CN112379017A - Screening kit for non-derivatization multiple neonatal hereditary metabolic diseases - Google Patents
Screening kit for non-derivatization multiple neonatal hereditary metabolic diseases Download PDFInfo
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- CN112379017A CN112379017A CN202011205019.1A CN202011205019A CN112379017A CN 112379017 A CN112379017 A CN 112379017A CN 202011205019 A CN202011205019 A CN 202011205019A CN 112379017 A CN112379017 A CN 112379017A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/045—Standards internal
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
Abstract
The invention provides a screening kit for underivation of various neonatal inherited metabolic diseases, which screens the neonatal inherited metabolic diseases including amino acid metabolic diseases, fatty acid oxidative metabolic diseases, organic acid metabolic diseases, purine metabolic diseases, peroxidase body diseases and the like by detecting 57 analytes. The kit comprises: a reagent bottle filled with dry powder inner standard substance, succinylacetone analysis solution, mobile phase solvent and extraction liquid; and a dry blood spot quality control product filter paper card and a U-shaped bottom heat-resistant microporous plate. The screening kit for underivatized multiple neonatal hereditary metabolic diseases can measure and evaluate amino acid, succinylacetone, free carnitine and acyl carnitine in a neonatal dry blood spot sample collected on a filter paper sheet, and can detect the concentrations of adenosine and lysolecithin, so that the screening kit is helpful for screening purine metabolic diseases and peroxidase diseases, and contributes to the health of neonates.
Description
Technical Field
The invention relates to the technical field of screening of metabolic diseases of newborns, in particular to a kit for screening multiple underivatized genetic metabolic diseases of newborns.
Background
The newborn metabolic disease screening is a simple, rapid and cheap blood spot test, and can be used for early finding whether a child has congenital genetic disease or not and timely treating the child to enable the child to grow healthily, wherein common metabolic diseases of the newborn include but are not limited to Amino Acid (AA) metabolic disease, Fatty Acid Oxidation (FAO) metabolic disease, Organic Acid (OA) metabolic disease, purine metabolic disease and peroxidase body disease. Wherein:
amino Acid (AA) metabolic disease: the enzymes necessary for the metabolism of certain amino acids are completely absent or their activity is reduced in the patient. This results in an increase or decrease in the concentration of the affected amino acids and other metabolites (e.g., succinylacetone) in the body. Too high a concentration can seriously impair health and even lead to death. Several amino acid metabolic diseases that have been extensively studied are as follows:
phenylketonuria (PKU) is a metabolic disorder of aromatic amino acids, in which phenylalanine cannot be converted to tyrosine in a patient. This disease, if left untreated, results in varying degrees of mental retardation. Hyperphenylalaninemia causes mental retardation and muscular rigidity. Cystinuria causes thrombotic diseases, osteoporosis, accumulation of homocysteine and methionine (methionine) and different types of developmental delay. Maple Syrup Urine Disease (MSUD) is a disease that results in elevated levels of leucine, isoleucine and valine in the blood due to metabolic abnormalities of branched chain amino acids. If left untreated, progressive lethargy occurs to coma, developmental delay and convulsions. Type I tyrosinemia can lead to acute liver failure or chronic cirrhosis and liver cancer. Citrullinemia can lead to convulsion, anorexia, vomiting and lethargy, which can lead to rapid coma that may be fatal.
Hyperammonemia or urea cycle disorders are caused by a deficiency in certain enzymes in the urea cycle. Severe hyperammonemia causes the accumulation of ammonia and its precursor metabolites in the body and may lead to coma, seizures and eventual death. In ornithine transaminase deficiency (OTCD), ornithine transcarbamylase deficiency results in elevated levels of glutamine and orotate in the blood. In argininosuccinase deficiency (ASA-LD), enzymes that cleave argininosuccinate into arginine and fumaric acid are lacking, thus resulting in elevated levels of argininosuccinate in the blood.
Fatty Acid Oxidation (FAO) metabolic disease: in the case of fatty acid oxidative metabolism diseases, enzymes necessary for the cleavage of fatty acids are lost or reduced in activity. When glucose is at a low level, energy production requires the cleavage or oxidation of fatty acids. In the absence of this energy supply, some patients experience repeated hypoglycemic symptoms. When the patient is not eating food (often due to diseases such as ear infections or influenza), metabolic crisis may occur. The patient may have symptoms of vomiting, diarrhea, lethargy, seizures, or coma. Fatty acid dysoxidation may result in excessive deposition of fat in the liver, heart and kidneys if not diagnosed in a timely manner. Causing a variety of symptoms including liver failure, encephalopathy, complications of the heart and eyes, and common problems with muscle development. Many of these clinical symptoms can lead to death. There are many cases where death due to abnormal oxidative metabolism of fatty acids is misdiagnosed as Sudden Infant Death Syndrome (SIDS) or reye's syndrome.
