Asta Literature Retrieval: Pathophysiology and clinical mechanisms of 3-Hydroxyacyl-CoA Dehydrogenase Deficiency. Core disease mechanisms, molec...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Diagnosis and Clinical Management of Long-chain Fatty-acid Oxidation Disorders: A Review.

• Authors: Joshua Baker, B. Burton
• Year: 2021
• Venue: TouchREVIEWS in endocrinology
• URL: https://www.semanticscholar.org/paper/952c303d9b7cbf2095eb0d1ae7c7b3ab0d92c08d
• DOI: 10.17925/ee.2021.17.2.108
• PMID: 35118456
• Citations: 17
• Summary: This article reviews the major LC-FAODs and their clinical presentation and indicates that triheptanoin approval has improved the outcome for affected individuals.
• Evidence snippets:
• Snippet 1 (score: 0.603) > Very long-chain acyl-CoA dehydrogenase (VLCAD) is the most common LC-FAOD. It is due to biallelic variants in ACADVL, which encodes an enzyme involved in the metabolism of acylcarnitines with 14-20 carbons. 1 Severely affected patients present in the neonatal period with the typical hypoketotic hypoglycaemia, hypotonia, myopathy, hepatic dysfunction, cardiomyopathy and cardiac arrythmias. > In the long-term, patients typically experience recurrent rhabdomyolysis and may exhibit cardiac disease progression with significant stress. With the expansion of newborn screening, many more individuals with a milder phenotype are being identified, with symptoms of skeletal myopathy and rhabdomyolysis not presenting until adolescence or adulthood; some may remain asymptomatic for life. 11 This milder form has now become the most commonly diagnosed phenotype. 11 ng-chain 3-hydroxyacyl-CoA dehydrogenase deficiency/trifunctional protein deficiency > Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and trifunctional protein (TFP) are two disorders that are clinically indistinguishable. > Molecularly, they can be differentiated through the evaluation of HADHA and HADHB. 1 Most affected patients present in infancy or early childhood with hypoglycaemia, hepatic dysfunction, cardiomyopathy and sudden death. LCHAD may also present with maternal HELLP (haemolysis, elevated liver enzymes, and a low platelet count) syndrome or acute fatty liver of pregnancy when the foetus is affected. Long-term sequelae include myopathy, recurrent rhabdomyolysis and exercise intolerance. > Unique phenotypic features of LCHAD/TFP include peripheral neuropathy and retinopathy. 12 Concern has also been raised for the increased comorbidities of intellectual disability and autism spectrum disorders in LCHAD. 13 Further research on the underlying mechanism is still required.

[2] Recent Advances in the Pathophysiology of Fatty Acid Oxidation Defects: Secondary Alterations of Bioenergetics and Mitochondrial Calcium Homeostasis Caused by the Accumulating Fatty Acids

• Authors: A. U. Amaral, M. Wajner
• Year: 2020
• Venue: Frontiers in Genetics
• URL: https://www.semanticscholar.org/paper/cdafd60b0b217c61de651cd70405b651277f5c6a
• DOI: 10.3389/fgene.2020.598976
• PMID: 33329744
• PMCID: 7729159
• Citations: 23
• Summary: The present knowledge on disturbances of mitochondrial bioenergetics, calcium homeostasis, uncoupling of oxidative phosphorylation, and mitochondrial permeability transition induction provoked by the major fatty acids accumulating in prevalent FAOD are updated.
• Evidence snippets:
• Snippet 1 (score: 0.562) > Deficiencies of medium-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, isolated long-chain 3-hydroxyacyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase activities are considered the most frequent fatty acid oxidation defects (FAOD). They are biochemically characterized by the accumulation of medium-chain, long-chain hydroxyl, and long-chain fatty acids and derivatives, respectively, in tissues and biological fluids of the affected patients. Clinical manifestations commonly include hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis. Although the pathogenesis of these diseases is still poorly understood, energy deprivation secondary to blockage of fatty acid degradation seems to play an important role. However, recent evidence indicates that the predominant fatty acids accumulating in these disorders disrupt mitochondrial functions and are involved in their pathophysiology, possibly explaining the lactic acidosis, mitochondrial morphological alterations, and altered mitochondrial biochemical parameters found in tissues and cultured fibroblasts from some affected patients and also in animal models of these diseases. In this review, we will update the present knowledge on disturbances of mitochondrial bioenergetics, calcium homeostasis, uncoupling of oxidative phosphorylation, and mitochondrial permeability transition induction provoked by the major fatty acids accumulating in prevalent FAOD. It is emphasized that further in vivo studies carried out in tissues from affected patients and from animal genetic models of these disorders are necessary to confirm the present evidence mostly achieved from in vitro experiments.

[3] A novel HADHA variant associated with an atypical moderate and late-onset LCHAD deficiency

