Severe Acute Motor Exacerbations (SAME) across Metabolic, Developmental and Genetic Disorders.

Acute presentation of severe motor disorders is a diagnostic and management challenge. We define severe acute motor exacerbations (SAME) as acute/subacute motor symptoms that persist for hours-to-days with a severity that compromise vital signs (temperature, breath, and heart rate) and bulbar function (swallowing/dysphagia). Phenomenology includes dystonia, choreoathetosis, combined movement disorders, weakness, and hemiplegic attacks. SAME can develop in diverse diseases and can be preceded by triggers or catabolic states. Recent descriptions of SAME in complex neurodevelopmental and epileptic encephalopathies have broadened appreciation of this presentation beyond inborn errors of metabolism. A high degree of clinical suspicion is required to identify appropriately targeted investigations and management. We conducted a comprehensive literature analysis of etiologies. Reported triggers are described and classified as per pathophysiological mechanism. A video of six cases displaying multiple SAME with diverse outcomes is provided. We identified 50 different conditions that manifest SAME, some associated with developmental regression. Etiologies include disorders of metabolism: energy substrate, amino acids, complex molecules, vitamins/cofactors, minerals, and neurotransmitters/synaptic vesicle cycling. Non-metabolic neurodegenerative and genetic disorders that present with movement disorders and epilepsy can additionally manifest SAME. A limited number of triggers are grouped here, together with an approach to investigations and general management strategies. Several neurogenetic and neurometabolic disorders manifest SAME. Identifying triggers can help in certain cases narrow the differential diagnosis and guide the expeditious application of targeted therapies to minimize adverse developmental and neurological consequences. This process may inform pathogenesis and eventually improve our understanding of the mechanisms that lead to the development of SAME. © 2024 International Parkinson and Movement Disorder Society.

Coenzyme Q deficiency may predispose to sudden unexplained death via an increased risk of cardiac arrhythmia.

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.

Identifying Metabolic Diseases That Precipitate Neonatal Seizures.

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.

Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity.

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.

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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.

Multisite Retrospective Review of Outcomes in Renal Replacement Therapy for Neonates with Inborn Errors of Metabolism.

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.

Observational study of birth outcomes in children with inborn errors of metabolism.

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.

Eye movement disorders in inborn errors of metabolism: A quantitative analysis of 37 patients.

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.

Hereditary Disorders of Cardiovascular Calcification.

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.

Acute hemodialysis therapy in neonates with inborn errors of metabolism.

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.

Characteristics of continuous venovenous hemodiafiltration in the acute treatment of inherited metabolic disorders.

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.

Risk factors for impaired health-related quality of life in a cohort of pediatric patients with inborn metabolic diseases.

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.

Inborn errors of metabolism and coronavirus disease 2019: Evaluation of the metabolic outcome.

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.

REVIEW: Practical strategies to maintain anabolism by intravenous nutritional management in children with inborn metabolic diseases.

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.

Neonatal seizures as onset of Inborn Errors of Metabolism (IEMs): from diagnosis to treatment. A systematic review.

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.

[Expert consensus of perioperative management in pediatric liver transplantation].

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.

Cause of recurrent rhabdomyolysis, carnitine palmitoyltransferase II deficiency and novel pathogenic mutation.

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal inherited metabolic disorder in which the ß-oxidation of the long chain fatty acids is defective. The clinical presentation may be in various forms; it presents itself in the severe form during neonatal and infantile periods and as the less severe myopathic form in the school age and adolescence. While the severity of the rhabdomyolysis attacks varies, occasionally the clinical course may be complicated with acute renal failure. Acylcarnitine analysis may help in the diagnosis of CPT II, but its normality does not indicate the absence of the disease. If there is strong suspicion, genetic analysis should be performed on the cases. In this article, we present a 15-year-old male patient who had two rhabdomyolysis attacks triggered by infection and starvation. Acylcarnitine analysis of the case was normal, CPT II deficiency was considered when the history was evaluated, and CPT II gene c.137A>G (p.Gln46Arg) homozygous novel pathogenic mutation was detected. CPT II deficiency is one of the most common causes of metabolic rhabdomyolysis in patients with recurrent episodes of rhabdomyolysis.

Cases of inborn errors of metabolism diagnosed in children with autism.

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.

Clinical and biochemical footprints of inherited metabolic diseases. III. Psychiatric presentations.

Psychiatric symptoms are common manifestations in many inborn errors of metabolism (IEMs), ranging from attention deficit, anxiety and mood and behavioral disorders to psychosis. Furthermore, IEMs represent a significant percentage of all autism cases. We reviewed and updated the list of metabolic disorders known to be associated with various psychiatric manifestations and found more than 100 relevant IEMs. This represents the third of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury.

Adiponectin (APN), an adipocyte-derived adipokine, has been shown to limit lung injury originating from endothelial cell (EC) damage. Previously we reported that obese mice with low circulatory APN levels exhibited pulmonary vascular endothelial dysfunction. This study was designed to investigate the cellular and molecular mechanisms underlying the pulmonary endothelium-dependent protective effects of APN. Our results demonstrated that in APN-/- mice, there was an inherent state of endothelium mitochondrial dysfunction that could contribute to endothelial activation and increased susceptibility to LPS-induced acute lung injury (ALI). We noted that APN-/- mice showed decreased expression of mitochondrial biogenesis regulatory protein peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and its downstream proteins nuclear respiratory factor 1, transcription factor A, mitochondrial, and Sirtuin (Sirt)3 and Sirt1 expression in whole lungs and in freshly isolated lung ECs from these mice at baseline and subjected to LPS-induced ALI. We further showed that treating APN-/- mice with PGC-1α activator pyrroloquinoline quinone enhances mitochondrial biogenesis and function in lung endothelium and attenuation of ALI. These results suggest that the pulmonary endothelium-protective properties of APN are mediated, at least in part, by an enhancement of mitochondrial biogenesis through a mechanism involving PGC-1α activation.-Shah, D., Torres, C., Bhandari, V. Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury.