Propionic/Methylmalonic AcidemiasNCT05910151
Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
An observational study of Propionic/Methylmalonic Acidemias and Maple Syrup Urine Disease, run by West Kazakhstan Medical University at 1 site in Kazakhstan.
Trial summary
Inborn errors of metabolism (IEM) are not have specific clinical signs, they masquerade as other diseases, and are difficult to diagnose using only clinical manifestations or routine laboratory tests. IEM most commonly manifest in early infancy and childhood. Read more about this study
- Who is it for?
- Ages 1 day to 18 yearsHealthy volunteers can take part
- Conditions the study is for
- Propionic/Methylmalonic Acidemias, Maple Syrup Urine Disease, Citrullinemia
- What is being tested?
- Obtaining Dry Blood Spots From Healthy Newborns (Aged 1-7 Days), Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 Years and Obtaining Dry Blood Spots From Healthy Children Aged 8-18 Years
- How many people
- 2,250 participants
- Where
- 1 siteKazakhstan
- Study dates
- 3 Oct 2022to 31 Dec 2024
- How long will I take part?
- 2250 Months
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 18 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Study population: To establish reference values for metabolites, healthy participants without any disease will be included in the study: 750 healthy male and female children aged 1 day to 18 years old from West Kazakhstan will be recruited and included in the study. Depending on age, healthy children will be divided into the following groups: group A (age 1-7 days), group B (age 8 days-7 years) and group C (age 8-18 years). A total of 1,500 children from the West Kazakhstan population (age 1 days -18 years) with suspected metabolic disorders will be referred by primary care neonatologists and pediatric consultants based on their clinical symptoms associated with metabolic disorders and examined for IEM.
Who may be able to join
- Referense group: Healthy male and female children aged 1 day to 18 years. Newborns born during the study period (all newborns will be included in this study will meet all selected inclusion criteria to ensure that they do not suffer from any disorder or disease. Healthy male and female newborns must weigh within 2500 -4000 g, gestational age 37-42 weeks, Apgar score above 7 for 10 min.) Sample group: children aged 1 day to 18 years will be selected if one of the main criteria or two or more additional criteria (symptoms) is identified.
- Main criteria (symptoms): 1) Sudden deterioration in the clinical condition of the child after a period of normal development (days, weeks, months): acute metabolic encephalopathy, lethargy (coma), seizures resistant to antiepileptic therapy. 2) Hepatomegaly (hepatosplenomegaly). 3) Metabolic acidosis with an increase in the anion gap. 4) Multiple fractures. 5) Child mortality in the family from diseases with similar symptoms.
- Additional criteria (symptoms): Treatment-resistant seizures; Abnormal muscle tone: dystonia, hyperkinesis, hypotension; Speech delay; Mental retardation of unknown cause; Cardiomyopathy; Tachypnoea; Frequent spitting up (vomiting); Osteo-articular abnormalities (joint stiffness, chest deformity, rickets-like changes); Hernias (umbilical, inguinal-scrotal); Persistent or recurrent hypoglycemia; Metabolic alkalosis; Increase in ketone bodies in the blood and (or) urine; Hyperammonemia; Increase in the level of liver enzymes (AlAT, AST) more than 1.5 times the norm; Increase in the level of creatine phosphokinase (CPK) more than 2 times the norm; Decrease in the level of alkaline phosphatase (AP) below the age norm; Imaging or electrophysiological studies suggesting metabolic disorders; Leukopenia; Thrombocytopenia; Abnormal urine, body, ear wax, any unusual smell; Hair growth disorders, alopecia; Ophthalmological anomalies; Unusual appearance, dysmorphic features; History of previous sibling death of unknown cause; Parents' consanguinity; A positive family history of metabolic disorders.