• Authors: A. Dessein, E. Hebbar, J. Vamecq, E. Lebredonchel, A. Devos et al.
• Year: 2022
• Venue: Molecular Genetics and Metabolism Reports
• URL: https://www.semanticscholar.org/paper/2b0c30eff5f9414ef4d5756652ae56d647a5387f
• DOI: 10.1016/j.ymgmr.2022.100860
• PMID: 35782617
• PMCID: 9248219
• Citations: 7
• Summary: This atypical LCHADD form report should encourage the early assessment of biochemical and genetic testing as a specific management is recommended (combination with fast avoidance, low fat-high carbohydrate diet, medium-even-chain triglycerides or triheptanoin supplementation).
• Evidence snippets:
• Snippet 1 (score: 0.531) > Background Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare inherited disease caused by pathogenic variants of HADHA gene. Along with signs common to fatty acid oxidation defects (FAOD), specific retina and heart alterations are observed. Because long-chain fatty acid oxidation is selectively affected, supplementations with short/medium-chain fats represent energetic sources bypassing the enzymatic blockade. Here, we report on an atypical presentation of the disease. Methods Clinical features were described with medical explorations including ophthalmic and cardiac examination. Biological underlying defects were investigated by measurements of biochemical metabolites and by fluxomic studies of mitochondrial β-oxidation. Whole exome sequencing and molecular validation of variants confirmed the diagnosis. Results The patient has developed at nine years an unlabeled maculopathy, and at 28 years, an acute cardiac decompensation without any premise. Blood individual acylcarnitine analysis showed a rise in hydroxylated long-chain fatty acids and fluxomic studies validated enzyme blockade consistent with LCHADD. Genetic analysis revealed the common p.(Glu510Gln) variant in HADHA, in trans with a novel variant c.1108G > A, p.(Gly370Arg) located in the NAD binding domain. Patient pathology was responsive to triheptanoin supplementation. Conclusion This atypical LCHADD form report should encourage the early assessment of biochemical and genetic testing as a specific management is recommended (combination with fast avoidance, low fat-high carbohydrate diet, medium-even-chain triglycerides or triheptanoin supplementation).

[4] Exploring the contribution of mitochondrial dynamics to multiple acyl-CoA dehydrogenase deficiency-related phenotype

• Authors: S. R. Brandão, Rita Ferreira, H. Rocha
• Year: 2019
• Venue: Archives of Physiology and Biochemistry
• URL: https://www.semanticscholar.org/paper/3fa2c0768599e679dca543d47a13fa756385ed12
• DOI: 10.1080/13813455.2019.1628065
• PMID: 31215835
• Citations: 6
• Summary: The role of mitochondria on the regulation of cell homeostasis through the production of ROS, mitophagy, apoptosis, and mitochondrial biogenesis is overviewed and multiple acyl-CoA dehydrogenase deficiency (MADD) is considered an interesting model to better understand this interplay.
• Evidence snippets:
• Snippet 1 (score: 0.496) > Mitochondrial fatty acid b-oxidation disorders (FAOD) are a group of inherited metabolic disorders, affecting mitochondrial enzymes involved in the b-oxidation of fatty acids (Kompare andRizzo 2008, Sahai andMarsden 2009). These disorders are usually transmitted in an autosomal recessive pattern being individually rare, but together they represent a large and important group of inherited metabolic disorders (Sahai and Marsden 2009). The main affected organs include heart, liver and skeletal muscles (Kompare and Rizzo 2008). The mortality and morbidity rates associated with these conditions can be prevented, or at least decreased, if disorders are early recognized and treated (Sahai and Marsden 2009). Indeed, fatty acid oxidation disorders can lead to serious health problems and even to death if not treated or when the diagnosis is done too late. The advantages of an early intervention make this group of disorders main targets of newborn screening (NBS) programs worldwide (Sahai and Marsden 2009, Lindner et al. 2010, Rocha et al. 2014. > Among FAOD, multiple acyl-CoA dehydrogenase deficiency (MADD) is one of the screened disorders that present heterogeneous clinical phenotypes Goodman 1985, 2001), being recognized three clinical forms. Two severe neonatal-onset forms: with (type I) and without (type II) congenital abnormalities. The late-onset form (type III) is associated to milder phenotypes (Vockley and Whiteman 2002). In most FAOD, including MADD, the association between the phenotype and the genotype is not straightforward (Gregersen et al. 2001, Kompare and Rizzo 2008, Olsen et al. 2013. The observed clinical spectrum in MADD patients suggests that other specific molecular and cellular mechanisms may have a key role in MADD pathogenesis, in addition to mutations in the genes associated to this disease (Olsen et al. 2003, Gr€ unert 2014. These findings make MADD an interesting model to better understand the molecular mechanisms underlying the pathophysiology associated with MADD and other FAOD. > Herein, we overview FAO metabolism, its regulation and contextualize MADD, the chosen model to study mitochondrial dynamics disturbances in FAO. We also critically analyze the potential contribution of the molecular pathways

[5] Mitochondrial Trifunctional Protein Deficiency due to HADHA Variants Masquerading as Charcot–Marie–Tooth Disease

• Authors: Farkhanda Qaiser, John C. McHugh, G. Mullins, M. Farrell, Loai Shakerdi et al.
• Year: 2025
• Venue: Journal of the Peripheral Nervous System
• URL: https://www.semanticscholar.org/paper/2347601554c9f2e4b9fc060205af6d8ad7778a3d
• DOI: 10.1111/jns.70048
• PMID: 40790338
• PMCID: 12340164
• Summary: Mitochondrial trifunctional protein deficiency (MTPD) is an inherited disorder of fatty acid β‐oxidation caused by mutations in HADHA or HADHB genes. It typically presents with cardiomyopathy or hepatic failure in early childhood; however, it may rarely present in adulthood with the neuromyopathic form.
• Evidence snippets:
• Snippet 1 (score: 0.493) > Long chain 3-hydroxyacyl CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD) are rare autosomal recessive disorders of fatty acid βoxidation. MTP is an enzyme complex consisting of four α and four β subunits encoded by HADHA and HADHB, respectively [1]. The α subunits contain the enzymes long chain enoyl CoA hydratase (LCEH), LCHAD and the β subunits contain long chain ketoacyl CoA thiolase (LCKT). > LCHADD due to isolated deficiency of LCHAD is more common, caused by HADHA variants, whereas MTPD due to deficiency of all three enzymes is much rarer and caused by HADHA or HADHB variants. Both of these conditions are part of newborn screening (NBS) in about 20 European countries but not in Ireland. > MTPD was first described in 1992 and may manifest with diverse clinical phenotypes including a severe neonatal form with cardiomyopathy, an infantile hepatic type and a milder lateonset neuromyopathic phenotype. The neuromyopathic presentation is the least common, presenting with repeated episodes of rhabdomyolysis, usually after metabolic decompensation, along with progressive peripheral sensory-motor neuropathy. Spiekerkoetter et al. described 11 patients with a neuromyopathic phenotype and reported that the combination of episodic rhabdomyolysis and peripheral neuropathy was present in almost all patients [2]. In another small study, 70% of patients had neuropathy as a long-term complication [3]. > We present a patient with MTPD due to compound heterozygous HADHA variants, one of them novel, with childhood onset isolated neuropathy initially diagnosed as Charcot-Marie-Tooth disease (CMT). While superimposed exacerbations occurred, there was no documented evidence of rhabdomyolysis or metabolic decompensation.

