Lipids: In Born Errors of Metabolism II

Suaib Luqman

epgp books

 

  1. Objectives
  • v To understand the lysosomal storage disorder with respect to inborn error of metabolism
  • v What are the plausible causes of lipidoses
  • v How many types of lipidoses occur
  1. Concept Map

3. Description

 

Lysosomal Storage diseases with respect to inborn errors of lipid metabolism

 

Lysosome, first coined by De Duve et al (1955) is the organelle credited for recycling and breakdown of cellular components. The physiological turnover is mainly caused by catabolic enzymes working at low pH within lysosomes. Hindrance in its function will ultimately leads to accrual and storage of components which leads to various clinical abnormalities and death.

 

Lysosomal storage diseases, in general is collection of hereditary metabolic disorders caused by flaw in protein responsible for proper functioning of lysosomes. Most of the lysosomal storage diseases are fatal. The major abnormality includes ocular pathology, organomegaly, connective tissue pathologies and mental retardation. Neurological problems of the lipidosis mainly are brain degeneration, ataxia, pain in the arms and legs, seizures, eye paralysis, learning troubles, swallowing food difficulties, spasticity, and failure of muscle tone, slurred speech, and hypersensitivity to touch and clouding of the cornea. It is now accepted that these disorders are not simply an outcome of storage, but an end result of perturbation of multifaceted cell signaling pathways which leads to specific structural and biochemical changes which can provide hint for therapy but still there exist challenges for treating the effects on central nervous system.

 

The main types of enzymes includes enzyme responsible for catabolism like hydrolase, post-translational lysosomal enzymes modification defects, metabolite proteins important for appropriate intracellular trafficking mainly in the trans-golgi network which involves lysosomes and activator proteins. The enzymes specifically responsible with respect to lipid metabolism are discussed in this section. They are caused by defect in proteins that are critical to the function of lysosomes.

 

Lipidoses

 

Lipidoses (or lipid storage diseases) are a collection of hereditary metabolic inborn errors in which detrimental quantity of lipids (fats) mount up in several of the body’s cells and tissues. Lipidoses are inborn metabolic errors, leading to the accumulation of various lipids in the nervous system and in the reticulo-endothelial system. These metabolic disorders can occur because of mainly two reasons, first is that enough enzyme production or improper functioning of enzymes. Therefore, unnecessary storage of fats can cause everlasting cellular and tissue harm, chiefly in the peripheral nervous system, brain, liver, bone marrow and spleen.

 

Lipids are generally distinct as any naturally occurring fat-soluble (lipophilic), such as oils, fats, steroids, waxes, and others. Lipids are vital parts of the membranes found within and between each cell and in the myelin sheath that coats and guards the nerves. Lysosomes are the main organelle which metabolize and converts lipids and proteins into smaller parts for energy production. Lipid storage diseases are related to diverse disorders which are hereditary mostly occurs due to deficiency of lysosomal enzymes.

 

Inheritance Pattern of Lipidoses

 

 

Lipid storage diseases are hereditary in which defective gene regulating a specific protein carried by one or both parents. These are inherited in two ways:

  • Autosomal recessive inheritance happens when both parents transmit and convey a copy of the defective gene, but neither parent is influenced by the disorder. Only 25% of children can be affected by an autosomal recessive inheritance.
  • X-linked (or sex-linked) recessive inheritance happens on the X-chromosomes, the mother carries the targeted gene that decide the child’s gender and passes it to her son with 50 percent possibility in carriers of disorder inheritance.

Types of Lipidoses

 

 

[1] Sphingolipidoses

 

Sphingolipidoses are the sphingolipid storage diseases essentially an autosomal recessive disease except Fabry disease which is X-linked. Broadly, Sphingophospholipids and Glycosphingolipids are the main groups of sphingolipidoses. Ceramides are the precursors of both phosphorylatred and glycosylated sphingolipids .

