Accreditation/Credit Designation

Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Ultragenyx Pharmaceutical Inc.

Advances in™ Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources


Release Date: December 31, 2018
Expiration Date: December 31, 2019
Media: Internet - based

Activity Overview

This activity, Advances in™ Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources, developed in Physicians’ Education Resource®, LLC, (PER®) established Advances in™ legacy format, will increase awareness of the presenting signs and symptoms of long-chain fatty acid oxidation disorders (LC-FAODs). Management strategies to improve quality of life (QoL) and emerging new therapies for LC-FAODs will be highlighted, with an emphasis on individualized treatment. Case vignettes throughout will bring important information on this uncommon but highly burdensome metabolic disorder into clinical practice.

You will hear experts discuss ongoing clinical trials and early experience with compassionate use of the novel agent triheptanoin, as they provide their perspectives on how new treatments may impact long-term outcomes of patients with LC-FAOD, and guide participants on potential application to clinical practice.

Benefits of Completing Activity

By participating in this exciting program, you will learn about:

  • The pathophysiology and symptoms of LC-FAODs phenotypes, especially in pediatric patients
  • Individualized management strategies to improve QoL and outcomes for patients with LC-FAOD
  • The latest clinical data to tailor therapeutic strategies for patients with LC-FAOD

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Ultragenyx Pharmaceutical Inc.

Instructions for This Activity and Receiving Credit

  • You will need to log in to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review audio files/content until you finish the presentation.
  • At the end of the activity, educational content/audio files will be available for your reference.
  • In order to receive a CME certificate, you must complete the activity.
  • Complete the Posttest and pass with a score of 70% or higher, complete the Evaluation, and then click on “Request for Credit.” You may immediately download a CME certificate upon completion of these steps.


Target Audience

This educational activity is directed toward pediatricians, PCPs, NPs, PAs, and other healthcare professionals involved in the care of patients with LC-FAOD.

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

  • Define the pathophysiology and symptoms of LC-FAOD
  • Identify disease management options to achieve individualized care for patients with LC-FAOD
  • Apply knowledge of the mechanisms of action and adverse drug reactions of emerging therapies to clinical management of patients with LC-FAOD

Faculty, Staff, and Planners' Disclosures

Faculty

Jerry Vockley, MD, PhD
University of Pittsburgh
Cleveland Family Endowed Chair in Pediatric Research
Professor of Human Genetics

Children's Hospital of Pittsburgh
Chief of Medical Genetics
Director, Center for Rare Disease Therapy
Pittsburgh, Pennsylvania

Disclosures: Grant/Research Support: NIH, Reno Pharmaceuticals, Ultragenyx Pharmaceuticals Inc. Investigational/Off-Label Use of Drugs/Devices Disclosure: Triheptanoin (in clinical trials)

Nicola Longo, MD, PhD
Professor and Chief
Division of Medical Genetics
Department of Pediatrics
University of Utah
Salt Lake City, Utah

Disclosures: Grant/Research Support: Ultragenyx Pharmaceuticals Inc. ( support for participation in clinical trials) Investigational/Off-Label Use of Drugs/Devices Disclosure: Triheptanoin (in clinical trials)

The staff of PER® have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.

PER Pulse™ Recaps

1 of 3
Insight from Jerry Vockley, MD, PhD — PER Pulse Recap:
Advances in: Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources

The online continuing medical education activity, Advances in: Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources, first describes the effects of genetic defects in enzymes needed for fatty acid metabolism and then uses patient cases to elaborate on presenting symptoms and current treatment strategies. Reviews of emerging treatments, including clinical trial experience with triheptanoin are then shared by international thought leaders Jerry Vockley, MD, PhD, and Nicola Long, MD, PhD, as part of a lifelong approach to management of fatty acid oxidation disorders.

This first of 3 PER Pulse Recaps for Advances in: Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources will focus on the pathophysiology of fatty acid oxidation disorders and recognition of symptoms.

Fatty acid oxidation disorders comprise a group of about 20 defects in fatty acid transport and mitochondrial β-oxidation, which are inherited as autosomal recessive mutations.1 In varying degrees, these defects prevent released stores of body fat from being broken down when glycogen reserves have already been consumed for energy production.