[6] iPSC‐Derived Liver Organoids as a Tool to Study Medium Chain Acyl‐CoA Dehydrogenase Deficiency

• Authors: L. A. Kiyuna, José M. Horcas-Nieto, Christoff Odendaal, M. Langelaar-Makkinje, A. Gerding et al.
• Year: 2025
• Venue: Journal of Inherited Metabolic Disease
• URL: https://www.semanticscholar.org/paper/547bf305207cfd00da79f778ed7ea7eb255f1018
• DOI: 10.1002/jimd.70028
• PMID: 40199742
• PMCID: 11978564
• Citations: 3
• Summary: iPSC‐derived organoids of MCADD patients recapitulated the major biochemical phenotype of the disease, and this patient‐specific hepatic organoid system is a promising platform to study the phenotypic heterogeneity between MCADD patients.
• Evidence snippets:
• Snippet 1 (score: 0.483) > Medium chain acyl‐CoA dehydrogenase deficiency (MCADD) is an inherited metabolic disease, characterized by biallelic variants in the ACADM gene. Interestingly, even with the same genotype, patients often present with very heterogeneous symptoms, ranging from fully asymptomatic to life‐threatening hypoketotic hypoglycemia. The mechanisms underlying this heterogeneity remain unclear. Therefore, there is a need for in vitro models of MCADD that recapitulate the clinical phenotype as a tool to study the pathophysiology of the disease. Fibroblasts of control and symptomatic MCADD patients with the c.985A>G (p.K329E) were reprogrammed into induced pluripotent stem cells (iPSCs). iPSCs were then differentiated into hepatic expandable organoids (EHOs), further matured to Mat‐EHOs, and functionally characterized. EHOs and Mat‐EHOs performed typical hepatic metabolic functions, such as albumin and urea production. The organoids metabolized fatty acids, as confirmed by acyl‐carnitine profiling and high‐resolution respirometry. MCAD protein was fully ablated in MCADD organoids, in agreement with the instability of the mutated MCAD protein. MCADD organoids accumulated medium‐chain acyl‐carnitines, with a strongly elevated C8/C10 ratio, characteristic of the biochemical phenotype of the disease. Notably, C2 and C14 acyl‐carnitines were found decreased in MCADD Mat‐EHOs. Finally, MCADD organoids exhibited differential expression of genes involved in ω‐oxidation, mitochondrial β‐oxidation, TCA cycle, and peroxisomal coenzyme A metabolism, particularly upregulation of NUDT7. iPSC‐derived organoids of MCADD patients recapitulated the major biochemical phenotype of the disease. Mat‐EHOs expressed relevant pathways involved in putative compensatory mechanisms, notably CoA metabolism and the TCA cycle. The upregulation of NUDT7 expression may play a role in preventing excessive accumulation of dicarboxylic acids

[7] Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

• Authors: Kyung-Jin Kim, P. Pearl, K. Jensen, O. Snead, P. Malaspina et al.
• Year: 2011
• Venue: Antioxidants & Redox Signaling
• URL: https://www.semanticscholar.org/paper/d95101b74cd56d93c2af4e68057a48c55fd6ff4a
• DOI: 10.1089/ars.2010.3470
• PMID: 20973619
• Citations: 80
• Influential citations: 6
• Summary: The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level.
• Evidence snippets:
• Snippet 1 (score: 0.474) > Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADH-deficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation/reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691–718. I. Historical Perspectives and Background A. Identification of succinic semialdehyde dehydrogenase deficiency B. Human SSADH deficiency: early clinical, metabolic, and enzymatic findings C. Pharmacology of GABA and GHB II. Molecular Genetics of SSADH Deficiency and Functional Polymorphisms of the SSADH Gene A. SSADH protein characterization B. Molecular genetics of SSADH deficiency–cDNA cloning and pathogenic mutations C. Variation

[8] The Hypoglycemic Phenotype Is Islet Cell–Autonomous in Short-Chain Hydroxyacyl-CoA Dehydrogenase–Deficient Mice