 

[1.1] Sphingophospholipidoses

The most important sphingophospholipid in human is sphingomyelin which is an important constituent of the myelin of nerve fibres and have a structure in which an alcohol group at carbon 1 of sphingosine is esterified to phosphorylcholine. Ceramide is the immediate precursor of sphingomyelin and it is the major constituent of skin and regulates skin`s water permeability. Sphingomyelin is degraded by Sphingomyelinase, a lysosomal enzyme that removes phosphorylcholine and leaving behind ceramide. Ceramidase cleaves ceramide into sphingosine and free fatty acid. Ceramide and sphingosine regulates many signal transduction pathways mostly PKC – dependent pathways and also promotes apoptosis.

 

Niemann-Pick Disease is actually a group of autosomal recessive disorders caused by its inability to degrade sphingomyelin by the deficient sphingomyelinase enzyme (type A and B) or lack of the NPC1 or NPC2 proteins (type C and D). Sphingomyelinase is a type of phospholipase C and the liver and spleen are the primary sites of deposition of lipid while the deposition of sphingomyelin in the central nervous system leads to progressive neurodegeneration.

 

[1.2] Glycosphingolipidoses

 

Transformed cells with dysregulated cell growth and division leads to a dramatic change in the glycosphingolipid composition of the plasma membrane. They are antigenic (blood group antigens or embryonic antigens specific for particular stages of fetal development and tumor antigens).

 

Glycosphingolipids consists of neutral and acidic types. Further within acidic glycosphingolipids, there are two types: Gangliosides and Sulfatides The main features of sphingolipidoses diseases are as follows:

 

GM1 Gangliosidoses

 

  1. In this there is an accumulation of gangliosides (GM1) and keratin sulphate.
  2. Neurologic deterioration
  • Hepatosplenomega ly
  1. Skeletal deformaties
  2. Cherry-red macula

 

Tay-Sachs Disease

 

  1. Accumulation of gangliosides (GM2)
  2. Rapid, progressive and fatal neurogeneration
  • Blindness
  1. Cherry-red macula
  2. Muscular weakness
  3. Seizures

 

Gaucher`s Disease

  1. Accumulation of glucocerebrosides
  2. Most common lysosomal storage disease
  • Hepatosplenomegaly
  1. Osteoporosis of long bones
  2. CNS involvement in rare infantile and juvenile forms

 

Figure 3. Hierarchial Breakdown from GM1 Gangliosides to Tte Main Precursor of Sphingolipidoses, Ceramide .

 

Figure 3. Breakdown of Globoside to Lactosylceramide .

 

 

Sandhoff Disease

 

i. Accumulation of GM2  and globosides

 

ii. Same neurologic symptoms as Tay-sachs but with visceral involvement as well.

 

Fabry Disease

 

i.  Accumulation of globosides

ii.  Reddish purple skin rash

 

 

  • Kidney and heart failure
  1. Burning pain in lower extremities

 

 

Figure 4: Inborn Errors Associated with the Converging Point to Ceramide Metachromatic leukodystrophy

 

  1. Accumulation of sulfatides
  2. Cognitive deterioration
  • Demyelination

iv.            Progressive paralysis and dementia in infantile form

v.            Nerves stain yellowish-brown with cresyl violet (metachromasia)

vi.            Multiple sulfatase deficiency due to defect in post-translational modification of several sulfatases

 

Niemann-Pick Disease (A+B)

i.            Accumulation of sphingomyelin

ii.            Hepatosplenomegaly

iii.            Neurodegenerative course (Type A)

iv.            Cherry-red macula

Krabbe Disease (Globoid Cell Leukodystrophy)

i.            Accumulation of galactocerobrosides

ii.            Mental and motor deterioration

iii.            Blindness and deafness

iv.            Near-total loss of myelin

v.            Globoid bodies (glycolipid-laden macrophages) in white matter of brain

Farber Disease

i.            Accumulation of ceremide

ii.            Painful and progressive joint deformity

iii.            Subcutaneous nodules of lipid-laden cells

iv.            Hoarse cry

 

v.            Tissue show granulomas

 

[2]  Acid Lipase Disease

 

 

The flaw in the ‘Acid lipase’ enzyme which is required to degrade mainly fatty acids, oils and cholesterol

resulting in the accumulation of these lipids. Two rare inborn lipidoses are because of lysosomal acid lipase

 

deficiency:

 

1.      Wolman’s disease

 

i.            It is an autosomal recessive disorder lipid storage disease in which cholesteryl esters and triglycerides are accumulated.

