RESUMEN
Purpose: Progressive choroid and retinal pigment epithelial (RPE) degeneration causing vision loss is a unique characteristic of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a fatty acid oxidation disorder caused by a common c.1528G>C pathogenic variant in HADHA, the α subunit of the mitochondrial trifunctional protein (TFP). We established and characterized an induced pluripotent stem cell (iPSC)-derived RPE cell model from cultured skin fibroblasts of patients with LCHADD and tested whether addition of wildtype (WT) HAHDA could rescue the phenotypes identified in LCHADD-RPE. Methods: We constructed an rAAV expression vector containing 3' 3xFLAG-tagged human HADHA cDNA under the transcriptional control of the cytomegalovirus (CMV) enhancer-chicken beta actin (CAG) promoter (CAG-HADHA-3XFLAG). LCHADD-RPE were cultured, matured, and transduced with either AAV-GFP (control) or AAV-HADHA-3XFLAG. Results: LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE. When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they have increased oxidative stress, lipid peroxidation, decreased viability, and are rescued by antioxidant agents potentially explaining the pathologic mechanism of RPE loss in LCHADD. Transduced LCHADD-RPE expressing a WT copy of TFPα incorporated TFPα-FLAG into the TFP complex in the mitochondria and accumulated significantly less 3-hydroxy-acylcarnitines, released more ketones in response to palmitate, and were more resistant to oxidative stress following DHA exposure than control. Conclusions: iPSC-derived LCHADD-RPE are susceptible to lipid peroxidation mediated cell death and are rescued by exogenous HADHA delivered with rAAV. These results are promising for AAV-HADHA gene addition therapy as a possible treatment for chorioretinopathy in patients with LCHADD.
Asunto(s)
Dependovirus , Vectores Genéticos , Células Madre Pluripotentes Inducidas , Peroxidación de Lípido , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga , Epitelio Pigmentado de la Retina , Transfección , Humanos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/citología , Células Madre Pluripotentes Inducidas/metabolismo , Dependovirus/genética , Células Cultivadas , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga/genética , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/terapia , Proteína Trifuncional Mitocondrial/genética , Proteína Trifuncional Mitocondrial/deficiencia , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/metabolismo , Terapia Genética/métodos , Cardiomiopatías , Enfermedades del Sistema Nervioso , RabdomiólisisRESUMEN
Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid ß-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and ß subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.
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Cardiolipinas , Metabolismo Energético , Fibroblastos , Errores Innatos del Metabolismo Lipídico , Subunidad alfa de la Proteína Trifuncional Mitocondrial , Cardiolipinas/metabolismo , Animales , Humanos , Ratones , Subunidad alfa de la Proteína Trifuncional Mitocondrial/metabolismo , Subunidad alfa de la Proteína Trifuncional Mitocondrial/genética , Metabolismo Energético/genética , Fibroblastos/metabolismo , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/patología , Subunidad beta de la Proteína Trifuncional Mitocondrial/metabolismo , Subunidad beta de la Proteína Trifuncional Mitocondrial/genética , Mitocondrias/metabolismo , Mutación , Proteína Trifuncional Mitocondrial/deficiencia , Proteína Trifuncional Mitocondrial/metabolismo , Proteína Trifuncional Mitocondrial/genética , Rabdomiólisis/metabolismo , Rabdomiólisis/genética , Rabdomiólisis/patología , Miopatías Mitocondriales/metabolismo , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/patología , Consumo de Oxígeno , Masculino , Modelos Animales de Enfermedad , Lisofosfolípidos , Cardiomiopatías , Enfermedades del Sistema NerviosoRESUMEN
D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.
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Proteína Trifuncional Mitocondrial/deficiencia , Proteína-2 Multifuncional Peroxisomal , Humanos , Proteína-2 Multifuncional Peroxisomal/deficiencia , Proteína-2 Multifuncional Peroxisomal/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Recién Nacido , Lactante , Masculino , Femenino , Secuenciación del Exoma , Mutación del Sistema de Lectura , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , 17-Hidroxiesteroide Deshidrogenasas/genética , Configuración de Recursos Limitados , Miopatías Mitocondriales , Cardiomiopatías , Enfermedades del Sistema Nervioso , RabdomiólisisRESUMEN
Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.
