Long-chain Fatty Acid Oxidation 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

Longitudinal aortic strain, ventriculo-arterial coupling and fatty acid oxidation: novel insights into human cardiovascular aging.

Aging-induced aortic stiffness has been associated with altered fatty acid metabolism. We studied aortic stiffness using cardiac magnetic resonance (CMR)-assessed ventriculo-arterial coupling (VAC) and novel aortic (AO) global longitudinal strain (GLS) combined with targeted metabolomic profiling. Among community older adults without cardiovascular disease, VAC was calculated as aortic pulse wave velocity (PWV), a marker of arterial stiffness, divided by left ventricular (LV) GLS. AOGLS was the maximum absolute strain measured by tracking the phasic distance between brachiocephalic artery origin and aortic annulus. In 194 subjects (71 ± 8.6 years; 88 women), AOGLS (mean 5.6 ± 2.1%) was associated with PWV (R = -0.3644, p < 0.0001), LVGLS (R = 0.2756, p = 0.0001) and VAC (R = -0.3742, p <0.0001). Stiff aorta denoted by low AOGLS <4.26% (25th percentile) was associated with age (OR 1.13, 95% CI 1.04-1.24, p = 0.007), body mass index (OR 1.12, 95% CI 1.01-1.25, p = 0.03), heart rate (OR 1.04, 95% CI 1.01-1.06, p = 0.011) and metabolites of medium-chain fatty acid oxidation: C8 (OR 1.005, p = 0.026), C10 (OR 1.003, p = 0.036), C12 (OR 1.013, p = 0.028), C12:2-OH/C10:2-DC (OR 1.084, p = 0.032) and C16-OH (OR 0.82, p = 0.006). VAC was associated with changes in long-chain hydroxyl and dicarboxyl carnitines. Multivariable models that included acyl-carnitine metabolites, but not amino acids, significantly increased the discrimination over clinical risk factors for prediction of AOGLS (AUC [area-under-curve] 0.73 to 0.81, p = 0.037) and VAC (AUC 0.78 to 0.87, p = 0.0044). Low AO GLS and high VAC were associated with altered medium-chain and long-chain fatty acid oxidation, respectively, which may identify early metabolic perturbations in aging-associated aortic stiffening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.

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.

Fatty acid oxidation fuels natural killer cell responses against infection and cancer

Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.

Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1

MCL-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to modulating mitochondrial metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that MCL-1 supports essential steps in long-chain (but not short-chain) fatty acid β-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of MCL-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic MCL-1 facilitates mitochondrial metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of MCL-1 inhibitors in clinical trials.

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.

Long-term monitoring of fatty acid oxidation defects: results from a MetabERN survey.

Implementation of long-chain fatty acid oxidation defects (LCFAOD) in newborn screening (NBS) programs allows for pre-symptomatic diagnosis and treatment. The long-term natural history of NBS LCFAOD patients is largely unknown and may differ from clinically diagnosed pre-NBS patients. This complicates long-term monitoring of LCFAOD and may cause high monitoring variability. To gain insight in current clinical practice, we performed a web-based questionnaire among all metabolic members of the European Reference Network for Hereditary Metabolic Disorders (MetabERN). Thirty-seven colleagues representing at least 35 European metabolic centres shared their experience and results were discussed at the European Metabolic Group (EMG) meeting 2022. The centres concurred in many aspects of long-term monitoring of LCFAOD including the frequency of clinical visits, determination of laboratory parameters, cardiac monitoring and retinopathy screening. Main discrepancies comprised hepatic imaging, glucose monitoring and electrophysiological investigations. Discrepancies may reflect differences in local availability of monitoring tools, the inclusion of LCFAOD in NBS programs as well as differences in local genotypes and phenotypes. Because monitoring strategies are largely based on the natural disease course of clinically identified patients, there might be over-monitoring of some NBS patients. Nevertheless, we advocate long-term monitoring because resulting information is essential to further characterize the natural disease course, develop evidence-based guidelines and provide a basis for evaluation of future therapies.

Stilbenes-enriched peanut sprouts alleviated physical fatigue via regulating interactions of nutrients-microbiota-metabolites revealed by multi-omics analysis.

In this study, the antifatigue effect and mechanism of peanut sprouts were explored. BALB/c mice divided into three groups (control, dark and UV-C) were respectively supplemented with a normal diet, peanut sprouts (dark germination) added diet and stilbenes-enriched peanut sprouts (UV-C radiated germination) added diet. Results showed that swimming time and levels of blood glucose and antioxidant enzymes significantly increased, while contents of triglyceride and malondialdehyde notably decreased by peanut sprout supplementation. Besides, combined analysis of gut microbiota gene sequencing and targeted metabolomics of fecal metabolites revealed that peanut sprout supplementation up-regulated abundances and metabolic transformations of Catenibacillus, Odoribacter, Prevotellaceae-UCG-001 and Butyricicoccus while it down-regulated the abundance of Parabacteroides. Consequently, contents of sebacic acid, azelaic acid, suberic acid, heptanoic acid, pimelic acid, aminoadipic acid and mono-phenolics notably increased, which were markedly correlated with the antifatigue effect. Compared with the dark group, the swimming time, glutathione peroxidase activity, methylmalonylcarnitine content and abundances of Butyricicoccus, Catenibacillus and Lachnospiraceae NK4A136 were higher in the UV-C group, while opposite results were obtained for the levels of triglyceride, malondialdehyde, alpha-linolenic acid, gamma-linolenic acid, 10Z-heptadecenoic acid and palmitelaidic acid. Overall, peanut sprout supplementation could alleviate fatigue by modulating gut microbiota composition to promote fatty acid oxidation and lysine and stilbene catabolism to increase energy supply and regulate redox balance. UV-C-radiated peanut sprout supplementation could alleviate fatigue more effectively by up-regulating abundances of Butyricicoccus, Catenibacillus and Lachnospiraceae NK4A136 to promote long-chain fatty acid oxidation and catabolism of flavonoids and stilbenes efficiently.

