Long-chain Fatty Acid Oxidation Disorders Research Articles

Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency

Recent trials have reported the ability of triheptanoin to improve clinical outcomes for the severe symptoms associated with long-chain fatty acid oxidation disorders, including very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.However, the milder myopathic symptoms are still challenging to treat satisfactorily. Myopathic pathogenesis is multifactorial, but oxidative stress is an important component. We have previously shown that metabolic stress increases the oxidative burden in VLCAD-deficient cell lines and can deplete the antioxidant glutathione (GSH).We investigated whether medium-chain fatty acids provide protection against GSH depletion during metabolic stress in VLCAD-deficient fibroblasts. To investigate the effect of differences in anaplerotic capacity, we included both even-(octanoate) and odd-numbered (heptanoate) medium-chain fatty acids. Overall, we show that modulation of the concentration of medium-chain fatty acids in culture media affects levels of GSH retained during metabolic stress in VLCAD-deficient cell lines but not in controls.Lowered glutamine concentration in the culture media during metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells, which could be rescued by both heptanoate and octanoate in a dose-dependent manner. Unlike GSH levels, the levels of total thiols increased after metabolic stress exposure, the size of this increase was not affected by differences in cell culture medium concentrations of glutamine, heptanoate or octanoate.Addition of a PPAR agonist further exacerbated stress-related GSH-depletion and viability loss, requiring higher concentrations of fatty acids to restore GSH levels and cell viability.Both odd- and even-numbered medium-chain fatty acids efficiently protect VLCADdeficient cells against metabolic stress-induced antioxidant depletion.

PSUN63 Approach to hyperlipidemia management in Carnitine Palmitoyltransferase II deficiency

Abstract Background Carnitine Palmitoyltransferase II deficiency (CPT II) is a disorder of long-chain fatty-acid oxidation. Clinical presentations include a lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form. The myopathic form is the most common disorder of lipid metabolism affecting skeletal muscle. Individuals with CPT II deficiency are unable to metabolize long-chain fatty acids and can have myalgia. The incidence of statin-induced muscle symptoms is 1.5% to 5%. Individuals with CPT II deficiency have been reported to have an increased incidence of statin-associated myopathy. Yet, it remains crucial to place patients with high ASCVD risk on the appropriate statin therapy. Case Presentation We present a 70-year-old male with medical history of CPT II deficiency (myopathic form), hyperlipidemia with significant hypertriglyceridemia, hypertension, type 2 diabetes mellitus, carotid artery stenosis, atrial fibrillation, and recurrent pancreatitis. Family history was positive for hyperlipidemia and premature coronary artery disease. After history of recurrent pancreatitis and severe myalgias, patient was diagnosed with CPT II deficiency at the age of 30 years. The myalgias were managed by increased carbohydrates intake for many years. Multiple low potency statins, and fenofibrate were attempted but he developed severe myalgia with elevated CPK levels. Eventually he was started on ezetimibe 10 mg daily with fish oil 2000 mg twice daily but his LDL-C continued to rise. CMP and TSH were within normal limits. Nuclear stress test was normal but his ASCVD risk score was 39%. Given the patient's CPT II deficiency and high risk for ASCVD score, statin was recommended for primary prevention. After a thorough discussion of risks and benefits of lipid-lowering therapy, the patient was started on pitavastatin 2 mg twice-weekly regimen and ezetimibe 10mg was continued. Eight weeks later, his LDL-C reduced from 132 mg/dl to 94 mg/dl (n <129mg/dl), TG from 449 mg/dl to 307 mg/dl (n 0-149 mg/dl). As he experienced no myalgias, an extra tablet of pitavastatin a week was added until he reached a daily regimen. He continued to tolerate this treatment and his LDL-C improved to 66 mg/dl with normal CPK levels. Clinical Lesson: We present a case of CPT II deficiency and significant hyperlipidemia successfully managed with pitavastatin and ezetimibe, which helped to achieve a desirable LDL-C. Pitavastatin is not metabolized by hepatic CYP3A4 isoenzyme as other statins and is minimally metabolized by CYP2C9. In addition, patients with CPT II deficiency may benefit from avoiding extended episodes of exertion and high-fat diet. When treating patients with CPT II deficiency and hyperlipidemia, close follow-up and laboratory monitoring will be needed. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

P.76 Gene variant and neuromuscular findings from a long-chain fatty acid oxidation disorder gene panel program

