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Cardiac arrhythmia is currently considered to be the direct cause of death in a majority of sudden unexplained death (SUD) cases, yet the genetic predisposition and corresponding endophenotypes contributing to SUD remain incompletely understood. In this study, we aimed to investigate the involvement of Coenzyme Q (CoQ) deficiency in SUD. First, we re-analyzed the exome sequencing data of 45 SUD and 151 sudden infant death syndrome (SIDS) cases from our previous studies, focusing on previously overlooked genetic variants in 44 human CoQ deficiency-related genes. A considerable proportion of the SUD (38%) and SIDS (37%) cases were found to harbor rare variants with likely functional effects. Subsequent burden testing, including all rare exonic and untranslated region variants identified in our case cohorts, further confirmed the existence of significant genetic burden. Based on the genetic findings, the influence of CoQ deficiency on electrophysiological and morphological properties was further examined in a mouse model. A significantly prolonged PR interval and an increased occurrence of atrioventricular block were observed in the 4-nitrobenzoate induced CoQ deficiency mouse group, suggesting that CoQ deficiency may predispose individuals to sudden death through an increased risk of cardiac arrhythmia. Overall, our findings suggest that CoQ deficiency-related genes should also be considered in the molecular autopsy of SUD., (© 2024. The Author(s).)

Introduction: Epilepsy is a common manifestation in inborn errors of metabolism, with varying degrees of severity and response to treatment., Objective: To determine its incidence and characteristics in metabolic diseases., Material and Methods: A retrospective review of neuropaediatric and metabolic databases was performed. Data on the type of epilepsy, age of onset and refractoriness were collected., Results: Two cases out of three (66%) with molybdenum cofactor deficiency and neonatal epileptic encephalopathy; three with vitamin-sensitive epilepsies: pyridoxamine sulphate oxidase deficiency, antichitin and biotinidase deficiency, early onset and good seizure control with biotin; one with homocystinuria, with late onset and polytherapy; one with Menkes disease difficult to control; two with GLUT-1 deficiencies with absent and generalized discharges in the electroencephalogram; five (33%) peroxisomes in monotherapy, except for a suspected peroxisome biogenesis deficiency; 13 (34%) lysosomal deficiencies; a glycosylation disorder, with infantile and refractory spasms; seven (8.5%) organic aminoacidopathies and acidurias, one with infantile spasms (propionic acidemia), three with nonketotic hyperglycinemia with neonatal epileptic encephalopathy, one with monotherapy (leukinosis) and two (3.3%) with unscreened hyperphenylalaninemia; and five (20%) mitochondrial, most of which had oxidative phosphorylation deficiencies., Conclusions: The diagnosis of metabolic epilepsy requires a high level of suspicion in unscreened diseases. The semiology of the seizures and the electrocardiogram data are not characteristic, but some clinical data may provide guidance, such as early onset and refractoriness, neuroimaging and some biochemical markers. Although genetic studies are increasingly cost-effective in epilepsy, we must continue to search for earlier biomarkers and test targeted therapeutic trials.

Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes seen in IMDs are sometimes associated with intellectual disability (ID) or neurocognitive decline, necessitating multidisciplinary input. We here describe our experience at one tertiary metabolic centre in the UK. We reviewed the case prevalence and existing service provision in one adult IMD service covering a multi-ethnic population of 10 million in North England. In our cohort of 2268 IMD patients, 1598 patients had general metabolic conditions (70.5%), and 670 had lysosomal storage disease/disorders (LSD)s (29.5%). The overall prevalence of ID and neurocognitive decline was found to be 15.7% ( n = 357), with patients with LSDs accounting for 23.5% ( n = 84) of affected patients. Given the prevalence of ID in adults with IMDs, access to multidisciplinary input from neuropsychology and neuropsychiatry services is important. Education of healthcare professionals to diagnose IMDs in patients with ID, in addition to neurocognitive and neuropsychiatric presentations, will avoid missed diagnoses of IMD and will have a positive effect on patient outcomes.

Inherited metabolic diseases (IMD) are caused by the functional defect of an enzyme, of genetic origin, that provokes a blockage in a specific metabolic pathway. Individually, IMD are considered rare diseases, with an incidence of less than 1/100,000 births. The symptoms are usually multisystemic, but frequently include cardiac manifestations. Of these, the most common are cardiomyopathies, especially hypertrophic cardiomyopathy. In addition, they can cause dilated or restrictive cardiomyopathy and non-compacted cardiomyopathy of the left ventricle. Characteristic signs also include rhythm alterations (atrio-ventricular conduction disturbances, Wolff-Parkinson-White syndrome or ventricular arrhythmias), valvular pathology and ischaemic coronary pathologies. The aim of this study is to present a narrative review of the IMD that may produce cardiac involvement. We describe both the specific cardiac manifestations of each disease and the systemic symptoms that guide diagnosis., Competing Interests: Declaration of competing interest The authors declare they have no conflicts of interest regarding this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Infantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies., Methods: This study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years., Results: Most patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication., Conclusion: This study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly controlled neonatal epilepsy. Diagnosing neonatal-onset metabolic conditions proves a difficult task for clinicians; however, routine state newborn screening panels now include many IEMs. Three in particular-pyridoxine-dependent epilepsy, maple syrup urine disease, and Zellweger spectrum disorders-are highly associated with neonatal epilepsy and neurocognitive injury yet are often misdiagnosed. As research surrounding biomarkers for these conditions is emerging and gene sequencing technologies are advancing, clinicians are beginning to better establish early identification strategies for these diseases. In this literature review, the authors aim to present clinicians with an innovative clinical guide highlighting IEMs associated with neonatal-onset seizures, with the goal of promoting quality care and safety., (© Copyright 2024 Springer Publishing Company, LLC.)

