Adrenoleucodystrophy

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Classification according to ICD-10
E71.3 Fatty acid metabolism disorders
Adrenoleukodystrophy
Addison-Schilder syndrome
ICD-10 online (WHO version 2019)

Adrenoleukodystrophy (X-ALD) or Addison-Schilder syndrome is an inherited metabolic disease that usually occurs in childhood and often causes rapid neurological deterioration. In the final stage, there is pronounced dementia , which ultimately leads to the loss of vital body functions and thus to death. Since the disease X-linked - recessive inherited, men are almost exclusively affected. Women are usually only female carriers ( conductor ) of the gene mutation . It is very rare that both X chromosomes in a woman have the defect, which then leads to the development of the symptoms of the disease.

frequency

The prevalence for males is around 1: 20,000. Adrenoleukodystrophy is roughly the same in all sections of the population worldwide.

causes

Genetic studies have shown that all those affected have mutations in the ABCD1 gene, which is a gene from the group of ABC transporters . This gene is located on the X chromosome , gene locus q28. It codes for the peroxisomal ABC semi-transporter ALD protein, a protein that is located in the membrane of the peroxisomes . It is controversial whether it is directly involved in the transport of excessively long chain fatty acids into the peroxisomes. These fats are usually broken down within the peroxisome. In X-ALD patients, however, there is an accumulation of fatty acids, especially in the adrenal cortex and in the white matter of the brain (hence from Latin : adreno `` concerning the adrenal gland ''; from Greek leukos `` white '', dys , wrong 'and trophein 'feed' with dystrophy in the sense of 'dysfunction'), as well as in the Leydig cells in the testes . Long-chain fatty acids are also stored in cell membranes . Therefore, some scientists propose the hypothesis that there is a change in the membrane structure of the myelin in X-ALD patients . This could be a cause of demyelination and ultimately hinder the transmission of impulses and cause mental and motor decline in the patient.

Diagnosis

This T 2 -weighted MRI of the brain in adrenoleukodystrophy shows demyelination in the medullary bed of the posterior brain segments (light), while the medullary bed in the anterior segments shows a normal signal (dark).

Clinically, adrenoleukodystrophy is heterogeneous, with different clearly distinguishable forms ( phenotypes ), which, however, have no clear correlation to the genotype . With about 35% of boys under 12 years of cerebral - inflammatory and type, cerebral adrenoleukodystrophy called, the most common form. This leads to severe disability or death within a maximum of two years after diagnosis.

Laboratory diagnostics can result in an increase in excessively long- chain fatty acids , v. a. of cerotic acid (C26: 0) and the quotients C26: 0 / C24: 0, C26: 0 / C22: 0 and C24: 0 / C22: 0 in the serum . Suitable imaging methods , especially magnetic resonance tomography , show a symmetrical, flat degeneration of the white matter with contrast medium uptake . The occipital lobes , the posterior area of ​​the corpus callosum , the pyramidal and auditory tracts are primarily affected .

therapy

The therapeutic options are mainly limited to alleviating the symptoms of the disease. Medicines are administered against spastic muscle cramps , as well as steroid hormones against the neurological side effects. Interferon and lovastatin rarely suppress inflammatory processes in the brain. The administration of 4-phenylbutyrate is considered to increase the number of peroxisomes .

The only curative therapy is bone marrow transplantation , which is particularly effective when done in the cerebral form in the early stages of neurodegeneration or pre-symptomatically. The mechanism is not yet understood, but it is assumed that the myeloid cells are exchanged for those from the donor, which may also include the microglia of the central nervous system. With HLA- identical donors and early stem cell transplantation, the long-term results are good.

research

After a French working group around N. Cartier et al. In 2009 a proof-of-concept study showed that an autologous transplantation of CD34- positive hematopoietic progenitor cells is possible, which were transfected ex vivo with a lentiviral vector , and thereby a copy of the ABCD1 gene could be incorporated, an open one could be incorporated Multi-center phase 2-3 study 2017 to demonstrate the safety and effectiveness of this gene therapy known as Lenti-D (Elivaldogene Tavalentivec) . 17 boys were treated with a median of 6 years. Two children died during the course of therapy, the other 15 boys were free of neurological disabilities with only minimal clinical symptoms after a mean 29 months of follow-up. In contrast to autologous stem cell transplantation, no graft-versus-host reaction was observed.

Lorenzo's oil

Some patients are given Lorenzo's oil as a dietary measure , a mixture of glycerine trioleate and glycerine trierucate in a ratio of 4 to 1. Hypothetically, the intake of these long-chain, monounsaturated fatty acids could lead to the enzymes that produce the extra-long-chain fatty acids being exhausted and the concentration of fatty acids drops to a more tolerable level.

