Long-chain Fatty Acid Oxidation Disorders Research Articles

What is the impact of long-chain fatty acid oxidation disorders on everyday life? Plain language summary of a survey

What is this summary about? Long-chain fatty acid oxidation disorders (LC-FAOD for short) are a group of rare conditions where the body cannot use stored fat for energy. This leads to symptoms and health problems that can be life-threatening, but the impact of LC-FAOD on the everyday life of people with LC-FAOD and their caregivers has not been well studied. What was done? We conducted a burden of illness survey in the United States of people with LC-FAOD and their caregivers to help show the impact of this condition on their everyday life. The survey had 44 people who completed the survey (respondents): 14 adults (≥18 years) living with LC-FAOD and 30 caregivers reporting on 37 people with LC-FAOD. People with LC-FAOD reported on in the survey were 8 months to 67 years old (the average age was 16 years). What were the results? We found that the LC-FAOD symptoms impact people differently through the stages of life. People with LC-FAOD and their caregivers reported an impact on school and work, including missing work; the main reasons were hospitalizations (staying in the hospital as an inpatient) and physical symptoms. In addition, many people had trouble performing everyday activities, such as standing for 2 hours, walking a quarter of a mile, moving heavy objects, and doing household chores. Using a standard questionnaire, we found that the overall quality of life of people with LC-FAOD was lower than for the average American who does not have LC-FAOD. What do the results mean? The findings from the survey help show how LC-FAOD can impact the everyday life of people living with LC-FAOD and their caregivers. The findings provide people with LC-FAOD a better understanding of their condition and what they might expect. The findings also help researchers and healthcare providers support people with an LC-FAOD and their caregivers.

Early results from a long-term disease monitoring program in patients with long-chain fatty acid oxidation disorders

Early results from a long-term disease monitoring program in patients with long-chain fatty acid oxidation disorders

Revealing the genetic complexity of long-chain fatty acid oxidation disorders: Insights from a dynamic locus-specific gene database

Revealing the genetic complexity of long-chain fatty acid oxidation disorders: Insights from a dynamic locus-specific gene database

Long-chain Fatty Acid Oxidation Disorders, Early Diagnosis and Role of Breastfeeding

ZusammenfassungEin männliches Neugeborenes, zweites Kind nichtkonsanguiner Eltern, wurde termingerecht per Kaiserschnitt mit 38 + 6 Schwangerschaftswochen und einem Geburtsgewicht von 3340 g geboren. Bereits am 4. Lebenstag zeigten sich auffallende Symptome, darunter rezidivierendes Erbrechen, Hypoglykämie-Episoden und eine Gewichtsabnahme von über 10 %. Das Kind wurde zur weiteren Abklärung an ein medizinisches Zentrum mit Neugeborenen-Intensivstation transferiert. Das Neugeborenen-Screening (NGS) traf am 5. Lebenstag ein und wies auf eine langkettige Fettsäureoxidationsstörung hin (LC-FAOD). Eine umfassende Stoffwechselabklärung und genetische Diagnostik wurden eingeleitet, welches die Diagnose LCHAD-Defizienz im Verlauf bestätigte. Während des stationären Aufenthalts wurde der Fokus auf regelmäßige Stillmahlzeiten gelegt, um katabolen Phasen vorzubeugen. Der Säugling wurde am 12. Lebenstag auf die Normalstation verlegt und am 14. Lebenstag entlassen. Die multidisziplinäre Betreuung, regelmäßige ärztliche Überwachung und eine angepasste Ernährung spielten eine entscheidende Rolle im erfolgreichen Management der seltenen angeborenen Stoffwechselstörung. Das NGS hat eine wesentliche Bedeutung bei der frühzeitigen Erkennung gut beherrschbarer angeborener Stoffwechselstörungen. LC-FAODs beeinträchtigen den Abbau von Fettsäuren und können zu schweren gesundheitlichen Problemen führen. Die Symptome variieren, erfordern jedoch eine enge Zusammenarbeit verschiedener medizinischer Fachkräfte. Stillen bei Neugeborenen gilt als adäquate, altersentsprechende Ernährung, da es – auch für Kinder mit metabolischen Erkrankungen – zahlreiche gesundheitliche Vorteile für Kind und Mutter bietet und auch die Bindung zwischen Mutter und Kind fördert. Die einzigartige Zusammensetzung der Muttermilch passt sich den Bedürfnissen des Kindes an. Der geschilderte Fall betont die Bedeutung des NGS, die Zusammenarbeit verschiedener Fachbereiche sowie die Rolle von Stillen, Triheptanoin-Supplementierung im Verlauf und angepasster Ernährung im Umgang mit langkettigen Fettsäureoxidationsstörungen. Frühe Diagnose und ein umfassender Ansatz sind entscheidend für die bestmögliche Betreuung und Lebensqualität.

