Cardiac phenotype in adolescents and young adults with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency.

PURPOSE: Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) is a rare fatty acid oxidation disorder characterized by recurrent episodes of metabolic decompensation and rhabdomyolysis, as well as retinopathy, peripheral neuropathy, and cardiac involvement, such as infantile dilated cardiomyopathy. Because LCHADD patients are surviving longer, we sought to characterize LCHADD-associated major cardiac involvement in adolescence and young adulthood. METHODS: A retrospective cohort of 16 adolescent and young adult participants with LCHADD was reviewed for cardiac phenotype. RESULTS: Major cardiac involvement occurred in 9 of 16 participants, including sudden death, out-of-hospital cardiac arrest, acute cardiac decompensations with heart failure and/or in-hospital cardiac arrest, end-stage dilated cardiomyopathy, and moderate restrictive cardiomyopathy. Sudden cardiac arrest was more common in males and those with a history of infant cardiomyopathy. CONCLUSION: The cardiac manifestations of LCHADD in adolescence and early adulthood are complex and distinct from the phenotype seen in infancy. Life-threatening arrhythmia occurs at substantial rates in LCHADD, often in the absence of metabolic decompensation or rhabdomyolysis. The potential risk factors identified here-male sex and history of infant cardiomyopathy-may hint at strategies for risk stratification and possibly the prevention of these events.

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.

Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy.

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.

Diverse and unselected adults with clinically relevant ACADS variants lack evidence of metabolic disease.

INTRODUCTION: The clinical significance of Short-chain acyl CoA dehydrogenase deficiency (SCADD), caused by biallelic variation in the ACADS gene, is contested. Clinically ascertained individuals have a range of reported metabolic and physical symptoms. Conversely, individuals identified through newborn screening remain overwhelmingly asymptomatic. Two common ACADS variants, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser) are known to reduce enzymatic activity with undetermined clinical correlate. We applied a genome-first approach to evaluate the prevalence and clinical consequences of ACADS variants in an ancestrally diverse and unselected patient population. MATERIAL AND METHODS: We used exome sequence data linked to electronic health records (EHRs) to identify clinically relevant ACADS variants, and estimate their prevalence and clinical implications in 27,447 ancestrally diverse and unrelated adults from the BioMe Biobank in New York, NY. We extracted International Classification of Diseases, ninth (ICD-9) and tenth (ICD-10) revision codes corresponding to eight SCADD-associated phenotypes relevant to adults from participants' EHRs. Phenotypes included intellectual disability, behavioral disorders with onset in childhood, epilepsy or seizure disorders, hypoglycemia, muscle weakness, metabolic acidosis, fatty liver, and a diagnosis of SCADD or disorder of fatty acid oxidation. We performed manual chart reviews for individuals homozygous for rare pathogenic variants. Multivariate logistic regression was used to determine the association between clinically relevant ACADS variants and phenotypes of interest. RESULTS: 1 in 10,000 BioMe participants were homozygous for rare pathogenic variants (PVs) in ACADS, 1 in 20 were homozygous or presumed compound heterozygous for common variants (CVs), and 1 in 300 harbored both a PV and a CV. Of the 2035 variant positive individuals, none had a documented diagnosis of SCADD. We identified five PV/PV positive individuals, none of whom had evidence of symptomatic SCADD on manual chart review. CV/CV positive and CV/PV positive individuals did not have increased odds of any of the eight ACADS phenotypes evaluated compared to variant negative individuals (OR for CV/CV 0.99, 95% CI 0.86-1.1, p = .88; OR for CV/PV OR 1.49, 95% CI 0.87-2.6, p = .15). CONCLUSIONS: The prevalence of clinically relevant ACADS variants in an unselected population was higher than previously reported SCADD prevalence of 1 in 35,000 in the United States. Clinically relevant variants in ACADS were not associated with evidence of metabolic disease in a large and ancestrally diverse adult population. These findings support the assertion that SCADD is more likely a biochemical entity without clinical correlate, in particular when caused by one or more common variants.

