Mucopolysaccharidoses (MPS) belong to the group of lysosomal storage diseases . They are based on inheritable disorders of the enzymatic breakdown of the acidic mucopolysaccharides ( glycosaminoglycans ) by lysosomal hydrolases . The non-degraded glycosaminoglycans are stored in the lysosomes. This ultimately leads to disorders of the cellular metabolism and, in severe cases, to cell death. Tissues of the skeletal system , the central nervous system , visceral organs, the skin and the inner lining of the heart are particularly affected .
There are four types of glycosaminoglycans stored. Depending on the different distribution pattern and according to clinical criteria, different main forms of mucopolysaccharidoses can be distinguished, which in turn are divided into different subtypes .
These subtypes describe either different clinical appearances of the same enzyme defect (e.g. mild and severe forms of Hunter's disease ) or different biochemical defects of a clinical appearance (e.g. Morquio A and B).
Almost all types have severe and mild (attenuated) forms. An assignment is only possible through the clinical course and the speed with which the disease is progressing.
There are currently seven types, with known mutations in eleven different enzymes:
|Hurler's disease (also Hurler-Pfaundler syndrome)
|Facial dysmorphism (gargoylism), cognitive retardation , skeletal malformation ( dysostosis ; kyphosis / gibbus), corneal opacity, short stature , hernias , hepatomegaly , heart valve defects
|not mentally impaired, hernias , joint contractures , skeletal malformation ( dysostosis ), corneal opacity, heart valve defects
IH / S
|Hurler / Scheie variant
|mentally between IH and IS, hernias, facial dysmorphia, corneal opacity, hepatomegaly, heart valve defects
|moderate cognitive retardation, skeletal malformation ( dysostosis ), significant somatic changes, early deafness
|Iduronate 2 sulfatase
|Cognitive retardation, dysmorphism , corneal opacity may be absent, often hearing loss, rapid progress
|Heparan sulfate sulfamidase
|Acetyl-CoA : α-glucosaminide-N-acetyltransferase
|usual cognitive development, skeletal malformation ( dysostosis ) very pronounced, corneal opacity
|similar to type A, but with a milder course
|now: IS type, like that
|Usual cognitive development, severe skeletal malformation ( dysostosis ), corneal opacity, short stature
|moderate dysmorphism and skeletal malformations, corneal opacity, normal to limited intelligence
|Short stature, periarticular soft tissue swelling
After it turned out that the original type V affected the same enzyme as type I, but with a significantly slower course, it was assigned as type IS ( Scheie disease ) to type MPS I and the number was not reassigned in the following.
A Type VIII was also originally described. In 1978 a research group led by N. DiFerrante found a five-year-old boy with a deficiency of the enzyme N-acetylglucosamine-6-sulfate sulfatase . However, in 1980 the working group had to report that this enzyme was normally present and that it was presumably fraudulent . It withdrew the previous publications, but a Type VIII was no longer reassigned either.
Symptoms vary depending on the type of mucopolysaccharidosis. At birth, the children are initially normal. Almost all types involve involvement of the skeleton and corresponding deformation of the bones, shortening of the tendons and ligaments in the joints ( contractures ), short stature and coarsened facial features. The storage also usually leads to a pronounced enlargement of the liver ( hepatomegaly ). Depending on the type, there is a progressive decline in mental abilities. The cornea can become cloudy and numb . Many children with mucopolysaccharidosis have abdominal wall and umbilical hernias and frequently recurring respiratory infections .
The diagnosis is first made by detecting an increased excretion of glycosaminoglycans in the urine . The increase in types III and IV is sometimes so small that rough search tests can be inconspicuous here. With a corresponding excretion pattern, a determination of the activity of the corresponding enzyme in white blood cells ( leukocytes ) or in fibroblasts , also as a simple dry blood test, can confirm the suspicion.
A dry blood test (Dried Blood Spot, DBS) that can be easily integrated into everyday practice is available both for measuring enzyme activity and 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 genetic analysis, the gene with the missing enzyme 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.
Since these are congenital, hereditary diseases, causal therapy has not yet been possible, although there are also research approaches for gene therapy for mucopolysaccharidoses . For some types there is enzyme replacement therapy with iduronidase , which can be used with proven benefit if it begins before the onset of symptoms. Patients with certain types can also benefit from timely stem cell transplantation because the transferred blood cells do not carry the enzyme defect and can take over the breakdown of glycosaminoglycans.
In 2003, Laronidase (trade name: Aldurazyme) was approved as a long-term enzyme replacement therapy for MPS-I patients for the treatment of non-neurological manifestations.
In June 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) approved vestronidase alfa (trade name: Mepsevii ; manufacturer: Ultragenyx ) as an enzyme replacement therapy in exceptional circumstances for the treatment of non-neurological manifestations of mucopolysaccharidosis VII (MPS VII ; Sly syndrome ) recommended for Europe. As a rule, such a positive vote is followed by approval for the European member states by the European Commission . Mepsevii was approved by the US Food and Drug Administration (FDA) back in November 2017 for the treatment of children and adults with MPS VII.
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- European Medicine Agency: Summary of Product Characteristics. In: European Medicine Agency. Accessed January 31, 2019 .
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- Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) June 25-28, 2018 , EMA press release of June 29, 2018, accessed on July 2, 2018
- Positive CHMP recommendation for Mepsevii® as the first drug for the treatment of mucopolysaccharidosis type VII , Ultragenyx press release of June 29, 2018, accessed on July 13, 2018