Fatty acid oxidation generates energy needed during fasting and stress by releasing fats from body stores and transporting them in the blood by specialized proteins so they can enter cells. Once in the mitochondria of cells, fats are activated to a chemical form that can be broken down by fatty acid oxidation. This process releases 2-carbon units, acetyl coenzyme A (acetyl-CoA), which enters the tricarboxylic acid (TCA) cycle. Both fatty oxidation and the TCA cycle produce reducing equivalents that are fed into the final pathway of energy generation, the respiratory chain. The respiratory chain then makes adenosine triphosphate, the cellular currency of energy. Anywhere in the process, from the release of fats to their breakdown inside the cells, if the process isn’t working properly due to genetic defects in the specialized proteins, there is an interruption in the ability of the body to make energy and symptoms develop.

Although state-mandated newborn screening detects the most commonly observed mutations, signs and symptoms can present a few hours after birth or not until childhood; they even present during adulthood2 with symptoms that can often be overlooked and confused with other disorders. Signs and symptoms of long chain-fatty acid oxidation disorders (LC-FAODs) characteristically manifest during higher energy demands, such as illness, fever, fasting, prolonged exercise, or a combination of these demands. The clinical presentations are typically hypoketotic hypoglycemia that can culminate in convulsions, coma, and brain damage; cardiomyopathy, which can be fatal, especially in infants; and myopathy, presenting as muscle weakness, myalgia, exercise intolerance, myoglobinuria, and recurring rhabdomyolysis.2

Potential warning signs of a FAOD during pregnancy include the appearance of acute fatty liver of pregnancy (AFLP) or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. These conditions occur for unknown reasons, but they are more frequent in women who are carriers for a FAOD, specifically a deficiency of LCHAD (long chain 3-hydroxyacyl coenzyme A dehydrogenase) and if the unborn child is affected with a LCHAD deficiency.2

References

  1. Vishwanath VA. Fatty acid Beta-oxidation disorders: a brief review. Ann Neurosci. 2016;23(1):51-55. doi: 10.1159/000443556.
  2. Knottnerus SJG, Bleeker JC, Wüst RCI, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 2018;19(1):93-106. doi: 10.1007/s11154-018-9448-1.

“Fatty acid oxidation disorders are identified by newborn screening, so most of the time, patients are referred to metabolic centers pre-symptomatically. Occasionally an infant with this disorder is severe enough to become symptomatic before that happens, either when becoming sick or if not eating. Young infants may present with just some irritability, feeding difficulties, or marginally low glucose, but the biggest concern is very rapid progression to life-threatening hypoglycemia ─reduction in level of consciousness, cold, clammy skin, tachycardia.”
— Jerry Vockley, MD, PhD


2 of 3
Insight from Nicola Long, MD, PhD — PER Pulse Recap:
Advances in: Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources

This second of 3 PER Pulse Recaps for Advances in: Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources will focus on current treatment and management of LC-FAODs.

Treatment for LC-FAODs generally involves adherence to a low-fat diet, with restricted long-chain fatty acid intake and substitution with shorter chain fatty acids, such as medium chain fatty acids (eg, MCT oil). Essential fatty acids must be supplemented in order for there to be synthesis of lipids in the brain and for brain development. Supplementation with carnitine is controversial for LC-FAODs as it could induce toxic accumulation of long-chain acyl-carnitines and CoA’s with associated ventricular fibrillation and rhabdomyolysis.1-2 If carnitine is used, it is only given in small doses. Fasting and exposure to environmental extremes must be rigorously avoided, and exercise should be limited.3

Although there are no published guidelines for treatment of FAODs, guidance is provided by expert consensus statements, which vary from country to country. These expert recommendations list specific dietary guidelines for percentages of long and medium chain acids, supplements, and nutrients needed, depending on the specific FAOD.

FAODs require very specific management by a metabolic specialist with experience in these disorders and through the collaboration of a multidisciplinary team consisting of a pediatrician or primary care physician, dietician, and additional specialists to address any comorbidities. The metabolic specialist ensures that all evaluations of organs are done at specified intervals to identify problems early and treat aggressively. The dietitian analyzes the diet and recommends supplements based on the specific FAOD, recognizing the status of the patient. The primary care practitioner should stay in contact with the metabolic specialist and other specialists, such as a cardiologist, to optimize the overall care of the patient.

