Fatty acid oxidation disorders
Fatty acid oxidation disorders are inherited metabolic conditions characterized by defects in the enzymes responsible for breaking down fatty acids to produce energy. At least fifteen of the twenty enzymes involved in this process can be affected, leading to various symptoms, primarily triggered during fasting or illness when the body relies more on fatty acids for energy. Symptoms can include vomiting, coma, and, in severe cases, death, due to energy deficits and the accumulation of toxic metabolic intermediates. While some individuals may experience life-threatening episodes early in life, others may remain largely asymptomatic.
Treatment typically focuses on preventing fasting, such as encouraging snacks before sleep and administering intravenous glucose during acute episodes to restore energy levels. Certain disorders may also benefit from dietary adjustments, including a reduced fat intake. Carnitine supplementation is effective for specific types of these disorders, particularly those involving impaired fatty acid transport into mitochondria. Despite the challenges, advancements in research since the early observations of these conditions suggest potential avenues for enzyme replacement or gene therapy, although these remain in the experimental stage. Understanding these disorders can help manage their impact on health and quality of life.
Fatty acid oxidation disorders
Anatomy or system affected: Heart, liver, muscles
Definition: Inherited metabolic defects that prevent the breakdown of fatty acids in the liver, muscles, and heart.
Causes: Genetic enzyme deficiency
Symptoms: Only under fasting conditions (overnight or when exacerbated by infection or fever), vomiting, coma, and sometimes death; some disorders largely asymptomatic
Duration: Chronic with acute episodes
Treatments: Minimizing of fasting (snacking before sleep), intravenous glucose for acute episodes
Causes and Symptoms
Fatty acid oxidation disorders are inherited defects in the enzymes that break down fatty acids to generate metabolic energy. Defects in at least fifteen of the twenty enzymes involved with this process have been identified and can be diagnosed by enzymatic analysis of a tissue biopsy. Some generate unique profiles of metabolites in the blood or urine that can be used for diagnosis. These disorders are inherited as autosomal recessive traits, and, in many cases, the causative deoxyribonucleic acid (DNA) mutations have been determined. Fatty acid oxidation disorders can affect the liver, which breaks down fatty acids for its own needs and, by converting them to ketone bodies, for energy generation in other body tissues; they can also affect muscles and the heart, which use fatty acids as a source of energy.
Symptoms appear only under fasting conditions, either overnight or when exacerbated by infection or fever. Under these conditions, as glycogen stores are depleted, the body depends increasingly on fatty acids for energy. If fatty acids cannot be broken down completely, an energy deficit and the accumulation of deleterious intermediates lead to vomiting, coma, and, in severe cases, death. The levels of blood glucose are low because the energy needed for its synthesis is lacking. The first episode may occur in the first two years of life; such an episode can be fatal and may be mistakenly attributed to Sudden infant death syndrome (SIDS). However, some fatty acid oxidation disorders are largely asymptomatic.
Treatment and Therapy
The general treatment for fatty acid oxidation disorders is to minimize fasting, as by snacking before sleep, and, in acute episodes, to administer intravenous glucose. This treatment restores depleted blood glucose and reduces the demand for fatty acid oxidation. Some defects also benefit from a low intake of dietary fat. Fasting or low carbohydrate diets, for weight loss or other reasons, are contraindicated for individuals with these disorders.
One of these diseases is attributable to the defective cellular uptake of carnitine, which is needed to transport fatty acids into mitochondria, where they are oxidized; this type can be treated with supplemental carnitine. In acute episodes with some other disorders, treatment with carnitine has proven beneficial in increasing the urinary excretion of deleterious intermediates.
Perspective and Prospects
The first observation of a defect in fatty acid oxidation was made in 1972. Although not reported until 1982, one such disorder, medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency, is among the most common inborn errors of metabolism, with a frequency of 1 in 9,000 live births. Each disorder of fatty acid oxidation is a candidate for enzyme replacement therapy or gene replacement therapy, although these remain experimental treatments.
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