Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders

Abstract

Fatty acid oxidation disorders (FAODs) are potentially fatal inherited disorders for which management focuses on early disease detection and dietary intervention to reduce the impact of metabolic crises and associated spectrum of clinical symptoms. They can be divided functionally into long-chain (LC-FAODs) and medium-chain disorders (almost exclusively deficiency of medium-chain acyl–coenzyme A dehydrogenase). Newborn screening (NBS) allows prompt identification and management. FAOD detection rates have increased following the addition of FAODs to NBS programs in the United States and many developed countries. NBS-identified neonates with FAODs may remain asymptomatic with dietary management. Evidence from numerous studies suggests that NBS-identified patients have improved outcomes compared with clinically diagnosed patients, including reduced rates of symptomatic manifestations, neurodevelopmental impairment, and death. The limitations of NBS include the potential for false-negative and false-positive results, and the need for confirmatory testing. Although NBS alone does not predict the consequences of disease, outcomes, or management needs, subsequent genetic analyses may have predictive value. Genotyping can provide valuable information on the nature and frequency of pathogenic variants involved with FAODs and their association with specific phenotypes. Long-term follow-up to fully understand the clinical spectrum of NBS-identified patients and the effect of different management strategies is needed.

Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program

“…In our families, no consanguinity was reported, and all patients are compound heterozygous. There are large differences in incidence of VLCADD between different populations, which are difficult to compare because of different size and characteristics of populations, details of screening methods, cutoffs, and use of different confirmatory methods (Arnold et al, 2009;Spiekerkoetter et al, 2009;Lindner et al, 2010;Marsden et al, 2021). It is known, that with expanded screening more patients are detected, which is in agreement with our study.…”

“…Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM 201475) is the second most common disorder of inborn errors of fatty acid metabolism; its incidence varies between 1:30,000 and 1:400,000 live births, with some outliers such as Saudi Arabia with reported incidence of 1:3200 and Taiwan with 1:1,400,000. In Europe incidence range from 1:77,000 in Germany and Netherlands to 1:400,000 in Czech Republic (Arnold et al, 2009;Spiekerkoetter et al, 2009;Lindner et al, 2010;Marsden et al, 2021). Incidence of VLCADD increased after the introduction of an expanded newborn screening program with the use of tandem mass spectrometry (MS/MS) allowing early detection of patients (Boneh et al, 2006;Merritt et al, 2014).…”

Use of Molecular Genetic Analyses in Danish Routine Newborn Screening

“…Second-tier molecular genetic testing may also provide the clinician with important prognostic information, where examples may be similar to those described for the mild variants in ACADM and IVD above. Additional examples could be predictions of vitamin B12-responsive cases with MMA, Kuvan-responsive cases with PKU or riboflavin-responsive cases with MADD-all very important and prognostic information to give parents as well as to direct therapy [31].…”

Diagnosis and Clinical Management of Long-chain Fatty-acid Oxidation Disorders: A Review

“…The current incidence estimate for all FAODs is 0.9-15.2 per 100,000, but there may be significant geographic variability. 15 The newborn screening programme in Tianjin, China, screened 220,443 infants from May 2013 to December of 2018, and diagnosed 15 individuals with FAODs, with the most common being CDSP. 16 A group from Italy also recently published their 5-year screening data, from February 2014 to April 2019.…”

“…The European guidelines allow slightly more liberalization of fats in asymptomatic individuals, with fats constituting 30-40% of total energy and only 10-15% from MCTs. 15 MCTs work well for LC-FAOD treatment, because these shorter-chain fats bypass the metabolic defect, are able to diffuse across the mitochondrial membrane without the requirement of transporters, and then undergo fewer rounds of beta oxidation to feed into the tricarboxylic acid cycle for energy production. 15 Essential fatty acids should also be monitored and appropriately supplemented.…”