ABSTRACT
Abstract Fatty acid oxidation defects (FAODs) are inherited metabolic disorders caused by deficiency of specific enzyme activities or transport proteins involved in the mitochondrial catabolism of fatty acids. Medium-chain fatty acyl-CoA dehydrogenase (MCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies are relatively common FAOD biochemically characterized by tissue accumulation of medium-chain fatty acids and long-chain 3-hydroxy fatty acids and their carnitine derivatives, respectively. Patients with MCAD deficiency usually have episodic encephalopathic crises and liver biochemical alterations especially during crises of metabolic decompensation, whereas patients with LCHAD deficiency present severe hepatopathy, cardiomyopathy, and acute and/or progressive encephalopathy. Although neurological symptoms are common features, the underlying mechanisms responsible for the brain damage in these disorders are still under debate. In this context, energy deficiency due to defective fatty acid catabolism and hypoglycemia/hypoketonemia has been postulated to contribute to the pathophysiology of MCAD and LCHAD deficiencies. However, since energetic substrate supplementation is not able to reverse or prevent symptomatology in some patients, it is presumed that other pathogenetic mechanisms are implicated. Since worsening of clinical symptoms during crises is accompanied by significant increases in the concentrations of the accumulating fatty acids, it is conceivable that these compounds may be potentially neurotoxic. We will briefly summarize the current knowledge obtained from patients with these disorders, as well as from animal studies demonstrating deleterious effects of the major fatty acids accumulating in MCAD and LCHAD deficiencies, indicating that disruption of mitochondrial energy, redox, and calcium homeostasis is involved in the pathophysiology of the cerebral damage in these diseases. It is presumed that these findings based on the mechanistic toxic effects of fatty acids may offer new therapeutic perspectives for patients affected by these disorders.
ABSTRACT
In recent years increasing evidence has emerged suggesting that oxidative stress is involved in the pathophysiology of a number of inherited metabolic disorders. However the clinical use of classical antioxidants in these diseases has been poorly evaluated and so far no benefit has been demonstrated. l-Carnitine is an endogenous substance that acts as a carrier for fatty acids across the inner mitochondrial membrane necessary for subsequent beta-oxidation and ATP production. Besides its important role in the metabolism of lipids, l-carnitine is also a potent antioxidant (free radical scavenger) and thus may protect tissues from oxidative damage. This review addresses recent findings obtained from patients with some inherited neurometabolic diseases showing that l-carnitine may be involved in the reduction of oxidative damage observed in these disorders. For some of these diseases, reduced concentrations of l-carnitine may occur due to the combination of this compound to the accumulating toxic metabolites, especially organic acids, or as a result of protein restricted diets. Thus, l-carnitine supplementation may be useful not only to prevent tissue deficiency of this element, but also to avoid oxidative damage secondary to increased production of reactive species in these diseases. Considering the ability of l-carnitine to easily cross the blood-brain barrier, l-carnitine supplementation may also be beneficial in preventing neurological damage derived from oxidative injury. However further studies are required to better explore this potential.
Subject(s)
Antioxidants/therapeutic use , Brain Diseases, Metabolic, Inborn/drug therapy , Carnitine/therapeutic use , Dietary Supplements , Neuroprotective Agents/therapeutic use , Animals , Carnitine/deficiency , Carnitine/pharmacology , Humans , Neuroprotective Agents/pharmacologyABSTRACT
La deficiencia de 3-hidroxiacil coA deshidrogenasa de cadena larga (LCHAD) es uno de los trastornos de la betaoxidación de ácidos grasos. La presentación clínica más frecuente incluye trastornos de conciencia, hipoglucemia y disfunción hepática gatillados por ayuno prolongado o infecciones. Una vez desencadenada, la crisis metabólica presenta alta mortalidad. El síndrome HELLP y la hepatitis grasa aguda del embarazo (AFLP) son trastornos del tercer trimestre del embarazo. Se ha asociado estas enfermedades durante la gestación con defectos hereditarios de la betaoxidación en el feto. Comunicamos el caso clínico de un trastorno de beta oxidación (deficiencia de LCHAD) asociado a HELLP materno. Describimos como hallazgos en la resonancia magnética espectroscópica un pico de ácido láctico y lípidos significativo. La pesquisa de estos trastornos de la betaoxidación al nacimiento, ante el antecedente de HELLP materno, permite el diagnóstico de la enfermedad previo al desarrollo de los síntomas.(AU)
LCHAD deficiency is a disorder of fatty acid beta oxidation. The most common clinical presentation includes disorders of consciousness, hypoglycemia and liver dysfunction triggered by prolonged fasting or infection. Once a metabolic crisis is triggered, there is a high mortality. HELLP syndrome and acute fatty liver failure of pregnancy (AFLP) are disorders of the third trimester of pregnancy. These diseases have been associated during pregnancy with hereditary defects of beta-oxidation in the fetus. We report a case of beta-oxidation disorder (LCHAD deficiency) associated with maternal HELLP. We described a peak of lipid and lactic on magnetic resonance spectroscopic of this patient. The investigation of these beta-oxidation disorders at birth, with a history of maternal HELLP, allows the diagnosis of the disease prior to developing symptoms.(AU)
Subject(s)
Female , Humans , Infant , Male , Pregnancy , 3-Hydroxyacyl CoA Dehydrogenases/deficiency , HELLP Syndrome , Metabolism, Inborn Errors/diagnosis , 3-Hydroxyacyl CoA Dehydrogenases/genetics , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Magnetic Resonance Spectroscopy , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/metabolismABSTRACT
La deficiencia de 3-hidroxiacil coA deshidrogenasa de cadena larga (LCHAD) es uno de los trastornos de la betaoxidación de ácidos grasos. La presentación clínica más frecuente incluye trastornos de conciencia, hipoglucemia y disfunción hepática gatillados por ayuno prolongado o infecciones. Una vez desencadenada, la crisis metabólica presenta alta mortalidad. El síndrome HELLP y la hepatitis grasa aguda del embarazo (AFLP) son trastornos del tercer trimestre del embarazo. Se ha asociado estas enfermedades durante la gestación con defectos hereditarios de la betaoxidación en el feto. Comunicamos el caso clínico de un trastorno de beta oxidación (deficiencia de LCHAD) asociado a HELLP materno. Describimos como hallazgos en la resonancia magnética espectroscópica un pico de ácido láctico y lípidos significativo. La pesquisa de estos trastornos de la betaoxidación al nacimiento, ante el antecedente de HELLP materno, permite el diagnóstico de la enfermedad previo al desarrollo de los síntomas.
LCHAD deficiency is a disorder of fatty acid beta oxidation. The most common clinical presentation includes disorders of consciousness, hypoglycemia and liver dysfunction triggered by prolonged fasting or infection. Once a metabolic crisis is triggered, there is a high mortality. HELLP syndrome and acute fatty liver failure of pregnancy (AFLP) are disorders of the third trimester of pregnancy. These diseases have been associated during pregnancy with hereditary defects of beta-oxidation in the fetus. We report a case of beta-oxidation disorder (LCHAD deficiency) associated with maternal HELLP. We described a peak of lipid and lactic on magnetic resonance spectroscopic of this patient. The investigation of these beta-oxidation disorders at birth, with a history of maternal HELLP, allows the diagnosis of the disease prior to developing symptoms.