Abstract
Mitochondrial trifunctional protein (TFP) deficiency is a rare inherited metabolic disorder caused by defects in fatty acid β-oxidation (FAO) of long-chain fatty acids, leading to impaired energy production. Fasting avoidance, fatty acid-restricted diets, and supplementation with medium-chain triglycerides are recommended as a treatment, but there are no pharmaceutical treatments available with strong evidence of efficacy. Bezafibrate, which enhances the transcription of FAO enzymes, is a promising therapeutic option for FAO disorders (FAODs). The effectiveness of bezafibrate for FAODs has been reported in some clinical trials, but few clinical studies have investigated its in vivo efficacy toward TFP deficiency.Herein, we describe two Japanese patients with TFP deficiency. Patient 1 presented with recurrent myalgia since the age of 5 years. Laboratory findings showed increased serum levels of long-chain fatty acids and reduced expression of TFPα and TFPβ in his skin fibroblasts. Based on these findings, he was diagnosed with the myopathic type of TFP deficiency. Patient 2 suddenly exhibited cardiopulmonary arrest one day after birth. Elevated levels of creatine kinase and long-chain acylcarnitines were observed. Genetic analysis identified compound heterozygous variants in HADHB (c.1175C>T/c.1364T>G). He was diagnosed with the lethal type of TFP deficiency. Although both patients were treated with dietary therapy and l-carnitine supplementation, they experienced frequent myopathic attacks associated with respiratory infections and exercise. After the initiation of bezafibrate, their myopathic manifestations were markedly reduced, leading to an improvement in quality of life without any side effects.Our clinical findings indicate that bezafibrate combined with other treatments such as dietary therapy may be effective in improving myopathic manifestations in TFP deficiency.
Highlights
Mitochondrial trifunctional protein (TFP) deficiency is a genetic disorder of the fatty acid β-oxidation (FAO) cycle [1]
TFP deficiency is classified into three types: (1) lethal type, which includes the development of hypoglycemia, lactic acidosis, and cardiomyopathy during the neonatal period and is associated with high mortality; (2) intermediate type, which is accompanied by hypoketotic hypoglycemia or hepatic dysfunction following infection and fasting; and (3) myopathic type, which is characterized by muscle symptoms including intermittent myalgia or rhabdomyolysis [4]
After bezafibrate initiation in two patients with TFP deficiency. Both patients had been treated with L-carnitine supplementation and dietary therapy, but myopathic attacks could not be prevented
Summary
Mitochondrial trifunctional protein (TFP) deficiency is a genetic disorder of the fatty acid β-oxidation (FAO) cycle [1]. TFP is a multienzyme complex composed of four α subunits possessing longchain enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activities (TFPα encoded by the HADHA gene) and four β subunits possessing long-chain 3-ketoacyl-CoA thiolase activity (TFPβ encoded by the HADHB gene) [2]. These three enzymes are impaired in general TFP deficiency, whereas only LCHAD activity is decreased in isolated LCHAD deficiency. Similar to other FAO disorders (FAODs), decreased ATP production through the FAO cycle in TFP deficiency results in various clinical outcomes, especially during infection, exercise, diarrhea, and fasting [3]. We describe two unrelated patients with TFP deficiency who showed a remarkable reduction in frequency of myopathic attacks with bezafibrate treatment
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