Who cannot join
- The study will exclude patients who has:
- perinatal brain injury,
- brain injuries,
- infections of the central nervous system,
- toxicological diseases,
- tumors,
- chromosomal abnormalities,
- with the symptoms specified in the inclusion criteria, but with a confirmed diagnosis of any disease other than amino acids disorders (AAD), fatty acid oxidation defects (FAOD) or organic academias (OA).
Trial locations and contacts
1 site in 1 country.
Kazakhstan1 site, 1 recruiting
- Recruiting
Regional perinatal center of Aktobe region
Aktobe, Aktobe, 030000
Zhanna T. Zhusupova, MD, +7701-791-0795 ext. +7132-24-9588, perinatal_centr@mail.ru, tleuzhanna@mail.ru
Zhanna Zh Baibosynova, nurse
About this study
Official title: Introduction of Tandem Mass Spectrometry (MS/MS) Technology in the Program of Selective Screening of Hereditary Metabolic Diseases in Kazakhstan
Inborn errors of metabolism (IEM) are not have specific clinical signs, they masquerade as other diseases, and are difficult to diagnose using only clinical manifestations or routine laboratory tests. IEM most commonly manifest in early infancy and childhood. Despite the fact that most IEM are rare in the population, they occupy one of the first places in the structure of childhood pathology, early infant mortality and disability. IEM often remains undiagnosed, while timely diagnosis and timely treatment started can prevent severe systemic damage leading to death and disability. The appointment of a special treatment (diet therapy, cofactors, enzyme replacement therapy) prevents or significantly inhibits the development of the pathological process, especially if the diagnosis is made in the early stages of the disease. To start pathogenetic treatment as early as possible, it is necessary to diagnose IEM as accurately and as early as possible.
Among the diseases included in mass screening programs IEM are especially important due to the development of disability and early mortality in the absence of timely diagnosis and treatment, as well as a high risk of recurrence in burdened families. In this connection, the main goals of mass screening - the prevention of disability in children and the reduction of early infant mortality - dictate the need to introduce modern technologies for preclinical diagnosis of IEM.
Read more
Based on the results of the study, it is planned to scientifically substantiate the need for the introduction of selective screening of children for hereditary metabolic diseases using the technology of tandem mass spectrometry in the Republic of Kazakhstan for timely diagnosis, therapy of IEM and prevention of disability. The introduction of a selective newborn screening program for IEM should always be preceded by a study aimed at studying the prevalence of the disease in a certain region, determining regional reference values of the studied metabolites. Local incidence and outcome data can be used to persuade health officials to prioritize screening in health care spending.
The main scientific question and hypothesis of the project is whether it is necessary to introduce tandem mass spectrometry technology in the neonatal screening program for IEM.
Read the detailed description
In Kazakhstan, the use of MS/MS in metabolic screening programs is in development. This is due to the high cost of equipment and consumables, as well as the lack of special screening centers and specialists.
Selective screening is an important tool for diagnosing various types of inborn errors of metabolism (IEM). Currently, MS/MS-based technologies are widely used, which allow the simultaneous determination of the amount of several metabolites (amino acids, acylcarnitines) from a very small amount of a biological sample. However, age reference cutoff ranges for each analyte should be established first for each population prior to screening as cutoffs depend on various factors such as genetic background, population geographic location, diet, sex, age.
Data on the prevalence of most IEMs, with the exception of phenylketonuria, are not available in Kazakhstan. The data obtained in this study will make it possible to conduct a comparative analysis of the prevalence of IEM in Asia and establish reference values for the concentrations of amino acids and acylcarnitines in the blood of newborns for the Kazakhstan population. Newborn sreening is currently being conducted in Kazakhstan for two hereditary diseases - phenylketonuria and congenital hypothyroidism, which are the most represented screening diseases in most countries. A nationwide newborn screening program for two mandatory diseases, congenital hypothyroidism and phenylketonuria (PKU), began in 2007. ENBS on aminoacid disorders (AAD), organic acidemias (OA) and fatty acid oxidation defects (FAOD) is not conducted in Kazakhstan.
