Fatty Acid Oxidation Disorders Research Articles

Moroccan Experience of Targeted Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry.

Expanded newborn screening using tandem mass spectrometry (MS/MS) for inborn errors of metabolism (IEM), such as organic acidemias (OAs), fatty acid oxidation disorders (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in Africa. With this study, we aim to establish the disease spectrum and frequency of inborn errors of OAs, FAODs, and AAs in Morocco. Selective screening was performed among infants and children suspected to be affected with IEM between 2016 and 2021. Amino acids and acylcarnitines spotted on filter paper were analyzed using MS/MS. Out of 1178 patients with a clinical suspicion, 137 (11.62%) were diagnosed with IEM, of which 121 (88.3%) patients suffered from amino acids disorders, 11 (8%) were affected by FAOD, and 5 (3.7%) by an OA. This study shows that various types of IEM are also present in Morocco. Furthermore, MS/MS is an indispensable tool for early diagnosis and management of this group of disorders.

Establishment of Age Specific Reference Interval for Aminoacids and Acylcarnitine in Dried Blood Spot by Tandem Mass Spectrometry.

The Extended Screening for Inborn Errors of Metabolism is done for aminoacidopathies, fatty acid oxidation disorders and organic acid disorders. In a single dried blood spot, the tandem mass spectrometry is capable of measuring multiple analytes like amino acids, acylcarnitines, nucleosides, succinylacetone and lysophosphatidylcholines. This study was proposed to establish age specific reference internal for aminoacids and acylcartinitine in dried blood spot by tandem mass spectrometry. A total of 480 apparently healthy children were enrolled for the study and sub classified into four groups as follows: Group A: 0-1month, Group B: 1month-1year, Group C: 1-5year and Group D: 5-12years each having 120 participants. Sample size were calculated as per CLSI approved guidelines. Tables 1 and 2 presents the age-specific percentile distribution of aminoacids and acylcarnitines established from healthy subjects as per rank-based method recommended by the IFCC and CLSI. Tables 3, 4 and 5 presents the cut-off values of primary and secondary marker/ratios for screening of aminoacidopathies, fatty acid oxidation disorders and organic acid disorders respectively. As a general principle, the interpretation of extended newborn screening results should be based on age specific cut-off established by the laboratory for primary analyte concentration and secondary analyte concentration/ ratios. This study was useful in establishing age specific cut-off values for various amino acids and acylcarnitines in South Indian population. [Table: see text] [Table: see text] [Table: see text] [Table: see text] [Table: see text].

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.

UPDATED CLINICAL PROTOCOLS OF INHERITED FATTY ACID OXIDATION DISORDERS IN NEWBORNS: CONSOLIDATED DATA FROM THE INTERNATIONAL CLINICAL GUIDELINES