• Authors: A. Molven, J. Hollister-Lock, Jiang Hu, Rachael Martinez, P. Njølstad et al.
• Year: 2016
• Venue: Diabetes
• URL: https://www.semanticscholar.org/paper/8cd034442e4ec920604efd679554a68fcfd71954
• DOI: 10.2337/db15-1475
• PMID: 26953163
• PMCID: 4878426
• Citations: 13
• Influential citations: 1
• Summary: It is concluded that hypoglycemia in SCHAD-CHI is islet cell–autonomous, and transplanted islets from global SCHAD knockout mice into mice with streptozotocin-induced diabetes, finding that intraperitoneal glucose tolerance was improved in animals receiving SCHADKO islets compared with those receiving normal islets.
• Evidence snippets:
• Snippet 1 (score: 0.464) > of insulin secretion. About half of the CHI cases are "channelopathies" being caused by inactivating mutations in the ABCC8 and KCNJ11 genes that encode subunits of the b-cells' K ATP channel (2,3). Most of the other genetic CHI etiologies can be classified as "metabolopathies," as they directly involve dysregulated metabolic pathways due to mutated enzyme genes (2). > A classic example of the latter category is CHI caused by recessive mutations in HADH (4,5). This gene encodes short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a mitochondrial enzyme that catalyzes the third of the four steps in fatty acid oxidation. More than 20 patients with SCHAD deficiency have now been reported. Intriguingly, they exhibit leucine-sensitive, diazoxide-responsive CHI rather than a phenotype typical for fatty acid oxidation disorders (6). The mechanism behind SCHAD CHI remained enigmatic for many years until Li et al. (7) investigated a global knockout mouse model (SCHADKO) and demonstrated that SCHAD serves to inhibit the enzyme glutamate dehydrogenase (GDH), another protein directly implicated in CHI (8). > However, HADH is ubiquitously expressed, suggesting that SCHAD deficiency is a metabolic disease with possible implications outside the context of the pancreatic b-cell. As such, in affected individuals there is abnormal accumulation of 3-hydroxybutyryl-carnitine in blood and 3-hydroxyglutaric acid in urine-metabolites that are both directly attributable to the enzymatic defect (4)(5)(6). To explore whether the impact of global knockout of the SCHAD enzyme on glucose homeostasis is secondary only to defects in the islets of Langerhans, we transplanted SCHADKO islets into mice with streptozotocin (STZ)induced diabetes.

[9] Frontiers in metabolic physiology grand challenges

• Authors: J. Imig
• Year: 2022
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/19e2780d459288513f034516e0a7d5fa4e12298f
• DOI: 10.3389/fphys.2022.879617
• PMID: 36035475
• PMCID: 9399398
• Citations: 2
• Summary: In this chapter seven subsequent studies of the determinants of infectious disease in eight operation rooms were studied.
• Evidence snippets:
• Snippet 1 (score: 0.450) > Research in this area will identify novel therapeutic targets for diabetic complications at the levels of transcription and translation, protein expression and activity, and cell and organ levels. Major challenges in diabetes include defining molecular mechanisms and pathways implicated in insulin metabolism, evaluating transcriptomics of high glucose on different cell types, defining the contribution of the innate immune response and NLRP3 inflammasome, understanding metabolic mechanisms that drive beta cell dysfunction, and defining metabolic processes in key insulin-target tissues. > NAFLD is a rapidly growing public health concern that occurs in 25% of the world population and is driven in large part by the obesity and type 2 diabetes epidemic (Caussy et al., 2021;Targher et al., 2021). Intriguingly, NAFLD can be as high as 75% in diabetic patients (Caussy et al., 2021;Targher et al., 2021). Non-alcoholic steatosis (NASH) is a type of NAFLD that is associated with inflammation and hepatocyte lipotoxicity which leads to liver fibrosis and cancer (Caussy et al., 2021;Targher et al., 2021). NASH is expected to become the leading cause for liver transplantation in the next decade (Nephew and Serper, 2021). Mechanisms that contribute to NAFLD and progression to NASH include regulation of de novo lipogenesis by acetyl-CoA carboxylase, regulation of bile acid signaling by farnesoid X receptor (FXR), or oxidative stress induced fibrogenesis and inflammation by apoptosis signal-regulating kinase 1 (ASK1) (Attia et al., 2021;Koo and Han, 2021). Although often associated with obesity and diabetes, understanding pathophysiological mechanisms at the cellular hepatocyte and organ liver levels that result in NAFLD and progression to NASH will be key to developing therapeutics. > Major challenges to the epidemic of metabolic diseases are the focus of several publications in Frontiers in Metabolic Physiology. Studies in mice with type 2 diabetes have revealed metabolites involved in diabetic kidney disease.

[10] Revealing the molecular relationship between type 2 diabetes and the metabolic changes induced by a very-low-carbohydrate low-fat ketogenic diet

• Authors: J. Farrés, Albert Pujol, M. Coma, J. L. Ruiz, J. Naval et al.
• Year: 2010
• Venue: Nutrition & Metabolism
• URL: https://www.semanticscholar.org/paper/19f76d9c9209540867c68b7741c2e70fdfa71dd9
• DOI: 10.1186/1743-7075-7-88
• PMID: 21143928
• PMCID: 3009973
• Citations: 24
• Summary: The molecular network analysis performed in theketogenic-diet map, from the diabetes perspective, has provided insights on the potential mechanism of action, but also has opened new possibilities to study the applications of the ketogenic diet in other situations such as CNS or other metabolic dysfunctions.
• Evidence snippets:
• Snippet 1 (score: 0.449) > Novel approaches to study human disease networks Efforts to link metabolic status or diseases by using simple, schematic biological pathways seldom offer the possibility to view the "broad picture", and are rarely able to explain the richness of the complex, redundant, intricate and sometimes blurry nature of human metabolism. Recently, the concept of "Diseaseome" [1] has arisen, as an essay to conceptualize at the highest level the relationship between observed phenotypes and underlying molecular and physiological disease mechanisms or disease cures. Although they are often treated separately, most human diseases are not independent of each other. Many diseases are associated with the breakdown of functional modules (subnetworks) of a complex network connecting many cellular components. Therefore, an understanding of the functionally relevant genetic, regulatory, metabolic and protein-protein interactions will play an important role in understanding the pathophysiology of human diseases [2]. > Specifically, for studying human diseases from this perspective, one has to use a Systems Biology or Network Medicine approach [3][4][5], which are based on the construction of a complex network or map, where nodes are usually proteins, and edges are relationships between nodes. Relationships can be of any type: physical interaction between proteins, metabolic relationships and relationships driven by signaling pathways, homology or other characteristics. The physical representation of this concept is a cell network that can be queried and modeled to identify new complex pathways, or to identify previously unknown effectors of observable characteristics, like for example new drug targets or new metabolic relationships between mechanisms and pathways previously poorly understood [4,5]. > In this work, we have applied these innovative concepts to suggest potential metabolic and molecular relationships between the observed clinical improvements in patients with type 2 diabetes and diet-induced ketosis.