For Kazakhstan, as a country that does not have a mandatory ENBS program, selective screening can be an important tool for diagnosing IEM. The present study aims to develop and validate an MS/MS method for the simultaneous determination of 51 metabolites in DBS for IEM screening, as well as the determination of age-related amino acid ranges, acylcarnitines and succinylacetone in children's population of Kazakhstan. Our selective screening was initiated to obtain data on the incidence of IEM in children at risk in Western Kazakhstan. From October 2022 to December 2024, the frequency of 37 AAD, OA and FAOD will be assessed using LC-MS/MS technology in a group of children at high risk. A summary report will be presented on the screening of high-risk children for IEM in Western Kazakhstan using the LC-MS/MS method.
The results of selective screening tests in different age groups of subjects should be interpreted by comparison with the reference values and/or cut-off levels established for these groups. It is generally accepted that children need to use reference populations that reflect changes associated with growth and development. Therefore, one of the objectives of this study is to establish reference intervals for the concentration of amino acids and acylcarnitines in dry blood spots for different age groups in the range from 1 day to 18 years.
The goal of this observational study is to сonduct selective screening for IEM among children of Kazakhstan aged from 1 day to 18 years using tandem mass spectrometry to determine the prevalence of IEM and reference values of metabolites followed by subsequent substantiation of the need to introduce selective screening of newborns for IEM by MS/MS.
The main questions it aims to answer are:
question 1: what are the reference values of metabolites (amino acids and acylcarnitines) in different age groups of children in Kazakhstan; question 2: what is the contribution of IEM to the structure of the pathology of the nervous system in young children and is it necessary to introduce tandem mass spectrometry technology in the neonatal screening program for IEM?
- Conditions
- Propionic/Methylmalonic Acidemias, Maple Syrup Urine Disease, Citrullinemia, Argininosuccinic Aciduria, Ornithine Transcarbamylase Deficiency, Carbamoyl Phosphate Synthetase I Deficiency
- Being tested
- Obtaining Dry Blood Spots From Healthy Newborns (Aged 1-7 Days), Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 Years, Obtaining Dry Blood Spots From Healthy Children Aged 8-18 Years, Obtaining Dry Blood Spots From High-risk Newborns (Aged 1-7 Days), Obtaining Dry Blood Spots From High-risk childrens (Aged 8 Days- 7 years)
- Keywords
- Inborn errors of metabolism, MS/MS, selective screening
- Medical subject headings
- Maple Syrup Urine Disease, Citrullinemia, Argininosuccinic Aciduria, Ornithine Carbamoyltransferase Deficiency Disease, Carbamoyl-Phosphate Synthase I Deficiency Disease, N-acetyl glutamate synthetase deficiency, Hyperglycinemia, Nonketotic, Tyrosinemias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Obtaining Dry Blood Spots From Healthy Newborns (Aged 1-7 Days)Diagnostic test
Neonatal blood samples will be taken from healthy infants no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs) for LC-MS/MS analysis. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers until analyzed by LC-MS/MS in accordance with standards from the Institute of Clinical and Laboratory Standards.
Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 YearsDiagnostic test
Blood samples will be taken from healthy childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs) for LC-MS/MS analysis. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers until analyzed by LC-MS/MS in accordance with standards from the Institute of Clinical and Laboratory Standards
Obtaining Dry Blood Spots From Healthy Children Aged 8-18 YearsDiagnostic test
Blood samples will be taken from healthy childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs) for LC-MS/MS analysis. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers until analyzed by LC-MS/MS in accordance with standards from the Institute of Clinical and Laboratory Standards
Obtaining Dry Blood Spots From High-risk Newborns (Aged 1-7 Days)Diagnostic test
Blood samples will be taken from high-risk infants no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs). The sample must be taken before transfusion therapy (or blood is taken no earlier than 48-72 hours after the transfusion) or extracorporeal membrane oxygenation. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers.