Major clinical events and healthcare resource use among patients with long-chain fatty acid oxidation disorders in the United States: Results from LC-FAOD Odyssey program

Major clinical events (MCEs) related to long-chain fatty acid oxidation disorders (LC-FAOD) in triheptanoin clinical trials include inpatient or emergency room (ER) visits for three major clinical manifestations: rhabdomyolysis, hypoglycemia, and cardiomyopathy. However, outcomes data outside of LC-FAOD clinical trials are limited. The non-interventional cohort LC-FAOD Odyssey study examines data derived from US medical records and patient reported outcomes to quantify LC-FAOD burden according to management strategy including MCE frequency and healthcare resource utilization (HRU).Thirty-four patients were analyzed of which 21 and 29 patients had received triheptanoin and/or medium chain triglycerides (MCT), respectively. 36% experienced MCEs while receiving triheptanoin versus 54% on MCT. Total mean annualized MCE rates on triheptanoin and MCT were 0.1 and 0.7, respectively. Annualized disease-related inpatient and ER events were lower on triheptanoin (0.2, 0.3, respectively) than MCT (1.2, 1.0, respectively). Patients were managed more in an outpatient setting on triheptanoin (8.9 annualized outpatient visits) vs MCT (7.9). Overall, this shows that those with LC-FAOD in the Odyssey program experienced fewer MCEs and less HRU in inpatient and ER settings during triheptanoin-treated periods compared with the MCT-treated periods. The MCE rate was lower after initiation of triheptanoin, consistent with clinical trials.

Using the C14:1/Medium-Chain Acylcarnitine Ratio Instead of C14:1 to Reduce False-Positive Results for Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency in Newborn Screening in Japan.

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a long-chain fatty acid oxidation disorder that manifests as either a severe phenotype associated with cardiomyopathy, a hypoglycemic phenotype, or a myopathic phenotype. As the hypoglycemic phenotype can cause sudden infant death, VLCAD deficiency is included in newborn screening (NBS) panels in many countries. The tetradecenoylcarnitine (C14:1) level in dried blood specimens is commonly used as a primary marker for VLCAD deficiency in NBS panels. Its ratio to acetylcarnitine (C2) and various other acylcarnitines is used as secondary markers. In Japan, tandem mass spectrometry-based NBS, initially launched as a pilot study in 1997, was introduced to the nationwide NBS program in 2013. In the present study, we evaluated levels of acylcarnitine with various chain lengths (C18 to C2), free carnitine, and their ratios in 175 infants who tested positive for VLCAD deficiency with C14:1 and C14:1/C2 ratios. Our analyses indicated that the ratios of C14:1 to medium-chain acylcarnitines (C10, C8, and C6) were the most effective markers in reducing false-positive rates. Their use with appropriate cutoffs is expected to improve NBS performance for VLCAD deficiency.

Neurological outcome in long-chain hydroxy fatty acid oxidation disorders.

This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes. Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.