[11] Long‐Chain Fatty Acid Oxidation Disorder Genes: A Comprehensive Genetic Database of LC‐FAOD Variants, Genotypes, and Phenotypes

• Authors: Heather A. Richbourg, Vanessa Rangel Miller, Omid Khazaie Japalaghi, M. AlSayed, Peter R Baker et al.
• Year: 2026
• Venue: Human Mutation
• URL: https://www.semanticscholar.org/paper/bebb7b03ea40592a428ee6217fe1e5bf5bf212e7
• DOI: 10.1155/humu/6864813
• PMID: 42422157
• PMCID: 13342283
• Summary: The LC‐FAOD gene database is a comprehensive archive of variants, genotypes, and phenotypes associated with this important group of FAODs.
• Evidence snippets:
• Snippet 1 (score: 0.448) > Long-chain fatty acid oxidation disorders (LC-FAODs) are rare, autosomal recessive diseases caused by abnormalities in nuclear genes that encode mitochondrial proteins essential for the oxidation of fatty acids of 12-18 carbons in chain length [1][2][3][4]. LC-FAODs are comprised of deficiencies in six different protein/protein activities: Carnitine Palmitoyltransferase 1 (CPT I), carnitine/acylcarnitine translocase (CACT), Carnitine Palmitoyltransferase 2 (CPT II), very-long-chain acyl-CoA dehydrogenase (VLCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and mitochondrial trifunctional protein (TFP), which are part of the carnitine shuttle system or the mitochondrial beta-oxidation pathway (Figure 1) [3,5]. In patients with LC-FAOD, there can be a deficit in energy production and accumulation of toxic metabolites such as long-chain acylcarnitines. > Common clinical features in LC-FAOD are hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis. TFP and LCHAD deficiency have neuropathy and retinopathy as unique features (Table 1). Patients with LC-FAOD require lifelong medical care from metabolic disease specialists. > Management involves avoidance of prolonged fasting, sometimes restriction of long-chain fats in the diet, and early intervention such as intravenous dextrose during illness, to avoid hypoglycemia and clinical decompensation [8]. One medication is approved in Brazil, Canada, Kuwait, Mexico, and the United States for treatment of LC-FAODs (triheptanoin). Clinical outcomes for patients were poor prior to the introduction of newborn screening (NBS), with up to 70% mortality by age 10 years; while survival is now higher with NBS, early death is still common, and morbidity is nearly ubiquitous [9]. Clinical manifestations of each LC-FAOD type, along with the associated gene and protein, are summarized in Table 1.

[12] One novel HSD17B4 mutation in association with D-bifunctional protein deficiency: a case report and literature review

• Authors: Lu Xiong, Shiqing Wang, Hui Sun, Tao Zhong, Li Li et al.
• Year: 2026
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/752f01aff130b933c06b51a39e6f9b15f9f7a038
• DOI: 10.3389/fped.2025.1689571
• PMID: 41567431
• PMCID: 12816375
• Citations: 1
• Summary: A case of a newborn who presented with hypotonia, feeding difficulties and refractory epilepsy shortly after birth, and was eventually diagnosed with D-bifunctional protein deficiency through whole-exome sequencing is presented.
• Evidence snippets:
• Snippet 1 (score: 0.447) > Peroxisomal diseases comprise a heterogeneous spectrum of rare, inherited metabolic disorders, with an estimated prevalence of 1 in 25,000 to 50,000 live births (1)(2)(3)(4). Peroxisomal diseases are categorized into two groups: peroxisome biogenesis disorders and single peroxisomal enzyme deficiencies. In patients with single enzyme deficiencies, peroxisome structure remains normal; the metabolic disorder(s) result exclusively from a functional impairment of a single enzyme protein within the peroxisome. D-Bifunctional protein deficiency (D-BPD),which belongs to single peroxisomal enzyme deficiencies, is a rare autosomal recessive disorder first reported in 1989 (5), with an estimated incidence of 1/100,000. D-bifunctional protein (DBP), which participates in the βoxidation of very-long-chain fatty acids (6), is a peroxisomal enzyme that consists of three catalytic domains: an N-terminal 2-enoyl-CoA hydratase, a central 3-hydroxyacyl-CoA dehydrogenase, and a C-terminal steroid carrier protein 2-like domain (SCP-2L). Pathogenic mutations in the HSD17B4 gene located at 5q21 are responsible for D-BPD. Based on the specific deficient enzymatic activity, D-BPD is categorized into four types. Type I is characterized by a combined deficiency of both dehydrogenase and hydratase activities. Type II presents with an isolated hydratase deficiency, whereas Type III features an isolated dehydrogenase deficiency. Type IV, which presents a less severe phenotype compared to types I-III, shares similarities with Perrault syndrome (PRLTS). Patients with D-BPD manifest a severe clinical course, marked by neonatal hypotonia, recurrent epileptic seizures, and a constellation of dysmorphic facial features. These features commonly include macrocephaly, a prominent forehead, hypertelorism, a at nasal bridge, and low-set ears.

