Cholesterol ester storage disease

from Wikipedia, the free encyclopedia
Classification according to ICD-10
E75.5 Other disorders of lipid storage
ICD-10 online (WHO version 2019)

The Cholesterinester Storage Disease , CESD (of . English : Cholesteryl Ester Storage Disease ), is an extremely rare autosomal - recessive inherited lysosomal storage disease .

Etiology and Genetics

A defect in the enzyme lysosomal acid lipase (LAL = lysosomal acid lipase ) leads to an accumulation (storage) of cholesterol esters and triglycerides in the affected patient . The gene that codes for acid lipase is located on chromosome 10 gene locus q23.2-23.3. It consists of ten exons . Nonsense and missense mutations , as well as frame shifts and the omission of exons, can lead to a reduction in the activity of the gene product .

Due to the reduced activity of the lysosomal acid lipase, hardly any lipids can get from the lysosome into the cytoplasm . This interrupts the control loop for regulating the intracellular cholesterol concentration. The low intracellular concentration of cholesterol in turn leads to an upregulation of the endogenous synthesis of cholesterol and the LDL receptor activity. The lysosome takes up the endocytosed cholesterol. Through the endogenous cholesterol synthesis, the cells are overloaded with cholesterol, whereby lipid vacuoles are formed. These cause a loss of function of the cells, fibrosis and ultimately cell death.

In contrast to Wolman's disease , which has the same genetic cause and which is always associated with a poor prognosis , the cholesterol ester storage disease is considerably milder. In CESD there is still residual activity of the lysosomal acid lipase. This residual activity is sufficient to break down the cholesterol ester - with the exception of the liver. The same gene is affected in both diseases, only different areas in the LAL gene are mutated. In one case (in Wolman's disease) this leads to a complete loss of enzyme activity , in the other (in cholesterol ester storage disease) only to a reduction in enzyme activity.

The genetic defect is inherited as an autosomal recessive trait.

Symptoms and diagnosis

Cholesterol ester storage disease is often only diagnosed after the age of 18 . The patients show a high accumulation of lipids in various organs and have pronounced hypercholesterolemia . The HDL cholesterol concentration, on the other hand, is reduced. The risk of arteriosclerosis is correspondingly increased. The liver and spleen are enlarged ( hepatosplenomegaly ).

A reliable diagnosis can be made after determining the enzyme activity. For this purpose, Hamilton et al described a simple method that enables the enzyme activity to be determined from blood droplets immobilized on filter paper .

Prevalence

Cholesterol ester storage disease is extremely rare. The prevalence is estimated at 1 in 700,000.

therapy

Until recently, there was no causal therapy for cholesterol ester storage disease. Treatment has so far been symptomatic, for example by administering HMG-CoA reductase inhibitors , inhibitors of cholesterol or apolipoprotein B synthesis.

Various clinical programs in recent years have successfully led to the development of enzyme replacement therapies for various lysosomal storage diseases. The affected enzyme is regularly supplied externally and can reverse or reduce the symptoms.

There have been several studies of enzyme replacement therapy for CESD and Wolman's disease. The effectiveness of the therapy could be demonstrated in these, although the number of test subjects was relatively small.

On the basis of these studies, a drug for the treatment of cholesterol ester storage disease and Wolman's disease was approved in the USA and Europe in autumn 2015. It is a recombinantly produced form of human lysosomal acid lipase in hen's eggs, which is referred to as "sebelipase alfa". The drug is manufactured by Alexion and sold under the brand name Kanuma .

Individual evidence

  1. ↑ RA Anderson et al .: In situ localization of the genetic locus encoding the lysosomal acid lipase / cholesteryl esterase (LIPA) deficient in Wolman disease to chromosome 10q23.2-q23.3. In: Genomics. 15, 1993, pp. 245-247. PMID 8432549 .
  2. ↑ C. Aslanidis et al .: Genomic organization of the human lysosomal acid lipase gene (LIPA). In: Genomics. 20, 1994, pp. 329-331. PMID 8020990
  3. ↑ GN Sando et al.: Intercellular transport of lysosomal acid lipase mediates lipoprotein cholesteryl ester metabolism in human vascular endothelial cell fibroblast coculture system. In: Cell Regulation. 1, 1990, pp. 661-672.
  4. ↑ T. Illies: Kinetics of lipid metabolism in the mouse model of overexpressed lysosomal acid lipases. Dissertation . University of Hamburg, 2005.
  5. ↑ a b G. F. Hoffmann: Metabolic diseases in neurology. Georg Thieme Verlag, 2004, ISBN 3-13-136321-5 , pp. 78-79.
  6. ↑ G. Assmann, U. Seedorf: Acid Lipase Deficiency: Wolman Disease and Cholesteryl Ester Storage Disease. In: The metabolic and molecular basis of inherited diseases. McGraw and Hill, 1995, pp. 2563-2587.
  7. ↑ Ü. Lohse et al: Molecular defects underlying Wolman disease appear to be more heterogeneous than they appear. In: Journal of Lipid Research. 40, 1999, pp. 221-228.
  8. ↑ C. Aslanidis et al .: Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. In: Genomics. Volume 33, 1996, pp. 85-93. PMID 8617513 .
  9. ↑ M. Pavelka, J. Roth: Functional ultrastructure. Verlag Springer, 2005, ISBN 3-211-83563-6 , pp. 110-111.
  10. ↑ D. Ganten: Handbook of molecular medicine. Verlag Springer, ISBN 3-540-65529-8 , pp. 361-362.
  11. ↑ Hamilton et al - Clinica Chimica Acta 2012 413 1207: A new method for the measurement of lysosomal acid lipase in dried blood spots using the inhibitor Lalistat 2
  12. ↑ Dairaku et al - Mol Gen Metabol 2014 111 193: A practical fluorometric assay method to measure lysosomal acid lipase activity in dried blood spots for the screening of cholesteryl ester storage disease and Wolman disease
  13. ↑ Civallerro et al - Gene 2014 539 154: Extended use of a selective inhibitor of acid lipase for the diagnosis of Wolman disease and cholesteryl ester storage disease
  14. ↑ Burton et al., N Engl J Med 2015 373 1010: "A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency"
  15. ↑ Valayannopoulos et al., J Hepatol 2014: "Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency"
  16. ↑ Balwani et al., Hepatology 3013: "Clinical Effect and Safety Profile of Recombinant Human Lysosomal Acid Lipase in Patients With Cholesteryl Ester Storage Disease"
  17. ↑ EMA / 446507/2015 Kanuma (PDF) European Medicines Agency. 2015. Accessed February 10, 2019.

Web links