Organic Acid (OA) metabolic disease: the organic acid metabolic pathway of the patient with the organic acid metabolic disease is abnormal, so that the accumulation of the organic acid in blood and urine occurs, and the acid-base balance of the human body is changed. This imbalance results in the body's regulation or adaptation of intermediary metabolic pathways, which may lead to a variety of clinical symptoms, including metabolic acidosis, ketosis, hyperammonemia, growth retardation, sepsis or coma.
Purine metabolic disease: adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID) is a hereditary disease of purine metabolism. Adenosine and 2' -deoxyadenosine accumulate in the blood due to the absence of the enzyme adenosine deaminase. ADA-SCID can damage the immune system, leading to chronic immune function deterioration and, in extreme cases, death if not properly treated.
Peroxidase body disease: in X-linked adrenoleukodystrophy (X-ALD), beta-oxidation of very long chain fatty acids is impaired, causing their accumulation in plasma and tissues. Depending on the extent of accumulation, x-ALD can lead to mild to severe brain damage.
The current kits for detecting metabolic disorders in newborns are the non-derivatized multiple amino acid, carnitine and succinylacetone assay kit from Perkinelmer (tandem mass spectrometry). The kit was used to measure and evaluate the concentrations of amino acids, succinylacetone, free carnitine and acyl carnitine in samples of dried newborn plaques collected on filter paper sheets. The concentration distribution of the analytes can be obtained by quantitative analysis of the analytes and the relationship among the analytes, thereby being beneficial to screening the metabolic diseases of the newborn.
However, at present, no mass spectrometry kit capable of detecting adenosine, deoxyadenosine and lysolecithin exists in China, mainly because the cost of the tandem mass spectrometry platform is high, and the kit of the tandem mass spectrometry is rapidly developed in China in recent years, cannot be popularized in a large number of hospitals, and related reagents are also in the development process. In addition, the kit can only detect non-derivatized various amino acids, carnitine and succinylacetone, and no kit capable of simultaneously detecting the concentrations of the amino acids, succinylacetone, free carnitine, acylcarnitine, adenosine and lysolecithin, which can screen Amino Acid (AA) metabolic diseases, Fatty Acid Oxidation (FAO) metabolic diseases, Organic Acid (OA) metabolic diseases, purine metabolic diseases and peroxidase body diseases, exists at present.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a non-derivatization screening kit for genetic metabolic diseases of multiple newborns, which can simultaneously detect 57 analytes (comprising 14 amino acids, 36 carnitines, 2 adenosines, succinylacetone and 4 lysolecithins).
The invention adopts the following technical scheme for solving the technical problems:
the invention provides a screening kit for underivatized multiple neonatal genetic metabolic diseases, which screens underivatized multiple neonatal genetic metabolic diseases comprising amino acid metabolic diseases, fatty acid oxidative metabolic diseases, organic acid metabolic diseases, purine metabolic diseases and peroxidase body diseases by detecting 57 analytes; the kit comprises:
a reagent bottle filled with dry powder inner standard substance, succinylacetone analysis solution, mobile phase solvent and extraction liquid;
a dry blood spot quality control filter paper card and a U-shaped bottom heat-resistant microporous plate;
the 57 analytes and their corresponding internal standards and quality controls are as follows:
further, the kit also comprises instructions for reconstituting the internal standard: and re-dissolving the dry powder of the internal standard substance by using the extract liquor, and thoroughly mixing until the dry powder is completely dissolved.
Further, the concentration of the dissolved internal standard substance is 0.0014-0.71 mmol/L.
Further, the kit also comprises instructions for preparing an extraction working solution: and mixing the succinylacetone analysis solution, the re-dissolved internal standard substance at room temperature and the extraction liquid to prepare an extraction working solution.
Further, the volume ratio of the succinylacetone analysis solution, the reconstituted internal standard at room temperature, and the extraction solution at the time of mixing was 2:1: 97.
Further, the kit comprises instructions for perforating a filter paper blood slide from the dried blood spot using an automatic or manual perforator and moving the filter paper blood slide into wells of a provided U-bottom heat-resistant microplate.
Further, the kit includes instructions for adding extraction medium to each well containing a filter paper blood slide.
Further, the mobile phase solvent includes acetonitrile, water and formic acid.
Further, the above extract includes methanol, water and oxalic acid.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the screening kit for underivatized multiple neonatal hereditary metabolic diseases can measure and evaluate amino acid, succinylacetone, free carnitine and acyl carnitine in a neonatal dry blood spot sample collected on a filter paper sheet, and can detect the concentrations of adenosine and lysolecithin, so that the screening kit is helpful for screening purine metabolic diseases and peroxidase diseases, and contributes to the health of neonates.