[13] Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria

• Authors: E. Richard, L. Gallego-Villar, A. Rivera-Barahona, A. Oyarzábal, B. Pérez et al.
• Year: 2018
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/a02a988d26ef8a032bade854c27c8c28792a6dfa
• DOI: 10.1155/2018/1246069
• PMID: 29743968
• PMCID: 5884027
• Citations: 35
• Influential citations: 2
• Summary: The published data on mitochondrial dysfunction, oxidative stress, and impaired redox signaling in branched-chain amino acid disorders, other organic acidurias, and homocystinuria are described, along with recent studies exploring the efficiency of antioxidants and mitochondria-targeted therapies as therapeutic compounds in these diseases.
• Evidence snippets:
• Snippet 1 (score: 0.439) > Dehydrogenase. MSUD (MIM #248600), caused by the deficiency of branched-chain α-ketoacid dehydrogenase complex (BCKDHc) activity, is characterized by elevated levels of BCAAs and their corresponding α-keto-acids (BCKAs) in body fluids and tissues, resulting in complex neurological phenotypes [37]. As the important gatekeeping enzyme that it is, BCKDHc is regulated by reversible phosphorylation catalyzed by a specific BCKD kinase (BCKDK) that inhibits BCKDHc function, halting the catabolic pathway of BCAAs [41], and a dephosphorylation catalyzed by the mitochondrial protein phosphatase PP2Cm (encoded by the PPM1K gene) that stimulates BCKDHc activity [42]. Optimal BCKDHc activity necessary to maintain BCAA homeostasis is achieved by the coordinated response of BCKDK and PP2Cm activities. Blockage or unrestrained BCAA metabolism through BCKDHc leads to a dysmetabolism of BCAAs resulting in MSUD or BCKDK deficiency (MIM #614923) (Figure 1), two different clinical conditions with a hallmark of neurological perturbation. > MSUD results from mutations in the genes E1α-BCKDHA (MIM #608348), E1β-BCKDHB (MIM #24861), and E2-DBT (MIM #248610) [37]. The disease affects 1 : 185,000 newborns worldwide and is manifested by diverse clinical phenotypes, ranging from the most severe form-seen in 70% of patients with MSUD and associated with a profound neurological impact and high mortality if not treated early-to mild forms that present during early development. The mechanisms underlying brain injury are not completely understood. Different studies have been carried out using chemical induction of the disease by BCAAs or BCKAs in cultured cells [43,44] and animal models [45][46][47][48].

[14] Complex changes in the liver mitochondrial proteome of short chain acyl-CoA dehydrogenase deficient mice

• Authors: Wei Wang, A. Mohsen, Guy T. Uechi, Emanuel M. Schreiber, M. Balasubramani et al.
• Year: 2014
• Venue: Molecular genetics and metabolism
• URL: https://www.semanticscholar.org/paper/e8bcfc0ce5c7d93a0021292722f92d5f695cf413
• DOI: 10.1016/j.ymgme.2014.02.014
• PMID: 24685553
• PMCID: 4167795
• Citations: 14
• Summary: Changes in the levels of multiple energy metabolism related proteins were identified indicating that a more complex mechanism for development of symptoms may exist and several candidate molecules are proposed that may serve as markers for recognition of clinical risk associated with this disorder.
• Evidence snippets:
• Snippet 1 (score: 0.439) > Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an autosomal recessive inborn error of metabolism that leads to the impaired mitochondrial fatty acid β-oxidation of short chain fatty acids. It is heterogeneous in clinical presentation including asymptomatic in most patients identified by newborn screening. Multiple mutations have been identified in patients; however, neither clear genotype–phenotype relationships nor a good correlation between genotype and current biochemical markers for diagnosis has been identified. The definition and pathophysiology of this deficiency remain unclear. To better understand this disorder at a global level, quantitative alterations in the mitochondrial proteome in SCAD deficient mice were examined using a combined proteomics approach: two-dimensional gel difference electrophoresis (2DIGE) followed by protein identification with MALDI-TOF/TOF and iTRAQ labeling followed by nano-LC/MALDI-TOF/TOF. We found broad mitochondrial dysfunction in SCAD deficiency. Changes in the levels of multiple energy metabolism related proteins were identified indicating that a more complex mechanism for development of symptoms may exist. Affected pathways converge on disorders with neurologic symptoms, suggesting that even asymptomatic individuals with SCAD deficiency may be at risk to develop more severe disease. Our results also identified a pattern associated with hepatotoxicity implicated in mitochondrial dysfunction, fatty acid metabolism, decrease of depolarization of mitochondria and mitochondrial membranes, and swelling of mitochondria, demonstrating that SCAD deficiency relates more directly to mitochondrial dysfunction and alteration of fatty acid metabolism. We propose several candidate molecules that may serve as markers for recognition of clinical risk associated with this disorder.

[15] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: Murat Uztimür, Cennet Nur Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Citations: 2
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.438) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[16] Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