Exercise testing and prescription in patients with inborn errors of muscle energy metabolism.

Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and primary mitochondrial myopathies.

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.

Successful orthotopic heart transplantation in CPTII deficiency.

Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders.

Clinical manifestations and management of fatty acid oxidation disorders.

Fatty acid oxidation disorders (FAOD) are a group of rare, autosomal recessive, metabolic disorders caused by variants of the genes for the enzymes and proteins involved in the transport and metabolism of fatty acids in the mitochondria. Those affected by FAOD are unable to convert fatty acids into tricarboxylic acid cycle intermediates such as acetyl-coenzyme A, resulting in decreased adenosine triphosphate and glucose for use as energy in a variety of high-energy-requiring organ systems. Signs and symptoms may manifest in infants but often also appear in adolescents or adults during times of increased metabolic demand, such as fasting, physiologic stress, and prolonged exercise. Patients with FAOD present with a highly heterogeneous clinical spectrum. The most common clinical presentations include hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Despite efforts to detect FAOD through newborn screening and manage patients early, symptom onset can be sudden and serious, even resulting in death. Therefore, it is critical to identify quickly and accurately the key signs and symptoms of patients with FAOD to manage metabolic decompensations and prevent serious comorbidities.

Cardiac tissue citric acid cycle intermediates in exercised very long-chain acyl-CoA dehydrogenase-deficient mice fed triheptanoin or medium-chain triglyceride.

Anaplerotic odd-chain fatty acid supplementation has been suggested as an approach to replenish citric acid cycle intermediate (CACi) pools and facilitate adenosine triphosphate (ATP) production in subjects with long-chain fatty acid oxidation disorders, but the evidence that cellular CACi depletion exists and that repletion occurs following anaplerotic substrate supplementation is limited. We exercised very long-chain acyl-CoA dehydrogenase-deficient (VLCAD-/-) and wild-type (WT) mice to exhaustion and collected cardiac tissue for measurement of CACi by targeted metabolomics. In a second experimental group, VLCAD-/- and WT mice that had been fed chow prepared with either medium-chain triglyceride (MCT) oil or triheptanoin for 4 weeks were exercised for 60 minutes. VLCAD-/- mice exhibited lower succinate in cardiac muscle at exhaustion than WT mice suggesting lower CACi in VLCAD-/- with prolonged exercise. In mice fed either MCT or triheptanoin, succinate and malate were greater in VLCAD-/- mice fed triheptanoin compared to VLCAD-/- animals fed MCT but lower than WT mice fed triheptanoin. Long-chain odd acylcarnitines such as C19 were elevated in VLCAD-/- and WT mice fed triheptanoin suggesting some elongation of the heptanoate, but it is unknown what proportion of heptanoate was oxidized vs elongated. Prolonged exercise was associated with decreased cardiac muscle succinate in VLCAD-/- mice in comparison to WT mice. VLCAD-/- fed triheptanoin had increased succinate compared to VLCAD-/- mice fed MCT but lower than WT mice fed triheptanoin. Cardiac CACi were higher following dietary ingestion of an anaplerotic substrate, triheptanoin, in comparison to MCT.