18 Months of Treatment with Triheptanoin in 2 Patients with Long Chain Fatty Acid Oxidation Disorders

Introduction:: Long-chain fatty acid oxidation disorders (LC-FAOD) are inborn errors of metabolism, also identified in newborn screening in Portugal. They interfere with adequate energy utilization, namely by muscles, heart, and liver. Treatment aims to maintain patients in an anabolic state, with increased caloric intake, using carbohydrates and medium-chain fatty acids. Treatment with triheptanoin (THP), a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect that increases energy availability to the cell, has been advocated as an efficacious and safe therapy in LC-FAOD. Methods:: Retrospective revision of clinical records of 2 LC-FAOD patients comparing number, severity and admissions for rhabdomyolysis crises, maximum CK values and weight gain in a period of 18 months before and after treatment with THP. Results/Case Report:: Patient 1 is a 12 year old male with VLCADD, with main manifestation being rhabdomyolysis crises. After he started THP we found a decrease in admissions (6 to 2), less rhabdomyolysis crises treated at home (5 to 3), and lower maximum CK values (72352 U/L to 13.000U/L). He had a large increase in weight - 13kg in 18 months. He was able to start pool exercises with no rhabdomyolysis associated. Patient 2 is an 8 year old male with LCAHDD, with main manifestations being rhabdomyolysis crises and retinopathy. After he started THP we found a decrease in admissions (4 to 1), no rhabdomyolysis crises treated at home, and lower maximum CK values (100.000U/L to 19848 U/L). He also increased his weight - 7kg in 18 months. He plays football in school and swims with no rhabdomyolysis associated. In both patients, no major side effects were observed. Conclusion:: In our patients, we could observe a reduction in the number of admissions, and less severe rhabdomyolysis crises after THP use. The weight gain was significant. There were no major side effects. Despite regarding only two patients, our findings are in line with the latest literature on THP and LC-FAOD, reinforcing the utility of THP as one more tool in the treatment of these disorders with rhabdomyolysis as the main manifestation. The weight increase is an issue to be aware of and to address from the start of the treatment.

Psychosocial issues and coping strategies in families affected by long-chain fatty acid oxidation disorders.

Long-chain fatty acid oxidation disorders (lcFAODs) are associated with a high disease burden due to both the risk of metabolic decompensation as well as chronic, partly irreversible complications in some. Little research has been performed on the impact of these disorders on the daily life of parents and caregivers. We performed a web-based questionnaire study among parents/caregivers of patients affected with lcFAODs. The questionnaire focused on challenges at different ages of the child, on disease management issues, schooling, family and social life as well as the parental job situation, and their overall attitude toward the disease and the future life of their child. Data were collected from parents/caregivers of 63 patients (87 respondents, 63% mothers, 36% fathers) with lcFAODs (median age of patients 8.0 years, range 0-25 years, long-chain 3-hydrocyacyl-CoA dehydrogenase deficiency 40%, mitochondrial trifunctional protein deficiency 14%, very long-chain acyl-CoA dehydrogenase deficiency 41%, carnitine palmitoyltransferase 2 deficiency 5%). The overall disease burden of parents was considered highest during infancy and decreased with increasing age of their child. More than one third of parents were afraid that their child's disease might have an impact on his/her career choice and adult life. Negative effects of the child's disease on the job situation and career development were more commonly reported by mothers compared to fathers. Although the majority of parents considered their child's metabolic disorder a severe disease, most parents had a positive attitude toward their child's disease and seemed to cope well with their situation.

Micronutrient Deficiency in Inherited Metabolic Disorders Requiring Diet Regimen: A Brief Critical Review

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.

Abstract 15278: Cardiac Assessments and Manifestations Among Individuals With Long-Chain Fatty Acid Oxidation Disorders: A Retrospective Claims Database Analysis

Introduction: Long-chain fatty acid oxidation disorders (LC-FAOD) are inherited autosomal recessive defects resulting in enzyme deficiencies in the carnitine cycle or the mitochondrial β-oxidation pathway leading to deficiencies in mitochondrial energy metabolism. Cardiac manifestations, specifically cardiomyopathy and arrhythmias, are common and are leading causes of mortality in individuals with LC-FAOD. Goal: The goal of this study was to better understand cardiac manifestations and long-term outcomes in this group of disorders. Methods: The analysis was done using IQVIA PharMetrics® claims data. Individuals with confirmed LC-FAOD were identified and a non-LC-FAOD comparators group was created using 1:20 exact matching on age, gender, payer type, and enrollment start year. Cardiac-related complications were examined using ICD-10 diagnosis codes at any billing position during the study period. Cardiac diagnoses and assessments were evaluated using Current Procedural Terminology (CPT®) codes in a non-inpatient setting. Results: A total of 337 pediatric (peds) and 86 adult individuals with LC-FAOD were included in the study. Cardiomyopathy (peds: 8.0%, adults: 10.5%) and arrhythmias (peds: 8.9%, adults: 14.0%) were common among individuals with LC-FAOD and were significantly higher than comparators. LC-FAOD adults had significantly more cardiac conditions compared with pediatric patients and comparators. The other most common cardiac conditions among adults with LC-FAOD were chronic ischemic heart disease (18.6%), non-rheumatic mitral or tricuspid valve disorders (11.6% and 12.8%, respectively), heart failure (10.5%), atrioventricular and left bundle-branch block (7.0%), and cardiomegaly (5.1%). Individuals with LC-FAOD had significantly more cardiac related procedures than comparators. EKGs (peds: 35.9%; adults: 77.9%) and echocardiograms (peds: 44.8%; adults: 53.5%) were common among individuals with LC-FAOD. Conclusions: This analysis shows the importance of assessing the cardiac status of individuals with LC-FAOD. More analyses and natural history studies are needed to inform healthcare providers of cardiac risks associated with LC-FAOD and reduce mortality in these individuals.

