Clinical Guidance

Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are caused by impairment of mitochondrial TFP. TFP has three enzymatic activities – long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase. Deficiency of the enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase occurs in individuals with LCHAD deficiency, while deficiency of all three enzymes occurs in individuals with TFP deficiency. LCHAD and TFP deficiency are disorders of long-chain fatty acid oxidation, which typically present with recurrent episodes of hypoketotic hypoglycemia precipitated by fasting or illness. In addition, the other characteristic manifestations of long-chain fatty acid oxidation defects (FAODs) such as cardiomyopathy, liver dysfunction, or rhabdomyolysis may be present. However, peripheral neuropathy and retinopathy are unique complications of these disorders not seen in other FAODs. The clinical presentation represents a continuous spectrum of severity ranging from severe neonatal-onset to mild late-onset forms. Individuals with LCHAD deficiency usually present with a severe-to-intermediate phenotype, while individuals with TFP deficiency typically present with a severe-to-mild phenotype. Table 2. LCHAD/TFP Deficiency: Frequency of Select Features

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Differential Diagnosis

Table 3. Genetic Disorders of Interest in the Differential Diagnosis of LCHAD/TFP Deficiency

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Clinical Guidance

Avoid the following:

• Fasting, including periods of preparation and recovery from planned surgery or anesthesia

• Inadequate caloric provision during stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

• Inadequate calories following vaccination

Note: Vaccination is safe.

• Dehydration (risk for rhabdomyolysis and acute renal failure)

• High-fat diet including ketogenic or carbohydrate-restricted diets for the purpose of weight loss, such as Atkins diet

• Administration of intravenous intralipids during an acute metabolic crisis

Anesthetics that contain high doses of long-chain fatty acids (e.g., propofol, etomidate) are avoided in long-chain fatty acid oxidation defects. However, a retrospective analysis revealed no adverse events with propofol for short-duration procedures in individuals with LCHAD/TFP deficiency . A combination of midazolam, thiopental, fentanyl, and remifentanil was used successfully in an individual with LCHAD deficiency .

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"

Therapies Under Investigation

Cardiac transplantation. Favorable outcome after cardiac transplantation in individuals with TFP deficiency has been reported . However, it is expected that with timely diagnosis, strict dietary therapy, and MCT or triheptanoin supplementation, cardiac transplantation may not be required. Bezafibrate is a hypolipidemic drug and an agonist of peroxisome proliferator-activated receptor (PPAR). It increases expression of several enzymes involved in mitochondrial fatty acid oxidation, including TFP . Bezafibrate was reported to have a favorable outcome in two individuals with TFP deficiency . Bezafibrate is not available in the United States. REN001 (Reneo Pharmaceuticals®) is a selective PPAR- agonist that increases transcription of genes involved in mitochondrial fatty acid oxidation.

Source: GeneReviews — "Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency/ Trifunctional Protein Deficiency"