Short-chain acyl-CoA dehydrogenase deficiency: from gene to cell pathology and possible disease mechanisms.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an inherited disorder of mitochondrial fatty acid oxidation that is characterized by the presence of increased butyrylcarnitine and ethylmalonic acid (EMA) concentrations in plasma and urine. Individuals with symptomatic SCADD may show relatively severe phenotype, while the majority of those who are diagnosed through newborn screening by tandem mass spectrometry may remain asymptomatic. As such, the associated clinical symptoms are very diverse, ranging from severe metabolic or neuromuscular disabilities to asymptomatic. Molecular analysis of affected individuals has identified rare gene variants along with two common gene variants, c.511C > T and c.625G > A. In vitro studies have demonstrated that the common variants as well as the great majority of rare variants, which are missense variants, impair folding, that may lead to toxic accumulation of the encoded protein, and/or metabolites, and initiate excessive production of ROS and chronic oxidative stress. It has been suggested that this cell toxicity in combination with yet unknown factors can trigger disease development. This association and the full implications of SCADD are not commonly appreciated. Accordingly, there is a worldwide discussion of the relationship of clinical manifestation to SCADD, and whether SCAD gene variants are disease associated at all. Therefore, SCADD is not part of the newborn screening programs in most countries, and consequently many patients with SCAD gene variants do not get a diagnosis and the possibilities to be followed up during development.

Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency can present at various ages from the neonatal period to adulthood, and poses the greatest risk of complications during intercurrent illness or after prolonged fasting. Early diagnosis, treatment, and surveillance can reduce mortality; hence, the disorder is included in the newborn Recommended Uniform Screening Panel (RUSP) in the United States. The Inborn Errors of Metabolism Information System (IBEM-IS) was established in 2007 to collect longitudinal information on individuals with inborn errors of metabolism included in newborn screening (NBS) programs, including VLCAD deficiency. We retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by NBS and describe initial presentations, diagnosis, clinical outcomes and treatment in a cohort of 52 individuals ages 1-18years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2/52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1-3years of age). Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified.

Long-term major clinical outcomes in patients with long chain fatty acid oxidation disorders before and after transition to triheptanoin treatment--A retrospective chart review.

BACKGROUND: Long chain fatty acid oxidation disorders (LC-FAODs) are caused by defects in the metabolic pathway that converts stored long-chain fatty acids into energy, leading to a deficiency in mitochondrial energy production during times of physiologic stress and fasting. Severe and potentially life threatening clinical manifestations include rhabdomyolysis, hypoglycemia, hypotonia/weakness, cardiomyopathy and sudden death. We present the largest cohort of patients to date treated with triheptanoin, a specialized medium odd chain (C7) triglyceride, as a novel energy source for the treatment of LC-FAOD. METHODS: This was a retrospective, comprehensive medical record review study of data from 20 of a total 24 patients with LC-FAOD who were treated for up to 12.5 years with triheptanoin, as part of a compassionate use protocol. Clinical outcomes including hospitalization event rates, number of hospitalization days/year, and abnormal laboratory values were determined for the total period of the study before and after triheptanoin treatment, as well as for specified periods before and after initiation of triheptanoin treatment. Other events of interest were documented including rhabdomyolysis, hypoglycemia, and cardiomyopathy. RESULTS: LC-FAOD in these 20 subjects was associated with 320 hospitalizations from birth to the end date of study. The mean hospitalization days/year decreased significantly by 67% during the period after triheptanoin initiation (n=15; 5.76 vs 17.55 vs; P=0.0242) and a trend toward a 35% lower hospitalization event rate was observed in the period after triheptanoin initiation compared with the before-treatment period (n=16 subjects >6 months of age; 1.26 vs 1.94; P=0.1126). The hypoglycemia event rate per year in 9 subjects with hypoglycemia problems declined significantly by 96% (0.04 vs 0.92; P=0.0091) and related hospitalization days/year were also significantly reduced (n=9; 0.18 vs 8.42; P=0.0257). The rhabdomyolysis hospital event rate in 11 affected subjects was similar before and after treatment but the number of hospitalization days/year trended lower in the period after triheptanoin initiation (n=9; 2.36 vs 5.94; P=0.1224) and peak CK levels trended toward a 68% decrease from 85,855 to 27,597 units in 7 subjects with reported peak CK values before and after treatment (P=0.1279). Triheptanoin was generally well tolerated. Gastrointestinal symptoms were the most commonly reported side effects. CONCLUSIONS: This retrospective study represents the largest analysis reported to date of treatment of LC-FAOD with triheptanoin. The data suggest that triheptanoin improves the course of disease by decreasing the incidence and duration of major clinical manifestations and should be the focus of prospective investigations. Significant heterogeneity in the routine clinical care provided to subjects during the periods studied and the natural variation of clinical course of LC-FAODs with time emphasize the need of additional study of the use of triheptanoin.

