ABSTRACT
Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients. The purpose of this review is to present the different FAOD mouse models and highlight the benefits and limitations of using these models. Specifically, we discuss the phenotypes of the available FAOD mouse models, the potential molecular causes of prominent FAOD phenotypes that have been studied using FAOD mouse models, and how FAOD mouse models have been used to evaluate treatments for patients.
Subject(s)
Disease Models, Animal , Fatty Acids , Lipid Metabolism, Inborn Errors , Oxidation-Reduction , Animals , Mice , Fatty Acids/metabolism , Humans , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/metabolism , Lipid Metabolism, Inborn Errors/pathology , Phenotype , Cardiomyopathies/metabolism , Cardiomyopathies/genetics , Cardiomyopathies/pathology , Cardiomyopathies/etiologyABSTRACT
Inborn errors of metabolism (IEM) represent a heterogeneous group of more than 1800 rare disorders, many of which are causing significant childhood morbidity and mortality. More than 100 IEM are linked to dyslipidaemia, but yet our knowledge in connecting genetic information with lipidomic data is limited. Stable isotope tracing studies of the lipid metabolism (STL) provide insights on the dynamic of cellular lipid processes and could thereby facilitate the delineation of underlying metabolic (patho)mechanisms. This mini-review focuses on principles as well as technical limitations of STL and describes potential clinical applications by discussing recently published STL focusing on IEM.
Subject(s)
Lipid Metabolism , Lipidomics , Humans , Lipidomics/methods , Lipid Metabolism/genetics , Lipid Metabolism, Inborn Errors/metabolism , Lipid Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/metabolism , Metabolism, Inborn Errors/genetics , Animals , Lipids/genetics , Isotope Labeling/methodsABSTRACT
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.
Subject(s)
Cardiomyopathies , Lipid Metabolism, Inborn Errors , Mitochondrial Myopathies , Mitochondrial Trifunctional Protein , Nervous System Diseases , Rhabdomyolysis , Humans , Infant, Newborn , Fatty Acids/metabolism , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/therapy , Lipid Metabolism, Inborn Errors/metabolism , Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase/metabolism , Mitochondrial Trifunctional Protein/metabolism , Mitochondrial Trifunctional Protein/deficiency , Infant , Child, Preschool , ChildABSTRACT
Several inherited metabolic fatty acid disorders present with myopathies. Skeletal muscle accounts for 40% of the body and is important for metabolism, exercise, and movement. Muscle energy failure is manifested by metabolic crises with muscle weakness, sometimes associated with muscle fatigue and failure resulting in acute necrosis or rhabdomyolysis/myoglobinuria episodes. Lack of energy leads to muscle necrosis. Other presentations are weakness and myalgias with lipid storage myopathies in the biopsy. The biomarkers of such disorders are acyl-carnitine with various profiles and need to be carefully evaluated to plan supplementary therapy and specific diets. If red flags are not distinctly followed and diagnosed in time they might lead to a metabolic or cardiac failure.
Subject(s)
Carnitine , Lipid Metabolism, Inborn Errors , Muscular Diseases , Humans , Muscular Diseases/metabolism , Muscular Diseases/therapy , Muscular Diseases/genetics , Carnitine/metabolism , Carnitine/analogs & derivatives , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/therapy , Lipid Metabolism, Inborn Errors/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular DystrophiesABSTRACT
Las miopatías por depósito de lípidos son la expresión fundamental de los trastornos del metabolismo lipídico muscular. En el presente estudio exponemos cuatro casos de la entidad y señalamos las características clínicas, histopatológicas y bioquímicas que están presentes en los defectos genéticos del metabolismo de los ácidos grasos del músculo esquelético. En tres casos los hallazgos fueron compatibles con el diagnóstico de la entidad por déficit de carnitina y en uno por déficit de flavoproteínas. Tres correspondieron a pacientes del sexo femenino. Concluimos que con una correlación sistemática de los datos clínicos y paraclínicos, así como también del estudio morfológico, se puede inferir la posible etiología de estas miopatías, cuyo diagnóstico definitivo es por medio del análisis bioquímico