Neonatal Screening By TMS

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Tandem mass spectrometry newborn screen.

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Neonatal Screening By TMS - Comprehensive Medical Guide

Section 1: Why is it done?
- Test Purpose: Tandem mass spectrometry (TMS) is a highly sensitive analytical technique used to screen newborns for inherited metabolic disorders, amino acid disorders, fatty acid oxidation defects, and organic acidemias within the first 24-48 hours of life
- Primary Indications: Universal screening of all newborns to identify treatable metabolic conditions before symptoms develop
- Conditions Detected Include: Phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, carnitine deficiency, glutaric acidemia, isovaleric acidemia, and propionic acidemia
- Specimen Collection: Performed 24-48 hours after birth using dried blood spot (DBS) from heel prick onto filter paper cards
- Clinical Significance: Early detection allows for immediate intervention to prevent serious neurological damage, developmental delays, intellectual disability, organ damage, and potentially life-threatening metabolic crises
- Timing: Part of mandatory newborn screening programs performed universally in hospitals before discharge or within 24-72 hours of birth
Section 2: Normal Range
- Normal Range Interpretation: Results are reported as positive (abnormal - condition detected), negative (normal - no condition detected), or inconclusive (requires repeat testing)
- Units of Measurement: Amino acids and acylcarnitines are measured in micromoles per liter (μmol/L) or micrometers (μM); reference ranges vary by age, specific analyte, and laboratory methodology
- Key Analytes and Normal Ranges (Typical Values - Laboratory Specific): Phenylalanine: 24-110 μmol/L Leucine: 50-170 μmol/L Tyrosine: 20-180 μmol/L Methionine: 6-30 μmol/L Free Carnitine (C0): 10-45 μmol/L Acetyl-carnitine (C2): 4-20 μmol/L
- Normal vs. Abnormal Results: NEGATIVE: All analyte levels fall within age-appropriate reference ranges, indicating no metabolic disorder detected. POSITIVE: One or more analyte levels exceed established cutoff values, suggesting possible metabolic disease requiring confirmatory testing. INCONCLUSIVE/BORDERLINE: Results near cutoff values requiring repeat testing within 24 hours
- Cutoff Values: Cutoff values are statistically derived and laboratory-specific, typically set to identify ~99% of normal infants while detecting cases of metabolic disease (sensitivity varies from 80-99% depending on disorder)
Section 3: Interpretation
- Elevated Phenylalanine (>360 μmol/L): Suggests phenylketonuria (PKU), a disorder of phenylalanine metabolism. Requires confirmatory testing (blood phenylalanine levels, liver function tests). Without early treatment, leads to intellectual disability, light skin, musty odor, seizures, and behavioral problems
- Elevated Leucine/Isoleucine/Valine Ratio: Indicates possible maple syrup urine disease (MSUD), affecting branched-chain amino acid metabolism. Results show characteristic sweet-smelling urine, neurological deterioration, and developmental delay if untreated
- Elevated Methionine (>40 μmol/L): May indicate homocystinuria or other methionine metabolism disorders. Clinical significance includes vascular thrombosis, lens dislocation, intellectual disability, and skeletal abnormalities if untreated
- Reduced Free Carnitine (<10 μmol/L): Suggests primary or secondary carnitine deficiency, affecting fatty acid oxidation. Critical for energy metabolism; deficiency causes cardiomyopathy, hypoglycemia, and hepatic encephalopathy
- Elevated Acylcarnitine Profiles: Elevated medium-chain acylcarnitine (C6-C12) may indicate MCAD deficiency, the most common fatty acid oxidation disorder. Other patterns may suggest glutaric acidemia, isovaleric acidemia, or propionic acidemia
- Factors Affecting Results: Sample timing (must be >24 hours after birth), inadequate blood spot, premature or low birth weight infants (may have false positives), maternal conditions, maternal medication exposure, contamination, and improper sample handling
- False Positives/Negatives: False positives occur in 1-2% of samples, particularly in premature infants. False negatives are rare (<1%) but may occur with late sampling, atypical presentations, or rare variants not included in screening panels. Repeat testing is always recommended for borderline results
Section 4: Associated Organs
- Primary Organ Systems Involved: Central nervous system (primary target organ), liver (metabolism and detoxification), heart (energy metabolism, cardiomyopathy risk), skeletal system, kidneys, and eyes
- Metabolic Pathways Affected: Amino acid metabolism, fatty acid β-oxidation, organic acid metabolism, and carbohydrate metabolism
- Conditions Diagnosable by TMS Screening: Phenylketonuria (PKU) Maple syrup urine disease (MSUD) Homocystinuria Tyrosinemia Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency Other fatty acid oxidation defects Primary carnitine deficiency Glutaric acidemia (Type I, II) Isovaleric acidemia Propionic acidemia Methylmalonic acidemia 3-Methylcrotonyl-CoA carboxylase deficiency