Obtaining Dry Blood Spots From High-risk childrens (Aged 8 Days- 7 years)Diagnostic test
Blood samples will be taken from high-risk childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs). The sample must be taken before transfusion therapy (or blood is taken no earlier than 48-72 hours after the transfusion) or extracorporeal membrane oxygenation. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers
Obtaining Dry Blood Spots From High-risk childrens (Aged 8 - 18 years)Diagnostic test
Blood samples will be taken from high-risk childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs). The sample must be taken before transfusion therapy (or blood is taken no earlier than 48-72 hours after the transfusion) or extracorporeal membrane oxygenation. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers
| Study group | Role | What they receive |
|---|---|---|
| reference group A | healthy newborns aged 1-7 days Receives: Diagnostic Test: Obtaining Dry Blood Spots From Healthy Newborns (Aged 1-7 Days) | |
| reference group B | healthy children aged 8 days - 7 years Receives: Diagnostic Test: Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 Years | |
| reference group C | healthy children aged 8 - 18 years Receives: Diagnostic Test: Obtaining Dry Blood Spots From Healthy Children Aged 8-18 Years | |
| selective group A | children aged 1 day - 7 days suspected with IEM Receives: Diagnostic Test: Obtaining Dry Blood Spots From High-risk Newborns (Aged 1-7 Days) | |
| Selective group B | children aged 8 days - 7 years suspected with IEM Receives: Diagnostic Test: Obtaining Dry Blood Spots From High-risk childrens (Aged 8 Days- 7 years) | |
| Selective group C | children aged 8-18 years suspected with IEM Receives: Diagnostic Test: Obtaining Dry Blood Spots From High-risk childrens (Aged 8 - 18 years) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Identification of the concentration value of amino acids and acylcarninits activity in Dry blood spots among Newborns and Children in Kazakhstan
Amino acids: Alanine (Ala), Arginine (Arg), Citrulline (Cit), Glutamine (Gln), Glutamic acid (Glu), Glycine (Gly), Leucine (Leu), Isoleucine (Leu), Hydroxyproline (Leu), Methionine (Met), Ornithine (Orn), Phenylalanine (Phe), Proline (Pro), Tyrosine (Tyr), Valine (Val). Acylcarninits: free carnitine (C0), Acetylcarnitine (C2), Propionylcarnitine (C3), Malonylcarnitine+3-Hydroxybutyrylcarnitine (C3DC/C4OH), Butyrylcarnitine (C4), Methylmalonylcarnitine+3-Hydroxyisovalerylcarnitine (C4DC/C5OH), Isovalerylcarnitine (C5), Tiglylcarnitine (C5:1), Glutarylcarnitine (C5DC), Hexanoylcarnitine (C6), Octanoylcarnitine (C8), Octenoylcarnitine (C8:1), Decanoylcarnitine (C10), Decenoylcarnitine (C10:1), Decadienoylcarnitine (C10:2), Dodecanoylcarnitine (C12), Hydroxydodecenoylcarnitine (C12:1), Myristoylcarnitine (C14), Tetradecenoylcarnitine (C14:1), Tetradecadienoyl-carnitine (C14:2), Hydroxytetradecanoylcarnitine (C14OH), Palmitoylcarnitine (C16), Hexadecenoylcarnitine (C16:1), Hydroxy-Hexad
Measured: Two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2023
- Study start3 Oct 2022
- Primary completion31 Dec 2024 (estimated)
- Study completion31 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Propionic/Methylmalonic AcidemiasStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Ecologic or community
- Time perspective
- Cross-sectional
- Enrolment
- 2,250 participants (estimated)
- Target duration
- 2250 Months
Sponsor and investigators
- Lead sponsor
- West Kazakhstan Medical University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Zharmakhanova Gulmira, West Kazakhstan Medical University
- Investigators
- Gulmira M. Zharmakhanova, MD, PhD, Principal investigator, West Kazakhstan Medical UniversityLyazzat M. Syrlybayeva, MD, Study chair, West Kazakhstan Medical UniversityVictoria I. Kononets, MD, MS, Study chair, West Kazakhstan Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05910151
- Sponsor's protocol ID
- IRN AP148699996
- Status last verified
- Jun 2023
- First submitted
- 8 Jun 2023
- Last updated
- 18 Jun 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Zharmakhanova G, Kononets V, Balmagambetova S, Syrlybayeva L, Nurbaulina E, Zhussupova Z, Sakhanova S, Ayaganov D, Kim S, Zhumalina A. Selective screening for inborn errors of metabolism using tandem mass spectrometry in West Kazakhstan children: study protocol. Front Genet. 2024 Jan 12;14:1278750. doi: 10.3389/fgene.2023.1278750. eCollection 2023.
