Wolman disease

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Classification according to ICD-10
E75.5 Other disorders of lipid storage (including Wolman disease)
ICD-10 online (WHO version 2019)

The Wolman Disease , also Wolman syndrome or Crohn Wolman called, 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 the acidic 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 loss of function of the LAL gene product .

Since the loss of function of the lysosomal acidic lipase prevents lipids from entering the cytoplasm from the lysosome , the control loop for regulating the intracellular cholesterol concentration is interrupted. The low concentration of intracellular 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 the milder, also extremely rare, cholesterol ester storage disease (CESD), on the other hand, there is still residual activity of the lysosomal acid lipase. With CESD, this residual activity is sufficient to largely manage the breakdown of cholesterol esters - with the exception of the liver. The first description of the CESD was made by the American physiologist Fredrickson in 1963.

The genetic defect is inherited as an autosomal recessive trait. There are connections between genotype and phenotype .

Symptoms

The symptoms are already present in the first days of life. These are gastrointestinal complaints (vomiting and diarrhea), bloated abdomen, atrophy and anemia , as well as an enlarged liver and spleen ( hepatosplenomegaly ). Transaminases, cholesterol and LDL are often increased. The patients have enlarged and calcified adrenal glands due to necrosis .

Prevalence and prognosis

Wolman disease is extremely rare. The prevalence is estimated at 1 in 700,000. It usually leads to death in early childhood, usually at the age of three to six months, in any case in the first year of life.

therapy

There is now a specific enzyme replacement therapy approved in Germany since 2015 (Sebelipase alfa, trade name: KANUMA). This takes place as an infusion every 2 weeks for life. The treatment is therefore no longer purely symptomatic, for example by the administration of 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.

The first clinical studies to develop an enzyme replacement therapy for lysosmal acid lipase (LAL) have been established and are recruiting patients worldwide.

Initial description

Wolman's disease was first described in 1961 by the Israeli neuropathologist Moshe Wolman (1914-2009). He is the namesake of the disease.

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 c d 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. ^ DS Fredrickson: Newly recognized disorders of cholesterol metabolism . Ed .: ANN INT MED 1963. Volume 85 , p. 309-31 .
  9. ↑ M. Pavelka, J. Roth: Functional ultrastructure. Verlag Springer, 2005, ISBN 3-211-83563-6 , pp. 110-111.
  10. ^ CP Speer, M. Gahr: Pediatrics. Verlag Springer, 2005, ISBN 3-540-20791-0 , p. 148.
  11. ↑ clinicaltrials.gov ( Memento of the original from July 14, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.  @1@ 2Template: Webachiv / IABot / www.clinicaltrials.gov
  12. ^ M. Wolman et al .: Primary family xanthomatosis with involvement and calcification of the adrenals: report of two more cases in siblings of a previously described infant. In: Pediatrics. 28, 1961, pp. 742-757. PMID 14008104

literature

  • AD Patrick, BD Lake: Deficiency of an acid lipase in Wolman's disease. In: Nature . 222, 1969, pp. 1067-1068. PMID 5787090
  • M. Roytta et al: Wolman disease: morphological, clinical and genetic studies on the first Scandinavian cases. In: Clin. Genet. 42, 1992, pp. 1-7. PMID 1516222

Web links