Inborn errors of metabolism (IEMs) are a vast array of inherited/congenital disorders, affecting a wide variety of metabolic pathways and/or biochemical processes inside the cells. Although IEMs are usually rare, they can be represented as serious health problems. During the neonatal period, these inherited defects can give rise to almost all key signs of liver malfunction, including jaundice, coagulopathy, hepato- and splenomegaly, ascites, etc. Since the liver is a vital organ with multiple synthetic, metabolic, and excretory functions, IEM-related hepatic dysfunction could seriously be considered life-threatening. In this context, the identification of those hepatic manifestations and their associated characteristics may promote the differential diagnosis of IEMs immediately after birth, making therapeutic strategies more successful in preventing the occurrence of subsequent events. Among all possible liver defects caused by IEMs, cholestatic jaundice, hepatosplenomegaly, and liver failure have been shown to be manifested more frequently. Therefore, the current study aims to review substantial IEMs that mostly result in the aforementioned hepatic disorders, relying on clinical principles, especially through the first years of life. In this article, a group of uncommon hepatic manifestations linked to IEMs is also discussed in brief., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this context, comprehensive descriptions of movement disorders are limited and primarily derived from single cases or small patient series, highlighting the need for increased awareness and additional research in this field., Methods: A systematic review was conducted using the MEDLINE database and GeneReviews. The search included studies on inborn errors of metabolism associated with chorea, athetosis, or ballismus. The review adhered to PRISMA guidelines., Results: The systematic review analyzed 76 studies out of 2350 records, encompassing the period from 1964 to 2022. Chorea was observed in 90.1% of the 173 patients, followed by athetosis in 5.7%. Various inborn errors of metabolism showed an association with chorea, with trace elements and metals being the most frequent. Cognitive and developmental abnormalities were common in the cohort. Frequent neurological features included seizures, dysarthria, and optic atrophy, whereas non-neurological features included, among others, facial dysmorphia and failure to thrive. Neuroimaging and biochemical testing played crucial roles in aiding diagnosis, revealing abnormal findings in 34.1% and 47.9% of patients, respectively. However, symptomatic treatment efficacy for movement disorders was limited., Discussion: This study emphasizes the complexities of chorea in inborn errors of metabolism. A systematic approach with red flags, biochemical testing, and neuroimaging is required for diagnosis. Collaboration between neurologists, geneticists, and metabolic specialists is crucial for improving early detection and individualized treatment. Utilizing genetic testing technologies and potential therapeutic avenues can aid in the improvement of patient outcomes., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

A 40-year-old Syrian man presented to the emergency department with a 5-day history of anuria. He had previously excreted dark urine. Major rhabdomyolysis and crush kidney were found, meaning that hemodialysis was immediately initiated. A detailed patient history in the patient's mother tongue revealed indications of metabolic myopathy. The PYGM-associated glycogen storage disease type V (McArdle disease) was confirmed by next generation sequencing panel diagnostics. The most important treatment approach is to avoid rhabdomyolysis through only moderate physical exertion., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.

Inborn errors of metabolism (IEMs) are characterized by deficits in metabolic enzymes as a result of an inherited disease, leading to the accumulation or decreased excretion of proteins, carbohydrates and lipids. Although IEMs are often diagnosed during childhood, adolescent and adult onset variants may be accompanied by less somatic and more psychiatric manifestations, which often hampers recognition by psychiatrists of the distinction between a primary and secondary psychiatric disorder. To help clinicians in the diagnostic process, we aimed to provide an overview of psychiatric manifestations in IEMs. Our literature search yielded 4380 records in total, of which 88 studies were included in the qualitative synthesis. Reported psychiatric disorders in adolescent and adult IEMs included depression, anxiety disorder, psychosis, attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder and obsessive-compulsive disorder as assessed by semi-structured diagnostic interviews and validated questionnaires. A diagnostic screener and multidisciplinary IEM clinics are proposed to help clinicians during the diagnostic process, to prevent diagnostic delay and to raise awareness of the psychiatric manifestations among IEMs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States. As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges. A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity. A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes., (© 2022 American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Introduction: Epilepsy is one of the leading chronic diseases of childhood, and an underlying IEM is an etiology that can easily be overlooked. The aim of this study was to determine the frequency of metabolic disease in patients diagnosed with epilepsy in the first two years of life, as well as to determine the clinical, radiological, and electroencephalographic (EEG) characteristics of the metabolic disease subtypes associated with epilepsy and evaluate treatment response in our study., Materials and Methods: The records of patients diagnosed with epilepsy before the age of 2 years in our pediatric neurology clinic between 2014 and 2021 were reviewed retrospectively. Those diagnosed with an IEM and followed up in the pediatric neurology and pediatric metabolism departments of our hospital were included in the study., Results: A total of 990 patients under the age of 2 years were diagnosed with epilepsy in the pediatric neurology clinic of our hospital and 74 (7.5%) of them had IEM. Thirty-nine (52.7%) of the 74 patients were female. The median age at admission was 144 days (min-max: 0-284). Of the 74 patients diagnosed with metabolic epilepsy, 38 patients were diagnosed with amino acid metabolism disorder, 17 with lysosomal storage disease, 9 with energy metabolism disorder, 5 with vitamin/cofactor/trace element metabolism disorders, 2 with fatty acid metabolism disorder, 2 with peroxisomal disease, and 1 with carbohydrate metabolism disorder. Epilepsy was refractory despite appropriate treatment in 39 patients (52.7%)., Conclusion: Inborn errors of metabolism are a rare cause of epilepsy, in regions like our country with high rates of consanguineous marriage, IEM should be considered in patients presenting with seizures that do not respond to conventional antiepileptic treatments., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Phosphoglycerate kinase (PGK) deficiency is an X-linked disorder characterized by a combination of hemolytic anemia, myopathy, and brain involvement. We herein report a Japanese man who had several episodes of rhabdomyolysis but was training strenuously to be a professional boxer. Mild hemolytic anemia was noted. The enzymatic activity of PGK was significantly reduced, and a novel missense mutation, p.S62N, was identified in the PGK1 gene. A literature review revealed only one case with a mixed hemolytic and myopathic phenotype like ours. This mild phenotype indicates the complex pathophysiology of PGK deficiency and suggests the benefits of dietary control and exercise.

