Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

NCT05910151 | Unknown

• 1 other identifier: IRN AP148699996
• Study Type: observational
• Target: 2,250
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Propionic/Methylmalonic Acidemias; Maple Syrup Urine Disease; Citrullinemia; Argininosuccinic Aciduria; Ornithine Transcarbamylase Deficiency; Carbamoyl Phosphate Synthetase I Deficiency; N-acetylglutamate Synthase Deficiency; Nonketotic Hyperglycinemia; Tyrosinemia; Homocystinuria; Arginase Deficiency; Isovaleric Acidemia; Short/Branched Chain Acyl-CoA Dehydrogenase Deficiency; Isobutyryl-CoA Dehydrogenase Deficiency; Glutaric Acidemia Type I; 3-methylcrotonyl-CoA Carboxylase Deficiency; Biotinidase Deficiency; Malonyl-CoA Decarboxylase Deficiency; Beta-ketothiolase Deficiency; 3-hydroxy-3-methylglutaryl-CoA Lyase Deficiency; 3-methylglutaconyl-CoA Hydratase Deficiency; Medium-chain Acyl-CoA Dehydrogenase Deficiency; Very Long-chain Acyl-CoA Dehydrogenase Deficiency; Long-chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency; Glutaric Acidemia Type II; Primary Carnitine Deficiency; Carnitine Palmitoyltransferase I Deficiency; Carnitine Palmitoyltransferase II Deficiency; Carnitine-acylcarnitine Translocase Deficiency

Keywords

Inborn errors of metabolism, MS/MS, selective screening

Outcome Measures

Primary Outcomes (1)

• 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

  Two years

Study Arms (6)

reference group A

healthy newborns aged 1-7 days

Diagnostic Test: Obtaining Dry Blood Spots From Healthy Newborns (Aged 1-7 Days)

reference group B

healthy children aged 8 days - 7 years

Diagnostic Test: Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 Years

reference group C

healthy children aged 8 - 18 years

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

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

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

Diagnostic Test: Obtaining Dry Blood Spots From High-risk childrens (Aged 8 - 18 years)

Interventions

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.

reference group A

Obtaining Dry Blood Spots From Healthy Children Aged 8 Days - 7 Years DIAGNOSTIC_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

reference group B

Obtaining Dry Blood Spots From Healthy Children Aged 8-18 Years DIAGNOSTIC_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

reference group C

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.

selective group A

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

Selective group B

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

Selective group C

Eligibility Criteria

• Age: 1 Day - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

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.

You may qualify if:

• 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.

You may not qualify if:

• The study will exclude patients who has:
• perinatal brain injury,
• brain injuries,
• infections of the central nervous system,
• toxicological diseases,
• tumors,
• chromosomal abnormalities,

Sponsors & Collaborators

• West Kazakhstan Medical University: lead

Study Sites (1)

Regional perinatal center of Aktobe region

Aktobe, Aktobe Region, 030000, Kazakhstan

RECRUITING

Related Publications (1)

• 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.

  PMID: 38283151 DERIVED

MeSH Terms

Conditions

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; Homocystinuria; Hyperargininemia; Acidemia, isovaleric; 2-Methylbutyryl-CoA Dehydrogenase Deficiency; Isobutyryl-CoA dehydrogenase deficiency; Glutaric Acidemia I; 3-methylcrotonyl CoA carboxylase 1 deficiency; Biotinidase Deficiency; Malonic aciduria; Beta ketothiolase deficiency; 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency; 3-Methylglutaconic Aciduria, Type I; Medium chain acyl CoA dehydrogenase deficiency; VLCAD deficiency; Trifunctional Protein Deficiency With Myopathy And Neuropathy; Multiple Acyl Coenzyme A Dehydrogenase Deficiency; Systemic carnitine deficiency; Carnitine palmitoyl transferase 1A deficiency; Carnitine palmitoyl transferase 2 deficiency; Carnitine-Acylcarnitine Translocase Deficiency; Metabolism, Inborn Errors

Interventions

Aging

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Urea Cycle Disorders, Inborn; Genetic Diseases, X-Linked; Mitochondrial Diseases; Hyperhomocysteinemia; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Multiple Carboxylase Deficiency; Carbohydrate Metabolism, Inborn Errors

Intervention Hierarchy (Ancestors)

Growth and Development; Physiological Phenomena

Study Officials

• Gulmira M. Zharmakhanova, MD, PhD

  West Kazakhstan Medical University

  PRINCIPAL INVESTIGATOR

• Lyazzat M. Syrlybayeva, MD

  West Kazakhstan Medical University

  STUDY CHAIR

• Victoria I. Kononets, MD, MS

  West Kazakhstan Medical University

  STUDY CHAIR

Central Study Contacts

Gulmira M. Zharmakhanova, MD, PhD

CONTACT

+701-644-5987; gmzh@list.ru

Gulmira M. Zharmakhanova, MD, PhD

CONTACT

+7-701-644-5987; gmzh@liat.ru

Study Design

• Study Type: observational
• Observational Model: ECOLOGIC OR COMMUNITY
• Time Perspective: CROSS SECTIONAL
• Target Duration: 2250 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Department of Natural Sciences disciplines (with course of Molecular Biology and Medical Genetic)

Study Record Dates

• First Submitted: June 8, 2023
• First Posted: June 18, 2023
• Study Start: October 3, 2022
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: June 18, 2023

Record last verified: 2023-06

Locations

KA (1)