- Neurological Complications (If Untreated): Intellectual disability, seizures, developmental delay, hypotonia or hypertonia, dystonia, and progressive neurodegeneration
- Cardiac Complications (If Untreated): Dilated cardiomyopathy, arrhythmias, heart failure, and sudden cardiac death (particularly in MCAD and carnitine deficiency)
- Hepatic Complications (If Untreated): Hepatomegaly, fatty infiltration, hepatic encephalopathy, liver failure, and cirrhosis
- Ocular Complications (If Untreated): Ectopia lentis (lens dislocation) in homocystinuria, retinal degeneration, and corneal scarring
- Skeletal Complications (If Untreated): Osteoporosis, skeletal deformities, marfanoid habitus, and height abnormalities in homocystinuria and other disorders
Section 5: Follow-up Tests
- Immediate Follow-up (If Positive Result): Confirmatory quantitative plasma amino acid analysis via high-performance liquid chromatography (HPLC) or mass spectrometry within 24-48 hours Quantitative urine organic acid analysis Repeat dried blood spot collection if initial sample was inadequate Consultation with metabolic genetics specialist
- PKU-Specific Follow-up Tests: Plasma phenylalanine and tyrosine levels Plasma tetrahydrofolate (BH4) level to rule out BH4-responsive PKU Dihydrofolate reductase deficiency screening if indicated Maternal phenylalanine levels (if positive in neonate)
- MCAD Deficiency-Specific Follow-up: Plasma acylcarnitine profile Urine organic acids (dicarboxylic acids, hexanoylglycine) Genetic testing for ACADM gene mutations (gold standard confirmation) Cardiac evaluation (ECG, echocardiography) to assess heart function
- Homocystinuria-Specific Follow-up: Plasma methionine and homocysteine levels Vitamin B12 and folate levels Genetic testing for CBS (cystathionine β-synthase) mutations Ophthalmologic examination (baseline) Baseline cardiac and skeletal evaluation
- MSUD-Specific Follow-up: Plasma branched-chain amino acid levels (leucine, isoleucine, valine, alloisoleucine) Urine organic acids (alpha-keto acids) Genetic testing (BCKDHA, BCKDHB, DBT genes) Neurological assessment baseline
- Monitoring and Long-term Follow-up: Regular plasma amino acid and acylcarnitine profiles (frequency determined by condition severity and treatment) Periodic metabolic assessments (at 1-2 weeks, 1 month, 3 months, and then quarterly) Developmental monitoring and neuropsychological assessment Ophthalmologic surveillance for PKU (visual development) and homocystinuria (lens) Cardiac monitoring as clinically indicated Genetic counseling for family members
- Related Complementary Tests: Expanded newborn screening panels (organic acids, fatty acids, amino acids by MS/MS) Individual genetic testing as indicated Enzyme activity assays (when available) Imaging studies (MRI brain for neurological assessment) Metabolic consultant evaluation
Section 6: Fasting Required?
- Fasting Requirement: NO - Fasting is NOT required for neonatal TMS screening
- Rationale: Newborns are routinely fed within the first 24-48 hours of life. The test detects metabolic markers that reflect systemic metabolism regardless of feeding status. Early detection is critical, and delaying the test for feeding would compromise screening effectiveness
- Optimal Timing: Specimen collection should occur 24-48 hours after birth to allow metabolic markers to accumulate to detectable levels; collection before 24 hours may result in false-negative results, particularly for fatty acid oxidation disorders
- Feeding Status: Newborns should be allowed normal feeding (breast milk or formula) according to standard nursery protocols. No special dietary modifications are required for this screening test
- Medications: Routine neonatal medications (prophylactic vitamin K, antibiotic eye ointment, hepatitis B vaccine) do not interfere with TMS results. However, inform the laboratory of any maternal medications administered during delivery or postpartum, as some medications may affect amino acid and acylcarnitine levels
- Sample Collection Requirements: Heel prick sampling (capillary blood) Collect after 24 hours of age (minimum) 5-6 blood spots (approximately 25 μL each) applied to filter paper card Allow complete air drying before transport Avoid contamination with antibacterial agents or talc Proper labeling with birth date, collection date and time, and patient identifiers
- Factors to Avoid: Do not collect sample before 24 hours of life Avoid excessive handling or touching of filter paper Do not expose to extreme heat or moisture before analysis Avoid blood spots from transfusion or blood bank products Do not use heparinized collection tubes Avoid collection from heel with poor perfusion
- Special Circumstances: PREMATURE INFANTS: Collect at 24-48 hours chronological age regardless of gestational age; report gestational age to laboratory TRANSFERRED INFANTS: Ensure screening was performed at originating facility; if not documented, perform test at receiving facility CRITICALLY ILL INFANTS: Screen as soon as clinical condition stabilizes and after 24 hours of life TRANSFUSED INFANTS: Collect sample before transfusion if possible; if transfusion has occurred, notify laboratory and may require repeat testing

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