PubMed 38283151
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Introduction of Tandem Mass Spectrometry (MS/MS) Technology in the Program of Selective Screening of Hereditary Metabolic Diseases in Kazakhstan
- ClinicalTrials.gov ID
- NCT05910151
- Acronym / sponsor ID
- IRN AP148699996
- Conditions
- Propionic/Methylmalonic Acidemias, Maple Syrup Urine Disease, Citrullinemia, Argininosuccinic Aciduria, Ornithine Transcarbamylase Deficiency, Carbamoyl Phosphate Synthetase I Deficiency
- Keywords
- Inborn errors of metabolism, MS/MS, selective screening
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 2,250 participants (estimated)
- Lead sponsor
- West Kazakhstan Medical UniversityUniversity, hospital or other
- Study start
- 3 Oct 2022 (actual)
- Primary completion
- 31 Dec 2024 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 18 Jun 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Inborn errors of metabolism (IEM) are not have specific clinical signs, they masquerade as other diseases, and are difficult to diagnose using only clinical manifestations or routine laboratory tests. IEM most commonly manifest in early infancy and childhood. Despite the fact that most IEM are rare in the population, they occupy one of the first places in the structure of childhood pathology, early infant mortality and disability. IEM often remains undiagnosed, while timely diagnosis and timely treatment started can prevent severe systemic damage leading to death and disability. The appointment of a special treatment (diet therapy, cofactors, enzyme replacement therapy) prevents or significantly inhibits the development of the pathological process, especially if the diagnosis is made in the early stages of the disease. To start pathogenetic treatment as early as possible, it is necessary to diagnose IEM as accurately and as early as possible.
Among the diseases included in mass screening programs IEM are especially important due to the development of disability and early mortality in the absence of timely diagnosis and treatment, as well as a high risk of recurrence in burdened families. In this connection, the main goals of mass screening - the prevention of disability in children and the reduction of early infant mortality - dictate the need to introduce modern technologies for preclinical diagnosis of IEM.
Based on the results of the study, it is planned to scientifically substantiate the need for the introduction of selective screening of children for hereditary metabolic diseases using the technology of tandem mass spectrometry in the Republic of Kazakhstan for timely diagnosis, therapy of IEM and prevention of disability. The introduction of a selective newborn screening program for IEM should always be preceded by a study aimed at studying the prevalence of the disease in a certain region, determining regional reference values of the studied metabolites. Local incidence and outcome data can be used to persuade health officials to prioritize screening in health care spending.
The main scientific question and hypothesis of the project is whether it is necessary to introduce tandem mass spectrometry technology in the neonatal screening program for IEM.
Detailed description
In Kazakhstan, the use of MS/MS in metabolic screening programs is in development. This is due to the high cost of equipment and consumables, as well as the lack of special screening centers and specialists.
Selective screening is an important tool for diagnosing various types of inborn errors of metabolism (IEM). Currently, MS/MS-based technologies are widely used, which allow the simultaneous determination of the amount of several metabolites (amino acids, acylcarnitines) from a very small amount of a biological sample. However, age reference cutoff ranges for each analyte should be established first for each population prior to screening as cutoffs depend on various factors such as genetic background, population geographic location, diet, sex, age.