Fatty acid oxidation disorders (FAODs) are a group of inherited metabolic diseases (IMDs) caused by impairments in mitochondrial β-oxidation of fatty acids (FA) due to defects in genes encoding enzymes, transporters, membrane channels, and receptors that mediate this process. A common characteristic of this group of IMDs is an energy deficit associated with suppression of energy metabolism in mitochondria due to a decrease in the production of ketone bodies and the substrate of the tricarboxylic acid cycle – acetyl-coenzyme A. Since energy deficiency is a common pathogenetic factor of the entire group of FAODs, the manifestation of these inherited diseases is similar, and only certain nosologies have specific differences in the clinical picture, accordingly, these disorders require similar treatment. Initial manifestations of FAODs in neonatal and early childhood most often include cardiomyopathy, liver dysfunction, and hypoketotic hypoglycemia. For newborns with FAOD, the main danger is rapidly progressing crisis states of metabolic decompensation with severe, often fatal consequences. In adolescence, in addition to the above severe symptoms, episodes of rhabdomyolysis may also occur.Since long intervals between meals are one of the main factors provoking episodes of metabolic decompensation in patients with FAODs, the key tool for their prevention is the avoidance of prolonged fasting. In cases of the development of metabolic crisis states, symptomatic treatment is used with the introduction of carnitine according to indications. The special role of carnitine is its involvement in the transport of long-chain fatty acids through the mitochondrial membrane. Treatment of FAODs caused by a deficiency of enzymes whose substrates are long-chain fatty acids involves the use of a low-fat diet and the addition of medium-chain triglycerides and docosahexaenoic acid to the diet. Success in treating IMDs as such and FAODs, particularly, is directly related to early detection of the disease and treatment beginning since the destructive effect of toxic metabolites on internal organs and the brain increases according to the duration of exposure, leading to their progressive damage and delay in physical and mental development.An effective tool for the early detection of newborns with IMDs is the extended neonatal screening program, the implementation of which, according to the WHO, has become the greatest achievement of the health care systems of the developed countries of the world in reducing the levels of child mortality and disability in the first 10 years of the 21st century. In 2019, the program of extended newborn screening of IMDs was started in Ukraine at the initiative of the State Institution “Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova of the National Academy of Medical Sciences of Ukraine”, “Association of Neonatologists of Ukraine” and “CDC Pharmbiotest” (Baby Screen, https://baby-screen.com.ua).One of the main reasons that limit the general use of this diagnostic procedure is doctors' lack of awareness and attention regarding IMDs, the causes of these serious diseases, diagnostic search algorithms, approaches to treatment, and patient follow-up. There is an urgent need for concise medical information that includes: a brief description of the individual genetic defect; characteristics of biochemical disorders and a list of marker substances that accumulate in the blood and urine of a newborn with IMDs; procedures of primary and clarifying laboratory studies; clinical manifestations of the disease; treatment strategy and prognosis. At the discretion of the Baby Screen team, this information is provided in the form of concise protocols.In this publication, we present eight Clinical Protocols, which were prepared by a team of specialists in metabolic pediatrics, medical genetics, and laboratory analytics, who were trained in the leading medical and genetic centers of the EU countries and regularly participate in training and scientific-practical seminars on this topic. The sources of information given in the protocols are international and national guidelines on extended neonatal screening, websites of leading organizations specializing in the diagnosis and treatment of IMDs, and well-known monographs and periodicals.

Incidence and genetic variants of inborn errors of metabolism identified through newborn screening: A 7-year study in eastern coastal areas of China.

The incidence of inborn errors of metabolism (IEM) varies across countries and areas. Currently, there are no studies on IEM using newborn screening (NBS) in eastern coastal areas of China. We aimed to estimate the incidence and genetic variants of IEM and understand the spectrum of diseases caused by IEM and variants among them in this area. The NBS performed by tandem mass spectrometry (MS/MS) from 2016 to 2021 was retrospectively reviewed. Heel blood was collected from all newborns 72 h after birth. Targeted massively parallel sequencing was performed for genetic analysis. Among 245,194 newborns, 95 were diagnosed with IEM, the overall incidence observed was-IEM: 1/2581; amino acid metabolism disorder: 1/4715; organic acid metabolism disorder: 1/11676; and fatty acid metabolism disorder: 1/11145. The incidence of different IEM was in the range of 1/245194 to 1/6452. Phenylketonuria (PKU, 1/7211) was the most common IEM, followed by methylmalonic acidemia (MMA, 1/27244), short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/30649), and citrin deficiency (CD, 1/35028). For genetic variants, the common hotspot variants found were-PAH gene for PKU: c.728G > A, c.442-1G > A, c.611A > G, c.721C > T; PTS gene for non-classical PKU: c.259C > T; MMACHC gene for MMA: c.658_660delAAG, c.609G > A; MMUT gene for MMA: c.1663G > A; ACADS gene for SCADD: c.1031A > G and c.1130C > T; and SLC25A13 gene for CD: c.1638_1660dup, c.852_855del. This study displayed the diseases and varied spectrum of IEM in eastern coastal areas of China. Implementing NBS for IEM by MS/MS combined with massively parallel sequencing can offer an improved plan for NBS to detect IEM.

