Clinical manifestations and management of fatty acid oxidation disorders
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Clinical manifestations and management of fatty acid oxidation disorders J. Lawrence Merritt 2nd 1 & Erin MacLeod 2 & Agnieszka Jurecka 3 & Bryan Hainline 4
# The Author(s) 2020
Abstract Fatty acid oxidation disorders (FAOD) are a group of rare, autosomal recessive, metabolic disorders caused by variants of the genes for the enzymes and proteins involved in the transport and metabolism of fatty acids in the mitochondria. Those affected by FAOD are unable to convert fatty acids into tricarboxylic acid cycle intermediates such as acetyl-coenzyme A, resulting in decreased adenosine triphosphate and glucose for use as energy in a variety of high-energy–requiring organ systems. Signs and symptoms may manifest in infants but often also appear in adolescents or adults during times of increased metabolic demand, such as fasting, physiologic stress, and prolonged exercise. Patients with FAOD present with a highly heterogeneous clinical spectrum. The most common clinical presentations include hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Despite efforts to detect FAOD through newborn screening and manage patients early, symptom onset can be sudden and serious, even resulting in death. Therefore, it is critical to identify quickly and accurately the key signs and symptoms of patients with FAOD to manage metabolic decompensations and prevent serious comorbidities. Keywords Fatty acid oxidation disorder . FAOD . Metabolism . Hypoglycemia . Cardiomyopathy . Rhabdomyolysis
Abbreviations FAOD fatty acid oxidation disorder CoA coenzyme A NBS newborn screening CACTD carnitine-acylcarnitine translocase deficiency CPT-IAD carnitine palmitoyltransferase I deficiency CPT-IID carnitine palmitoyltransferase II deficiency LC-FAOD long-chain fatty acid oxidation disorder VLCADD very-long-chain acyl-CoA dehydrogenase deficiency LCHADD long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency While this manuscript was in press, the U.S. Food and Drug Administration approved triheptanoin for the treatment of pediatric and adult patients with molecularly confirmed LC-FAOD. * J. Lawrence Merritt, 2nd [email protected] 1
Pediatrics, University of Washington, Seattle, WA, USA
2
Children’s National Hospital, Washington, DC, USA
3
Ultragenyx Pharmaceutical Inc., Novato, CA, USA
4
Indiana University School of Medicine, Indianapolis, IN, USA
TFPD MCADD QoL MCT
tri-functional protein deficiency medium-chain acyl-CoA dehydrogenase deficiency quality of life medium-chain triglyceride
1 Introduction 1.1 Mitochondrial fatty acid oxidation and energy homeostasis Energy needs vary markedly based on nutritional intake and exertion. Therefore, the ability to utilize different energy sources and store excess energy for later use is critical for maintaining proper homeostasis. Glucose is the primary fuel for the brain, whereas ketone bodies meet a large portion of energy needs of the skeletal muscle and heart [1,
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