Newborn screening for primary carnitine deficiency: who will benefit? - a retrospective cohort study.

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.

Fasting and fat-loading tests provide pathophysiological insight into short-chain acyl-coenzyme a dehydrogenase deficiency.

OBJECTIVE: To gain insight into the pathophysiological and clinical consequences of short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD). STUDY DESIGN: A retrospective study of 15 fasting and 6 fat-loading tests in 15 Dutch patients with SCADD, divided into 3 genotype groups. Metabolic and endocrinologic measurements and the biochemical characteristics of SCADD, ethylmalonic acid (EMA), and C4-carnitine were studied. RESULTS: Three patients had development of hypoglycemia during fasting; all of these had originally presented with hypoglycemia. Metabolic and endocrinologic measurements remained normal during all tests. The EMA excretion increased in response to fasting and fat loading, and plasma C4-carnitine remained stable. Test results did not differ between the 3 genotype groups. CONCLUSIONS: The metabolic profiles of the 3 patients with development of hypoglycemia resemble idiopathic ketotic hypoglycemia. Because hypoglycemia generally requires a metabolic work-up and because SCADD is relatively prevalent, SCADD may well be diagnosed coincidently, thus being causally unrelated to the hypoglycemia. If SCADD has any other pathologic consequences, the accumulation of potentially toxic metabolites such as EMA is most likely involved. However, the results of our study indicate that there is no clear pathophysiological significance, irrespective of genotype, supporting the claim that SCADD is not suited for inclusion in newborn screening programs.