Free amino acid and acylcarnitine values in Ursus americanus Pallas 1780 (black bear) from Northeastern Mexico.

Ursus americanus Pallas 1780 is the largest carnivore and the only ursid in Mexico. It is considered an endangered species in the country because its distribution and population have been reduced by up to 80% because of habitat loss or furtive hunting. These problems can lead to a diet change, which could result in metabolic disorders, such as fatty acid β-oxidation defects or organic acid metabolism disorders. In our study, a free amino acid and acylcarnitine profile was characterized. Peripheral blood samples were drawn from nine free-ranging black bears in a period of five months, from June to October of 2019 in Northeastern Mexico, and 12 amino acids and 30 acylcarnitines were determined and quantified. Age differences were observed in the samples through ANOVA and post-hoc Tukey test. Only three metabolites showed a significant difference with age: alanine (Ala) [cubs vs juvenile], free-carnitine (C0) [juvenile vs cubs] and acetylcarnitine (C2) [cubs vs adults and juvenile vs cubs]. Metabolites with variability due to age were identified, making them potential biomarkers to monitor metabolic status as early diagnosis in endangered species. This is the first study of black bear amino acid and acylcarnitine profiles, and the values found could be used as reference for free amino acid and acylcarnitine concentrations in further studies of the species.

Newborn Screening of Primary Carnitine Deficiency: An Overview of Worldwide Practices and Pitfalls to Define an Algorithm before Expansion of Newborn Screening in France.

Primary Carnitine Deficiency (PCD) is a fatty acid oxidation disorder that will be included in the expansion of the French newborn screening (NBS) program at the beginning of 2023. This disease is of high complexity to screen, due to its pathophysiology and wide clinical spectrum. To date, few countries screen newborns for PCD and struggle with high false positive rates. Some have even removed PCD from their screening programs. To understand the risks and pitfalls of implementing PCD to the newborn screening program, we reviewed and analyzed the literature to identify hurdles and benefits from the experiences of countries already screening this inborn error of metabolism. In this study, we therefore, present the main pitfalls encountered and a worldwide overview of current practices in PCD newborn screening. In addition, we address the optimized screening algorithm that has been determined in France for the implementation of this new condition.

Unexpected neonatal death due to medium-chain acyl-CoA deficiency

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder, with an incidence of 1:19,000 live births in Australia.1 The typical presentation of MCADD is between 3 and 24 months of age and include hypoglycaemia, hepatomegaly and sudden death.2 Our case is a full term well grown male baby who was born in good condition. He became lethargic and had long periods without feeds on day 2 of life. On day 3 of life, he developed tachypnoea and grunting and was admitted to the Neonatal Intensive Care Unit at The Royal Children’s Hospital.

Postmortem Genetic Testing in Sudden Unexpected Death: A Narrative Review.

Sudden unexpected death (SUD) is one of the challenging situations encountered in forensic medicine. As a rule, a comprehensive forensic assessment is performed to identify the cause of death in such cases; however, the absence of findings suggestive of a cause, i.e., a negative autopsy, warrants further investigation such as a molecular autopsy. In this review, we aim to highlight the genetic causes of SUD, tools used in a molecular autopsy, and the role of screening in surviving relatives. As per several guidelines, the most preferred samples for DNA extraction are whole blood and fresh frozen tissues. Furthermore, Sanger sequencing and next-generation sequencing are the technologies that are used for genetic analysis; the latter overcomes the former's drawbacks in terms of cost-effectiveness, time consumption, and the ability to sequence the whole exome. SUD have diverse etiologies; we can generally classify them into cardiac and non-cardiac causes. Regarding cardiac causes, many conditions having an underlying genetic basis are included, such as channelopathies and cardiomyopathies. Regarding non-cardiac causes of SUD, the main etiologies are epilepsy and metabolic disorders. Nevertheless, it has been proposed that there is a genetic overlap between channelopathies, especially long QT syndromes and epilepsy. Additionally, fatty acid oxidation disorders are major metabolic conditions that are caused by certain genetic mutations that can lead to SUD in infancy. Since many SUD causes have an underlying genetic mutation, it is important to understand the genetic variations not only to recognize the cause of death but also to undertake further preventive measures for surviving relatives. In conclusion, a molecular autopsy has a major role in the forensic examination of cases of SUD.

