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Abstract
Screening for inborn metabolic errors began in the early 1970s; tandem mass spectrometry (MS-MS) is an improved technique of mass spectrometry. It has the potential of performing one test to detect many inborn metabolic errors. The question of cost-effectiveness is an obstacle to extending its use as a first-line screening tool. This essay aims to provide a brief yet comprehensive review on the use of tandem mass spectrometry in screening for inborn errors of metabolism.
Introduction
The theory of mass spectrometry (MS) is to spawn ions from a substance (organic or inorganic), separate them according to their mass-charge (m/z) ratio, and finally, quantitative and qualitative ion detection based on their m/z ratio.
The substance is called analyte and might be ionized thermally, electrically, or by the impact of high-speed electrons, protons, or ions. The resulting ions can be single, clusters or fragments of molecules. Thus, a mass spectrometer has three main parts, an ion source, a mass analyzer and a detector; all operate under high vacuum conditions (Gross 2004, p. 3).
Principle of Tandem mass spectrometry
Tandem mass spectrometry (MS-MS) is an improved technique of mass spectrometry where a four-pole (quadrupole) mass filter selects the intact ions produced from the analyte stream of ions. When the original ions stream passes through the collision cell (into which argon gas flows at a slow rate), the energy produced by collision results in fragmentation and rearrangement of the analyte stream ions to productions. Next, the productions go to a second quadrupole filter, allowing selected defined intact ions to the detector (Figure 1) (Vogeser et al, 2007).
The need for vacuum is to minimize the pressure with the spectrometer well below atmospheric pressure to prevent ions’ collision with air molecules. The basic idea of quadrupoles is through them, in a specific frequency pattern, only ions of a specified mass can pass. In the detector, ions’ analysis depends on their different accelerations, which depends in turn on their mass, in an electric field (Vogeser et al, 2007).
Inborn metabolic errors
Sir Archibald Garrod brought the term inborn error of metabolism to attention, for the first time, during his lecture at the Royal College of Physicians in London in 1908. Sir Garrod identified alkaptonuria, benign pentosuria, albinism and cystinuria as a group of diseases that appear to occur because of failure in some steps of chemical changes constituting metabolism. Sir Garrod added these disorders present at birth, continue for the rest of life, are benign in nature and show little if any response to therapy. They constitute a wide variety of diseases classified according to the metabolic pathway affected (Clarke 2005, p.1). Table 1 shows examples of inborn metabolic disorders.
Table (1) Examples of inborn metabolic disorders (adapted from Kumta 2005, p. 326).
In cases of inborn metabolic disorders, history of pregnancy and delivery is usually uneventful, and the infant may be normal for the first few hours. There are certain specific features for these disorders with abnormal urine or body odor, diarrhea, cardiomyopathy or failure, hepatomegaly and seizures are the most alarming. A characteristic feature of these disorders is although they are individually rare; yet together they form a significant morbidity to the pediatric population with disabling outcomes and even death in some cases.
The basic management strategy is to prevent the accumulation of toxic precursors, supply the defective product or essential nutrients. Therefore, early screening and prompt diagnosis of inborn errors of metabolism are significant (Kumta, 2005). The aim of this essay is to review the use of tandem mass spectrometry in screening for inborn errors of metabolism.
The use of tandem mass spectrometry in screening for inborn metabolic errors
Screening for inborn metabolic errors began in the early 1970s by assessment of phenylalanine in infants with phenylketonuria, since then technological advancement and development of advanced instruments enabled screening of many other errors. Tandem mass spectrometry is advantageous over ordinary screening methods in detecting many metabolites from one blood spot, thus allowing screening of many inborn metabolic errors simultaneously (Pasquali, 2005).
Pandor and colleagues (2004, pp. 15-25) reviewed the clinical efficacy of MS-MS in screening neonates for inborn errors of metabolism. They suggested that although tandem mass spectrometry can successfully detect many disorders; yet, the best candidates for MS-MS screening are MCAD (Medium Chain aceyl-coenzyme Dehydrogenase) deficiency causing disordered fatty acids metabolism. This co-enzyme deficiency can result in increased infant mortality and morbidity and is preventable by diet regulation. The second best candidate for MS-MS screening is for amino acids and acylcarnitines enabling early diagnosis of amino acids inborn errors of metabolism like phenylketonuria, maple syrup urine disease and tyrosinemia.