Data on the prevalence of most IEMs, with the exception of phenylketonuria, are not available in Kazakhstan. The data obtained in this study will make it possible to conduct a comparative analysis of the prevalence of IEM in Asia and establish reference values for the concentrations of amino acids and acylcarnitines in the blood of newborns for the Kazakhstan population. Newborn sreening is currently being conducted in Kazakhstan for two hereditary diseases - phenylketonuria and congenital hypothyroidism, which are the most represented screening diseases in most countries. A nationwide newborn screening program for two mandatory diseases, congenital hypothyroidism and phenylketonuria (PKU), began in 2007. ENBS on aminoacid disorders (AAD), organic acidemias (OA) and fatty acid oxidation defects (FAOD) is not conducted in Kazakhstan.
For Kazakhstan, as a country that does not have a mandatory ENBS program, selective screening can be an important tool for diagnosing IEM. The present study aims to develop and validate an MS/MS method for the simultaneous determination of 51 metabolites in DBS for IEM screening, as well as the determination of age-related amino acid ranges, acylcarnitines and succinylacetone in children's population of Kazakhstan. Our selective screening was initiated to obtain data on the incidence of IEM in children at risk in Western Kazakhstan. From October 2022 to December 2024, the frequency of 37 AAD, OA and FAOD will be assessed using LC-MS/MS technology in a group of children at high risk. A summary report will be presented on the screening of high-risk children for IEM in Western Kazakhstan using the LC-MS/MS method.
The results of selective screening tests in different age groups of subjects should be interpreted by comparison with the reference values and/or cut-off levels established for these groups. It is generally accepted that children need to use reference populations that reflect changes associated with growth and development. Therefore, one of the objectives of this study is to establish reference intervals for the concentration of amino acids and acylcarnitines in dry blood spots for different age groups in the range from 1 day to 18 years.
The goal of this observational study is to сonduct selective screening for IEM among children of Kazakhstan aged from 1 day to 18 years using tandem mass spectrometry to determine the prevalence of IEM and reference values of metabolites followed by subsequent substantiation of the need to introduce selective screening of newborns for IEM by MS/MS.
The main questions it aims to answer are:
question 1: what are the reference values of metabolites (amino acids and acylcarnitines) in different age groups of children in Kazakhstan; question 2: what is the contribution of IEM to the structure of the pathology of the nervous system in young children and is it necessary to introduce tandem mass spectrometry technology in the neonatal screening program for IEM?
Study design
- Observational model
- Ecologic or community
- Time perspective
- Cross-sectional
- Target follow-up
- 2250 Months
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| reference group A | – | Diagnostic Test: Obtaining Dry Blood Spots From Healthy Newborns (Aged 1-7 Days)healthy newborns aged 1-7 days |
| reference group B | – | Diagnostic Test: Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 Yearshealthy children aged 8 days - 7 years |
| reference group C | – | Diagnostic Test: Obtaining Dry Blood Spots From Healthy Children Aged 8-18 Yearshealthy children aged 8 - 18 years |
| selective group A | – | Diagnostic Test: Obtaining Dry Blood Spots From High-risk Newborns (Aged 1-7 Days)children aged 1 day - 7 days suspected with IEM |
| Selective group B | – | Diagnostic Test: Obtaining Dry Blood Spots From High-risk childrens (Aged 8 Days- 7 years)children aged 8 days - 7 years suspected with IEM |
| Selective group C | – | Diagnostic Test: Obtaining Dry Blood Spots From High-risk childrens (Aged 8 - 18 years)children aged 8-18 years suspected with IEM |
Who may qualify
- Ages
- 1 day to 18 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- Study population
- To establish reference values for metabolites, healthy participants without any disease will be included in the study: 750 healthy male and female children aged 1 day to 18 years old from West Kazakhstan will be recruited and included in the study. Depending on age, healthy children will be divided into the following groups: group A (age 1-7 days), group B (age 8 days-7 years) and group C (age 8-18 years). A total of 1,500 children from the West Kazakhstan population (age 1 days -18 years) with suspected metabolic disorders will be referred by primary care neonatologists and pediatric consultants based on their clinical symptoms associated with metabolic disorders and examined for IEM.