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.

A different perspective into clinical symptoms in CPT I deficiency

Carnitine palmitoyltransferase I (CPT I) deficiency is an autosomal recessive disorder causing long-chain fatty acid oxidation defect, characterized by metabolic decompensation episodes accompanied by hypoketotic hypoglycemia, hepatomegaly, seizures, renal tubular acidosis, and hyperammonemia. The aim of this study was to investigate the neurological symptoms in CPT I deficiency and different outcomes with respect to predisposing factors for sequela and to draw attention to the neurological impairment that may develop during the course of the disease. The retrospective study reviewed clinical characteristics of 14 patients. Mean follow-up period was 10.3 ± 4.7 (range: 8 months-18.6 years; median: 10 years) years. Three patients were diagnosed with newborn screening. In the symptomatic group (n = 12) most common presenting symptoms were psychomotor retardation (n = 6), seizures (n = 5), encephalopathy (n = 5), dystonia (n = 1), Reye-like syndrome (n = 5), muscle weakness (n = 3), and autism (n = 1). Neurologic findings detected in the follow-up period included speech disorder (n = 9), abnormal cranial MRI findings (n = 5), neuropathy (n = 1), and attention deficit hyperactivity disorder (n = 1). Speech disorders collectively included delayed expressive language development, speech articulation disorder, speech delay, stuttering, and specific speech difficulties. After starting treatment for CPT I deficiency, speech disorders improved in 3 patients. Our findings confirmed that the clinical manifestations of CPT I deficiency is wider than previously thought, causing specific neurologic dysfunction, mainly speech disorders at a large scale, that were unexpected in a fatty acid oxidation disorder. We suggest that early diagnosis and treatment is the key factor to prevent neurologic sequelae while an extensive neurological evaluation is essential in patients with CPT I deficiency both at the time of diagnosis and during the follow-up period.

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.

Experience with carnitine palmitoyltransferase II deficiency: diagnostic challenges in the myopathic form.

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of long-chain fatty acid oxidation. Three clinical phenotypes, lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form, have been described in CPT II deficiency. The myopathic form is usually mild and can manifest from infancy to adulthood, characterised by recurrent rhabdomyolysis episodes. The study aimed to investigate the clinical features, biochemical, histopathological, and genetic findings of 13 patients diagnosed with the myopathic form ofCPT II deficiency at Ege University Hospital. A retrospective study was conducted with 13 patients with the myopathic form of CPT II deficiency. Our study considered demographic data, triggers of recurrent rhabdomyolysis attacks, biochemical metabolic screening, and molecular analysis. Ten patients were examined for rhabdomyolysis ofunknown causes. Two patients were diagnosed during family screening, and one was diagnosed during investigations due to increased liver function tests. Acylcarnitine profiles were normal in five patients during rhabdomyolysis. Genetic studies have identified a c.338C>T (p.Ser113Leu) variant homozygous in 10 patients. One patient showed a novel frameshift variant compound heterozygous with c.338C>T (p.Ser113Leu). Plasma acylcarnitine analysis should be preferred as it is superior to DBS acylcarnitine analysis in diagnosing CPT II deficiency. Even if plasma acylcarnitine analysis is impossible, CPT2 gene analysis should be performed. Our study emphasizes that CPT II deficiency should be considered in the differential diagnosis of recurrent rhabdomyolysis, even if typical acylcarnitine elevation does not accompany it.

Heptanoate Improves Compensatory Mechanism of Glucose Homeostasis in Mitochondrial Long-Chain Fatty Acid Oxidation Defect.

Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. Very-long-chain acyl-CoA dehydrogenase (VLCADD; OMIM 609575) deficiency is the most common long-chain mitochondrial FAO disorder presenting with hypoglycemia as a common clinical manifestation. To prevent hypoglycemia, triheptanoin-a triglyceride composed of three heptanoates (C7) esterified with a glycerol backbone-can be used as a dietary treatment, since it is metabolized into precursors for gluconeogenesis. However, studies investigating the effect of triheptanoin on glucose homeostasis are limited. To understand the role of gluconeogenesis in the pathophysiology of long-chain mitochondrial FAO defects, we injected VLCAD-deficient (VLCAD-/-) mice with 13C3-glycerol in the presence and absence of heptanoate (C7). The incorporation of 13C3-glycerol into blood glucose was higher in VLCAD-/- mice than in WT mice, whereas the difference disappeared in the presence of C7. The result correlates with 13C enrichment of liver metabolites in VLCAD-/- mice. In contrast, the C7 bolus significantly decreased the 13C enrichment. These data suggest that the increased contribution of gluconeogenesis to the overall glucose production in VLCAD-/- mice increases the need for gluconeogenesis substrate, thereby avoiding hypoglycemia. Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.

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.