Background: Inborn errors of metabolism (IEM), including organic acidemias and urea cycle defects, are characterized by systemic accumulation of toxic metabolites with deleterious effect on the developing brain. While hemodialysis (HD) is most efficient in clearing IEM-induced metabolic toxins, data regarding its use during the neonatal period is scarce., Methods: We retrospectively summarize our experience with HD in 20 neonates with IEM-induced metabolic intoxication (seven with maple syrup urine disease, 13 with primary hyperammonia), over a 16-year period, between 2004 and 2020. All patients presented with IEM-induced neurologic deterioration at 48 h to 14 days post-delivery, and were managed with HD in a pediatric intensive care setting. HD was performed through an internal jugular acute double-lumen catheter (6.5-7.0 French), using an AK-200S (Gambro, Sweden) dialysis machine and tubing, with F3 or FXpaed (Fresenius, Germany) dialyzers., Results: Median (interquartile range) age and weight at presentation were 5 (3-8) days and 2830 (2725-3115) g, respectively. Two consecutive HD sessions decreased the mean leucine levels from 2281 ± 631 to 179 ± 91 μmol/L (92.1% reduction) in MSUD patients, and the mean ammonia levels from 955 ± 444 to 129 ± 55 μmol/L (86.5% reduction), in patients with hyperammonemia. HD was uneventful in all patients, and led to marked clinical improvement in 17 patients (85%). Three patients (15%) died during the neonatal period, and four died during long-term follow-up., Conclusions: Taken together, our results indicate that HD is safe, effective, and life-saving for most neonates with severe IEM-induced metabolic intoxication, when promptly performed by an experienced and multidisciplinary team. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Inborn metabolic diseases or inborn errors of metabolism comprise a large number of rare and heterogeneous genetic diseases categorized in several subgroups depending on their pathophysiologic mechanisms. In this review, we focus on different metabolic diseases with respiratory symptoms in adults: lysosomal glycosphingolipidoses such as acid sphingomyelinase deficiency (Niemann-Pick types A and B disease), Gaucher, Fabry, Pompe diseases and mucopolysaccharidoses in general. We also address classical homocystinuria, which is a monogenic vascular disease, Hermansky-Pudlak syndrome, which is associated with disorders in the lysosomal-related-organelles, and lysinuric protein intolerance, which is due to an amino-acid transporter defect. Presentation and prognosis of these diseases are highly heterogeneous, and respiratory impairment may be central and prognostic. Many are primarily pediatric, and diagnoses are often delivered during childhood. Improved pediatric management has enabled better prognosis and new phenotype of the diseases in the adulthood. Some others can be diagnosed during adulthood. While some diseases call for specific, specialized treatment, all necessitate systematic multidisciplinary management. It is of paramount importance that a pneumologist be familiar with these phenotypes, most of which can benefit from early diagnosis and early therapeutic management with dedicated innovative treatments., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: We examined the birth outcomes of children with inborn errors of metabolism detected at birth or later in life., Methods: We carried out a retrospective cohort study of 1733 children with inborn errors of metabolism and 1,033,693 unaffected children born in Canada between 2006 and 2019. Primary outcomes included preterm birth, low birth weight, congenital anomalies, and other neonatal complications. We estimated adjusted risk ratios (RR) and 95% confidence intervals (CI) for the association of inborn errors of metabolism with each outcome., Results: Children with inborn errors of metabolism had 2.51 times the risk of preterm birth (95% CI 2.27-2.77) and 3.08 times the risk of low birth weight (95% CI 2.77-3.42) compared with unaffected children. Disorders of mineral and lipoprotein metabolism were more strongly associated with adverse birth outcomes. Inborn errors of metabolism were associated with congenital anomalies (RR 2.62; 95% CI 2.36-2.90), particularly abdominal wall defects (RR 8.35; 95% CI 5.18-13.44). Associations were present for errors of metabolism diagnosed both at birth and later in life., Conclusions: Children with inborn errors of metabolism, whether detected at birth or later, are at high risk of adverse birth outcomes and congenital anomalies., Impact: Inborn errors of metabolism may affect fetal development, but the association with adverse birth outcomes is not well characterized. This study indicates that children with inborn errors of metabolism are at risk of preterm birth, neonatal jaundice, congenital anomalies, and a range of other adverse birth outcomes. Mothers of children with inborn errors of metabolism are at risk of preeclampsia and cesarean delivery. Adverse birth outcomes may be a first sign of inborn errors of metabolism that merit increased screening., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Aim: To investigate the prevalence of biopsy-proven non-alcoholic steatohepatitis (NASH) in a cohort of patients with morbid obesity and with or without type 2 diabetes (T2D) and to find non-invasive predictors of NASH severity., Methods: We evaluated a cohort of 412 subjects (age 19-67 years, body mass index-BMI: 44.98 kg/m 2 ), who underwent fine-needle liver biopsy during bariatric surgery. Thirty-six percent of the subjects were affected by T2D. Liver biopsies were classified according to the Kleiner's NAFLD Activity Score (NAS). NAFLD Fibrosis Score (NFS), AST/ALT ratio, AST to Platelet ratio (APRI), fibrosis-4 score (FIB4) were calculated. A neural network analysis (NNA) was run to predict NASH severity., Results: The prevalence of biopsy-proven NASH was 63% and 78% in subjects with obesity and without or with T2D, respectively. T2D doubled the risk of NASH [OR 2.079 (95% IC=1.31-3.29)]. The prevalence of NAFL increased with the increase of BMI, while there was an inverse correlation between BMI and NASH (r=-0.145 p=0.003). Only mild liver fibrosis was observed. HOMA-IR was positively associated with hepatocyte ballooning (r=0.208, p<0.0001) and fibrosis (r=0.159, p=0.008). The NNA highlighted a specificity of 77.3% using HDL-cholesterol, BMI, and HOMA-IR as main determinants of NASH., Conclusions: Our data show a higher prevalence of NASH in patients with morbid obesity than reported in the literature and the pivotal role of T2D among the risk factors for NASH development. However, the inverse correlation observed between BMI and biopsy-proven NASH suggests that over a certain threshold adiposity can be somewhat protective against liver damage. Our model predicts NASH presence with high specificity, thus helping identifying subjects who should promptly undergo liver biopsy., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking. We describe and analyze eye movements in patients with an inborn error of metabolism, and see whether they can serve as an additional clue in the diagnosis of particularly late-onset inborn errors of metabolism. Demographics, disease characteristics, and treatment data were collected. All patients underwent a standardized videotaped neurological examination and a video-oculography. Videos are included. We included 37 patients with 15 different inborn errors of metabolism, including 18 patients with a late-onset form. With the exception of vertical supranuclear gaze palsy in Niemann-Pick type C and external ophthalmolplegia in Kearns-Sayre syndrome, no relation was found between the type of eye movement disorder and the underlying metabolic disorder. Movement disorders were present in 29 patients (78%), psychiatric symptoms in 14 (38%), and cognitive deficits in 26 patients (70%). In 87% of the patients with late-onset disease, eye movement disorders were combined with one or more of these core symptoms. To conclude, eye movement disorders are present in different types of inborn errors of metabolism, but are often not specific to the underlying disorder. However, the combination of eye movement disorders with movement disorders, psychiatric symptoms, or cognitive deficits can serve as a diagnostic clue for an underlying late-onset inborn error of metabolism., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Objective: To assess the outcomes of neonates in a contemporary multi-institutional cohort who receive renal replacement therapy (RRT) for hyperammonemia., Study Design: We performed a retrospective analysis of 51 neonatal patients with confirmed inborn errors of metabolism that were treated at 9 different children's hospitals in the US between 2000 and 2015., Results: Twenty-nine patients received hemodialysis (57%), 21 patients received continuous renal replacement therapy (41%), and 1 patient received peritoneal dialysis (2%). The median age at admission of both survivors (n = 33 [65%]) and nonsurvivors (n = 18) was 3 days. Peak ammonia and ammonia at admission were not significantly different between survivors and nonsurvivors. Hemodialysis, having more than 1 indication for RRT in addition to hyperammonemia, and complications during RRT were all risk factors for mortality. After accounting for multiple patient factors by multivariable analyses, hemodialysis was associated with a higher risk of death compared with continuous renal replacement therapy. When clinical factors including evidence of renal dysfunction, number of complications, concurrent extracorporeal membrane oxygenation, vasopressor requirement, and degree of hyperammonemia were held constant in a single Cox regression model, the hazard ratio for death with hemodialysis was 4.07 (95% CI 0.908-18.2, P value = .067). To help providers caring for neonates with hyperammonemia understand their patient's likelihood of survival, we created a predictive model with input variables known at the start of RRT., Conclusions: Our large, multicenter retrospective review supports the use of continuous renal replacement therapy for neonatal hyperammonemia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To study the clinicoetiological profile of children presenting with acute noninfectious encephalopathy (NIE) and identify the proportion of children having inborn errors of metabolism (IEM)., Method: This descriptive cross sectional study was conducted in a tertiary care centre in Northern India. Consecutive children, aged more than 28 d and less than 12 y, with acute encephalopathy were enrolled after ruling out CNS infection. All children were evaluated on an internally validated structured proforma. A sequential pre-decided battery of tests was applied to determine the cause of encephalopathy. IEM suspects were subjected to TMS/GCMS followed by mutation analysis for confirmation., Results: Fifty children with noninfectious encephalopathy (NIE) were recruited and metabolic causes were detected in 9 of these children (18%), aged 3 to 42 mo, with female preponderance. The IEMs included lactic acidosis (4), glutaric aciduria (3), isovaleric academia (1), and hyperhomocysteinemia (1). History of previously affected siblings and consanguinity between the parents were important indicators of IEM. MS/MS and mutation analysis were the mainstay of diagnosis in these patients. IEMs contributed to the most common cause amongst cases of NIE., Conclusion: IEMs constitute a significant proportion of NIE in India and a high index of suspicion is required to make the diagnosis., (© 2022. Dr. K C Chaudhuri Foundation.)

