Intellectual developmental disorders (IDD) affect 2.5% of the population. Inherited metabolic disorders (IMD’s) may present with IDD and often other neurologic or systemic features and some IMD’s are treatable. Despite years of implementing a biochemical testing algorithm on a research basis in one province, the yield of testing was not increased for IMD’s.
There are significant harms associated with over-investigation. Although the cost of biochemical testing is inexpensive compared to molecular or specialized tests, it is still a significant burden on the health care system. The cost of the tests is not the only consideration, since significant human resources are required for pre-test counselling, coordination of sample collection, transport and analysis, interpretation of results and follow-up. Even more importantly, there may be harm to children and families subjected to further blood draws and urine tests, extending the diagnostic odyssey as repeat testing is often required for a positive or uncertain result. There is extensive literature on the harms of false positives from newborn screening, but this is balanced against the yield of testing for treatable IMD’s on the newborn screen and efficacy of early intervention. Similar data of the benefits of screening all children with IDD for IMD’s does not exist.
There are well-recognized red flags suggestive of an IMD in children with IDD and it would be appropriate to do targeted metabolic testing in those situations (so called “intellectual disability plus”). Consideration should also be given to patients who did not have newborn screening (NBS) for IMD. Further biochemical testing may also be a valuable tool when molecular testing is negative or uncertain, to provide functional evidence of pathogenicity.
Sources:
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Gross SD et al. From public health emergency to public health service: the implications of evolving criteria for newborn screening panels. Pediatrics. 2006 Mar;117(3):923-9. PMID: 16510675.
Kwon C and Farrell PM. The Magnitude and Challenge of False-Positive Newborn Screening Test Results. Arch Pediatr Adolesc Med. 2000;154(7):714-718. PMID: 10891024.
Richards S. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. PMID: 25741868.
Sayson B et al. Retrospective analysis supports algorithm as efficient diagnostic approach to treatable intellectual developmental disabilities. Mol Genet Metab. 2015 May;115(1):1-9. PMID: 25801009.
Vallance et al. Diagnostic yield from routine metabolic screening tests in evaluation of global developmental delay and intellectual disability. Paediatr Child Health. 2020 Dec 19;26(6):344-348. PMID: 34676012.