Key inclusion criteria (3 listed)
- Referense group: Healthy male and female children aged 1 day to 18 years. Newborns born during the study period (all newborns will be included in this study will meet all selected inclusion criteria to ensure that they do not suffer from any disorder or disease. Healthy male and female newborns must weigh within 2500 -4000 g, gestational age 37-42 weeks, Apgar score above 7 for 10 min.) Sample group: children aged 1 day to 18 years will be selected if one of the main criteria or two or more additional criteria (symptoms) is identified.
- Main criteria (symptoms): 1) Sudden deterioration in the clinical condition of the child after a period of normal development (days, weeks, months): acute metabolic encephalopathy, lethargy (coma), seizures resistant to antiepileptic therapy. 2) Hepatomegaly (hepatosplenomegaly). 3) Metabolic acidosis with an increase in the anion gap. 4) Multiple fractures. 5) Child mortality in the family from diseases with similar symptoms.
- Additional criteria (symptoms): Treatment-resistant seizures; Abnormal muscle tone: dystonia, hyperkinesis, hypotension; Speech delay; Mental retardation of unknown cause; Cardiomyopathy; Tachypnoea; Frequent spitting up (vomiting); Osteo-articular abnormalities (joint stiffness, chest deformity, rickets-like changes); Hernias (umbilical, inguinal-scrotal); Persistent or recurrent hypoglycemia; Metabolic alkalosis; Increase in ketone bodies in the blood and (or) urine; Hyperammonemia; Increase in the level of liver enzymes (AlAT, AST) more than 1.5 times the norm; Increase in the level of creatine phosphokinase (CPK) more than 2 times the norm; Decrease in the level of alkaline phosphatase (AP) below the age norm; Imaging or electrophysiological studies suggesting metabolic disorders; Leukopenia; Thrombocytopenia; Abnormal urine, body, ear wax, any unusual smell; Hair growth disorders, alopecia; Ophthalmological anomalies; Unusual appearance, dysmorphic features; History of previous sibling death of unknown cause; Parents' consanguinity; A positive family history of metabolic disorders.
Key exclusion criteria (8 listed)
- perinatal brain injury,
- brain injuries,
- infections of the central nervous system,
- toxicological diseases,
- tumors,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Obtaining Dry Blood Spots From Healthy Newborns (Aged 1-7 Days)Neonatal blood samples will be taken from healthy infants no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs) for LC-MS/MS analysis. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers until analyzed by LC-MS/MS in accordance with standards from the Institute of Clinical and Laboratory Standards. | Diagnostic test | reference group A |
| Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 YearsBlood samples will be taken from healthy childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs) for LC-MS/MS analysis. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers until analyzed by LC-MS/MS in accordance with standards from the Institute of Clinical and Laboratory Standards | Diagnostic test | reference group B |
| Obtaining Dry Blood Spots From Healthy Children Aged 8-18 YearsBlood samples will be taken from healthy childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs) for LC-MS/MS analysis. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers until analyzed by LC-MS/MS in accordance with standards from the Institute of Clinical and Laboratory Standards | Diagnostic test | reference group C |
| Obtaining Dry Blood Spots From High-risk Newborns (Aged 1-7 Days)Blood samples will be taken from high-risk infants no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs). The sample must be taken before transfusion therapy (or blood is taken no earlier than 48-72 hours after the transfusion) or extracorporeal membrane oxygenation. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers. | Diagnostic test | selective group A |
