Clinical efficacy and cost-effectiveness of newborn screening for medium chain acyl–CoA dehydrogenase deficiency using tandem mass spectrometry
Introduction
Medium chain acyl–CoA dehydrogenase deficiency (MCADD) is one of the rare but potentially fatal inborn errors of metabolism in the category of fatty acid oxidation disorders. It is an autosomal recessive inherited abnormality, more prevalent in people of northern European descent, particularly Germany, the UK and English-speaking countries [1], [2].
In Germany, the incidence was found to be 1:9,773 [3] and in the UK between 1:20,000 and 1:9,091 [4]. Given the Canadian birthrate and immigration history, it is expected that Canada would have about 20 new cases of MCADD per year, based on an estimated incidence of 1:16,000.
Common clinical symptoms of MCADD are hypoglycaemia and acute encephalopathy, usually within the first 2 months of life. In those cases, up to one-quarter will die and one-third of survivors will have irreversible neurological damage, some requiring hospital care for the rest of their lives [5], [6], [7]. Those who have been clinically diagnosed have been able to avoid repeat episodes through high carbohydrate intake, either orally or intravenously, during fasting or gastrointestinal infection and by monitoring by a metabolic disease clinic [6], [8]. Since newborn screening for MCADD is relatively new, it is not known how affected individuals identified this way will fare in the long-term.
Approximately 30 mutations have been found in the MCADD gene [9], but in clinically diagnosed patients more than 80% are homozygous for the A985G mutation and 18% are compound heterozygous [5]. In patients identified through screening, about half are homozygous for the A985G mutation. Screening frequently detects another mutation that causes MCADD, T199C, but for unknown reasons it is not prevalent in children presenting symptomatically [10].
Screening for MCADD using tandem mass spectrometry (MS/MS) is based on the premise that individuals with the disorder have increased plasma levels of octanoylcarnitine (AC8) in their blood or an increased ratio of AC8 to decanoylcarnitine (AC10). When energy is needed during fasting or exercise, the body releases fatty acids from adipose tissue. These fatty acids are converted to acyl–CoA esters by cells in the heart, muscle and liver, then cross the mitochondria membranes as acylcarnitines, before returning to their original form. Inside the mitochondria, acyl–CoA are progressively catabolized to acetyl-CoA by β-oxidation through a series of dehydrogenation reactions mediating by long, medium and short chain acyl–CoA dehydrogenases. If there is a defect in one of the enzymes and the acyl chain is incompletely oxidized, it accumulates in the plasma as acylcarnitines and can be measured.
Screening for MCADD is not consistently practiced across Canadian health jurisdictions. Researchers in the US, Germany, the UK and Australia have advocated the use of MS/MS in newborn screening for MCADD and other disorders. In the US, 40 states already do so, and in 31 of these states MCADD screening is mandatory [11]. There is a need to determine whether Canadian jurisdictional screening programs should be expanded to include MCADD.
Section snippets
Methods
For clinical review, we obtained published literature by cross-searching MEDLINE®, BIOSIS Previews®, PASCAL, Social SciSearch®, PSYCInfo®, ERIC and EMBASE® databases beginning at 1995. Search terms included subject headings neonatal screening, newborn screening, spectrum analysis, “mass, tandem mass spectrometry”, mass spectrometry, medium-chain acyl–coenzyme A dehydrogenase, acyl–CoA dehydrogenase, medium chain acyl coenzyme a dehydrogenase and keywords mass screening, truncated terms such as
Quantity and quality of clinical studies
Out of 957 citations found in our literature search, we identified 48 potentially relevant clinical studies. These were further reduced to 21 [3], [5], [10], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. Our reasons for excluding the other articles included lack of specific data about MCADD, duplication of some included studies, a focus on establishing test criteria and inappropriate design.
Of the 21 included studies, 14 studies were
Discussion
Studies on newborn screening for MCADD scored poorly on some items covering bias, variability and reporting, using the QUADAS tool. As there was no long-term follow-up, the outcomes of true- and false-positives over time are uncertain. Also, there was no follow-up to determine if the asymptomatic cases from the MS/MS-based screening would become symptomatic over time. There was limited evidence on the outcomes of MCADD patients whose conditions were detected at birth by MS/MS, compared to those
Acknowledgments
This project was funded by the Canadian Agency for Drugs and Technologies in Health (CADTH). We would like to acknowledge Suzanne Morphet for her writing assistance. We wish to thank Tammy Clifford and Mike Gaucher for general supports.
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2012, Public HealthCitation Excerpt :The test is highly specific and sensitive. Its cost-effectiveness has been well documented.13–19 Wilson–Jungner criteria are the renowned traditional criteria for population screening published by WHO in 1968.20
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2012, Value in HealthCitation Excerpt :A few studies have been based on the cost-effectiveness of this condition alone. Insinga et al. [4], Venditti et al. [5], and Tran et al. [6] reported that universal screening for MCADD by using MS/MS is a cost-effective option. Two studies based in California focused on MCADD and several other conditions and reported that MS/MS screening is a cost-effective strategy for most conditions, except congenital adrenal hyperplasia or galactosemia [7,8].
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