Studying acylcarnitines profiles in newborn infants identifies fatty acid oxidation defects and organic acidaemia. Pandor and colleagues (2004, pp. 15-25) emphasized this does not represent the full spectrum of using tandem mass spectrometry for screening of inborn metabolic errors and suggested future research should focus on the impact of early diagnosis on impairment and disability adverse outcomes of these disorders.
Tandem mass spectrometry: Technique and advantages
The sample needed for tandem mass spectrometry is a drop of blood (obtained by a small punch) and collected on a filter paper. Sample extraction is by methanol, and then dried; next water and acetonitrile are added to the sample, which is next injected into the tandem spectrometer. In the spectrometer, all molecules are ionized commonly by electrospray (electrical charging of the molecules), then the resulting charged ions (positive or negative) are separated according to the m/z ratio.
In the collision cell, ions’ fragmentation by collision with argon gas occurs and is then separated according to the m/z ratio. Single charged ions will have a mass-charge ratio equal to the mass of molecules ionized, further, each molecule has a specific fragmentation pattern with some compounds as acylcarnitines have a similar fragmentation pattern. This is unlike what happens to amino acids as they lose a neutral fragment of 102 mass-charge ratios after fragmentation. Therefore, tandem mass spectrometers are set up to measure metabolites according to available information about their masses and fragmentation patterns (Dettmer et al, 2007).
An advantage of tandem mass spectrometry is interpretation of results depend on fragmentation pattern and does not measure the concentration of different metabolites. Besides, the capability of detecting many metabolites allows using the metabolites ratios to identify whether an elevated value (measured by traditional screening methods) is because of a metabolic disorder or secondary to nutritional status.
Another advantage of MS-MS is clear on screening of acylcarnitines. Whereas amino acids concentrations do not change much with age, acylcarnitines concentrations do being highest at the first week then decrease rapidly afterward. Therefore, traditional methods need to set a cut-off value for acylcarnitines assessment according to age groups, which is not the case with MS-MS (Pasquali, 2005).
Tandem mass spectrometry: Current and future strategies
The current strategy of tandem mass spectrometry is to provide accurate measures of both molecular (precursor) and productions after fragmentation. Quadrupoles make this possible where scanning of precursor molecules takes place in a first mass analyzer (in space-based MS equipment, which involves physical separation of components). Next, a second experiment on selected precursor ions allowed them to fragment then scan for quantification of productions.
This strategy is known as MSE where precursor ion selection is automatic with no human factor interference; thus, no need for new data of which metabolites are expected to be present. Further developments in quadrupoles would increase mass accuracy, sensitivity and dynamic range; thus, allowing the use of tandem mass spectrometers in the framework of a new strategy, that is more targeted and more selective analysis (selected reaction monitoring); thus allowing higher sensitivity. Another alternative is developing instruments with a single quadrupole, which will make unlimited quantification possible (Dunn, 2008).
Cost-effectiveness
Despite more than 30 inborn errors of metabolism that can be diagnosed by MS-MS; yet, its universal routine use in neonatal screening is a matter of discussion, primarily for its high cost. Schoen and colleagues (2002, p. 781) conducted a cost-benefit analysis to assess routine use of MS-MS in screening neonates for inborn errors of metabolism. They estimated the cost (adjusted per quality life-year saved by MS-MS) to range from $ 11,419 (in worst scenarios) to $ 736 (in best scenarios) with an average of $ 5872.
They assumed this high cost in newborn screening to other factors included but not concrete as the costs of personnel, training, tracking test results, parents’ counseling, supplying special diets and care. They inferred that adjusted costs compare promisingly to policy encouraged screening methods; however, whether diagnosis of these disorders is pre-symptomatic or after manifested the cost is still high.
Pandor et al, (2006, p. 321) examined cost-effectiveness of MS-MS in a different economic model. They compared the cost of tandem mass spectrometry to the cost of traditional technologies in diagnosing phenylketonuria. Then they added diagnosis of MCAD and evaluated cost-effectiveness within a UK NHS perspective. Their results suggested adding MCAD to the diagnostic battery of MS-MS produced a cost-saving accompanied by a mean incremental gain in life/years rate. Pandor colleagues (2006, P. 231) inferred the introduction of MCAD screening should result in better cost-effectiveness and a better neonatal health outcome.
