Lipids: In Born Errors of Metabolism III

Suaib Luqman

epgp books

 

  1. Objectives
  • v To understand the inborn errors of fatty acid oxidation
  • v What are long, medium and short chain fatty oxidation defects
  • v When and how carnitine disorder takes place

 

  1. Concept Map

Functions & relationships to energy and biochemical aspect of defects in fatty acid oxidation and

 

oxidative phosphorylation

 

3. Description

 

 

The trio, i.e. mitochondrial fatty acid oxidation (mFAO), tri-carboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) which occurs in mitochondria are processes which are interlinked. Problems in fatty acid oxidation leads to increased energy demand and consequently low production of ketone bodies which is abnormal as depicted in Figure 1.

 

Since the first description of carnitine palmitoyltransferase (CPT) deficiency in 1973, there has been a steady increase in both the number of different fatty acid oxidation disorders recognized and the number of affected patients identified. Defects involving many of the different enzymes and transport proteins involved in fatty acid oxidation have been described. The clinical features in these patients are diverse and depend on the nature and severity of the biochemical defect. However, the most prevalent symptoms are related to neuromuscular, cardiac, and hepatic involvement.

 

The difference between prenatal (during fetal life) and neonatal life (after birth) especially in the case of lipid metabolism is drastically impressive. Lipids for fetal life before birth are entirely used for anabolic pathways specifically in cell growth and synthesis as well as for tissue differentiation and are not used as a fuel for energy production as indicated by fetal respiratory quotient of approximately 1.0. Thus drastic change is observed in case of lipid metabolism of fetal life after birth i.e. mitochondrial oxidation of stored fat while ketone biosynthesis becomes a crucial passage for survival.

 

Fatty acids oxidation defects mostly  β-oxidation occurs in mitochondria, are mainly of three main types:

 

  1. Carnitine uptake defect which is the primary carnitine deficiency can because of three enzyme defects which are important in the carnitine shuttle.
  2. Problems associated with the processing of long chain fatty acids in which problem is because of main protein complex [Trifunctional protein] which is a trimer and thus are of two types
  • (a) Trifunctional protein deficiency type 1
  • (b) Trifunctional protein deficiency type 2
  1. Medium chain acyl –CoA dehydrogenase deficiency : Most common fatty acid oxidation defect

 

Figure 2.  Major types of Fatty acid oxidation disorders

 

 

For heart and aerobically exercising skeletal muscle, fatty acids are the chosen energy source. Further as steady supply of energy source by means of the placenta is substituted by series of discontinuous feeding, fat becomes an indispensable store of fuel during long-term fasting for energy production. Developmental impediment in maturation of fatty acid oxidation plays a significant task in the receptiveness of the normal neonate to hypo-glycemia in the immediate postnatal time. Additionally, over a dozen genetic faults in mitochondrial fatty acid oxidation have been recognized that may be present in the post-neonate with life-threatening disease. But overall if β-oxidation is considered there are main five types of fatty acid oxidation defects which are mostly the number of carbon atoms in the fatty acids or the transport of fatty acids ranging from short chain (carbon atoms 4-6), medium chain ( carbon atoms 6-10), long chain (carbon atoms 10-12) and very long chain (carbon atoms 12-18). Except very long chain fatty acids oxidation which primarily occurs in peroxisomes while other types of fatty acid oxidation occurs in mitochondria.

.

Long chain fatty acid oxidation

 

 

Long chain fatty acid oxidation defects can be due to defect in one of the enzyme of protein trimer complex, i.e.

Trifunctional protein. This protein complex is made up of three proteins:

 

  1. Long chain enoyl-CoA hydratase
  2. Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase
  3. Long chain 3-ketothiolase

Figure 4. Functions of different proteins within the protein complex, Trifunctional protein

 

 

Trifunctional protein is specific for long chain fatty acids oxidation and it is composed of 4α and 4β subunits and it is trimer protein catalyzing the three steps:

 

  1. long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
  2. long-chain enoyl-CoA hydratase (LCEH),
  3. long-chain thiolase (LCTH)

 

 

The first two enzymes are encoded with HADHA gene and it comes under the Trifunctional protein deficiency type I while the third enzyme is encoded by the HADHB gene and it comes under Trifunctional protein deficiency type II

 

Trifunctional protein deficiency type I is because of defective long-chain 3-hydroxyacyl-coenzyme A dehydrogenase [LCHAD] deficiency, which is a rare genetic autosomal recessive disorder which occurs because of mutations in HADHA gene. This disorder causes damage of muscles, liver, retina and heart, characteristic aspect of this deficiency is hypoglycaemia and lethargy. The relationship between Long chain mitochondrial fatty acid oxidation with the oxidative phosphorylation is being depicted in Figure ultimately leading to lactic academia and gluconeogenesis