Acute fatty liver of pregnancy associated with fetal mitochondrial trifunctional protein deficiency.

Acute fatty liver of pregnancy (AFLP) is a devastating disorder of the maternal liver in the third trimester. Recent studies have demonstrated an association between AFLP and fetal fatty acid oxidation disorders. Here, we report a case of AFLP caused by fetal mitochondrial trifunctional protein (TFP) deficiency. A 21-year-old parous woman presented with nausea, genital bleeding and abdominal pain at 33 weeks of gestation. Laboratory data revealed hepatic failure and disseminated intravascular coagulopathy. The patient underwent emergency cesarean section and was diagnosed with AFLP from the clinical characteristics. She was successfully treated with frequent plasma exchange. The newborn presented severe heart failure and died on the 39th day after birth. Tandem mass spectrometry indicated long-chain fatty acid oxidation disorder. Gene analysis demonstrated homozygous mutation in exon 13 of HADHB, the gene responsible for mitochondrial TFP deficiency. The parents carried a heterozygous mutation at the same location in HADHB.

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

OBJECTIVES: 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 of CPT II deficiency at Ege University Hospital. METHODS: 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. RESULTS: Ten patients were examined for rhabdomyolysis of unknown 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). CONCLUSIONS: 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.

Understanding patient, caregiver, and healthcare provider perspectives of the management of long-chain fatty acid oxidation disorders.

Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of rare, inherited, metabolic disorders that can lead to a wide range of symptoms that predominantly affect organ systems with high energy needs, such as the heart, liver, skeletal muscle, and nervous system. Clinical management primarily consists of close attention to and monitoring of diet and activity and avoidance of prolonged fasting. In addition, patients and caregivers must be alert for signs of life-threatening metabolic decompensation. As a result, LC-FAODs can have significant and wide-ranging impacts on the lives of patients and their caregivers. This article describes the effects of LC-FAODs at different life stages and in the context of the North American healthcare system from the perspective of a group of patients, caregivers, and healthcare providers (n = 6). We explain how challenges and needs change throughout life. Following an early diagnosis, an adjustment phase occurs during which caregivers may feel overwhelmed by their new roles and deeply concerned for their children's futures. As children grow, they become more aware of the differences between themselves and their peers, and with increasing independence comes more responsibility for managing their own condition. Major life events, such as new employment and moving house, pose challenges for people of all ages. In addition, it may be difficult to find and connect with qualified and experienced healthcare providers; navigate the health insurance system; and educate and align primary, specialist, and emergency care providers. We propose several strategies to improve the care of patients with LC-FAODs, such as educating local healthcare teams, improving trust between patients/caregivers and healthcare providers, and raising awareness of the challenges faced by patients and caregivers across the different life stages.

Living with long-chain fatty acid oxidation disorders from the point of view of patient, caregiver, and healthcare providers. What is a long-chain fatty acid oxidation disorder? Long-chain fatty acid oxidation disorders (or LC-FAODs for short) are rare health conditions in which the body cannot use certain types of fats for energy.People with LC-FAODs may have many symptoms. The symptoms mainly affect the muscles, heart, nerves, and liver.LC-FAODs are managed by closely watching what is eaten and when, and how much activity is done. This can be very stressful.Looking out for signs of serious health problems and working out which healthcare team to see and when can also be worrying.For this reason, LC-FAODs can have an impact on the mental health of people living with LC-FAODs and their caregivers. What is this article about? We describe how LC-FAODs affect people at different times in their lives.We write from our point of view as patients, caregivers, and healthcare providers in the United States.We explain how challenges and needs change over time. Initially, parents may find it hard to adjust to caring for a child with an LC-FAOD. They may also be very worried about their child.As people grow older, they must learn to manage their condition on their own.They also need to adjust to major life changes such as moving house and starting a new job.We also talk about how it can be hard to find doctors who know about LC-FAODs because the conditions are so rare.We suggest ways to improve care for people with LC-FAODs and their families, for example: Getting healthcare teams to help each other learn about LC-FAODs by sharing knowledge with each otherHelping people learn about the challenges faced by people with LC-FAODsImproving the trust between patients and healthcare providers.