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Diagnóstico Precoz , Errores Innatos del Metabolismo Lipídico , Proteína Trifuncional Mitocondrial , Tamizaje Neonatal , Enfermedades de la Retina , Agudeza Visual , Humanos , Masculino , Femenino , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/terapia , Niño , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Proteína Trifuncional Mitocondrial/deficiencia , Adulto , Lactante , Preescolar , Adolescente , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Adulto Joven , Carnitina/análogos & derivados , Carnitina/uso terapéutico , Electrorretinografía , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , 3-Hidroxiacil-CoA Deshidrogenasas/deficiencia , 3-Hidroxiacil-CoA Deshidrogenasas/genética , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Resultado del Tratamiento , Rabdomiólisis/diagnóstico , Rabdomiólisis/genética , Enfermedades del Sistema NerviosoRESUMEN
Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid ß-oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore the presence of disease-specific markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease-specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease-specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.
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Cardiomiopatías , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Errores Innatos del Metabolismo Lipídico , Lipidómica , Enfermedades Mitocondriales , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades Musculares , Enfermedades del Sistema Nervioso , Rabdomiólisis , Humanos , Enfermedades Mitocondriales/diagnóstico , Carnitina , Cisteamina , LípidosRESUMEN
Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.
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Acil-CoA Deshidrogenasa/deficiencia , Cardiomiopatías , Carnitina O-Palmitoiltransferasa/deficiencia , Errores Innatos del Metabolismo Lipídico , Errores Innatos del Metabolismo , Proteína Trifuncional Mitocondrial/deficiencia , Tamizaje Neonatal , Rabdomiólisis , Humanos , Recién Nacido , Estudios Retrospectivos , Masculino , Femenino , Tamizaje Neonatal/métodos , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/complicaciones , Bélgica/epidemiología , Lactante , Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Síndromes Congénitos de Insuficiencia de la Médula Ósea/diagnóstico , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Ácidos Grasos/metabolismo , Preescolar , Enfermedades Musculares/diagnóstico , Niño , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/complicaciones , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/complicaciones , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/diagnósticoRESUMEN
OBJECTIVE: This study aims to elucidate the long-term benefit of newborn screening (NBS) for individuals with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency, inherited metabolic diseases included in NBS programs worldwide. METHODS: German national multicenter study of individuals with confirmed LCHAD/MTP deficiency identified by NBS between 1999 and 2020 or selective metabolic screening. Analyses focused on NBS results, confirmatory diagnostics, and long-term clinical outcomes. RESULTS: Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived, but four with MTP deficiency (14.8%) died during the study period. Despite NBS and early treatment neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%), hepatopathy (32%), retinopathy (17%), and/or neuropathy (22%) occurred. Hospitalization rates were high (up to a mean of 2.4 times/year). Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). Achievement of dietary goals decreased with age, from 75% in the first year of life to 12% at age 10, and consensus group recommendations on dietary management were often not achieved. INTERPRETATION: While NBS and early treatment result in improved (neonatal) survival, they cannot reliably prevent long-term morbidity in screened individuals with LCHAD/MTP deficiency, highlighting the urgent need of better therapeutic strategies and the development of disease course-altering treatment.
