Newborn screening for long-chain fatty acid oxidation disorders
Authors:   , Schwantje Marit 
Published: August 2024

Long-chain fatty acid oxidation disorders (lcFAOD) are a group of metabolic disorders where the body cannot properly use dietary long-chain fatty acids (LCFAs) for energy. LCFAs are crucial energy sources, particularly during fasting, fever, or exercise. Genetic variants in the proteins or enzymes involved in the long-chain fatty acid oxidation pathway can cause lcFAOD, leading to the accumulation of specific long-chain acyl-CoAs and their carnitine derivatives, known as long-chain acylcarnitines. Symptoms of lcFAOD include hypoglycemia, myopathy, rhabdomyolysis, exercise intolerance, cardiomyopathy, and arrhythmia, which typically manifest during metabolic stress. Mitochondrial trifunctional protein (MTP) disorders uniquely present with pigmentary retinopathy and peripheral neuropathy.

Newborn screening (NBS) aims to promptly diagnose conditions that can cause irreversible harm early in life, preventing severe outcomes through early treatment. Mass spectrometry allows for the detection of multiple metabolites in dried blood spots, enabling the inclusion of numerous disorders in NBS programs worldwide. In 2007, the Netherlands included two lcFAOD, very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), in their NBS program, showing benefits in preventing severe hypoglycemia.

Despite its benefits, NBS also presents several challenges. Utilizing a wide variety of methods, including in vitro experiments, innovative monitoring techniques, testing protocols, questionnaires, and retrospective chart research, the research described in this thesis aimed to identify and clarify some of the challenges introduced by NBS with a focus on lcFAOD.

One of the discussed challenges is the risk of over- and underdiagnosis. Sensitive methods detect minor biochemical abnormalities, potentially identifying mildly affected or asymptomatic individuals, raising questions about the benefits of NBS for these cases. Conversely, some patients, particularly those with thermo-sensitive lcFAOD may be missed due to the absence of characteristic acylcarnitine abnormalities at normal temperatures. To enhance early recognition, genetic screening may be beneficial.

Predicting prognosis after NBS diagnosis is crucial to balance early disease detection and avoiding unnecessary treatment, but remains difficult. Studies identified candidate biomarkers for disease severity, such as C18:2-carnitine for VLCADD, which can predict severe phenotypes, and lysophosphatidylcholine (LPC)(14:1), a potential severity marker for VLCADD. For LCHADD, a novel lipid class, S-(3-hydroxyacyl)cysteamines, was discovered as a specific biomarker.

Understanding the natural history of NBS-diagnosed lcFAOD patients is vital for prognosis and personalized treatment. Research involving exercise tests and quantitative MRI (qMRI) in adolescent lcFAOD patients revealed variable exercise capacities and potential disease markers. These insights may help tailor monitoring and treatment strategies, though long-term monitoring remains necessary to understand the disease course and develop evidence-based guidelines.

Current treatments, such as dietary management and preventing catabolism, do not completely prevent symptoms in all lcFAOD patients. Future approaches may involve gene therapy, aiming to correct the genetic root cause of the disorders. The ultimate goal is personalized treatment and early disease stratification to provide optimal care while minimizing unnecessary interventions and burden.