Inborn errors of metabolism constitute a differential diagnosis in infants presenting with encephalopathy in developing countries where expanded newborn screening is not a state health programme. Acute neurological presentation with encephalopathy is documented in paediatric COVID-19. The pandemic has also altered parents' healthcare-seeking behaviour, leading to delays in emergency care. We illustrate the challenges faced in diagnosing and managing an 18-month-old child who presented with acute metabolic crisis due to methylmalonic acidaemia on the background of the COVID-19 pandemic. We discuss the current global status of expanded newborn screening services for inborn error of metabolism and the impact of the pandemic on the healthcare of children., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Continuous kidney replacement therapies (CKRT) have been reported to be an effective approach to removing toxic metabolites in inborn errors of metabolism (IEM). The present study evaluates efficiency and complications of CKRT in children with IEM., Methods: Patients diagnosed with IEM who underwent CKRT in pediatric and neonatal intensive care units were analyzed. CKRT were initiated in patients with persistently high blood ammonia levels (≥ 500 μmol/L), blood ammonia levels > 250 μmol/L in the presence of moderate encephalopathy, high blood leucine levels (≥ 1500 μmol/L), and blood leucine levels < 1500 μmol/L in the presence of deteriorating neurological status or persistent metabolic acidosis., Results: Of 22 patients enrolled, nine (40.9%) Maple syrup urine disease (MSUD), eight (36.4%) urea cycle disorders (UCD), and five (22.7%) organic acidemias (OA). Median age was 72.3 [9.9-1040.8] days. In total, 28 dialysis sessions were analyzed [16 (57.1%) continuous venovenous hemodialysis, and 12 (42.9%) continuous venovenous hemodiafiltration]. A significant decrease was noted in leucine levels (from 1608.4 ± 885.3 to 314.6 ± 109.9 µmol/L) of patients with MSUD, while ammonia levels were significantly decreased in patients with UCD and OA (from 1279.9 ± 612.1 to 85.1 ± 21.6 µmol/L). The most frequent complications of CKRT were thrombocytopenia (60.7%), hypotension (53.6%), and hypocalcemia (42.9%). Median age of patients with hypotension treated with vasoactive medications was significantly lower than median age of those with normal blood pressure., Conclusion: CKRT is a reliable approach for effective and rapid removal of toxic metabolites in children with IEM, and CKRT modalities can be safely used and are well-tolerated in infants., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan disorder' status. However, collectively they constitute a relatively common group of disorders that affect not only the skeletal muscle but also the heart, liver, and brain among others. Mitochondrial disorders, with a frequency of 1/8000 population, are the commonest cause of metabolic myopathies. Three main groups that cause metabolic myopathy are glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial myopathies. Clinically, patients present with varied ages at onset and neuromuscular features. While newborns and infants typically present with hypotonia and multisystem involvement chiefly affecting the liver, heart, kidney, and brain, patients with onset later in life present with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, GSDs result in high-intensity exercise intolerance while, FAODs, and mitochondrial myopathies predominantly manifest during endurance-type activity, fasting, or metabolically stressful conditions. Evaluation of these patients comprises a meticulous clinical examination and a battery of investigations which includes- exercise stress testing, metabolic and biochemical screening, electrophysiological studies, neuro-imaging, muscle biopsy, and molecular genetics. Accurate and early detection of metabolic myopathies allows timely counseling to prevent metabolic crises and helps in therapeutic interventions. This review summarizes the clinical features, diagnostic tests, pathological features, treatment and presents an algorithm to diagnose these three main groups of disorders., Competing Interests: None

