Gaucher's disease

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Classification according to ICD-10
E75.2 Other sphingolipidoses
Gaucher disease
ICD-10 online (WHO version 2019)

Gaucher's disease [ goˈʃe ], also Gaucher syndrome and Gaucher's disease , is a rare hereditary disease and the most common of the lysosomal storage diseases , a disorder of lipid metabolism . In the autosomal - recessive inherited disease is a mutation in the gene of β- glucosidase (EC 3.2.1.45; chromosome 1; locus 1q21; gene symbol GBA) in front; over 400 variants are known. This leads to a reduced activity of this enzyme , which is localized in the lysosomes , so that glucocerebrosides (fatty substances containing sugar) are only insufficiently broken down into glucose and ceramide. Glucocerebrosides are e.g. T. itself a direct component of cell membranes (especially of the erythrocytes) but above all intermediate products in the construction and breakdown of numerous other, more complex glycolipids of the cell membranes. Due to the disrupted breakdown, they therefore accumulate in the body's phagocytes ( macrophages ) and in monocytes , which subsequently become so-called Gaucher cells. These release numerous cytokines and factors that ultimately determine the symptoms of the disease: a (sometimes massive) enlargement of the spleen ( splenomegaly ), enlargement of the liver ( hepatomegaly ), disruption of blood formation in the bone marrow with a lack of blood platelets ( thrombocytopenia ), red blood cells (anemia) and white blood cells (leukocytopenia). Involvement of the bone marrow and the entire skeletal system (especially the hip and thigh) leads to the destruction of the bone, which sometimes manifests itself in the form of feverish, painful attacks, so-called bone crises. Sometimes other organ systems such as the nervous system or the lungs are also affected.

Often there is exhaustion of those affected that cannot be explained by the physical findings alone, so that they are initially misunderstood as simulants or hypochondriacs . Patients with Gaucher disease have a significantly higher risk of developing malignancy (especially of the blood or lymphatic system such as multiple myeloma , non-Hodgkin lymphoma and the liver ( hepatocellular carcinoma )) or Parkinson's disease . Because the disease is rare and the spectrum of symptoms overlaps with various other, more common diseases, it often takes many years to make a correct diagnosis. With enzyme replacement therapy (an infusion therapy) and the substrate reduction therapy (oral treatment with capsules) two effective treatment options are available.

The disease (Latin: Morbus ) is named after Philippe Gaucher (1854–1918), a French dermatologist who first described the increased storage cells in the spleen in 1882. They have been known to contain glucocerebrosides since 1934.

Classification

In the past, Gaucher disease was very strictly divided into three types: Gaucher disease type 1, type 2 and type 3. This classification was based on the time of onset of the disease, the respective symptoms, the involvement of the nervous system and the life expectancy of the patient. This separation is increasingly abandoned, among other things because there are transitional forms that cannot be clearly assigned to a type. Today there is an increasing distinction between a neuronopathic and a non-neuronopathic form, i.e. H. the occurrence or absence of nerve damage decides on the assignment to the two main groups. However, this historical classification is still very common.

Gaucher disease type I (also non-neuronopathic Gaucher disease); approx. 94% of the patients

This is the most common form of Gaucher's disease. The first manifestation can appear at any age. In this form, the nervous system is not involved (not neuronopathic). The course of the disease can be very different, some patients have few symptoms and lead largely normal lives, while others have diverse and severe symptoms. The genotype-phenotype correlation is very low.

Gaucher disease type II (also acute neuronopathic Gaucher disease); about 1% of patients

This type is very rare and only occurs in childhood. Because of the severe neurological involvement, affected children rarely grow older than 2 years. Unfortunately, the currently available therapeutic options for this have no relevant influence on the course. Some authors distinguish this from a perinatally lethal form.

Gaucher's disease type III (also chronic neuronopathic form); about 5% of the patients

This type is also rare and usually manifests itself in early to late childhood, the symptoms are moderate to severe, and the course of the disease is progressive. Life expectancy may be reduced in these patients.