 

Median chain fatty acid oxidation

 

Similarly for median chain fatty acid oxidation, there is no trifunctional complex but separate enzymes doing their function. This is the most common type of fatty acid oxidation present in childhood and the symptoms appeared by trigerring via a period of catabolic stress like exercise, fasting or illness ultimately it leads to neurological problems. The relationship between median chain fatty acid oxidation defect and oxidative phosphorylation as given in the Figure

 

Since the first description of carnitine palmitoyltransferase (CPT) deficiency in 1973, there has been a steady increase in both the number of different fatty acid oxidation disorders recognized and the number of affected patients identified. Defects involving many of the different enzymes and transport proteins involved in fatty acid oxidation have been described. The clinical features in these patients are diverse and depend on the nature and severity of the biochemical defect. However, the most prevalent symptoms are related to neuromuscular, cardiac, and hepatic involvement.

 

Carnitine uptake defect

 

 

Carnitine is mostly present in meat and it is obtained from the diet and distributed by the blood. It can also be synthesized inherently from the lysine and methionine. The overall steps and importance of carnitine shuttle is being depicted in Figure

 

Figure 6. Transport of fatty acids by Carnitine and concept of carnitine shuttle

 

Carnitine deficiencies resulted from limited ability of various organs and tissues to use long chain fatty acids as a metabolic fuel. It is because of many reasons like food intake which consists of least carnitine mostly present in persons suffering from malnutrition or people strictly taking vegetarian diet Deficency in hereditary carnitine deficiency can be because of mutation in CPTI, CPTII or SLC25A20 gene which results in defective carnitine palmitoyltransferase I, carnitine palmitoyltransferase II or carnitine – acylcarnitine translocase enzyme.

 

  1. Summary

 

In this lecture we learnt about:

 

  • Fatty acid oxidation defects
  • Long chain defects
  • Medium chain defects
  • Short chain defects
  • Carnitine uptake defects

 

you can view video on Lipids: In Born Errors of Metabolism III

 

Weblinks

 

Books

 

  1. G. Schettler. 2012. Lipids and Lipidoses https://books.google.co.in/books?isbn=3642873677
  2. John Fernandes, Jean‎-Marie Saudubray, Georges‎ van den Berghe. 2013. Inborn Metabolic Diseases: Diagnosis and Treatment. https://books.google.co.in/books?isbn=3662042851
  3. Patti A. Quant, Simon‎ Eaton. 2006. Current Views of Fatty Acid Oxidation and Ketogenesis. Page 328. https://books.google.co.in/books?isbn=0306468182
  4. Joe T. R. Clarke. 2005. A Clinical Guide to Inherited Metabolic Diseases. Page 131. https://books.google.co.in/books?isbn=1139447181
  5. Ronald Kleinman. 2008. Walker’s Pediatric Gastrointestinal Disease. Page 978. https://books.google.co.in/books?isbn=1550093649

Journals

 

  1. Kompare M, Rizzo WB. Mitochondrial fatty-acid oxidation disorders. Semin Pediatr Neurol. 2008 Sep;15(3):140-9.
  2. Prem S Shekhawat, Dietrich Matern, Arnold W Strauss. Fetal Fatty Acid Oxidation Disorders, Their Effect on Maternal Health and Neonatal Outcome: Impact of Expanded Newborn Screening on Their Diagnosis and Management. Pediatric Research (2005) 57, 78R–86R.
  3. Deficiency of carnitine and its pathway of biosynthesis. Nutr Rev. 1978 Oct;36(10):305-9.
  4. Mitchell ME. Carnitine metabolism in human subjects. III. Metabolism in disease. Am J Clin Nutr. 1978 Apr;31(4): 645-59.
  5. Vianey-Liaud C, Divry P, Gregersen N, Mathieu M. The inborn errors of mitochondrial fatty acid oxidation. J Inherit Metab Dis. 1987;10 Suppl 1:159-200.
  6. Kendler BS. Carnitine: an overview of its role in preventive medicine. Prev Med. 1986 Jul;15(4):373-90.
  7. Wanders RJ, van Roermund CW, Schutgens RB, Barth PG, Heymans HS, van den Bosch H, Tager JM. The inborn errors of peroxisomal beta-oxidation: a review. J Inherit Metab Dis. 1990;13(1):4-36.