In the last decade, health-related quality of life (HrQoL) has become an increasingly important outcome parameter in children and adolescents with chronic health conditions; among them are pediatric patients with inborn metabolic diseases (IMDs). Hence, knowledge on this topic is increasing, but findings on non-medical influences on the HrQoL of IMD patients are still scarce. In the present study, we retrospectively evaluated the self-reported generic HrQoL of a cohort of pediatric patients (ages 7 to 17 years) with diverse IMDs (n = 204) and explored associations between HrQoL and psychosocial and medical characteristics of the patients. We aimed to identify risk factors for impaired HrQoL to improve and tailor support for the patients and economize resources. Generic HrQoL was assessed with the KINDL-R questionnaire. We compared the HrQoL scores to published German normative data and analyzed the impact of demographic variables and intellectual and psychosocial functioning on the HrQoL. Moreover, we examined the influence of the diagnostic category and the health impairment (as judged by the physicians) on our patients' HrQoL. Overall, the HrQoL of the adolescent patients was comparable to the HrQoL of the norm group. Disorders of intellectual development, impaired psychosocial functioning, and a severe health impairment were associated with lower HrQoL scores.Conclusion: We recommend evaluating these factors in children and adolescents with IMDs to identify patients at risk for impaired HrQoL. What is Known: • Studies on HrQoL in pediatric patients with IMDs mainly focused on subgroups with specific diagnoses and found normal HrQoL in some of those subgroups. • In healthy children and adolescents as well as in pediatric patients with various chronic diseases, associations between psychosocial factors and HrQoL are well known. What is New: • Impaired psychosocial functioning, disorders of intellectual development, and a significant disease and/or treatment burden are risk factors for impaired HrQoL in pediatric patients with IMDs. • Evaluating these factors in children and adolescents with IMDs can help identify patients and families in need of enhanced psychological support., (© 2021. The Author(s).)

