extra tests to MS/MS screening is negligible
acidaemia, those diagnosed by MS/MS screening exhibited less in itself. Although confirmatory tests generate costs, these must
early mortality and less severe symptoms at diagnosis. Their be weighed against the costs that would have been incurred had
short-term neurodevelopmental outcome was more favourable. the child presented clinically, which are likely to be considerable
However, screening may have diagnosed some milder cases of greater.
isovaleric acidaemia that may have never developed abnormal-
ities.18 The way forward
Wilcken et al.14 assessed the outcome of MCADD patients The introduction of whole population screening by MS/MS for
diagnosed by screening or clinically. The risk of a severe adverse MCADD in England has come after one of the few screening
event was significantly higher in those diagnosed clinically evaluation exercises to be conducted anywhere in the world.
(57%) than in those diagnosed by screening (8%). One patient in MCADD screening requires laboratories to use MS/MS, with the
each group had an intellectual outcome more than one standard potential to undertake expanded MS/MS screening. Wilson and
deviation below the mean. In other studies, the outcome in those Jungers third principle may be an obstacle for universal MCADD
who present clinically has been less good. Despite early screening, and hence expanded screening; a recent review of
detection, several programmes have found MCADD to be services for IMDs has highlighted great inequalities of service
associated with subsequent death, though, overall, screening is provision across the UK.
of benefit. Evidence from overseas supports the introduction of expanded
MS/MS screening for some of the detectable disorders. By
Wilson and Junger in the era of MS/MS screening learning from those programmes with the best performance we
The first principle states the disorder sought should be an can adopt the optimal criteria for extended MS/MS screening.
important health problem. To those with a disorder detected by Such screening would have to be initiated on a pilot basis and
MS/MS screening, their disorder is an important problem. Rare would represent a substantial undertaking. Specific centres could
PAEDIATRICS AND CHILD HEALTH 17:7 276 r 2007 Elsevier Ltd. All rights reserved.
SYMPOSIUM: METABOLIC MEDICINE
take responsibility for collating data for certain groups of normal outcome or a reduction in disability. Experience with PKU
disorders and share the burden of analysing test performance has clearly demonstrated the benefits of screening, and a number
and outcomes. Expanded MS/MS screening in the UK seems of additional screening tests have been highly effective on a
feasible. smaller scale.
Worldwide experience has shown that MS/MS screening is
Other screens highly effective in detecting more than 30 IMDs, with evidence of
Newborn screening is undertaken for various other metabolic improved outcomes. MS/MS screening is being universally
disorders around the world. In certain circumstances, the high adopted in the UK for MCADD, and there is an opportunity to
local prevalence of a disorder may render it attractive for take advantage of the MCADD screening infrastructure to expand
screening. Glucose-6-phosphate dehydrogenase deficiency, a it to include urea cycle disorders, aminoacidpathies, fat oxidation
treatable enzyme deficiency resulting in severe haemolytic defects and organic acidaemias. There is also the potential to
anaemia, is especially prevalent in the Far East and Mediterra- develop MS/MS screening for LSDs, especially as effective
nean areas, where screening programmes are highly effective. therapies are becoming available. ~
Individual non-MS/MS screens for homocystinuria, galacto-
saemia, 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 REFERENCES
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13 Oerton J, Downing M, Andresen B et al. Predictive value, clinical
Conclusion
status, and genotype of medium chain acyl CoA dehydrogenase
The principles of screening are applicable to IMDs, especially as deficiency (MCADD) ascertained by newborn screening at one week
many IMDs have a latent phase and are now treatable with a of age using electrospray tandem mass spectrometry of under-
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