| Obtaining Dry Blood Spots From High-risk childrens (Aged 8 Days- 7 years)Blood samples will be taken from high-risk childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs). The sample must be taken before transfusion therapy (or blood is taken no earlier than 48-72 hours after the transfusion) or extracorporeal membrane oxygenation. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers | Diagnostic test | Selective group B |
| Obtaining Dry Blood Spots From High-risk childrens (Aged 8 - 18 years)Blood samples will be taken from high-risk childrens no earlier than 3 hours after feeding by heel prick with a heel stick. Five drops of whole blood (~75 µl each) will be applied to Guthrie cards, Ahlstrom 226 filter paper, PerkinElmer 226 Five-Spot Card (PerkinElmer Health Sciences, Greenville, USA) to form dried blood spots (DBSs). The sample must be taken before transfusion therapy (or blood is taken no earlier than 48-72 hours after the transfusion) or extracorporeal membrane oxygenation. Samples will be dried for 4 hours at room temperature and then stored at 4°C in individually labeled zippered plastic bags with desiccants or other sealed containers | Diagnostic test | Selective group C |
Primary outcome
Identification of the concentration value of amino acids and acylcarninits activity in Dry blood spots among Newborns and Children in Kazakhstan
Time frame: Two years
Amino acids: Alanine (Ala), Arginine (Arg), Citrulline (Cit), Glutamine (Gln), Glutamic acid (Glu), Glycine (Gly), Leucine (Leu), Isoleucine (Leu), Hydroxyproline (Leu), Methionine (Met), Ornithine (Orn), Phenylalanine (Phe), Proline (Pro), Tyrosine (Tyr), Valine (Val). Acylcarninits: free carnitine (C0), Acetylcarnitine (C2), Propionylcarnitine (C3), Malonylcarnitine+3-Hydroxybutyrylcarnitine (C3DC/C4OH), Butyrylcarnitine (C4), Methylmalonylcarnitine+3-Hydroxyisovalerylcarnitine (C4DC/C5OH), Isovalerylcarnitine (C5), Tiglylcarnitine (C5:1), Glutarylcarnitine (C5DC), Hexanoylcarnitine (C6), Octanoylcarnitine (C8), Octenoylcarnitine (C8:1), Decanoylcarnitine (C10), Decenoylcarnitine (C10:1), Decadienoylcarnitine (C10:2), Dodecanoylcarnitine (C12), Hydroxydodecenoylcarnitine (C12:1), Myristoylcarnitine (C14), Tetradecenoylcarnitine (C14:1), Tetradecadienoyl-carnitine (C14:2), Hydroxytetradecanoylcarnitine (C14OH), Palmitoylcarnitine (C16), Hexadecenoylcarnitine (C16:1), Hydroxy-Hexad
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2023.
- Derived from this study: PubMed 38283151Zharmakhanova G, Kononets V, Balmagambetova S, Syrlybayeva L, Nurbaulina E, Zhussupova Z, Sakhanova S, Ayaganov D, Kim S, Zhumalina A. Selective screening for inborn errors of metabolism using tandem mass spectrometry in West Kazakhstan children: study protocol. Front Genet. 2024 Jan 12;14:1278750. doi: 10.3389/fgene.2023.1278750. eCollection 2023.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gulmira M. Zharmakhanova, MD, PhD principal investigator
West Kazakhstan Medical University
Lyazzat M. Syrlybayeva, MD study chair
West Kazakhstan Medical University
Victoria I. Kononets, MD, MS study chair
West Kazakhstan Medical University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Propionic/Methylmalonic Acidemias and Maple Syrup Urine Disease, run by West Kazakhstan Medical University at 1 site in Kazakhstan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Kazakhstan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Gulmira M. Zharmakhanova, MD, PhD (+701-644-5987, gmzh@list.ru), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identification of the concentration value of amino acids and acylcarninits activity in Dry blood spots among Newborns and Children in Kazakhstan (time frame: Two years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05910151, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2023.