Who to screen
Inborn errors of metabolism have characteristic clinical criteria, the age of onset is at early infancy and may extend to early childhood, second is the characteristic temporal disorder profile that is evolution of clinical features as the disease progresses. Third is the characteristic mode of inheritance, which is generally autosomal dominant and rarely X-linked recessive mode of inheritance like Hunter’s disease and Menkes disease. Finally, these disorders have characteristics triggers, which may be dietary (galactosemia, hereditary fructose intolerance), Infection, fasting, fever, anesthesia (homocystinuria) or drug-induced (G6 PD deficiency (Kumta, 2005).
Sharma et al, (2008, p. 272) agreed that screening for metabolic errors should begin as early as possible based on high suspicion index. They suggested a first line of investigations (metabolic screen) for all infants suspected to suffer from this metabolic error. This line comprises the following investigations; complete blood count where neutropenia and thrombocytopenia can raise suspicion of propionic and methylmalonic acidaemias, and plasma ammonia.
They also recommended estimation of arterial blood gases and electrolytes, blood glucose, arterial blood lactate, urine ketones, urine reducing substances, liver function tests, and serum uric acid. Based on results of the metabolic screen, investigation may proceed to the second line of confirmative tests (to support the diagnosis).
Second-line investigations are many and performed on targeted selective basis, these tests include gas chromatography of urine for organic acidaemia, lactate-pyruvate ratio, urinary orotic acid for urea cycle errors, and enzyme assay. They also include MRI neuroimaging for maple syrup urine disease (brainstem and cerebellar edema), propionic and methylmalonic acidaemias (basal ganglia signal change). In addition, EEG may help to point to some metabolic errors as holocarboxylase synthetase deficiency (Sharma et al, 2008).
The current place of Tand2em screening
Tandem mass spectrometry is used for neonatal screening (first or second line) variably in many countries. It can diagnose amino acids inborn metabolic disorders (as phenylketonuria), fatty acids oxidation defects, and organic acidaemia (Jilkhani et al, 2008).
Conclusion
Tandem mass spectrometry is a technological advancement that can diagnose a variety of inborn errors of metabolism and has the potential for expanding neonatal screening for these disorders. Its main advantage is pre-symptomatic of these disorders enabling early management, however, proper interpretation of results needs training and familiarity with these disorders. The technique is promising one test to diagnose many disorders and can have a favorable impact on the health of infants with inborn metabolic disorders and their families.
References
Clarke, J TR, 2005. A Clinical Guide to Inherited Metabolic Diseases. Third edition. Cambridge, UK: Cambridge University Press.
Dettmer, KA, Aronov, PA., and Hammock, B, 2007. Mass Spectrometry-Based Metabolomics. Mass Spec Rev, (26), 51-78.
Dunn, W, 2008. Current trends and future requirements for the mass spectrometric investigation of microbial, mammalian and plant metabolomes. Phys. Biol, (5), 1-24.
Gross, J. H., 2004. Mass Spectrometry: A Textbook. Heidelberg, Germany: Springer-Verlag.
Jailkhani, R, Ptail, VS, Laxman, HB, Shivashankara, AR, et al,, 2008. Selective screening for inborn errors of metabolism in children: Single center experience from Karnataka. Journal of Clinical and Diagnostic Research, (4), 952-958.
Kumta, N. B., 2005. Inborn Errors of Metabolism (IEM)-An Indian Perspective. Indian Journal of Pediatrics, (72), 325-332.
Schoen, EJ, Baker, JC, Colby, CJ, and To, TT, 2002. Cost-Benefit Analysis of Universal Tandem Mass Spectrometry for Newborn Screening. Pediatrics, 110(4), 781-786
Pandor,A, Eastham, J, Beverley, C. Chilcott, J, and Paisley, S, 2004. Clinical effectiveness and cost effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review. Health Technol Assess, 8(12), 1-144.
Pandor,A, Eastham, J, Beverley, C. Chilcott, J, and Paisley, S, et al, 2006. Economics of tandem mass spectrometry screening of neonatal inherited disorders. International Journal of Technology Assessment in Health Care, 22(3), 321-326.
Pasquali, M, 2005. Tandem Mass Spectrometry: Principles and Interpretation of Results. Genetic Drift, 7-9.
Sharma, S, Kumar, P, Agarwal, R, Kabra, M, et al,, 2008. Approach to Inborn Errors of Metabolism Presenting in the Neonate. Indian J pediatr, 75(3), 271-276.
Vogeser, M., Kobold, U. and Seidel, D., 2007. Mass Spectrometry in Medicine – the Role of Molecular Analyses. Dtsch Arztebl, (104), A2194-2200.
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