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive conditions that can be diagnosed clinically with plasma acylcarnitine analysis and molecular testing. Undiagnosed LC-FAOD may present with hypoglycemia, cardiomyopathy, cardiac arrhythmias, and neuromuscular symptoms. Patients with a clinical diagnosis or suspicion of LC-FAOD are eligible for this no-charge, next-generation sequencing gene panel which includes 6 genes associated with LC-FAOD plus 18 genes associated with disorders that cause abnormal acylcarnitine profiles. As of 28 October 2021, LC-FAOD gene variants were identified in 153 (37%) of 417 patients tested, including 83 variants of uncertain significance (VUS), 8 likely pathogenic (LP), and 102 pathogenic (P) variants. Twenty-three patients had positive (2 P/LP) LC-FAOD results and 19 had potential positive (2 variants, at least 1 VUS) results. VUS resolution analysis led to the reclassification of 6 variants from VUS to LP or P. Five patients had variants in two or more LC-FAOD genes and 22 had variants in one LC-FAOD gene and one or more non-LC-FAOD genes. Fifty-one patients had only one LC-FAOD gene variant identified. The most common neuromuscular symptoms among patients ages ≥13 (76 reported) were myopathy (42), elevated creatine kinase (36), and rhabdomyolysis (30), and among patients <13 years (83 reported) were elevated creatine kinase (22), and myopathy (12). Program results demonstrate the diverse composition of gene variants in patients referred for LC-FAOD genetic testing. Approaches to resolve VUS and identify previously undetected variants in patients with suspected LC-FAOD are important and necessary.

Understanding the impact of long-chain fatty acid oxidation disorders for patients and caregivers

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare, autosomal recessive genetic disorders that impair conversion of long-chain fatty acids into energy. Here we describe the impact of LC-FAOD in terms of effects on work and school, absenteeism and presenteeism at work, importance of symptoms, physical activity, participation in social activities, and quality of life (QoL). A convenience sample of adults (≥18 years) and caregivers of patients with LC-FAOD was invited to take the online survey (Confirmit). To be included, patients must have been receiving medical care from a healthcare provider for their LC-FAOD, and caregivers must not have been compensated for their care. Degree of physical activity, represented by metabolic equivalents (METs), was calculated using the NHANES Physical Activity Questionnaire. Absenteeism and presenteeism at work were calculated using the WHO Health Productivity Questionnaire. QoL was assessed using the 12-Item Short Form of the Medical Outcomes Survey. Significance was assessed using two tailed independent sample t-tests and z-tests at α = 0.1. Fourteen adults and 30 caregivers of LC-FAOD patients (answering for 37 patients) answered the survey (51 unique respondents). 59.2% of LC-FAOD patients experienced effects on their schooling due to LC-FAOD. 84.2% of working patients experienced effects on their work due to LC-FAOD. 70% of caregivers experienced effects on their work due to their child's LC-FAOD. Unique respondents report that muscle weakness (69%), physical fatigue (49%), and rhabdomyolysis (39%) are the most impactful symptoms of LC-FAOD. Adults (n = 14) scored significantly below the normalized average (50) on both physical (34.51, p < 0.001) and mental (45.27, p = 0.04) component scores of the SF-12 health-related quality of life measure. LC-FAOD impart a high disease impact on patients and their caregivers. In particular, symptoms relating to energy production were rated as highly impactful and limiting. Activities that may be considered normal for many people can prove to be very difficult or impossible for respondents with LC-FAOD, with respondents reporting lower physical and mental health-related quality of life measures than the average American.

Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin.

Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of three fatty acids with seven carbons each on a glycerol backbone, indicated for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). A total of 562 plasma concentrations of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, from 13 healthy adult subjects and 30 adult and pediatric subjects with LC-FAOD were included in the population pharmacokinetic (PK) analyses. Multiple peaks of heptanoate observed in several subjects were characterized by dual first-order absorption with a lag time in the second absorption compartment. The disposition of heptanoate in human plasma was adequately described by one-compartmental distribution with a linear elimination. The apparent clearance (CL/F) and apparent volume of distribution were allometrically scaled with body weight to describe PK data across a wide range of age groups in subjects with LC-FAOD. The typical CL/F in adult subjects with LC-FAOD was ≈19% lower than that in healthy subjects. Model-estimated elimination half-life for LC-FAOD patients was ∼1.7hours, supporting a recommended dosing frequency of ≥4 times per day. Covariate analyses indicate that age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate.

CO42 Major Clinical Manifestations and Events Among Patients with Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) in the United States: Real-World Results from LC-FAOD Odyssey

Data are limited for real-world LC-FAOD outcomes. Major clinical manifestations of LC-FAOD were assessed as primary outcomes in triheptanoin clinical trials and include rhabdomyolysis, hypoglycemia, and cardiomyopathy. This analysis aims to quantify the real-world burden of LC-FAOD in terms of major clinical manifestations by treatment periods.