Division into subtypes

Some authors still differentiate between subtypes:

  • Gaucher's disease type IIIA: Characterized by myoclonus and dementia
  • Gaucher's disease type IIIB: Characterized by the early onset of an isolated supranuclear, horizontal paralysis and an aggressive course
  • Gaucher's disease type IIIC: Characterized by cardiovascular calcifications

frequency

The gene defects in question, with the exception of some cases of type 2 autosomal - recessive inherited. The frequency of the disease varies greatly from region to region. In Western Europe, 1 in 40,000–60,000 people is believed to be affected. In contrast, one in 1,000 people in the Ashkenazi Jewish population is affected in relative terms. The frequency of the heterozygous mutation is estimated at 1:30. This makes Gaucher's disease the most common lysosomal storage disease. There is also an increased incidence of these mutations among the Turkish population compared to Western Europeans.

root cause

The human body needs the enzyme glucocerebrosidase (also known as glucocerebrosidase in German-speaking countries) to break down aged cell membrane components. A deficiency is therefore particularly noticeable in cells with a short lifespan, such as the white and red blood cells . Without sufficient activity of the enzyme, the membrane components are deposited in the lysosomes, especially the macrophages. Depending on the type of mutation in the gene coding for the enzyme, there is a more or less severe or complete functional failure of the enzyme. More than 400 different mutations have now been described.

Symptoms

The severity of the enzyme defect determines the age at the first symptoms and the organs in which the symptoms mainly occur:

In the non-neuronopathic type (formerly type I), the enzyme activity is still relatively high. The first symptoms can only appear in adulthood; the course can be mild. Changes occur primarily in internal organs (“visceral type”) in the form of extreme enlargement of the liver and spleen . The enlargement of the spleen results in an increased breakdown of blood cells . This leads to anemia and platelet deficiency . This results in an increased risk of bleeding and possibly circulatory problems. The skeleton is also often involved. This manifests itself in chronic but sudden, severe pain, especially in the hip joints , which can be accompanied by fever and signs of inflammation. Osteolysis can also occur as part of the bone damage.

In the acute neuronopathic type (formerly type II) the enzyme activity is particularly low; even infants show severe disorders of the nervous system with intellectual disabilities , cramps and pronounced failure to thrive . Most of the children die before they are two years old. Type II can also occur in the dominant inheritance.

In the chronic neuronopathic type (formerly type III), the enzyme activities are usually between type I and type II. Nerve damage and failure to thrive occur from around the age of two . This form occurs more frequently in Sweden .

diagnosis

The main symptom is the enlargement of the spleen (usually by means of ultrasound examination), which is found in practically all patients in the course of the disease, often paired with an enlargement of the liver. Often there are more or less pronounced changes in the blood count, in particular the number of platelets is often reduced. The involvement of the bones is particularly evident in magnetic resonance imaging, whereas a conventional X-ray image often shows no changes. However, typical manifestations such as the so-called Erlenmeyer deformity can also be found here.

In the routine laboratory there is often an increase in ferritin , ACE and acid, non-tartrate-inhibitable phosphatase . However, this is very unspecific, so that in the event of suspicion or exclusion, a targeted enzyme test to detect a reduced β-glucocerebrosidase activity in leukocytes (from EDTA whole blood or by means of a dry blood test (DBS)) - possibly supplemented by the determination of glucosylsphingosine (lyso- Gb1 / lysoGL1) - should be done. The sometimes performed bone marrow puncture can be false negative in up to a third of the cases. It is therefore obsolete today for the detection or exclusion of Gaucher's disease.

If Gaucher's disease is suspected, the enzyme activity of beta- glucocerebrosidase in the blood is determined in the laboratory . If it is lowered, the diagnosis of Gaucher's disease is confirmed. In addition, a genetic analysis is almost always carried out today.

A dry blood test (Dried Blood Spot, DBS) that can be easily integrated into everyday practice is available for measuring enzyme activity as well as for genetic analysis: a few drops of blood are placed on a dry blood card for this purpose. After they have dried, the card is mailed to a specialized laboratory. There the blood is removed from the filter card and processed for the following tests.

To determine the enzyme activity, a defined amount of substrate is added to a defined amount of blood. After a certain time z. B. analyzed by mass spectroscopy how much product was created by the enzyme reaction. This shows how active the enzyme is. It is important that a certified assay is used to ensure the reliability of the readings.

For the genetic analysis, the beta-glucocerebrosidase gene is sequenced. Both tests - the measurement of the enzyme activity and the genetic analysis - can - depending on the laboratory - be carried out from the material of a dry blood card.

treatment

The lack of glucocerebrosidase activity in Gaucher's disease leads to an imbalance between the build- up and breakdown of glucosylceramide (often abbreviated as GL1 or Gb1). Particularly in type 1, the non-neuronopathic form, and partly in type 3, the storage of GL1 and thus the disease can be treated very well using two different therapy principles - enzyme replacement therapy and substrate reduction therapy. For this reason, stem cell transplantation , which was sometimes used in the past - through which macrophages are formed without enzyme defects - is hardly used any longer due to the considerable risks involved.

