mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
Last edited 06/2019
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
- 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
- harbours three enzyme activities:
- composed of 4 alpha and 4 beta subunits encoded by the HADHA
and HADHB gene, respectively
- 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
- defined by reduced LCHAD activity with substantial
preservation of the other two MTP enzyme activities
- LCHAD is responsible for the third step in the oxidation
of long-chain fatty acids (LCFA). Deficiency of LCHAD was
described in 1989 (2)
- most common defect of the MTP complex is isolated LCHAD deficiency
(LCHADD) (OMIM# 609016)
- 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.
- 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.
- 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
- 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
- MTP is an octameric multienzyme complex
- 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