• Authors: G. del Favero, A. Bonifacio, T. Rowland, Shanshan Gao, Kunhua Song et al.
• Year: 2020
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/98c99997015d4b753548454628875ce01936b442
• DOI: 10.3390/jcm9082457
• PMID: 32751926
• PMCID: 7465084
• Citations: 20
• Influential citations: 1
• Summary: Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
• Evidence snippets:
• Snippet 1 (score: 0.438) > Because Danon disease is very rare, with <100 clinical reports and <200 families reported in the literature [12], there is poor availability of material for diagnosis and characterization [13]. Hence, research toward the creation of reliable models, such as animal models [14] or iPSC-CMs, enabling the study of this complex pathology even in a limited manner are essential and constantly evolving. > To determine the molecular and cellular mechanisms by which LAMP-2 deficiency results in metabolic changes, here we combined Raman spectroscopy, transcriptomics, and metabolomics approaches on cardiac tissue and cellular models derived from Danon patients. Analyses were performed on cardiac tissue biopsies from Danon patients, as well as from patient-derived hiPSC-CMs. Even with limited patient cardiac tissue, we were able to identify pathways that were similarly impacted in our cellular models, supportive of these pathways being significantly affected in Danon disease. LAMP-2 deficiency appeared to promote specific metabolic switch in cardiomyocytes, possibly adaptive, given that cardiomyocytes have a high metabolic need. The pathway analyses suggest that LAMP-2 deficiency favors glycolysis to oxidative phosphorylation (OXPHOS) and promotes alternative metabolic pathways, such as with the mobilization of tryptophan. This contributes to preserving high nicotinamide adenine dinucleotide (NAD + ) levels despite mitochondrial aging. Similarly, fibroblasts respond to LAMP-2 deficiency with a stress-associated phenotype pointing toward fibrosis progression. This was accompanied by impairment of biomechanical properties, which retraces the clinical phenotype of Danon disease.

[17] Acute fatty liver of pregnancy associated with severe acute pancreatitis: A case report.

• Authors: Cássio Vieira de Oliveira, Alecsandro Moreira, J. Baima, Leticia de C Franzoni, T. Lima et al.
• Year: 2014
• Venue: World journal of hepatology
• URL: https://www.semanticscholar.org/paper/9ef0a611fa9ce7e0027e52aa89f6aaea59899a63
• DOI: 10.4254/wjh.v6.i7.527
• PMID: 25068005
• Citations: 13
• Summary: A previously healthy 26-year-old woman at a gestational age of 27 wk and 6 d who was admitted with severe abdominal pain and vomiting is described, highlighting the difficulties in differentiating each disease.
• Evidence snippets:
• Snippet 1 (score: 0.436) > However, in the case presented, the recurrent episodes of hypoglycemia, even with appropriate correction, were the main diagnostic clue. > The association between AFLP and inherited defects in the mitochondrial beta-oxidation of fatty acids, especially the impairment of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), suggests that some affected women and fetuses have an inherited enzyme deficiency in beta-oxidation that predisposes the mother to this disorder [15][16][17] . LCHAD catalyzes the third step of the betaoxidation of fatty acids in the mitochondrion (the formation of 3-ketoacyl-CoA from 3-hydroxyacyl-CoA). The accumulation of long-chain metabolites of 3-hydroxyacyl produced by the fetus or placenta is toxic to the liver and can serve as the cause of the liver disease. The role of the pathogenesis of LCHAD in AFLP has been illustrated in various studies [18][19][20] . > The mechanism by which pancreatitis may develop as a complication of fatty liver of pregnancy is not well understood because this association is rare. Our hypothesis is that the accumulation of long-chain metabolites of 3-hydroxyacyl is toxic to the liver and the pancreatic tissue. Thus, the pancreas could be affected when an increased concentration of these metabolites is present, as occurs in cases of severe hepatic disease. This hypothesis serves as a reasonable explanation for the pancreatic impairment displayed in this case of hepatic failure. > The diagnosis of LCHAD deficiency in newborns can save lives; therefore, all women with AFLP and their children should be administered a molecular test for LCHAD, which should at least evaluate the most common mutation, namely, G1528C [21,22] . In the present case, it was not possible to perform this type of test because it was not available. > The clinical diagnosis of AFLP is typically performed according to the definition, presentation, and laboratorycompatible image results. The liver imaging is primarily used to exclude other diagnoses, such as hepatic infarction and hematoma [23] .

[18] A Deep Intronic HADH Splicing Mutation (c.636+471G>T) in a Congenital Hyperinsulinemic Hypoglycemia Case: Long Term Clinical Course

• Authors: Emine Çamtosun, S. Flanagan, S. Ellard, Z. Şıklar, K. Hussain et al.
• Year: 2015
• Venue: Journal of Clinical Research in Pediatric Endocrinology
• URL: https://www.semanticscholar.org/paper/bccdfdb6794aa98a27a2a9070b2b8fa2661190d5
• DOI: 10.4274/jcrpe.1963
• PMID: 26316438
• PMCID: 4563187
• Citations: 15
• Summary: Clinical and laboratory findings are presented together with the long-term clinical course of a case with a deep intronic HADH splicing mutation causing neonatal-onset hyperinsulinemic hypoglycemia with mild progression.
• Evidence snippets:
• Snippet 1 (score: 0.436) > Persistent congenital hyperinsulinemic hypoglycemia (CHH) can be caused by mutations in the ABCC8/KCNJ11, GLUD1, HADH, GCK, HNF4A, HNF1A, SLC16A1 and UCP2 genes (1,2). ABCC8/KCNJ11 mutations are most common (33-66%) and GLUD1 mutations are the second commonest cause of CHH, identified in approximately 5% of the cases. Mutations in other known genes (including HADH) together account for less than 4% of CHH (1). > Loss of function mutations in the HADH (HADHSC, SCHAD) gene, causing short-chain L-3-hydroxyacyl-CoA (SCHAD) deficiency, were first reported to cause persistent CHH in 2001 (3). SCHAD catalyses the penultimate step in the mitochondrial fatty acid oxidation pathway, the NAD +dependent conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA (1). The main clinical feature of this metabolic disease is hypoketotic hypoglycemia with hyperinsulinism which is different from other inherited defects of fatty acid β-oxidation that can present with symptoms such as hepatomegaly, myopathy and cardiomyopathy. HADH mutations are recessively inherited and most of the reported cases are from consanguineous families. So far, approximately 40 patients with CHH resulting from a mutation in the HADH gene have been reported (Table 1) (3,4,5,6,7,8,9,10,11,12,13,14,15).The mechanism behind unregulated insulin secretion in SCHAD deficiency is currently not understood but may involve changes in protein-protein interactions with glutamate dehydrogenase (GDH) (16,17). > Emine Çamtosun1 , Sarah E. Flanagan2 , Sian Ellard 2 , Zeynep Şıklar 1 , Khalid Hussain The clinical presentation is mainly neonatal-or early infancy-onset HH and patients are diazoxide-responsive.