Estimating the Prevalence of Rare Diseases: Long-Chain Fatty Acid Oxidation Disorders as an Illustrative Example.

IntroductionDetermining the epidemiology of disease is critical for multiple reasons, including to perform risk assessment, compare disease rates in varying populations, support diagnostic decisions, evaluate health care needs and disease burden, and determine the economic benefit of treatment. However, establishing epidemiological measures for rare diseases can be difficult owing to small patient populations, variable diagnostic techniques, and potential disease and diagnostic heterogeneity. To determine the epidemiology of rare diseases, investigators often develop estimation models to account for missing or unobtainable data, and to ensure that their findings are representative of their desired patient population.MethodsA modeling methodology to estimate the prevalence of rare diseases in one such population—patients with long-chain fatty acid oxidation disorders (LC-FAOD)—as an illustrative example of its applicability.ResultsThe proposed model begins with reliable source data from newborn screening reports and applies to them key modifiers. These modifiers include changes in population growth over time and variable standardization rates of LC-FAOD screening that lead to (1) a confirmed diagnosis and (2) improvements in standards of care and survival estimates relative to the general population. The model also makes necessary assumptions to allow the broad applicability of the estimation of LC-FAOD prevalence, including rates of diagnosed versus undiagnosed patients in the USA over time.ConclusionsAlthough each rare disease is unique, the approach described here and demonstrated in the estimation of LC-FAOD prevalence provides the necessary tools to calculate key epidemiological estimates useful in performing risk assessment analyses; comparing disease rates between different subgroups of people; supporting diagnostic decisions; planning health care needs; comparing disease burden, including cost; and determining the economic benefit of treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02186-2.

Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program.

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.

Neonatal Long-Chain 3-Ketoacyl-CoA Thiolase deficiency: Clinical-biochemical phenotype, sodium-D,L-3-hydroxybutyrate treatment experience and cardiac evaluation using speckle echocardiography

Isolated long-chain 3-keto-acyl CoA thiolase (LCKAT) deficiency is a rare long-chain fatty acid oxidation disorder caused by mutations in HADHB. LCKAT is part of a multi-enzyme complex called the mitochondrial trifunctional protein (MTP) which catalyzes the last three steps in the long-chain fatty acid oxidation. Until now, only three cases of isolated LCKAT deficiency have been described. All patients developed a severe cardiomyopathy and died before the age of 7 weeks. Here, we describe a newborn with isolated LCKAT deficiency, presenting with neonatal-onset cardiomyopathy, rhabdomyolysis, hypoglycemia and lactic acidosis. Bi-allelic 185G > A (p.Arg62His) and c1292T > C (p.Phe431Ser) mutations were found in HADHB. Enzymatic analysis in both lymphocytes and cultured fibroblasts revealed LCKAT deficiency with a normal long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD, also part of MTP) enzyme activity. Clinically, the patient showed recurrent cardiomyopathy, which was monitored by speckle tracking echocardiography. Subsequent treatment with special low-fat formula, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT) and ketone body therapy in (sodium-D,L-3-hydroxybutyrate) was well tolerated and resulted in improved carnitine profiles and cardiac function. Resveratrol, a natural polyphenol that has been shown to increase fatty acid oxidation, was also considered as a potential treatment option but showed no in vitro benefits in the patient's fibroblasts. Even though our patient deceased at the age of 13 months, early diagnosis and prompt initiation of dietary management with addition of sodium-D,L-3-hydroxybutyrate may have contributed to improved cardiac function and a much longer survival when compared to the previously reported cases of isolated LCKAT-deficiency.

Resting and total energy expenditure of patients with long-chain fatty acid oxidation disorders (LC-FAODs)

Resting and total energy expenditure of patients with long-chain fatty acid oxidation disorders (LC-FAODs)

Introduction to Odyssey: real-world rare disease data collection program for patients with long-chain fatty acid oxidation disorders in the US

Introduction to Odyssey: real-world rare disease data collection program for patients with long-chain fatty acid oxidation disorders in the US

Management and symptoms of people living with long-chain fatty acid oxidation disorders (LC-FAOD) in the United States: Results from LC-FAOD Odyssey Study

Management and symptoms of people living with long-chain fatty acid oxidation disorders (LC-FAOD) in the United States: Results from LC-FAOD Odyssey Study

Triheptanoin (Dojolvi)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses triheptanoin (Dojolvi), 100% w/w oral liquid.&#x0D; Indication: As a source of calories and fatty acids for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders.&#x0D;

EP165: Improvement in left ventricular ejection fraction in patients treated with triheptanoin for Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)

In situations of energy crises or fasting, the inability to convert long-chain fats into energy can cause unpredictable, life-threatening, cardiomyopathic events in people with long-chain fatty acid oxidation disorders (LC-FAOD). Triheptanoin, a seven carbon, medium-chain triglyceride (MCT) approved in the United States, Canada and Brazil as a source of calories and fatty acids for the treatment of LC-FAOD, demonstrated increases in left ventricular ejection fraction (LVEF) in a double-blind, randomized clinical trial (RCT).