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Cardiomiopatías , Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial , Enfermedades del Sistema Nervioso , Rabdomiólisis , Humanos , Recién Nacido , Ácidos Grasos/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/terapia , Errores Innatos del Metabolismo Lipídico/metabolismo , 3-Hidroxiacil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Proteína Trifuncional Mitocondrial/metabolismo , Proteína Trifuncional Mitocondrial/deficiencia , Lactante , Preescolar , NiñoRESUMEN
OBJECTIVE: To develop an updated staging system for long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHADD) chorioretinopathy based on contemporary multimodal imaging and electrophysiology. METHODS: We evaluated forty cases of patients with genetically confirmed LCHADD or trifunctional protein deficiency (TFPD) enrolled in a prospective natural history study. Wide-field fundus photographs, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ffERG) were reviewed and graded for severity. RESULTS: Two independent experts first graded fundus photos and electrophysiology to classify the stage of chorioretinopathy based upon an existing published system. With newer imaging modalities and improved electrophysiology, many patients did not fit cleanly into a single traditional staging group. Therefore, we developed a novel staging system that better delineated the progression of LCHADD retinopathy. We maintained the four previous delineated stages but created substages A and B in stages 2 to 3 to achieve better differentiation. DISCUSSION: Previous staging systems of LCHADD chorioretinopathy relied on only on the assessment of standard 30 to 45-degree fundus photographs, visual acuity, fluorescein angiography (FA), and ffERG. Advances in recordings of ffERG and multimodal imaging with wider fields of view, allow better assessment of retinal changes. Following these advanced assessments, seven patients did not fit neatly into the original classification system and were therefore recategorized under the new proposed system. CONCLUSION: The new proposed staging system improves the classification of LCHADD chorioretinopathy, with the potential to lead to a deeper understanding of the disease's progression and serve as a more reliable reference point for future therapeutic research.
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Cardiomiopatías , Enfermedades de la Coroides , Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso , Enfermedades de la Retina , Rabdomiólisis , Humanos , Estudios Prospectivos , Enfermedades de la Retina/diagnóstico , Retina/metabolismo , Tomografía de Coherencia Óptica , Angiografía con Fluoresceína/métodosRESUMEN
During Mycobacterium tuberculosis (Mtb) infection, the virulence factor PtpA belonging to the protein tyrosine phosphatase family is delivered into the cytosol of the macrophage. PtpA interacts with numerous eukaryotic proteins modulating phagosome maturation, innate immune response, apoptosis, and potentially host-lipid metabolism, as previously reported by our group. In vitro, the human trifunctional protein enzyme (hTFP) is a bona fide PtpA substrate, a key enzyme of mitochondrial ß-oxidation of long-chain fatty acids, containing two alpha and two beta subunits arranged in a tetramer structure. Interestingly, it has been described that the alpha subunit of hTFP (ECHA, hTFPα) is no longer detected in mitochondria during macrophage infection with the virulent Mtb H37Rv. To better understand if PtpA could be the bacterial factor responsible for this effect, in the present work, we studied in-depth the PtpA activity and interaction with hTFPα. With this aim, we performed docking and in vitro dephosphorylation assays defining the P-Tyr-271 as the potential target of mycobacterial PtpA, a residue located in the helix-10 of hTFPα, previously described as relevant for its mitochondrial membrane localization and activity. Phylogenetic analysis showed that Tyr-271 is absent in TFPα of bacteria and is present in more complex eukaryotic organisms. These results suggest that this residue is a specific PtpA target, and its phosphorylation state is a way of regulating its subcellular localization. We also showed that phosphorylation of Tyr-271 can be catalyzed by Jak kinase. In addition, we found by molecular dynamics that PtpA and hTFPα form a stable protein complex through the PtpA active site, and we determined the dissociation equilibrium constant. Finally, a detailed study of PtpA interaction with ubiquitin, a reported PtpA activator, showed that additional factors are required to explain a ubiquitin-mediated activation of PtpA. Altogether, our results provide further evidence supporting that PtpA could be the bacterial factor that dephosphorylates hTFPα during infection, potentially affecting its mitochondrial localization or ß-oxidation activity.
