Abstract
Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.
Highlights
Long-chain fatty acid oxidation disorders (LC-FAODs) represent a group of autosomal recessive inborn errors of metabolism with an estimated prevalence of ~1:17,000 in the US, based on newborn screening data
The reported case histories are from all patients treated with investigational triheptanoin for whom clinical data were provided by the treating physicians as of September 2015.The series includes patients with very long-chain acyl-CoA dehydrogenase (VLCAD) (n=4), carnitine/acylcarnitine translocase (CACT) (n=2), trifunctional protein (TFP) (n=2) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) (n=2)
A LC-FAOD was detected via newborn screening in all patients except case 8, in whom VLCAD deficiency diagnosed at age 3.5 months of age, and case 10 in whom CACT deficiency was diagnosed during the first month of life
Summary
Long-chain fatty acid oxidation disorders (LC-FAODs) represent a group of autosomal recessive inborn errors of metabolism with an estimated prevalence of ~1:17,000 in the US, based on newborn screening data. LC-FAOD are caused by defects in nuclear genes that encode six mitochondrial enzymes involved in the oxidation of long chain fats for energy during times of fasting and physiologic stress. The genes and their associated diseases include carnitine palmitoyl transferase 1 (CPT-I), carnitine palmitoyl transferase 2 (CPT-II), carnitine/acylcarnitine translocase (CACT), very long-chain acyl-CoA dehydrogenase (VLCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and mitochondrial trifunctional protein (TFP) deficiencies. A comprehensive clinical survey over 30 years of experience and 187 cases at one center suggests LC-FAODs as a group have a mortality rate of 50% or higher when diagnosed symptomatically, despite increased awareness of the disorders and management over the last 2 decades [3]. Newborn screening and early treatment have reduced mortality, but carefully followed cohorts indicate major medical events continue to occur despite newborn screening diagnosis and management [1, 2]
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