[19] Mitochondrial morphology, bioenergetics and proteomic responses in fatty acid oxidation disorders

• Authors: Serena Raimo, Gabriella Zura-Miller, Hossein Fezelinia, L. Spruce, Iordanis Zakopoulos et al.
• Year: 2021
• Venue: Redox Biology
• URL: https://www.semanticscholar.org/paper/e4ffce5f0f56f0638a6921b7ebe8393b18b033d1
• DOI: 10.1016/j.redox.2021.101923
• PMID: 33725513
• PMCID: 7970426
• Citations: 12
• Summary: Collectively the data indicate that despite the metabolic deficits, cells with VLCAD and TFP mutations maintain their proteomic integrity to preserve cellular and mitochondria architecture, support energy production and protect against oxidative stress.
• Evidence snippets:
• Snippet 1 (score: 0.434) > Fatty acid β-oxidation is the primary pathway for the metabolism and conversion of long-chain fatty acids (LCFA) to energy [1][2][3]. Approximately 25 proteins that are broadly subdivided into three functional clusters participate in this metabolic pathway. The first cluster includes transporters and enzymes that import and convert fatty acids to acyl CoA species. The second group includes proteins that participate in the carnitine cycle, which transforms fatty acids to acylcarnitines and actively transport acylcarnitines into mitochondria. Finally, proteins embedded within the inner mitochondrial membrane execute the β-oxidation of fatty acids in a series of four cyclical reactions to generate acetyl-CoA. The β-oxidation of fatty acids also generates NADH and FADH 2 to support oxidative phosphorylation and ATP production. The first step in the oxidation of fatty acids with 14 or more carbons is executed by VLCAD, a homodimer encoded by the ACADVL gene. The next 3 enzymatic steps are executed by TFP, which is composed of four α and four β subunits (α 4 β 4 ) that are encoded by two different genes HADHA and HADHB, respectively. The HADHA encoded α-subunits contain the activities of enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and the HADHB encoded β-subunits the 3-ketoacyl-CoA thiolase activity. > Defects in nuclear genes encoding for VLCAD and TFP cause rare inherited autosomal recessive diseases that present primarily with hypoglycemia, cardiomyopathy, intermittent muscle breakdown (rhabdomyolysis), and liver failure [1][2][3][4][5][6][7][8][9]. Clinical management includes reduction of dietary intake of LCFA, fasting avoidance, high carbohydrate diet supplemented with medium chain triglycerides and in some cases carnitine [10,11]. Despite the advances in detection and clinical management, patients with these disorders still experience life-long symptoms since the molecular and biochemical mechanisms that drive disease phenotypes remain insufficiently characterized.

[20] Lipidomics reveals effect of EHHADH in lung squamous cell

• Authors: Jianan Huang, Linlin Zhang, Wanxin Duan, Liyang Li, Xiao-Xia Liu et al.
• Year: 2025
• Venue: Cell Biology and Toxicology
• URL: https://www.semanticscholar.org/paper/eefaef17d013540c6c38fe4ad520168f381a0c9f
• DOI: 10.1007/s10565-025-10044-4
• PMID: 40450155
• PMCID: 12126335
• Citations: 3
• Summary: Identifying and characterizing EHHADH as a key regulator of medium-chain fatty acid metabolism in LUSC and playing a key role in the occurrence, progression, and treatment of lung cancer is concluded.
• Evidence snippets:
• Snippet 1 (score: 0.434) > The present study furthermore observed that the changed expression of lipid metabolism-related genes varied among lung cancer types and some appeared type-specific. For example, the expression of EHHADH, ACSM1, and ACSM2 A, encoding proteins involved in the synthesis of medium-chain fatty acids, showed LUSC-specific, suggesting that the reprogramming of medium-chain fatty acids-dominated lipid metabolism plays important roles in the development of LUSC, although the exact mechanisms by which EHHADH regulates lipid metabolisms of LUSCs remain unclear. > The EHHADH belongs to the hydroxyacyl-CoA dehydrogenase (HAD) superfamily, which is broadly involved in the β-oxidation of fatty acid metabolism in peroxisomes and mitochondria (genecards.org; Yang G et al. 2023b). The EHHADH subfamily mainly includes peroxisomal enzymes such as enoyl-CoA hydratase (ECH) which hydrate 2-trans-enoyl-CoA to L-3-hydroxyacyl-CoA, and 3-hydroxyacyl-CoA dehydrogenase (HADH), which oxidize L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA, particularly for long-chain fatty acids, and EHHADH-like enzymes such as sterol carrier protein X (SCPx) in sterol metabolisms. To date, there are limited pre-clinical and clinical studies to investigate the roles of EHHADH in lung diseases, especially in LUSC. EHHADH was found to be one of the top single-nucleotide variation and mutation genes related with the metabolic reprogramming and metabolism-related pathways in the early stage of LUAD as well as poorer prognosis in patients with LUAD (Wang Z et al. 2024). Additionally, EHHADH as one of four genes related to acyl-coenzyme A cholesterol acyltransferase was found to be associated with LUAD cell cycle and proliferation, DNA repair and damage, and cell survival rates (Lee et al. 2024).

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