Drawings
FIG. 1 shows a standard curve for the internal standard of D-ADO;
FIG. 2 shows a standard curve for an internal ADO standard;
FIG. 3 shows a standard curve for the C26:0-LPC internal standard;
FIG. 4 shows a standard curve for the internal standard C26;
FIG. 5 shows ADO calibration curves for samples tested;
FIG. 6 shows a D-ADO calibration curve for a sample to be tested;
FIG. 7 shows a C26 calibration curve for the sample to be tested;
FIG. 8 shows the C26:0-LPC calibration curve for the samples tested.
Detailed Description
The invention provides a screening kit for underivatized multiple neonatal inherited metabolic diseases. As shown in table 1, the underivatized multiple neonatal genetic metabolic disease screening kit (tandem mass spectrometry) can simultaneously detect 57 analytes (including 14 amino acids, 36 carnitines, 2 adenosines, succinylacetone, and 4 lysolecithins). In fact, the kit provides 30 quality controls and 30 internal standards. This is because some analytes have similar chain lengths or similar chemical structures, and they also have similar characteristics in tandem mass spectrometry, so for these analytes, we need only use one of the internal standards (or quality controls). For example, C18, C18:1, C18:2, C18OH, C18:1OH, C18:2OH have similar performance characteristics, and the concentration of these analytes can be estimated using C18 internal standards. It is believed that this method will affect accuracy, but not accuracy. Furthermore, due to the similarity of their properties, unlabeled C18 can be used throughout the C18 acylcarnitine family as a replacement for external quality controls. Thus, as long as the internal standard and external quality control surrogate selected to quantitatively measure a particular analyte remain constant in the analysis of a patient sample, a distinction can be made between speculatively normal and speculatively elevated samples.
For the long-chain carnitine C20-C26 and Lysolecithin (LPC), the longest-chain C26 and C26:0-LPC and their corresponding markers can be used as internal standards for the two groups of analytes due to the extremely similar structures and characteristics. Similarly, an arginine (Arg) internal standard can be used to test arginine and argininosuccinic acid simultaneously, even though they have different quality control analytes. The relationship between the analyte and the internal standard and the quality control product is shown in the following.
TABLE 1 analysis of non-derivatized multiple neonatal metabolic screening kits (tandem mass spectrometry) for the measurement of analytes and their corresponding internal standards and quality controls
It can be seen that, compared to the kit for measuring underivatized various amino acids, carnitine and succinylacetone of the company Perkinelmer, the kit provided by the invention can also detect the analysis related to purine metabolic disease and peroxidase body disease. Standard curves for internal standards for these analytes, see fig. 1-4.
As shown in fig. 5-8, the concentration of the analyte in the sample to be tested can be determined from the calibration curve. The specific algorithm is as follows:
the measurement of amino acids, free carnitine, acylcarnitines, succinylacetone, adenosine and lysolecithin involves extraction of dried newborn blood spots using a solution containing internal standards and analysis using a tandem mass spectrometry (MSMS) system. The extent to which each analyte responds to its corresponding internal standard is proportional to the concentration of that analyte, and the concentration of that analyte is calculated as follows:
the present invention will be described in detail and specifically with reference to the following examples and drawings so as to provide a better understanding of the invention, but the following examples do not limit the scope of the invention.
In the examples, the conventional methods were used unless otherwise specified, and reagents used were those conventionally commercially available or formulated according to the conventional methods without specifically specified.
Example 1
This example provides a 480 or 960 human underivatized multiple neonatal genetic metabolic disease screening kit (tandem mass spectrometry) comprising an a-box (table 2) and a B-box (table 3).
TABLE 2A Box Components (stored at 2-8 deg.C)
TABLE 3B Box Components (stored at 2-30 deg.C)
Wherein the approximate contents (μmol) per vial in the internal standard are shown in Table 4, and the analytes and the approximate average concentration values (μmol/L) contained in the quality control substances are shown in Table 5.
TABLE 4 approximate content of internal standard per vial
TABLE 5 analytes contained in the quality control substances and approximate mean concentration values (. mu. mol/L)
Example 2
This example provides a method of use of the kit according to example 1, comprising the steps of:
1. preparing an internal standard substance and an extraction working solution:
1.1 reconstitute the internal standard dry powder in the vial with 0.7mL of extract, mix the liquid thoroughly until completely dissolved (typically 60-70 minutes, if not completely dissolved, mix by sonication for about 3 minutes). The compound solution can be stored in a small bottle for 4 weeks in a sealed and stable manner at the temperature of 2-8 ℃.
1.2 ensure that the desired reconstituted internal standard and the extract have been brought back to room temperature (18-25 ℃ C.) before the preparation of the working extract.