Acute management of patients with LC-FAODs is required during metabolic crisis and should be aimed at supplying sufficient glucose to prevent cell damage, especially in muscles. Glucose should be administered even if the patient is normoglycemic as rhabdomyolysis can develop without hypoglycemia. While rhabdomyolysis can be monitored by plasma creatine kinase levels, symptoms usually occur several hours before an elevation of plasma creatine kinase is detected. Hyperglycemia should be treated with insulin and not by reducing glucose intake. Sodium and potassium should be monitored and supplemented, if necessary. In case of fever, antipyrogenic medication should be prescribed. Besides dietary management, aggressive treatment of comorbidities is essential.3

References

  1. Exil VJ, Gardner CD, Rottman JN, et al. Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking very-long-chain acyl-CoA dehydrogenase. Am J Physiol Heart Circ Physiol. 2006;290(3):H1289–97.
  2. Watanabe K, Yamada K, Sameshima K, et al. Two siblings with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency suffered from rhabdomyolysis after L-carnitine supplementation. Mol Genet Metab Rep.2018;(15):121-123.
  3. Knottnerus SJG, Bleeker JC, Wüst RCI, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 2018;19(1):93-106. doi: 10.1007/s11154-018-9448-1.

“The mainstay of treatment is avoidance of fasting. Babies are recommended to be fed every 2 to 3 hours, but as children develop, the fasting can be prolonged between meals. Another consideration is how aggressively to treat illness and fever, because when children become sick, they stop eating and can become acutely sick. The primary care provider and emergency room physician should be familiar with a precise emergency treatment plan specific for these patients.”
— Nicola Long, MD, PhD


3 of 3
Insight from Jerry Vockley, MD, PhD — PER Pulse Recap:
Advances in: Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources

This third of 3 PER Pulse™ Recaps for the Advances in: Rare Diseases: Fatty Acid Oxidation Disorders – Improving Energy Production Through Alternative Sources will focus on emerging treatments for LC-FAODs.

Currently, the only FDA-approved treatment for FAODs is carnitine. Carnitine is therapeutic for carnitine transporter deficiency but is not necessary in medium chain acyl-coenzyme-A dehydrogenase deficiency, and there are concerns for its use in LC-FAODs. Accumulations of long-chain acylcarnitines in animal models have triggered an arrythmia. This hasn’t been validated in humans, and supplementation when carnitine reaches single-digit levels is used for patients with LC-FAODs. Otherwise, its use is avoided.

Several therapies are currently being evaluated for FAODs. Triheptanoin (UX007),1 a C7 fatty acid, addresses an imbalance that occurs in FAODs with sole treatment of MCT oil, a C8 fatty acid, which metabolizes to the 2-carbon substrate acetyl-CoA to enter the TCA cycle. The TCA cycle also requires 3-carbon propionyl-CoA, which is provided by triheptanoin along with two C2 acetyl CoAs. In clinical trials, triheptanoin has been shown to be very effective in treating hypoglycemia and relatively effective in cardiomyopathy. However, a reduction in frequency or intensity of rhabdomyolysis occurred in only about a third of those treated with triheptanoin, and ongoing clinical studies are required to demonstrate clinical significance.

Other drug classes proposed to treat LC-FAODs include peroxisome proliferator–activated receptor (PPAR) agonists, a genetic element that regulates genes of FAODs and energy enzymes within the mitochondria. One of these PPAR agonists that has been evaluated is bezafibrate, but with equivocal results. A new subgroup is a PPAR-δ agonist (REN001), which has demonstrated more potency than bezafibrate and is currently being evaluated in a safety and tolerability study for treatment of LC-FAODs.2 Other potential novel interventions for FAODs include TCA-cycle intermediates and mitochondrial-targeted antioxidants.

References

  1. Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Extension Study for Subjects Previously Enrolled in Triheptanoin Studies. clinicaltrials.gov/ct2/show/NCT02214160. Updated March 4, 2019. Accessed March 21, 2019.
  2. A Study of the Safety of REN001 in Patients With Fatty Acid Oxidation Disorders. clinicaltrials.gov/ct2/show/NCT03833128. Updated February 6, 2019. Accessed March 21, 2019.

“Triheptanoin has been shown in clinical trials to be very effective in treating hypoglycemia, which is very valuable in the first couple years of life for patients with LC-FAODs. In fact, in all the patients who have ever been treated with triheptanoin, there are no bona fide episodes of anyone ever having an episode of hypoglycemia again.”
— Jerry Vockley, MD, PhD


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