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Proteínas Bacterianas , Proteína Trifuncional Mitocondrial , Mycobacterium tuberculosis , Humanos , Metabolismo de los Lípidos , Filogenia , Ubiquitinas , Proteína Trifuncional Mitocondrial/metabolismo , Proteínas Bacterianas/metabolismoRESUMEN
Tumor occurrence and progression are closely associated with abnormal energy metabolism and energy metabolism associated with glucose, proteins and lipids. The reprogramming of energy metabolism is one of the hallmarks of cancer. As a form of energy metabolism, fatty acid metabolism includes fatty acid uptake, de novo synthesis and ßoxidation. In recent years, the role of abnormal fatty acid ßoxidation in tumors has gradually been recognized. Mitochondrial trifunctional protein (MTP) serves an important role in fatty acid ßoxidation and HADH (two subtypes: α subunit, HADHA and ß subunit, HADHB) are important subunits of MTP. HADH participates in the steps of 2, 3 and 4 fatty acid ßoxidation. However, there is no review summarizing the specific role of HADH in tumors. Therefore, the present study focused on HADH as the main indicator to explore the changes in fatty acid ßoxidation in several types of tumors. The present review summarized the changes in HADH in 11 organs (cerebrum, oral cavity, esophagus, liver, pancreas, stomach, colorectum, lymph, lung, breast, kidney), the effect of up and downregulation and the relationship of HADH with prognosis. In summary, HADH can be either a suppressor or a promoter depending on where the tumor is located, which is closely associated with prognostic assessment. HADHA and HADHB have similar prognostic roles in known and comparable tumors.
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Subunidad beta de la Proteína Trifuncional Mitocondrial , Neoplasias , Humanos , Ácidos Grasos/metabolismo , Glucosa , Proteína Trifuncional Mitocondrial , Neoplasias/genéticaRESUMEN
Hypertriglyceridemia-induced acute pancreatitis (HTGP) is characterized by the acute and excessive release of FFA produced by pancreatic lipases. However, the underlying mechanisms of this disease remain poorly understood. In this study, we describe the involvement of the RNA binding protein hnRNPA2B1 in the development of HTGP. We used palmitic acid (PA) and AR42J cells to create a model of HTGP in vitro. RT-PCR and western blot analyses revealed a decrease in the level of hnRNPA2B1 protein but not mRNA expression in PA-treated cells. Further analyses revealed that hnRNPA2B1 expression was regulated at the post-translational level by neddylation. Restoration of hnRNPA2B1 expression using the neddylation inhibitor MLN4924 protected AR42J cells from PA-induced inflammatory injury by preventing NF-κB activation and restoring fatty acid oxidation and cell proliferation. Furthermore, RNA immunoprecipitation studies demonstrated that hnRNPA2B1 orchestrates fatty acid oxidation by regulating the expression of the mitochondrial trifunctional protein-α (MTPα). Administration of MLN4924 in vivo restored hnRNPA2B1 protein expression in the pancreas of hyperlipidemic mice and ameliorated HTGP-associated inflammation and pancreatic tissue injury. In conclusion, we show that hnRNPA2B1 has a central regulatory role in preventing HTGP-induced effects on cell metabolism and viability. Furthermore, our findings indicate that pharmacological inhibitors that target neddylation may provide therapeutic benefits to HTGP patients.
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Ribonucleoproteína Heterogénea-Nuclear Grupo A-B , Hipertrigliceridemia , Pancreatitis , Enfermedad Aguda , Animales , Ciclopentanos , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ratones , Proteína Trifuncional Mitocondrial/metabolismo , FN-kappa B/metabolismo , Ácido Palmítico/farmacología , Pancreatitis/metabolismo , Pirimidinas , ARNRESUMEN
PURPOSE: The purpose of this case study is to describe the outpatient rehabilitation program for a 15-year-old girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). SUMMARY OF KEY POINTS: The child presented with sudden-onset muscle weakness and fatigue with resultant dependence for all mobility and self-care. After 12 months of therapy, which included aquatic interventions and robotic-assisted gait training, the patient demonstrated independence with transfers, ambulation with a rolling walker, and stair navigation. Functional mobility, gross motor skills, and participation in activities of daily living significantly improved per the Gross Motor Function Measure and the Pediatric Evaluation of Disability Inventory. STATEMENT OF CONCLUSION AND RECOMMENDATIONS FOR CLINICAL PRACTICE: This is the first case in the literature to outline an outpatient physical therapy treatment plan to address mobility deficits secondary to exacerbation of LCHADD. This patient's rehabilitative course will hopefully add to future research and provide patients with guidelines for their recovery.