1.3 Succinylacetone assay and reconstituted internal standard were mixed into the extracts according to Table 6. This is the extraction working solution containing the amino acids, (free/acyl) carnitine, adenosine and the lysolecithin internal standard.
TABLE 6 preparation of extraction working solution
1.4 if the prepared extraction working solution is placed in a glass bottle, the extraction working solution can be stored in a dark place at the temperature of 2-8 ℃ and can be stabilized for 2 weeks.
2. A filter paper blood slide is punched out of the dried blood spot using an automatic or manual puncher and transferred into wells of a provided U-bottomed heat-resistant microplate. The diameter of the filter paper blood piece should be about 3.2mm (1/8 inches). Only one filter paper blood sheet was added to each well. It is suggested to set 2 plate holes in each microplate for blank (only adding extraction working solution containing internal standard), so as to realize synchronous operation of the liquid chromatography system and the mass spectrometer.
3. Using the reverse phase, 125. mu.L of the extraction medium was added to each well containing a filter paper blood slide. The microplate is covered with an adhesive microplate envelope to ensure good sealing and minimize evaporation.
4. Immediately after capping, the plate was placed in an incubation/shaker and shaken at 45. + -. 5 ℃ for 30. + -.2 minutes. The microplate was oscillated at a speed in the range of 650-750 rpm.
5. The plate was carefully removed from the incubator/shaker to avoid splashing.
6. Transfer 100. mu.L of solution from each well to a new microplate, noting that the positions are one-to-one.
7. The microplate is covered again with an adhesive microplate envelope, ensuring good sealing and minimizing the amount of volatilization.
8. If used to test succinylacetone, it must be left for at least 1 hour between the 1 st measurements after the solution is transferred to allow complete derivatization of the succinylacetone. Routine maintenance and operational set-up of the instrument can be performed during this period. This step can be omitted if succinylacetone is not tested.
9. The microplate was placed in an autosampler.
10. System control software is started, a worklist is created, and tests are run using appropriate data acquisition methods.
Verification examples
This example uses the kit provided in example 1 and the method in example 2 to analyze a sample confirmed to be positive to verify the accuracy of the kit.
During the evaluation of the performed kit clinical tests, archived confirmatory positive samples and daily screening positive samples were analyzed using a non-derivative MSMS test. These samples were provided and tested by three clinical institutions in china. The test results summary of table 7 lists the test results for all true positive samples obtained using the non-derivatized MSMS test.
TABLE 7 summary of test results of positive samples confirmed by all three clinical institutions in China
As can be seen from table 7, the kit can correctly detect all 153 confirmed positive (CTP) samples covering 30 different congenital metabolic diseases.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications or alterations to this practice will occur to those skilled in the art and are intended to be within the scope of this invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (8)
1. A screening kit for underivatized multiple neonatal inherited metabolic diseases, characterized in that the kit screens neonatal inherited metabolic diseases including amino acid metabolic diseases, fatty acid oxidative metabolic diseases, organic acid metabolic diseases, purine metabolic diseases and peroxidase body diseases by detecting 57 analytes; the kit comprises:
a reagent bottle filled with dry powder inner standard substance, succinylacetone analysis solution, mobile phase solvent and extraction liquid; and
a dry blood spot quality control filter paper card and a U-shaped bottom heat-resistant microporous plate;
the 57 analytes and their corresponding internal standards and quality controls are as follows:
2. the kit of claim 1, further comprising instructions for reconstituting an internal standard: and re-dissolving the dry powder of the internal standard substance by using the extract liquor, and thoroughly mixing until the dry powder is completely dissolved.
3. The kit of claim 2, further comprising instructions for preparing an extraction working fluid: and mixing the succinylacetone analysis solution, the re-dissolved internal standard substance at room temperature and the extraction liquid to prepare an extraction working solution.
4. A kit according to claim 3, wherein the succinylacetone assay solution, the reconstituted internal standard at room temperature and the extraction fluid are mixed at a volume ratio of 2:1: 97.
5. The kit of claim 1, wherein the kit comprises instructions for perforating a filter paper blood slide from a dried blood spot using an automatic or manual perforator and moving the filter paper blood slide into wells of a provided U-bottom heat-resistant microplate.
6. The kit of claim 1, further comprising instructions for adding extraction medium to each well containing a filter paper blood slide.
7. The kit of claim 1, wherein the mobile phase solvent comprises acetonitrile, water, and formic acid.
8. The kit of claim 1, wherein the extraction solution comprises methanol, water, and oxalic acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114152706A (en) * | 2021-04-14 | 2022-03-08 | 上海义准生物有限公司 | Method for simultaneously detecting various newborn screening metabolites in dried blood slices |
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