Inborn errors of metabolism (IEM) encompass a group of monogenic diseases affecting both pediatric and adult populations and currently lack effective treatments. Some IEM such as familial hypercholesterolemia or X-linked protoporphyria are caused by gain of function mutations, while others are characterized by an impaired protein function, causing a metabolic pathway blockage. Pathophysiology classification includes intoxication, storage and energy-related metabolic disorders. Factors specific to each disease trigger acute metabolic decompensations. IEM require prompt and effective care, since therapeutic delay has been associated with the development of fatal events including severe metabolic acidosis, hyperammonemia, cerebral edema, and death. Rapid expression of therapeutic proteins can be achieved hours after the administration of messenger RNAs (mRNA), representing an etiological solution for acute decompensations. mRNA-based therapy relies on modified RNAs with enhanced stability and translatability into therapeutic proteins. The proteins produced in the ribosomes can be targeted to specific intracellular compartments, the cell membrane, or be secreted. Non-immunogenic lipid nanoparticle formulations have been optimized to prevent RNA degradation and to allow safe repetitive administrations depending on the disease physiopathology and clinical status of the patients, thus, mRNA could be also an effective chronic treatment for IEM. Given that the liver plays a key role in most of metabolic pathways or can be used as bioreactor for excretable proteins, this review focuses on the preclinical and clinical evidence that supports the implementation of mRNA technology as a promising personalized strategy for liver metabolic disorders such as acute intermittent porphyria, ornithine transcarbamylase deficiency or glycogen storage disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Infectious diseases can result in a catabolic state and possibly trigger an acute metabolic decompensation in inborn errors of metabolism (IEM), which could be life threatening. Studies regarding the course of severe acute respiratory syndrome coronavirus 2 infections in patients with IEM are generally limited to case reports. Here, we aimed to evaluate the clinical findings of coronavirus disease 2019 (COVID-19) and describe the impact of severe acute respiratory syndrome coronavirus 2 infections on metabolic outcomes in IEM patients., Methods: Patients who were diagnosed with different types of IEM and developed microbiologically confirmed COVID-19 infection were included. Clinical findings and laboratory results were recorded retrospectively in terms of both IEM and COVID-19., Results: Eleven patients with diagnosis of intoxication type metabolic disorders, five patients with energy metabolism disorders, and six patients with complex molecular disorders were enrolled. The most frequent clinical finding was fever (52.1%) followed by fatigue/myalgia (47.8%). None of the patients was younger than 1 year. None of the patients presented severe or critical disease. In terms of metabolic decompensation, two patients diagnosed with propionic acidemia, one patient with methylmalonic acidemia and one patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency presented clinical and biochemical findings of an acute metabolic attack., Conclusions: Based on our results, IEM are not found to be an additional risk factor for severe COVID-19 infection. However, patients with intoxication type and energy metabolism disorders should be considered as a vulnerable population for COVID-19 and have a major risk of developing acute metabolic decompensation that can lead to life-threatening complications., (© 2021 Japan Pediatric Society.)

Neonatal seizures (NS) occur in the first 28 days of life; they represent an important emergency that requires a rapid diagnostic work-up to start a prompt therapy. The most common causes of NS include: intraventricular haemorrhage, hypoxic-ischemic encephalopathy, hypoglycemia, electrolyte imbalance, neonatal stroke or central nervous system infection. Nevertheless, an Inborn Error of Metabolism (IEM) should be suspected in case of NS especially if these are resistant to common antiseizure drugs (ASDs) and with metabolic decompensation. Nowadays, Expanded Newborn Screening (ENS) has changed the natural history of some IEMs allowing a rapid diagnosis and a prompt onset of specific therapy; nevertheless, not all IEMs are detected by such screening (e.g. Molybdenum-Cofactor Deficiency, Hypophosphatasia, GLUT1-Deficiency Syndrome) and for this reason neonatologists have to screen for these diseases in the diagnostic work-up of NS. For IEMs, there are not specific semiology of seizures and EEG patterns. Herein, we report a systematic review on those IEMs that lead to NS and epilepsy in the neonatal period, studying only those IEMs not included in the ENS with tandem mass, suggesting clinical, biochemical features, and diagnostic work-up. Remarkably, we have observed a worse neurological outcome in infants undergoing only a treatment with common AED for their seizures, in comparison to those primarily treated with specific anti-convulsant treatment for the underlying metabolic disease (e.g.Ketogenic Diet, B6 vitamin). For this reason, we underline the importance of an early diagnosis in order to promptly intervene with a targeted treatment without waiting for drug resistance to arise., (© 2021. The Author(s).)

Carnitine palmitoyltransferase-II deficiency, an autosomal recessive disorder, is the most common cause of recurrent rhabdomyolysis in adults. Recognition and avoidance of triggers, such as heavy exercise and stress, is key in prevention of further episodes; however, even with preventative measures, many patients will continue to experience periodic symptoms, including rhabdomyolysis. Avoidance of renal failure, correction of electrolyte disturbances and halting further muscle breakdown are the goals of treatment. It is essential for clinicians to recognize the signs and symptoms of acute disease in CPT-II deficiency. We present a case of recurrent rhabdomyolysis requiring hospitalization in a patient with CPT-II deficiency and review the literature for common clinical manifestations, diagnostics, and treatment strategies., (© 2021 Benjamin J. Mccormick et al., published by Sciendo.)