 

  1. appear normal at birth but quickly develop progressive mental deterioration.
  • Hardened adrenal glands because of calcium deposits
  1. Enlarged liver and spleen with gastrointestinal problems like anaemia, jaundice and vomiting
  2. Low muscle tone
  3. Cholesteryl ester storage disease (CESD)

 

  1. It is an exceedingly uncommon disorder where cells of blood and lymph accumulate cholesteryl esters and triglycerides.
  2. Diagnosis is not easy as the onset fluctuates and sometimes diagnosis occurs on adulthood.
  • Enlarged liver and problems associated with it like cirrhosis and thus before adulthood chronic liver failure most probably occur.
  1. Jaundice as well as calcium deposits occurs in the adrenal glands.
  • [3] Neuronal ceroid lipofuscinoses

 

Neuronal ceroid lipofuscinoses (NCL) results from unnecessary accretion of lipofuscin (lipopigments) which are made up of coloured proteins (greenish-yellow color when viewed under an ultraviolet light microscope) and lipids in the body’s tissues mostly in the neuronal cells while it is also present in myocardium, spleen, liver and kidneys. The main types are described below (Figure 5).

 

 

 

Figure 5. Types of Neural Ceroid Lipofucinoses

 

Diagnoses of Lipid Storage Disease

Diagnosis is possible through various modes described below.

 

1.      Clinical examination of urine analysis: discover the existence of stored material

2.       Genetic testing and molecular enzymatic analysis of cells of affected tissues or blood or body fluids .

3.      Genotyping is a process in which some specific tests can done which verify the person carrying the defective gene that can be passed on to her or his children.

4.      Biopsy for lipid storage disorders involves study of cells and tissues like liver by removing a small amount of tissue done through surgery or by needle biopsy.

  1. Genetic testing mostly prenatal testing is done during early pregnancy through chorionic villus sampling where little placenta tissue sample is removed and tested. This can help in detecting lipid storage diseases of individuals who have a family history.

Prognosis & Treatment

 

The prognosis for a lipidosis is determined by the kind of illness, the severity of symptoms and the age of commencement. Children with Niemann-Pick disorders mostly die at early age with problems like progressive neurological loss or infection while children with Gaucher disorders may live healthy upto adulthood. Most children having Farber’s disease die with lung problems before the age of 2 as well as children affec ted with Fabry disease often die prematurely of complications from renal failure, heart disease or stroke. Tay-Sachs disorders may ultimately want a feeding tube and thus they often die by age 4 from chronic infection.

 

At present there is no precise treatment available for most of the lipidosis (lipid storage diseases) like that of Niemann-Pick disease, even though Fabry and Gaucher disorders have extremely successful enzyme replacement therapies. To relieve pain in Farber’s disorders, doctors often advise corticosteroids while in Tay-Sachs disease, to control seizures anticonvulsant medications are often prescribed.

  1. Summary

 

In this lecture we learnt about:

 

  • Lipid Storage Diseases
  • Lipidoses & its Types
  • Diagnosis, Prognosis and Treatment

 

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

Weblinks

 

Books

 

  1. G. Schettler. 2012. Lipids and Lipidoses https://books.google.co.in/books?isbn=3642873677
  2. Siegfried Thannhauser. 1958. Lipidoses: Diseases of the Intracellular Lipid Metabolism. https://books.google.co.in/books?id=PwNsAAAAMAAJ
  3. Siegfried J. Thannhauser, Henry‎ A. Christian. 1940. Lipidoses: Diseases of the Cellular Lipid Metabolism. https://books.google.co.in/books?id=EuZKjgEACAAJ
  4. Gunter Schlierf. 1967. Lipids and Lipidoses. https://books.google.co.in/books?isbn=3642873685
  5. Randall McPartland. 2016. Tay-Sachs Disease. https://books.google.co.in/books?isbn=1502609460
  6. Fabry Disease: New Insights for the Healthcare. 2013. Page 37. https://books.google.co.in/books?isbn=1481658700
  7. Roger N. Rosenberg. 2003. The Molecular and Genetic Basis of Neurological disease. Page 304. https://books.google.co.in/books?isbn=0750673605