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Actividades Cotidianas , Procedimientos Quirúrgicos Robotizados , Adolescente , Cardiomiopatías , Niño , Femenino , Marcha , Humanos , Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso , Modalidades de Fisioterapia , RabdomiólisisRESUMEN
BACKGROUND Acute fatty liver of pregnancy (AFLP) is a rare obstetric emergency that most commonly occurs in the third trimester and has high mortality rates for the mother and fetus. AFLP is a diagnosis of exclusion supported by identifying 6 or more of the 15 Swansea criteria. This report is of a 24-year-old woman presenting in the third trimester of pregnancy with nausea, vomiting, and abdominal pain and diagnosed with AFLP. CASE REPORT A 24-year-old woman presented at 36 weeks of gestation with nausea, vomiting, and abdominal pain. Investigations showed leukocytosis, hyperbilirubinemia, increased liver enzymes, hypoglycemia, hyperuricemia, acute kidney injury (AKI), and coagulopathy. Ten of the 15 Swansea criteria were fulfilled. An emergency cesarean section resulted in the delivery of a healthy infant, followed by a normalization of the mother's liver function. Because long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency in the infant can be associated with maternal AFLP, genotyping of the infant was planned. CONCLUSIONS This report has shown the importance of clinical awareness, rapid diagnosis, and management of AFLP. Screening for fetal LCHAD deficiency could help decrease mortality.
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Cesárea , Complicaciones del Embarazo , Dolor Abdominal/etiología , Cardiomiopatías , Hígado Graso , Femenino , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Náusea/etiología , Enfermedades del Sistema Nervioso , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/etiología , Tercer Trimestre del Embarazo , Rabdomiólisis , Vómitos/etiología , Adulto JovenRESUMEN
Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast identification at neonatal screening, LCHADD/MTPD present with progressive neurodegenerative symptoms originally attributed to the accumulation of toxic hydroxyl acylcarnitines and energy deficiency. Recently, it has been shown that LCHADD human fibroblasts display a disease-specific alteration of complex lipids. Accumulating fatty acids, due to defective ß-oxidation, contribute to a remodeling of several lipid classes including mitochondrial cardiolipins and sphingolipids. In the last years the face of LCHADD/MTPD has changed. The reported dysregulation of complex lipids other than the simple acylcarnitines represents a novel aspect of disease development. Indeed, aberrant lipid profiles have already been associated with other neurodegenerative diseases such as Parkinson's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis and retinopathy. Today, the physiopathology that underlies the development of the progressive neuropathic symptoms in LCHADD/MTPD is not fully understood. Here, we hypothesize an alternative disease-causing mechanism that contemplates the interaction of several factors that acting in concert contribute to the heterogeneous clinical phenotype.
Asunto(s)
Errores Innatos del Metabolismo Lipídico , Coenzima A , Ácidos Grasos/metabolismo , Humanos , Errores Innatos del Metabolismo Lipídico/genética , Proteína Trifuncional Mitocondrial/genética , Proteína Trifuncional Mitocondrial/metabolismo , Factores de Riesgo , EsfingolípidosRESUMEN
ECHS1 gene encodes a mitochondrial enzyme, short-chain enoyl-CoA hydratase (SCEH). SCEH is involved in fatty acid oxidation ([Sharpe and McKenzie (2018); Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency, 7: 46]) and valine catabolism ([Fong and Schulz (1977); Purification and properties of pig heart crotonase and the presence of short chain and long chain enoyl coenzyme A hydratases in pig and guinea pig tissues, 252: 542-547]; [Wanders et al. (2012); Enzymology of the branched-chain amino acid oxidation disorders: The valine pathway, 35: 5-12]), and the dysfunction of SCEH leads to a severe Leigh or Leigh-like Syndrome phenotype in patients ([Haack et al. (2015); Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement, 2: 492-509]; [Peters et al. (2014); ECHS1 mutations in Leigh disease: A new inborn error of metabolism affecting valine metabolism, 137: 2903-2908]; [Sakai et al. (2015); ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome, 36: 232-239]; [Tetreault et al. (2015); Whole-exome sequencing identifies novel ECHS1 mutations in Leigh, 134: 981-991]). This study aims to further describe the ECHS1 deficiency phenotype using medical history questionnaires and standardized tools assessing quality of life and adaptive skills. Our findings in this largest sample of ECHS1 patients in literature to date (n = 13) illustrate a severely disabling condition causing severe developmental delays (n = 11), regression (n = 10), dystonia/hypotonia and movement disorders (n = 13), commonly with symptom onset in infancy (n = 10), classical MRI findings involving the basal ganglia (n = 11), and variability in biochemical profile. Congruent with the medical history, our patients had significantly low composite and domain scores on Vineland Adaptive Behavior Scales, Third Edition. We believe there is an increasing need for better understanding of ECHS1 deficiency with an aim to support the development of transformative genetic-based therapies, driven by the unmet need for therapies for patients with this genetic disease.