Inborn errors of metabolism (IEM) are genetic disorders due to a defective metabolic pathway. The incidence of each disorder is variable and depends on the respective population. Some disorders such as urea cycle disorders (UCD) and organic acidurias, pose a high risk for a metabolic crisis culminating in a life-threatening event, especially during infections; thus, vaccines may play a crucial role in prevention. However, there are different triggers for decompensations including the notion that vaccines themselves can activate fever and malaise. Additionally, many of the IEM include immunodeficiency, placing the patients at an increased risk for infectious diseases and possibly a weaker response to immunizations. Since metabolic crises and vaccine regimens intersect in the first years of life, the question whether to vaccinate the child occupies parents and medical staff. Many metabolic experts hesitate to vaccinate IEM patients, disregarding the higher risk from the direct infections. In this paper we summarize the published data regarding the safety and recommendations for vaccinations in IEM patients, with reference to the risk for decompensations and to the immunogenic component., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to investigate the frequency and status of depression and anxiety among mothers of children with inborn errors of metabolism (IEM) who were on a restricted diet and previously experienced metabolic crises., Methods: This cross-sectional multicenter descriptive study included 93 children with IEM who were on restricted diet. The patients were divided into two groups: those who had experienced metabolic crises (n=44, urea cycle defect, organic acidemia, maple syrup urine disease, hereditary fructose intolerance) and those who had not experienced previous metabolic crises (n=49; phenylketonuria, galactosemia, and non-ketotic hyperglycinemia). The control group comprised 37 healthy children. The mothers of the patients and control participants answered a questionnaire about their and their children's demographic and clinical characteristics and completed the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-S and STAI-T)., Results: The maternal BDI, STAI-S, and STAI-T scores were 6.3±5.2, 36.1±11.2, and 39.9±8.8, respectively, in the control group. The maternal BDI, STAI-S, and STAI-T scores of the children who had experienced (19.2±9.7; 44.0±12.4; 47.9±10.6) and those who had not experienced (13.9±9.1; 40.7 ±8.6; 45.3±8.3) a crisis were significantly higher than for the controls. The BDI score was significantly higher for the mothers of children who had experienced a crisis (p=0.011), whereas no significant difference was determined between the two patient groups regarding STAI-S and STAI-T scores. The mothers of four children who had experienced metabolic crises were on antidepressant therapy., Conclusion: Although their children were on a similar restricted diet, the mothers of children who previously experienced or who had the risk of experiencing metabolic crises had higher depression scores as compared with the mothers of children who did not experience a previous crisis. Early supportive therapy may be required for the families of these patients to lower the burden of stress., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2021 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Inborn errors of metabolism have been considered as an infrequent cause of epilepsy. Improvement in diagnostics has improved the detection of a metabolic basis of recurrent seizures in neonates and children. The term 'metabolic epilepsy' is used to suggest inherited metabolic disorders with predominant epileptic manifestations as well as those where epilepsy is part of the overall neurological phenotype. Several of these disorders are treatable, and the physician should bear in mind the classical ages of presentation. As there are no specific clinical or electrographic features suggestive of metabolic epilepsies, an early suspicion is based on clinical and laboratory clues. Fortunately, with the advancement of gene sequencing technology, a diagnosis of these rare conditions is more straightforward and may not require invasive procedures such as biopsies, multiple metabolic stress-induced testing for abnormalities, and cerebrospinal fluid analysis. A gene panel may suffice in most cases and can be done from a blood sample. In many countries, many treatable metabolic disorders are now part of the neonatal screen. Early diagnosis and treatment of these disorders can result in the prevention of a full-scale metabolic crisis and improvement of neurological outcomes. Long-term neurological outcomes are variable and additional therapies may be required., (© 2020. Dr. K C Chaudhuri Foundation.)

»: Inborn errors of metabolism are disorders of carbohydrate, amino acid, organic acid, or purine and pyrimidine metabolism; disorders of fatty acid oxidation; disorders of metal metabolism; and lysosomal storage defects that can cause metabolic derangements that have secondary musculoskeletal effects., »: Orthopaedic surgeons should be aware that patients with inborn errors of metabolism may be at high risk for spasticity, which may cause joint subluxations, scoliosis, and contractures, as well as poor bone quality, which is caused by malnutrition or disordered bone growth., »: Multidisciplinary care and follow-up are important to identify musculoskeletal problems in a timely manner in order to provide effective treatment., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/A715)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A small amount of methanol is produced endogenously in the human body but it is efficiently metabolized by alcohol dehydrogenase (ADH) and other enzymes, and the products eliminated without harm. In this study, we present a new entity of inborn error of methanol metabolism due to a mutation in the ADH1C gene coding for the γ subunit that is part of several ADH isoenzymes., Results: This disorder was discovered in an 11.58-year-old boy. During one 9-month hospital admission, he had periods of 1-4 days during which he was comatose, and between these periods he was sometimes verbose and euphoric, and had ataxia, dysarthria. Following hemodialysis treatments, he became conscious and appeared healthy. Organ evaluations and his laboratory tests were normal. Toxicological evaluation of his blood showed a high methanol level [12.2 mg/dL (3.8 mmol/L), normal range up to 3.5 mg/dL (1.09 mmol/L) while the formaldehyde level was undetectable. The finding of liver function tests that were within normal limits, coupled with a normal eye examination and size of the liver, elevated blood methanol levels and an undetectable formaldehyde level, suggested ADH insufficiency. Adding zinc to the drug regimen 15 mg/daily dramatically reduced the patient's methanol level and alleviated the abnormal symptoms. When zinc supplementation was discontinued, the patient relapsed into a coma and hemodialysis was once again required. A homozygous mutation in ADH1C gene located at exon 3 was found, and both parents were heterozygous for this mutation., Conclusion: Accumulation of methanol due to mutation in ADH1C gene may result in drunkenness and ataxia, and leads to coma. This condition can be successfully treated with zinc supplementation as the cofactor of ADH., (Copyright © 2021. Published by Elsevier Inc.)