EP222: Gene variant and neuromuscular findings from a long-chain fatty acid oxidation disorder gene panel program

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive conditions that impair the utilization of fats for energy production. LC-FAOD may initially be suspected based on clinical symptoms or positive results from newborn screening and can be confirmed clinically with plasma acylcarnitine analysis and molecular testing. Undiagnosed LC-FAOD may present with hypoglycemia, cardiomyopathy, cardiac arrhythmias, and with neuromuscular involvement, including rhabdomyolysis and myopathy.

EP495: Introduction to Odyssey: Real-world rare disease data collection program for patients with long-chain fatty acid oxidation disorders in the US

The long-chain fatty acid oxidation (LC-FAOD) Odyssey study, conducted with PicnicHealth, uses a novel patient (pt)-centered design to collect prospective and retrospective data on the real-world impact of LC-FAOD, and prospective data of pt- and caregiver-reported outcomes (PROs). The goal is to fill the current data gap in real-world LC-FAOD management and outcomes, and ultimately identify areas in which to improve care.

Triheptanoin (Dojolvi)

&#x0D; CADTH recommends that Dojolvi should be reimbursed by public drug plans as a source of calories and fatty acids for the treatment of adult and pediatric patients with a long-chain fatty acid oxidation disorders (LC-FAOD) if certain conditions are met.&#x0D; Dojolvi should only be covered to treat patients with and without a confirmed LC-FAOD diagnosis if they present with acute life-threatening symptoms that are consistent with those of LC-FAOD. Dojolvi should only be covered in patients who need a different treatment than over-the-counter even-chain medium-chain triglyceride (MCT) oil.&#x0D; Dojolvi should only be reimbursed if prescribed by clinicians experienced in the management of LC-FAOD and if the price of Dojolvi is reduced. Reimbursement of Dojolvi should be renewed every 12 months if individual patient treatment goals are being met.&#x0D;

Qualitative evaluation of the symptoms and quality of life impacts of long-chain fatty acid oxidation disorders.

Background:Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare autosomal-recessive genetic disorders characterized by metabolic deficiencies in which the body is unable to convert long-chain fatty acids into energy. To date, however, there is limited understanding of the patient experience of LC-FAOD.Methods:The symptoms, observable signs, and quality of life (QoL) impacts associated with LC-FAOD were explored via a focus group (n = 8) and semi-structured interviews (n = 6) with patients and caregivers of patients with LC-FAOD, and interviews (n = 4) with expert clinicians. Data were analyzed via thematic analysis and summarized in a conceptual model.Results:Participants reported a wide range of signs and symptoms associated with LC-FAOD, broadly categorized as musculoskeletal, endocrine/nutritional/metabolic, neurological, gastrointestinal/digestive, sensory, cardiovascular, respiratory, urological, and constitutional. LC-FAOD were reported to have a significant impact on various aspects of patients’ lives including physical functioning, participation in daily activities, emotional/psychological wellbeing, and social functioning. Lifestyle modifications (such as diet and exercise restrictions) were necessary because of the condition. Symptoms were typically episodic in presentation often arising or exacerbated during catabolic conditions such as prolonged exercise, fasting, physiological stress, and illness/infection. Symptoms were also commonly reported to lead to emergency room visits, hospitalization, and clinical complications.Conclusion:LC-FAOD have a considerable impact on patients’ lives. There is a high degree of concordance in the signs, symptoms, and impacts of LC-FAOD reported by patients, caregivers, and clinicians; however, there were many symptoms and impacts that were only reported by patients and caregivers, thus demonstrating that insights from patient/caregiver experience data are integral for informing medical product development and facilitating patient-centered care.

Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders.

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of β-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions.

METABOLIC MYOPATHIES: EP.207 Clinical findings of late-onset long-chain fatty acid oxidation disorders overlap with neuromuscular conditions in a sponsored genetic testing program

METABOLIC MYOPATHIES: EP.207 Clinical findings of late-onset long-chain fatty acid oxidation disorders overlap with neuromuscular conditions in a sponsored genetic testing program