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Newborn screening for primary carnitine deficiency: who will benefit? - a retrospective cohort study
Loek Crefcoeur1,2,3, Sacha Ferdinandusse2,3, Saskia N van der Crabben4,5
1Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands l.l.crefcoeur@umcutrecht.nl.
Insights
Newborn screening for primary carnitine deficiency (PCD) identifies many asymptomatic individuals. Genetic testing and carnitine transport activity can predict severe PCD cases that benefit from early treatment.
Area of Science:
- Biochemistry
- Genetics
- Newborn Screening
Background:
- Newborn screening (NBS) identifies diverse disease phenotypes, prompting evaluation of early treatment benefits.
- Primary carnitine deficiency (PCD) screening identifies both newborns and mothers, necessitating phenotype assessment.
Purpose of the Study:
- To determine the benefit of early identification and treatment for primary carnitine deficiency (PCD) detected through NBS.
- To differentiate between asymptomatic and severe PCD cases identified via NBS.
Main Methods:
- Investigated clinical, genetic (SLC22A5 variants), and functional (carnitine transport) characteristics.
- Analyzed data from newborns, mothers, and clinically diagnosed PCD patients.
- Predicted newborn disease phenotype using maternal data and literature.
Main Results:
- PCD confirmed in 19/131 newborns, 37/82 mothers, and 5 clinical patients.
- Severe symptoms occurred in all clinical patients and 1 newborn, but no mothers identified by NBS.
- Carnitine transport activity distinguished severe (median 4.0%) from benign (median 26%) phenotypes.
Conclusions:
- Most mothers and many newborns identified by NBS for PCD remain asymptomatic without treatment.
- A subset of newborns with predicted severe PCD could benefit significantly from early intervention.
- Genetic variants and carnitine transport activity are key for distinguishing PCD severity.
Background:
Newborn screening (NBS) programmes identify a wide range of disease phenotypes, which raises the question whether early identification and treatment is beneficial for all. This study aims to answer this question for primary carnitine deficiency (PCD) taking into account that NBS for PCD identifies newborns with PCD and also until then undiagnosed mothers.
Methods:
We investigated clinical, genetic (variants in SLC22A5 gene) and functional (carnitine transport activity in fibroblasts) characteristics of all referred individuals through NBS (newborns and mothers) and clinically diagnosed patients with PCD (not through NBS). Disease phenotype in newborns was predicted using data from PCD mothers and cases published in literature with identical SLC22A5 variants.
Results:
PCD was confirmed in 19/131 referred newborns, 37/82 referred mothers and 5 clinically diagnosed patients. Severe symptoms were observed in all clinically diagnosed patients, 1 newborn and none of the mothers identified by NBS. PCD was classified as severe in all 5 clinically diagnosed patients, 3/19 newborns and 1/37 mothers; as benign in 8/19 newborns and 36/37 mothers and as unknown in 8/19 newborns. Carnitine transport activity completely separated severe phenotype from benign phenotype (median (range): 4.0% (3.5-5.0)] vs 26% (9.5-42.5), respectively).
Conclusion:
The majority of mothers and a significant proportion of newborns with PCD identified through NBS are likely to remain asymptomatic without early treatment. Conversely, a small proportion of newborns with predicted severe PCD could greatly benefit from early treatment. Genetic variants and carnitine transport activity can be used to distinguish between these groups.