Newborn Screening with (C16 + C18:1)/C2 and C14/C3 for Carnitine Palmitoyltransferase II Deficiency throughout Japan Has Revealed C12/C0 as an Index of Higher Sensitivity and Specificity.

Carnitine palmitoyltransferase (CPT) II deficiency is a long-chain fatty acid oxidation disorder. It manifests as (1) a lethal neonatal form, (2) a hypoglycemic form, or (3) a myopathic form. The second form can cause sudden infant death and is more common among Japanese people than in other ethnic groups. Our study group had earlier used (C16 + C18:1)/C2 to conduct a pilot newborn screening (NBS) study, and found that the use of C14/C3 for screening yielded lower rates of false positivity; in 2018, as a result, nationwide NBS for CPT II deficiency started. In this study, we evaluated the utility of these ratios in 71 NBS-positive infants and found that the levels of both C14/C3 and (C16 + C18:1)/C2 in patients overlapped greatly with those of infants without the disease. Among the levels of acylcarnitines with various chain lengths (C18 to C2) and levels of free carnitine (C0) as well as their ratios of various patterns, C12/C0 appeared to be a promising index that could reduce false-positive results without missing true-positive cases detected by current indices. Although some cases of the myopathic form may go undetected even with C12/C0, its use will help prevent life-threatening onset of the hypoglycemic form of CPT II deficiency.

PCR226 Symptoms, Treatment Effectiveness and Quality of Life for Patients Living with Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) in the United States: Patient and Caregiver Reported Outcomes from LC-FAOD Odyssey

The LC-FAOD Odyssey study collects medical record data and prospective patient- and caregiver-reported outcomes (PROs). Data are used to assess the real-world impact of LC-FAOD and treatment effectiveness.

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

The basis of medical nutrition therapy for patients with LC-FAODs is to provide adequate energy to maintain anabolism and prevent catabolism. In practice, energy needs are estimated based on formulas derived from normal populations but it is unknown if energy expenditure among patients with LC-FAODs is similar to the normal population. We measured resting energy expenditure (REE), total energy expenditure (TEE) and body composition in 31 subjects with LC-FAODs ranging in age from 7 to 64 years. Measured REE was lower than estimated REE by various prediction equations and measured TEE was lower than estimated TEE. It is possible that the lower energy expenditure based on prediction formulas from the normal population is due to differences in body composition; we compared body composition to normal data from the 2017-18 National Health and Nutrition Examination Survey (NHANES). Fat free mass and fat mass was similar between subjects with an LC-FAOD and NHANES normal data suggesting no difference in body composition. We then compared measured REE and TEE to normal published data from the Dietary Reference Intakes (DRI). Measured REE and TEE were significantly lower among subjects with LC-FAODs compared to normal published energy expenditure data. Our results suggests patients with a LC-FAOD exhibit a lower REE and therefore actually have a slightly lower TEE than estimated. Current prediction equations may overestimate energy expenditure of patients with a LC-FAOD.

P041: Real-world major clinical events and healthcare resource use among patients with long-chain fatty acid oxidation disorders in the United States

P041: Real-world major clinical events and healthcare resource use among patients with long-chain fatty acid oxidation disorders in the United States

P276: Long-chain fatty acid oxidation disorder genotypes, clinical signs and symptoms, and newborn screening history from a gene panel sponsored program

P276: Long-chain fatty acid oxidation disorder genotypes, clinical signs and symptoms, and newborn screening history from a gene panel sponsored program

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.