Improving diagnosis of mitochondrial fatty-acid oxidation disorders

Improving diagnosis of mitochondrial fatty-acid oxidation disorders

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

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. 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. 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). 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.

Mass spectrometry for screening of metabolic disorders

Background/aim Inborn errors of metabolism (IEM) are a group of congenital disorders that result from deficiency of enzymes or transporters involved in different metabolic pathways in the human body. The most severe form of these disorders appears early in the neonatal period; however, most types of IEMs are responsive to treatment if started early enough before the appearance of serious complications. The introduction of mass spectrometric techniques for analysis of metabolites accumulated in IEM facilitates the early diagnosis through enabling analysis of a large number of samples in a short period of time using small sample sizes suitable for patients in the neonatal period. The aim of this study was to find out the prevalence of amino acids, fatty acids, and organic acids disorders, using mass spectrometry among Egyptian children with metabolic disorders who were referred to the Biochemical Genetics Lab, Human Genetics, and Genome Research Institute, National Research Centre, Cairo, Egypt, over a period of 9 years. Patients and methods The present study enrolled 9245 children who visited Biochemical Genetics Department, Human Genetics, and Genome Research Institute, National Research Centre Cairo, Egypt, during the period from 2013 to 2021. All children were subjected to quantitative analysis of amino acids and acylcarnitine profiles in blood, using liquid chromatography/tandem mass spectrometry, whereas qualitative analysis of organic acids was done in urine by gas chromatography/mass spectrometry. Results Of 9245 suspected patients, 552 (5.97%) patients were diagnosed with 13 different types of IEM. A total of 383 (4.1%) patients were diagnosed with aminoacidopathies, 167 (1.8%) patients were diagnosed with organic acidurias, and two (0.02%) patients were diagnosed with fatty acid oxidation disorders. Phenylketonuria is the most prevalent IEM of this study (2%) followed by maple syrup urine disease (0.98%). Conclusion The simultaneous analysis of amino acids and acylcarnitines in dried blood spots with analysis of organic acids in urine using mass spectrometry provides an integrated panel for the early detection of IEMs in early years of life, facilitating prompt provision of treatment and avoiding serious complications that can be fatal.

Genetic background and clinical characteristics of infantile hyperammonemia.

This study was conducted to analyze the genetic spectrum and clinical characteristics of infantile hyperammonemia. Between January 2016 and June 2020, we retrospectively enrolled infantile hyperammonemia patients with definitive genetic diagnosis at the Children's Hospital of Fudan University. Based on the age of hyperammonemia onset, patients were grouped into neonatal and post-neonatal subgroups to compare their genetic and clinical features. Collectively, 136 pathogenic or likely pathogenic variants of the 33 genes were identified. Fourteen genes were reported with hyperammonemia (42%, 14/33), with SLC25A13 and MUT being the top two detected genes. In contrast, 19 genes, which have not been previously reported with hyperammonemia, were detected (58%, 19/33), in which JAG1 and ABCC8 were the most frequently mutated genes. Compared with post-neonatal hyperammonemia, neonatal patients with hyperammonemia presented with higher rates of organic acidemia (P=0.001) and fatty acid oxidation disorder (P=0.006), but a lower rate of cholestasis (P<0.001). Patients with neonatal hyperammonemia had a higher ratio of peak plasma ammonia level ≥500 µmol/L (P=0.003) and were more likely to receive precision medicine (P=0.027); however, they had a refractory clinical course (P=0.001) and poorer prognosis than the infantile group. There were significant differences in the genetic spectrum, clinical features, clinical course, and outcomes between infants with different hyperammonemia onset ages.

