Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are long-chain fatty acid oxidation disorders with particularly high morbidity and mortality

• deficiencies of the mitochondrial trifunctional protein (MTP) (OMIM# 609015)
  • autosomal recessively inherited disorders of long-chain fatty acid oxidation
  • estimated frequency of 1:140,000 (1,2,3,4)
    
    
    • MTP is an octameric multienzyme complex
      • composed of 4 alpha and 4 beta subunits encoded by the HADHA and HADHB gene, respectively
        • harbours three enzyme activities:
          • long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and longvchain 3-ketoacyl-CoA thiolase (LCKAT) catalyzing the last three steps of long-chain fatty acid oxidation
            
            
    • general MTP deficiency is characterized by reduced activities of all three MTP enzymes
      
      
      • most common defect of the MTP complex is isolated LCHAD deficiency (LCHADD) (OMIM# 609016)
        • LCHAD is responsible for the third step in the oxidation of long-chain fatty acids (LCFA). Deficiency of LCHAD was described in 1989 (2)
          • defined by reduced LCHAD activity with substantial preservation of the other two MTP enzyme activities
            
            
    • both MTP deficiency and isolated LCHADD lead to an accumulation of toxic beta-oxidation intermediates causing acute symptoms as well as long-term complications
      
      
      • clinical symptoms mainly develop during periods of illness or fasting and affect organs preferring long-chain fat as primary source of energy, such as heart and skeletal muscle
        • biochemically characterized by accumulation of long-chain 3-hydroxylated fatty acids (LCHFA) in body fluids and tissues, as well as by episodes of lactic acidaemia and hypoketotic hypoglycaemia, particularly during periods of intense catabolism, such as prolonged fasting and infections
          • children with a defect in the degradation of long-chain fatty acids and are at risk of hypoketotic hypoglycaemia and insufficient energy production as well as accumulation of toxic fatty acid intermediates.
            • encephalopathy, hypoketotic hypoglycaemia, lactic acidosis, and liver dysfunction are clinical manifestations most often found
          • long-term complications include:
            • recurrent episodes of metabolic derangement
            • recurrent episodes of rhabdomyolysis
            • cardiomyopathy, feeding difficulties
            • peripheral neuropathy
            • retinopathy
          • clinical manifestations of LCHAD deficiency are more severe than the beta-oxidation disorders of medium and short chain fatty acids (4) suggesting a high toxicity for the accumulating LCHFA.
            
            
• MTP and LCHAD deficiency are associated with particularly high morbidity and mortality if untreated
  
  
• therapy aims to prevent catabolic episodes inducing endogenous long-chain fatty acid oxidation as well as to restrict the intake of exogenous long-chain fatty acids
  • further treatment options under evaluation include anaplerotic therapy with heptanoate
  • treated in time, outcome of MTP/LCHAD deficiency can be favorable, prompting the inclusion of MTP and LCHAD deficiency into newborn screening programs (5)

Reference:

• Wanders RJ el al. Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem Biophys Res Commun. 1992;188:1139-45.
• Wanders RJ et al. Sudden infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase. Lancet. 1989;2:52-3.
• Ushikubo S et al. Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits. Am J Hum Genet. 1996;58: 979-88.
• Jones PM, Bennett MJ. The changing face of newborn screening: diagnosis of inborn errors of metabolism by tandem mass spectrometry. Clin Chim Acta. 2002;324:121-8
• Ventura FV et al. Lactic acidosis in long-chain fatty acid beta-oxidation disorders J. Inherit. Metab. Dis 1998; 21:645-654
• Kang E et al. Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening.BMC Pediatr. 2018 Mar 8;18(1):103