Enzyme Replacement Therapy (EET or ERT)

The causal lack of glucocerebrosidase activity (EC 3.2.1.45) can be compensated for by a lifelong, usually bi-weekly infusion of biotechnologically produced glucocerebrosidase. Imiglucerase , velaglucerase alfa and taliglucerase alfa are currently approved and available in Europe . Because imiglucerase was approved in the USA in 1994, most of the data and the longest practical experience are currently available (first approval for velaglucerase alfa: 2010; taliglucerase alfa: 2012).

The uptake takes place via terminal mannose residues glycosylation , whereby the infused enzyme is preferentially absorbed in macrophages (also mainly affected in Gaucher's disease) , so it reaches their lysosomes and can break down the storage substance glucosylceramide there .

Substrate Reduction Therapy (SRT)

The imbalance between build-up and breakdown on which the storage of glucosylceramide is based can also be compensated for by (partial) inhibition of glucosylceramide synthesis or the enzyme responsible for this, glucosylceramide synthase . Less glucosylceramide is formed, so there is less substrate available for the insufficient or active enzyme glucocerebrosidase in M. Gaucher, which would have to break it down. Corresponding inhibitors are mostly small molecules and can also be administered orally as a capsule, which saves the patient the time-consuming injections and the necessary scheduling.

The first preparation approved for substrate reduction therapy for Gaucher's disease was Miglustat (first approval: 2002). Miglustat is an imino sugar and an analogue of glucose . It binds to its binding site and thus prevents the synthesis of glucosylceramide . Since glucose is involved in many processes in the body, other enzymes are also inhibited by miglustat. These include some sugar-splitting enzymes in the intestine, which can subsequently lead to stressful side effects such as (osmotically caused) diarrhea , but also central nervous symptoms. The use of miglustat is therefore restricted to patients with mild to moderate, non-neuronopathic Gaucher disease, for whom enzyme replacement therapy is unsuitable ( second-line therapy ).

The second preparation for substrate reduction therapy, Eliglustat , approved in January 2015, is an analogue of ceramide . It is much more specific and selective for glucosylceramide synthase than miglustat, so that it is much better tolerated. For example, gastrointestinal complaints were significantly more common in the approval studies in the placebo group. In contrast to miglustat, it hardly reaches the CNS , so that hardly any side effects were observed here either. The effectiveness is comparable to enzyme replacement therapy in both previously untreated patients and those previously treated with enzyme replacement therapy. Long-term data over 8 years also show that severely affected Gaucher patients benefit particularly. Eliglustat is broken down via the cytochrome P450 system , in particular CYP2D6 and to a lesser extent also via CYP3A4 . The activity of these enzyme systems varies from person to person, so that a one-time genetic determination of the corresponding metabolic type must be carried out prior to prescription. Eliglustat is approved for adult type 1 patients who are slow, intermediate, or rapid metabolisers for CYP2D6.

In addition to clinical parameters, magnetic resonance imaging , ultrasound and blood count , the activity or concentrations of chitotriosidase , glucosylsphingosine (= lyso-Gb1 or lyso-GL1) or CCL18 are also suitable for therapy control .

Therapy control

Reaction of the glucosylceramide build-up and breakdown as well as influence of the substrate reduction therapy preparations eliglustat and miglustat or enzyme replacement therapy
Reaction of glucosylceramide build-up and breakdown. In M. Gaucher the activity of glucocerebrosidase is reduced. By inhibiting glucosylceramide synthase, the substrate of glucocerebrosidase (i.e. glucosylceramide) can be reduced and the structure can be adapted to the breakdown. The orally usable substances miglustat and eliglustat can be used for this. The structural components of the inhibitors that are homologous to glucose (miglustat) or ceramide (eliglustat) are highlighted in color and bold. The thickness of the red or green arrows indicates the different levels of effectiveness, or specificity and selectivity. In enzyme replacement therapy, the balance between build-up and breakdown occurs by supplying the missing enzyme via infusion.