Масло Лоренцо: панацея, паллиативная помощь или маркетинговый ход. Взгляд неонатолога, педиатра, диетолога

The spectrum of neonatal diagnostic methods for severe hereditary disorders has been expanding since December 31, 2022. In most cases, causal therapy, including diet therapy, can prevent early death and disability in children. X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal fatty acid oxidation characterized by accumulation of very long-chain saturated fatty acids. There are three clinical forms of this disease. The first one is infantile cerebral form accounting for 48% of all cases. Its onset is usually observed at the age of 2.5–10 years after normal development of a child, manifesting with progressive decortication. The second form is adrenomyelopathy (25% of cases) which starts with adrenal insufficiency at the age of 12–55 years, followed by neurological symptoms. The adult form (3% of cases) manifests after the age of 30 years and combines clinical phenotypes resembling schizophrenia with dementia. A low-fat diet with Lorenzo oil is believed to be effective, because it normalizes plasma levels of C24:0 and C26:0 in X-ALD patients; however, it does not prevent or alleviate neurological symptoms if they have already developed. Diet therapy increases plasma levels of C22:1 and C24:1 fatty acids, although their effect on X-ALD is yet to be elucidated. This review describes the mechanism of Lorenzo oil action, its side effects, case series, and analysis of dietary correction in various groups of patients. A modified diet with dietary fats replaced by Lorenzo oil is effective only in people with asymptomatic X-ALD, as a preventive measure for asymptomatic boys at risk of developing the cerebral form. Lorenzo oil is capable of alleviating and preventing ALD progression in patients without brain lesions. However, in symptomatic patients, the restriction of dietary fats and their replacement by Lorenzo oil is associated with a high risk of life-threatening complications. In this case, nutrition should meet special requirements of a patient, for example, the ability to chew and swallow, while the therapy should be primarily substitutive and symptomatic. Key words: adrenoleukodystrophy, diet therapy, Lorenzo oil

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

311: SEVERE HYPERAMMONEMIA CAUSED BY CARNITINE DEFICIENCY DURING ADULTHOOD

Introduction: Carnitine is a necessary co-factor in the oxidation of fatty acids as part of the urea cycle; deficiency of which may lead to heart or liver failure. Primary carnitine deficiency due to transporter defects or mutations is seen in infants. Secondary carnitine deficiency is the result of whole-body carnitine deficiency. Here, we discuss a case of secondary deficiency due to vegetarianism, leading to severe hyperammonemia. Description: A 23-year-old woman was admitted with one day of vomiting and diarrhea. On arrival, she was confused but alert, though rapidly decompensated and developed obtundation, clonus, rigidity, posturing, and non-reactive mydriatic pupils, requiring emergent intubation. Work-up was significant for elevated ammonia to 581 umol/L with CT head showing severe brain edema prompting placement of external ventricular drain for intracranial hypertension and frequent hypertonic saline administration. Given significant hyperammonemia with otherwise negative work-up, the patient’s presentation was concerning for a urea cycle defect. The patient was dialyzed and started on arginine, sodium benzoate/phenylacetate, citrulline, and buphenyl. Further history revealed a diet devoid of meat. Plasma amino acid analysis revealed decreased total carnitine 3 umol/L (27-73) and free carnitine 2 umol/L (20-55). There were no mutations in the carnitine transport gene or deficient enzymatic activity for the urea cycle. After one week, she was awake, alert, and was extubated shortly thereafter. Once tolerating oral intake, her diet of was supplemented with oral carnitine. She was able to make a full recovery and return home without deficits from baseline prior to admission. Discussion: Common causes of hyperammonemia are hepatic failure, genetic urea cycle defects, and organic academies, which were ruled out in this case. Carnitine is an important co-factor in the metabolism of long-chain fatty acids and its disruption impairs ammonia excretion through inhibition of the urea cycle. Secondary carnitine deficiency is seen in severe malnutrition, and causes hyperammonemia and encephalopathy. This case is particularly important to note, as fatty acid oxidation disorders based on pure dietary deficiency that presents during adulthood are uncommon and not frequently considered in the differentials.

