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Portuguese Neonatal Screening Programme: A Retrospective Cohort Study of 18 Years of MS/MS
Maria Miguel Gonçalves1, Ana Marcão2, Carmen Sousa2
1Animal Biology, Faculty of Sciences of the University of Lisbon, Lisbon, Portugal.
Insights
The Portuguese Neonatal Screening Programme identified 681 newborns with Inborn Errors of Metabolism (IEM) using tandem mass spectrometry. This study details the molecular epidemiology of these IEM cases, aiding future diagnostic and treatment strategies.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- The Portuguese Neonatal Screening Programme (PNSP) screens for rare diseases, including 24 Inborn Errors of Metabolism (IEM).
- Tandem mass spectrometry (MS/MS) implementation in 2004 enhanced IEM detection, improving treatment and outcomes.
- The PNSP covers nearly all neonates, providing a robust dataset for epidemiological studies.
Purpose of the Study:
- To establish the molecular epidemiology of IEM diagnosed through the Portuguese Neonatal Screening Programme.
- To analyze genetic profiles and mutation patterns of IEM identified via MS/MS screening.
- To provide insights into the management of rare metabolic diseases based on screening data.
Main Methods:
- Screening of 1,764,830 neonates using MS/MS technology from 2004 to 2022.
- Molecular characterization of IEM cases through DNA extraction, PCR, and Sanger sequencing.
- Retrospective analysis of biochemical and genetic data for diagnosed IEM.
Main Results:
- A total of 681 newborns were diagnosed with an IEM.
- MCAD deficiency was the most frequent IEM, with 233 cases, often showing the c.985A>G mutation.
- Specific homozygous mutations were identified in Glutaric Aciduria type I (GCDH) and MAT II/III deficiency (MAT1A).
Conclusions:
- The study presents the molecular epidemiology of IEM detected by neonatal screening in Portugal.
- MS/MS implementation has significantly advanced IEM screening and diagnosis over 18 years.
- Understanding mutation patterns, including de novo mutations, can guide the approach to diverse IEM phenotypes.
Introduction:
The Portuguese Neonatal Screening Programme (PNSP) identifies patients with rare diseases through nationwide screening. Currently, 27 diseases are diagnosed, amongst which are 24 Inborn Errors of Metabolism (IEM), covering approximately 100% of neonates (1). In 2004, the national laboratory implemented a new screening method, tandem mass spectrometry (MS/MS) to test for amino acids and acylcarnitines. This new protocol revolutionized the PNSP and allowed for the analysis of an increased number of IEM, with clear improvements in treatment timings and clinical outcomes (2).
Methods:
From 2004 to 2022, 1 764 830 neonates were screened with MS/MS technology. Those who displayed biochemical profiles indicating an IEM were subjected to molecular characterization via genomic DNA extraction, PCR amplification, and direct Sanger sequencing method of dried blood spot samples.
Results/Case Report:
A cohort of 681 newborns were diagnosed with an IEM. MCAD deficiency is the most frequent, with 233 confirmed diagnoses, showing predominantly c.985A>G (p.K329E) mutation of the ACADM gene in homozygosity. Approximately 1/3 of the 33 confirmed cases of Glutaric Aciduria type I present homozygous for the c.1204C>T (p.Arg402Trp) mutation in GCDH. Around 60% of cases of MAT II/III deficiency display the dominant mutation of the MAT1A gene, c.791G>A (p.Arg264His). These genetic profiles and others were determined as diagnostic confirmation for 24 of the IEM screened.
Conclusion:
This data shows the molecular epidemiology of patients with confirmed IEM diagnosis identified by neonatal screening. Some diseases out of the scope of the PNSP were also detected as a differential diagnosis after biochemical suspicion in the dried blood spot sample. The retrospective analysis of the PNSP allows for an overview of 18 years of achievements accomplished by the national screening for IEM since MS/MS was implemented. For some pathologies with low incidence, it's difficult to trace a discernible pattern. However, presenting de novo mutations for these diseases might provide insights on how to approach different phenotypes. The aim of this work is to establish the molecular epidemiology of metabolic diseases screened.