In addition to the clinical parameters, the therapy is checked by means of imaging ( magnetic resonance imaging , ultrasound, if necessary X-ray and bone density measurement) and laboratory tests. In addition to the blood count , the activity of the enzyme chitotriosidase is a marker for the memory load. However, the measurement is not a little standardized and laboratory-specific. In addition, an increase is not Gaucher-specific and about 5-10% of the patients do not have no chitotriosidase activity. Therefore, glucosylsphingosine (= lyso-Gb1 or lyso-GL1) is increasingly establishing itself as a new monitoring parameter.

outlook

The prognosis depends on the type and severity of the disease, on the availability and the actual use of the treatment: A definitive cure can only be achieved by eliminating the genetic defect through gene therapy . However, such a solution is not yet in sight. Until then, the goal is to eliminate the consequences of the genetic defect and thus the symptoms as early as possible and completely. With type I this works well as long as the treatment is carried out consistently. Even with type III, the prognosis is then rather favorable: There are then no neurological restrictions such as a reduction in intelligence . With type II of the disease, on the other hand, there is often a fatal outcome. In many countries, the medically necessary use of the therapy is offset by the high costs.

literature

  • O. Harmanci, Y. Bayraktar: Gaucher disease: new developments in treatment and etiology. In: World J Gastroenterol. 2008 Jul 7; 14 (25), pp. 3968-3973. Review. PMID 18609679
  • J. Schmitz, LW Poll, S. vom Dahl: Therapy of adult Gaucher disease. In: Haematologica . 2007 Feb; 92 (2), pp. 148-152. Review. PMID 17296562

Web links

swell

  1. ↑ HGMD® gene result. Accessed August 21, 2020 .
  2. ↑ a b OMIM Entry - # 230800 - GAUCHER DISEASE, TYPE I. Accessed January 31, 2019 (American English).
  3. ↑ a b OMIM Entry - # 231000 - GAUCHER DISEASE, TYPE III. Retrieved January 31, 2019 (American English).
  4. ↑ a b c Th. Stallmach, G. Klöppel, J. Roth, GA Spinas: Metabolic diseases. In: W. Böcker, H. Denk, Ph. U. Heitz, H. Moch: Pathology. 4th edition. Munich, 2008, pp. 1126-1127.
  5. ↑ a b Gerd Herold and others: Internal medicine. Cologne, 2009, p. 111.
  6. ^ A b Robert J. Hopkin, Gregory A. Grabowski: Lysosomal Storage Diseases. In: Anthony Faucy et al .: Harrison's Principles of Internal Medicine. 17th edition. New York, 2008, pp. 2452-2456.
  7. ↑ The Human Gene Mutation Database. Accessed January 31, 2019 .
  8. ↑ a b M. Beck: full text pdf therapy of lysosomal storage diseases. In: Deutsches Ärzteblatt. Volume 98, Numbers 34-35, pp. 2188-2192.
  9. ↑ Gaucher disease . Retrieved December 7, 2015.
  10. ↑ ENZYME entry: EC 3.2.1.45 ( English ) expasy.org. Retrieved September 11, 2019.
  11. ^ Drugs @ FDA: FDA Approved Drug Products. Retrieved October 22, 2018 .
  12. ↑ Entry on Taliglucerase alfa in the DrugBank of the University of Alberta , accessed on October 22, 2018.
  13. ↑ Pramod K. Mistry, Elena Lukina, Hadhami Ben Turkia, Suma P. Shankar, Hagit Baris: Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial . In: American Journal of Hematology . tape 92 , no. 11 , October 3, 2017, ISSN  0361-8609 , p. 1170–1176 , doi : 10.1002 / ajh.24877 , PMID 28762527 , PMC 5656936 (free full text) - ( wiley.com [accessed October 22, 2018]).
  14. ↑ Lesley J. Scott: Eliglustat: A Review in Gaucher Disease Type 1 . In: Drugs . tape 75 , no. September 14 , 2015, ISSN  0012-6667 , p. 1669–1678 , doi : 10.1007 / s40265-015-0468-9 ( springer.com [accessed October 22, 2018]).
  15. ↑ Elena Lukina, Nora Watman, Marta Dragosky, Heather Lau, Elsa Avila Arreguin: Outcomes after 8 Years of Eliglustat Therapy for Gaucher Disease Type 1: Final Results from the Phase 2 Trial . In: American Journal of Hematology . September 28, 2018, ISSN  0361-8609 , doi : 10.1002 / ajh.25300 ( wiley.com [accessed October 22, 2018]).
  16. ↑ Cerdelga®. Retrieved October 22, 2018 .
  17. ↑ I. Maire, N. Guffon, R. Froissart: [Current development and usefulness of biomarkers for Gaucher disease follow up]. In: La Revue de médecine internal. Volume 28 Suppl 2, October 2007, pp. S187-S192, ISSN  0248-8663 . PMID 18228687 . (Review).