VLCAD deficiency in a patient who recovered from ventricular fibrillation, but died suddenly of a respiratory syncytial virus infection.

VLCAD deficiency is an autosomal recessive disorder caused by a defect of fatty acid oxidation. The phenotype is classified into three clinical forms on the basis of the onset of symptoms: a severe form with neonatal onset; a milder form with childhood onset; and a late-onset form. The neonatal form is the most common, and has a higher mortality rate than the others. We report the case of a newborn infant with VLCAD deficiency who developed ventricular fibrillation, which was successfully treated by intensive care, but who suddenly died after a respiratory syncytial virus infection. Early institution of i.v. glucose treatment and active immunization with vaccine, such as palivizumab (anti-RSV mAb), may be important to reduce the frequency and severity of life-threatening episodes.

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

Defects in mitochondrial fatty acid ß-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.

Anthropometric Parameters in Patients with Fatty Acid Oxidation Disorders: A Case-Control Study, Systematic Review and Meta-Analysis.

This study compared the anthropometric parameters of patients with fatty acid oxidation disorders (FAOD) and healthy controls, showing an increased prevalence of abnormal body weight (overweight and obesity) in the FAOD group. First, differences in BMI, BMI percentiles and z-scores, and weight and weight percentiles were compared in a cohort of 39 patients with FAOD and 156 healthy controls, as well as between patients born before and after the introduction of a populational newborn screening programme (NBS) in 2014 in Poland. We also performed a systematic literature review yielding 12 studies mentioning anthropometric parameters in 80 FAOD patients and 121 control subjects, followed by a meta-analysis of data from 8 studies and our cohort. There were significant differences in body weight percentiles (p = 0.001), BMI (p = 0.022), BMI percentiles (p = 0.003) and BMI z-scores (p = 0.001) between FAOD patients and controls in our cohort but not between pre- and post-newborn-screening patients. The meta-analysis did not show any differences in weight and BMI in all tested subgroups, i.e., all FAOD patients vs. controls, medium-chain acyl-CoA dehydrogenase (MCADD) patients vs. controls and patients with FAOD types other than MCAD vs. controls. These results, however, should be interpreted with caution due to the overall low quality of evidence as assessed by GRADE, the small sample sizes and the significant heterogeneity of the included data.

Epilepsy and inborn errors of metabolism in adults: The diagnostic odyssey of a young woman with medium-chain acyl-coenzyme A dehydrogenase deficiency.

We describe a case of epileptic encephalopathy in a young woman with undiagnosed medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), who presented with an early-onset focal motor status epilepticus (SE) then followed by permanent left hemiplegia and drug-resistant epilepsy with neurodevelopmental delay. Throughout her clinical history, recurrent episodes of lethargy, feeding difficulties, and clustering seizures occurred, progressing into a super refractory SE and death at the age of 25 years. Although epilepsy is not a distinctive feature of MCADD, we advise considering this metabolic disease as a possible etiology of epileptic encephalopathy and hemiconvulsion-hemiplegia-epilepsy syndrome of unknown origin, on the chance to provide a timely and targeted treatment preventing development delay and evolution to SE. Adult patients with epilepsy of unknown etiology not screened at birth for inborn errors of metabolism, such as MCADD, should be promptly investigated for these treatable conditions.

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.