Asunto(s)
Enfermedad de Leigh , Calidad de Vida , Animales , Cardiomiopatías , Enoil-CoA Hidratasa , Ácidos Grasos , Cobayas , Enfermedad de Leigh/genética , Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso , Fenotipo , Rabdomiólisis , Valina/metabolismoRESUMEN
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is included in many newborn screening (NBS) programs. Acylcarnitine-based NBS for LCHADD not only identifies LCHADD, but also the other deficiencies of the mitochondrial trifunctional protein (MTP), a multi-enzyme complex involved in long-chain fatty acid ß-oxidation. Besides LCHAD, MTP harbors two additional enzyme activities: long-chain enoyl-CoA hydratase (LCEH) and long-chain ketoacyl-CoA thiolase (LCKAT). Deficiency of one or more MTP activities causes generalized MTP deficiency (MTPD), LCHADD, LCEH deficiency (not yet reported), or LCKAT deficiency (LCKATD). To gain insight in the outcomes of MTP-deficient patients diagnosed after the introduction of NBS for LCHADD in the Netherlands, a retrospective evaluation of genetic, biochemical, and clinical characteristics of MTP-deficient patients, identified since 2007, was carried out. Thirteen patients were identified: seven with LCHADD, five with MTPD, and one with LCKATD. All LCHADD patients (one missed by NBS, clinical diagnosis) and one MTPD patient (clinical diagnosis) were alive. Four MTPD patients and one LCKATD patient developed cardiomyopathy and died within 1 month and 13 months of life, respectively. Surviving patients did not develop symptomatic hypoglycemia, but experienced reversible cardiomyopathy and rhabdomyolysis. Five LCHADD patients developed subclinical neuropathy and/or retinopathy. In conclusion, patient outcomes were highly variable, stressing the need for accurate classification of and discrimination between the MTP deficiencies to improve insight in the yield of NBS for LCHADD. NBS allowed the prevention of symptomatic hypoglycemia, but current treatment options failed to treat cardiomyopathy and prevent long-term complications. Moreover, milder patients, who might benefit from NBS, were missed due to normal acylcarnitine profiles.