The first advocate of oil therapy is Augusto Odone, the father of Lorenzo, who was affected by X-ALD. The medical layman was forced to take the search for a cure into his own hands after the treating doctors could not give him high hopes for the survival of his son. The neurologist Hugo Moser, who came from Switzerland, gave decisive impulses, who carried out a study with Lorenzo's oil on 89 boys with his research group from Baltimore. The children were asymptomatic and a mean age of 4.7 years at the start of treatment. After a mean 6.9 years of follow-up, 24% only showed changes in MRI images of the brain, 11% developed MRI abnormalities and neurological disorders. However, different phenotypes were taken together and not differentiated, so that it is unclear whether and how many of the children had cerebral adrenoleukodystrophy, which is a very severe form.

media

  • The story of Lorenzo's oil about the Odone family was filmed in 1992 with Susan Sarandon , Nick Nolte and Peter Ustinov .
  • Even Phil Collins honored Lorenzo's will to survive and the success of his father, who is also a project to investigate the myelination of nerve cells has launched in the published 1996 song Lorenzo on the album Dance into the Light .
  • Accompaniment of Keno, who had adrenoleucodystrophy, and his mother for a period of 6 years until the boy's death on December 24, 2017.

Synonyms

  • Addison-Schilder Syndromes
  • Fanconi-Prader syndrome
  • Siemerling-Creutzfeldt syndrome
  • Adrenoleucomyeloneuropathy (ALMN)
  • Adrenomyeloneuropathy (AMN)

See also

literature

  1. ^ A b H. W. Moser, A. Mahmood, GV Raymond: X-linked adrenoleukodystrophy. In: Nature clinical practice. Neurology. Volume 3, Number 3, March 2007, pp. 140-151, ISSN  1745-8358 . doi : 10.1038 / ncpneuro0421 . PMID 17342190 . (Review).
  2. ↑ a b c Florian Eichler, Christine Duncan, Patricia L. Musolino, Paul J. Orchard, Satiro De Oliveira, Adrian J. Thrasher, Myriam Armant, Colleen Dansereau, Troy C. Lund, Weston P. Miller, Gerald V. Raymond, Raman Sankar, Ami J. Shah, Caroline Sevin, H. Bobby Gaspar, Paul Gissen, Hernan Amartino, Drago Bratkovic, Nicholas JC Smith, Asif M. Paker, Esther Shamir, Tara O'Meara, David Davidson, Patrick Aubourg, David A Williams: Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy New England Journal of Medicine 2017, Volume 377, Issue 17, October 26, 2017, pages 1630-1638, [DOI: 10.1056 / NEJMoa1700554]
  3. ^ Z. Patay: Diffusion-weighted MR imaging in leukodystrophies. In: European radiology. Volume 15, Number 11, November 2005, pp. 2284-2303, ISSN  0938-7994 . doi : 10.1007 / s00330-005-2846-2 . PMID 16021451 . (Review).
  4. ↑ JH Kim, HJ Kim: Childhood X-linked adrenoleukodystrophy: clinical-pathologic overview and MR imaging manifestations at initial evaluation and follow-up. In: Radiographics: a review publication of the Radiological Society of North America, Inc. Volume 25, Number 3, 2005 May-Jun, pp. 619-631, ISSN  1527-1323 . doi : 10.1148 / rg.253045118 . PMID 15888613 . (Review).
  5. ↑ C. Gondcaille, M. Depreter a. a .: Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator. In: Journal of Cell Biology . Volume 169, Number 1, April 2005, pp. 93-104, ISSN  0021-9525 . doi : 10.1083 / jcb.200501036 . PMID 15809314 . PMC 2171887 (free full text).
  6. ↑ N. Cartier, S. Hacein-Bey-Abina, CC Bartholomae et al .: Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy Science 2009, Volume 326, pages 818-823.
  7. ↑ E. Simon, Efficacy of Lorenzo oil in adrenomyeloneuropathy. In: Annals of neurology . Volume 36, Number 1, July 1994, pp. 116-117, ISSN  0364-5134 . doi : 10.1002 / ana.410360126 . PMID 8024253 .
  8. ^ HW Moser: Lorenzo oil therapy for adrenoleukodystrophy: a prematurely amplified hope. In: Annals of neurology. Volume 34, Number 2, August 1993, pp. 121-122, ISSN  0364-5134 . doi : 10.1002 / ana.410340202 . PMID 8338333 .
  9. Jump up ↑ HWI Moser, GV Raymond, SE Lu, LR Muenz, AB Moser, J. Xu, RO Jones, DJ Loes, ER Melhem, P. Dubey, L. Bezman, NH Brereton, A. Odone: Follow-up of 89 asymptomatic Patients with adrenoleukodystrophy treated with Lorenzo's oil Archives of Neurology 2005, Volume 62, Issue 7 of July 2005, pages 1073-80.
  10. ↑ Keno's short life. Retrieved February 8, 2019 .

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