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.

Deep-fried Atractylodes lancea rhizome alleviates spleen deficiency diarrhea–induced short-chain fatty acid metabolic disorder in mice by remodeling the intestinal flora

Ethnopharmacological relevanceAtractylodes lancea (Thunb.) DC. is a Chinese herb that has been commonly used to treat spleen-deficiency diarrhea (SDD) in China for over a thousand years. However, the underlying mechanism of its antidiarrheal activity is not fully understood. Aim of the studyThe antidiarrheal effects of the ethanol extract of deep-fried A. lancea rhizome (EEDAR) due to spleen deficiency induced by folium sennae (SE) were determined on the regulation of the short-chain fatty acid (SCFA) metabonomics induced by the intestinal flora. Materials and methodsThe effects of EEDAR on a SE-induced mouse model of SDD were evaluated by monitoring the animal weight, fecal water content, diarrhea-grade rating, goblet cell loss, and pathological changes in the colon. The expression of inflammatory factors (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6, IL-10), aquaporins (AQP3, AQP4, and AQP8), and tight junction markers (ZO-1, occludin, claudin-1) in colon tissues were determined using quantitative polymerase chain reaction and western blotting. SCFA metabonomics in the feces of mice treated with EEDAR was evaluated using gas chromatography–mass spectrometry. Furthermore, 16S rDNA sequencing was used to determine the effect of EEDAR on the intestinal flora of SDD mice, and fecal microbiota transplantation (FMT) was used to confirm whether the intestinal flora was essential for the anti-SDD effect of EEDAR. ResultsTreatment with EEDAR significantly improved the symptoms of mice with SDD by inhibiting the loss of colonic cup cells, alleviating colitis, and promoting the expression of AQPs and tight junction markers. More importantly, the effect of EEDAR on the increase of SCFA content in mice with SDD was closely related to the gut microbiota composition. EEDAR intervention did not significantly improve intestinal inflammation or the barrier of germ-free SDD mice, but FMT was effective. ConclusionEEDAR alleviated SE-induced SDD in mice, as well as the induced SCFA disorder by regulating the imbalance of the intestinal microbiota.

Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review.

Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism (IEMs) caused by defects in the fatty acid (FA) mitochondrial β-oxidation. The most common FAODs are characterized by the accumulation of medium-chain FAs and long-chain (3-hydroxy) FAs (and their carnitine derivatives), respectively. These deregulations are associated with lipotoxicity which affects several organs and potentially leads to life-threatening complications and comorbidities. Changes in the lipidome have been associated with several diseases, including some IEMs. In FAODs, the alteration of acylcarnitines (CARs) and FA profiles have been reported in patients and animal models, but changes in polar and neutral lipid profile are still scarcely studied. In this review, we present the main findings on FA and CAR profile changes associated with FAOD pathogenesis, their correlation with oxidative damage, and the consequent disturbance of mitochondrial homeostasis. Moreover, alterations in polar and neutral lipid classes and lipid species identified so far and their possible role in FAODs are discussed. We highlight the need of mass-spectrometry-based lipidomic studies to understand (epi)lipidome remodelling in FAODs, thus allowing to elucidate the pathophysiology and the identification of possible biomarkers for disease prognosis and an evaluation of therapeutic efficacy.