Asunto(s)
Cardiomiopatías , Hipoglucemia , Errores Innatos del Metabolismo Lipídico , Rabdomiólisis , 3-Hidroxiacil-CoA Deshidrogenasas , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Humanos , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Biología Molecular , Tamizaje Neonatal , Enfermedades del Sistema Nervioso , Países Bajos , Estudios Retrospectivos , Rabdomiólisis/diagnóstico , Rabdomiólisis/genéticaRESUMEN
Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid ß-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
Asunto(s)
Errores Innatos del Metabolismo Lipídico , Miopatías Mitocondriales , Enfermedades Musculares , 3-Hidroxiacil-CoA Deshidrogenasas , Adolescente , Cardiomiopatías , Niño , Preescolar , Coenzima A , Diagnóstico Tardío , Ácidos Grasos/metabolismo , Humanos , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades del Sistema Nervioso , RabdomiólisisRESUMEN
This is the first report of the concurrent development of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and Crigler-Najjar syndrome type 1 (CNs1) inherited via uniparental disomy of chromosome 2, which are both autosomal recessive pathologies. Through an expanded newborn metabolic panel, a male infant was identified as having an acylcarnitine pattern typical for LCHADD, later confirmed to be caused by a well-characterized pathogenic variant in the HADHA gene located at 2p23. Prolonged non-hematologic jaundice requiring repetitive phototherapy prompted further genetic analysis, leading to the identification of another genetic abnormality consistent with CNs1, which was caused by a novel pathogenic variant in the UGT1A1 gene located at 2q37. The two identified point mutations in chromosome 2 were homozygous and present on separate arms, which indicated potential uniparental disomy. Microarray analysis of the genetic material from the patient and his parents confirmed paternal isodisomy of chromosome 2. Further studies are needed to identify other possible pathogenic variants located on the same defective chromosome, evaluate the combined effect of the two metabolic abnormalities, and plan the best possible treatment and care.
Asunto(s)
Síndrome de Crigler-Najjar , Cardiomiopatías , Cromosomas Humanos Par 2/genética , Síndrome de Crigler-Najjar/genética , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico , Masculino , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso , Rabdomiólisis , Disomía Uniparental/genéticaRESUMEN
BACKGROUND: Short-chain enoyl-CoA hydratase (ECHS1) deficiency is a rare metabolic disorder. Concerned patients present with Leigh syndrome symptoms or a Leigh-like syndrome. Only 58 patients are known worldwide. The ECHS1 is a key component in ß-oxidation and valine catabolic pathways. CASE: Here we report a 6-month-old Lebanese boy born to consanguineous parents. He presented an increased muscle tone, hyperexcitability, feeding problems, horizontal nystagmus, and developmental delay. Magnetic resonance imaging of the brain revealed frontal brain atrophy, corpus callosum atrophy, and T2 hyperintensity in pallidum, internal capsule, pons, and thalamus. In the postsedation phase, the patient displayed a sudden generalized seizure with transition to status epilepticus. Therefore, we conducted metabolic examinations, which showed elevated levels of 2-methyl-2,3-DiOH-butyrate and 3-methylglutaconate in urine. Single exome sequencing revealed the homozygous mutation c.476A > G in the ECHS1 gene. CONCLUSION: This case report describes the clinical symptoms and the diagnostics of ECHS1 deficiency. It shows the importance of further metabolic and genetic testing of patients with motoric conspicuities and developmental delay. It is important to be cautious with propofol sedation of patients who present an unknown neurological disorder, when metabolic disturbance or especially mitochondriopathy is suspected.
Asunto(s)
Enfermedad de Leigh , Propofol , Estado Epiléptico , Atrofia , Cardiomiopatías , Enoil-CoA Hidratasa/genética , Enoil-CoA Hidratasa/metabolismo , Humanos , Lactante , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Errores Innatos del Metabolismo Lipídico , Masculino , Miopatías Mitocondriales , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso , Propofol/efectos adversos , Rabdomiólisis , Estado Epiléptico/etiología , Estado Epiléptico/genéticaRESUMEN
PURPOSE: To report the first case describing choroidal neovascularization in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. METHODS: Case report including multimodal imaging discussion. RESULTS: A 21-year-old woman affected by LCHAD deficiency (confirmed by 1528 G>C homozygous mutation) was referred to our department for progressive visual decline in both eyes. Best-corrected visual acuities were 20/40 and 20/1,000 in the right and left eye, respectively. Ultra-widefield imaging, fluorescein angiography, structural optical coherence tomography, and optical coherence tomography angiography revealed the presence of macular and midperipheral chorioretinal atrophy complicated by a choroidal neovascularization in the left eye. CONCLUSION: Ocular changes in LCHAD deficiency are long-term complications and severely affect the quality of life of patients. We report for the first time the evidence that choroidal neovascularization could complicate ocular changes accelerating the progressive vision impairment.