Pediatric liver transplantation (PLT) is an effective strategy of treating various acute or chronic end-stage liver diseases and inherited metabolic diseases in children.PLT has been applied in many transplant centers nationwide and has achieved satisfactory results.However,the development of transplant centers is uneven,and there is a lack of consensus and standards within the industry.In order to reduce post-operative complications,accelerate post-operative recovery,and improve the short-and long-term quality of life of children,the Enhanced Recovery After Surgery Committee of Chinese Research Hospital Association organized multidisciplinary experts to summarize the progress of domestic and international research,and formulated a perioperative consensus on PLT based on the principles of evidence-based medicine.The consensus provides recommendations for perioperative PLT from three aspects:preoperative assessment and preparation,intraoperative management and postoperative management,in order to provide reference guidelines for centers that are conducting or preparing to conduct PLT.

Hepatocellular neoplasms can develop in multiple genetic metabolic disorders. While there have been rare case reports, clinical and pathological characterizations have not been systematically performed. We conducted a retrospective study in 9 patients with these rare genetic metabolic disorders, including glycogen storage disease type 1, ornithine carbamyl transferase deficiency, hereditary tyrosinemia type 1, and Navajo neurohepatopathy, who developed hepatocellular neoplasms. Our results show that steatosis is a common finding in both tumor (6/9 cases, 67%) and background liver parenchyma (8/9 cases, 89%), underlying a possible role for steatosis in tumorigenesis in these genetic metabolic disorders. Our findings also raise a consideration of underlying genetic metabolic disorder when young patients with hepatocellular neoplasm show steatosis in both the tumor and background liver., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Autism spectrum disorder is a neurodevelopmental disorder with a heterogeneous presentation, the etiology of which is not clearly elucidated. In recent years, comorbidity has become more evident with the increase in the frequency of autism and diagnostic possibilities of inborn errors of metabolism., Methods: One hundred and seventy-nine patients with diagnosis of autism spectrum disorder who presented to the Pediatric Metabolism outpatient clinic between 01/September/2018-29/February/2020 constituted the study population. The personal information, routine and specific metabolic tests of the patients were analyzed retrospectively., Results: Out of the 3261 patients who presented to our outpatient clinic, 179 (5.48%) were diagnosed with autism spectrum disorder and were included in the study. As a result of specific metabolic examinations performed, 6 (3.3%) patients were diagnosed with inborn errors of metabolism. Two of our patients were diagnosed with classical phenylketonuria, two with classical homocystinuria, one with mucopolysaccharidosis type 3D (Sanfilippo syndrome) and one with 3-methylchrotonyl Co-A carboxylase deficiency., Conclusion: Inborn errors of metabolism may rarely present with autism spectrum disorder symptoms. Careful evaluation of the history, physical examination and additional findings in patients diagnosed with autism spectrum disorder will guide the clinician in the decision-making process and chose the appropriate specific metabolic investigation. An underlying inborn errors of metabolism may be a treatable cause of autism.

To extract energy from stored lipids, fatty acids must first be liberated from triglyceride before their β-oxidation in mitochondria in a coordinated and stepwise manner. To determine the independent and interdependent roles of hepatic triglyceride hydrolysis and fatty acid oxidation, mice were generated with a liver-specific defect in triglyceride hydrolysis (AtglL-/-), fatty acid oxidation (Cpt2L-/-), or both (double knockout). The loss of either gene resulted in the compensatory increase in the other, demonstrating their coordination. The loss of individual components of fatty acid catabolism (carnitine palmitoyl transferase 2 [Cpt2], adipose triglyceride lipase [Atgl], and Pparα) resulted in largely independent effects on hepatocyte morphology, intermediary metabolism, and gene expression in response to fasting. However, high-fat feeding revealed the interdependent role of Atgl and Cpt2, as the loss of only one of the genes resulted in steatosis (fatty liver) but the loss of both components resulted in significant steatohepatitis (inflammation and fibrosis). Lipolysis and β-oxidation are intimately linked within a continuous pathway, and disruption of their coordination leads to unique cellular and molecular phenotypes that ultimately result in liver disease.

The gut microbiota is very important in the initiation, progression, and dissemination of cancer, and the regulation of microbiota has been employed as a novel strategy to enhance the effect of immunotherapy. Adiponectin (APN), an adipocyte-derived hormone, plays a vital role in regulating the immune response of innate immune cells. The deficiency of APN inhibits rhabdomyosarcoma growth. However, whether this function is associated with regulating gut microbiota remains unknown. To investigate, we performed 16S ribosomal RNA (rRNA) gene sequencing on the fecal microbiome of APN gene knockout mice to determine whether APN deletion affects the gut microbiota. We found APN deficiency alters gut microbial functions involved in metabolism, genetic information processing, and cellular processes. In addition, a decreased abundance of Bacteroides and an increased abundance of Prevotella and Helicobacter were observed in rhabdomyosarcoma-bearing APN knockout mice; these bacteria were associated with the inhibition of rhabdomyosarcoma growth. These findings suggest that gut microbiota may be a potential target of APN deficiency against rhabdomyosarcoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiao Peng et al.)

Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.