The Medical University of Vienna’s Susanne Gerit Kircher highlights the importance of providing multidisciplinary care to children and adults living with mucopolysaccharide storage diseases
Mucopolysaccharide storage diseases (MPS) are a group of rare, hereditary metabolic diseases. MPSs is an abbreviation for ‘muco-poly-saccharides’, which have a thick, jelly-like consistency of mucus consisting of many (‘poly’) sugars (‘saccharides’). The chemical name for them is acid glycosaminoglycans or GAGs. This name immediately implies that amino groups and acid sulfate groups are attached to the sugar chains. Usually we find these chemical substances in the connective tissue, where they are responsible for different properties of tissues and organs.
Understanding mucopolysaccharide storage diseases
It is easy to understand that bones, cartilage, tendons, joint surfaces, heart valves, and corneas require different properties and therefore have different compositions. However, in all instances the basic principle holds true that the tissue-specific cells are embedded in the so-called ‘extracellular matrix’, which is made of GAGs (or MPSs) in varying compositions.
Another important function of GAGs is on the surface of each cell forming a coat made of brush-like macromolecules, the so-called ‘glycocalyx’. In this case, GAG chains combined with proteins or lipids form little structures responsible for the interaction with the extracellular space or other neighboring cells. As GAGs (or MPSs) are present in all parts of the body, it is obvious that any disturbance in their metabolism has severe and widespread consequences. MPS disorders may involve many different tissues and organs, which is why they are also known as multi-systemic diseases.
Children inherit this disorder from healthy parents. One (in MPS type II) or two (in all other types) genetic defects (mutations) in one of the 12 known genes cause impaired function of the respective gene product, i.e. the proteins encoded by these genes. These proteins are enzymes, biological tools for cutting off different residues from GAG-chains.
Within the group of mucopolysaccharide storage diseases, 12 different enzymes are responsible for the stepwise degradation process of
GAG-chains. They remove sugars, amino groups, and sulfate groups in an ordered manner to recycle them for processes of GAG-chain biosynthesis or to prepare them for excretion as defective material from cells.
In MPS disorders, due to genetic defects, one of these enzymes has an altered protein chain and consequently lack of or severely decreased function. In connective tissue, there are 12 enzymes necessary for the breakdown of GAGs, and any damage in any single one of these 12 enzymes will lead to the accumulation of debris in organs, including bones and brain, which in turn results in severe bodily and intellectual disabilities.
Very rarely, several enzymes are defective at the same time, which causes a disease known as ‘multiple sulfatase deficiency’. This disease, however, is very severe, with clinical symptoms similar to mucopolysaccharide storage diseases. It is one of the diseases added to the group of MPS-related diseases such as alpha-mannosidosis, fucosidosis, sialidosis, mucolipidosis, and several others.
The enzymatic degradation process of GAG-chains takes place in lysosomes. These subcellular structures are vesicles full of enzymes in every cell of the body. Their job is to take care of old or defective components of the body via processes of elimination or recycling.
In MPS, the glycosaminoglycans of connective tissue cannot be broken down properly and remain within the lysosomes of cells. This causes cells and organs to swell up and lose function, and eventually leads to cell death. All types of MPS (numbered from I to IX) share this accumulation of material in lysosomes of every single cell, which hampers proper functioning of all metabolic processes located in the lysosomes. Usually, nothing seems out of the ordinary at birth, but the irreversible process of accumulation has already begun before birth – it is simply not yet evident. Although there is only one very specific causative enzyme defect in each of the MPS types, the clinical course is similar, and symptoms can be seen in many different organs.
MPS – a disease with many faces
The wide spectrum of symptoms and severity makes it difficult to diagnose MPS patients easily. No two patients are the same, even within one family. Regarding the predominant clinical symptoms, one can differentiate three groups:
- First, the group with storage predominantly in skin, brain, heart muscle and heart valves, liver, spleen and corneas, and many other organs, resulting in an increasing enlargement of liver, spleen, tongue, as well as cardiomyopathy or hydrocephalus. Additional symptoms are impaired heart valve function, constriction of airways and breathing problems, including apnoea, corneal clouding and optic nerve involvement, hearing loss, reduced mobility of joints, skeletal changes, and short stature (Fig. 1);
- In the second group of MPS types, skeletal and joint problems predominate, with short stature (even dwarfism), hyperlaxity of ligaments with hypermobility and instability of joints, especially the upper part of the cervical spine, thoracic deformation, and severe hip dysplasia. Skeletal changes seen in X-ray radiographs known as ‘dysostosis multiplex’ are very typical for MPS disorders (Fig. 2); and
- The third group is characterised primarily by impaired function of the cell-to-cell interaction in the central and vegetative nervous system, resulting in slowly progressive loss of all intellectual capabilities and motoric functions, including reflexes such as swallowing, coughing or breathing. These patients display a stepwise loss of all abilities they have ever acquired and need gastric tubes, sucking off mucus, supplementary oxygen, and 24/7 care.
Independent of MPS type, some of the severe symptoms can be observed in all patients. Alongside the specific skeletal changes, a small or completely missing dens of the second vertebral body can often be seen, which leads to instability of the cervical spine and danger of paraplegia. Storage of GAGs in the brain or membranes around the brain and spinal cord results in increased brain pressure or myelopathy. Some patients may develop epileptic seizures.
MPS types with neuronopathic clinical course
Not all MPS patients show a neurological affectation, but those who suffer from neuronopathic symptoms show a reversal of the milestones in development. Children with neurological affectation become increasingly difficult to reach as they seem more and more to live in a different world. They will communicate less, fail to understand what they are told, and forget all they have ever learned.
This process develops very slowly and leads to many misunderstandings and misinterpretations. Due to hyperactivity and restlessness, parents are often told that they are unable to bring up their child properly. Very cruel of MPS is the observation that children forget how to speak, walk, and, later, swallow, cough or breathe. As if physical disabilities were not harsh enough, life-threatening situations may occur: choking fits, cramping fits, and sleep apnoea (Fig. 3).
Frequently one of the parents spends all their time taking care of the child, to feed it by feeding tube, to suck off the continuously accumulating mucus in the airways that makes breathing so difficult, and to supply oxygen. Care will become necessary day and night and changes the life of a family in a disadvantageous manner. Partnerships can break up due to the enormous demands on the parents of a child with MPS.
MPS – a multisystemic disease
Mucopolysaccharidoses are chronic, progressive diseases, with frequently prevalent problems in the musculoskeletal system. As GAGs are main components of bone and cartilage, ligaments, tendons and joint capsules, typical symptoms include joint stiffness or abnormal laxity, contractures, hip dysplasia, genua valga, feet deformities, kyphoscoliosis, carpal tunnel syndrome, trigger finger, and growth retardation. All these symptoms worsen over time, and surgical intervention may be inevitable to preserve as much mobility of the patient as possible.
Due to the many organs involved in this disease, such as narrowing of airways or heart problems, any operation has a high risk of complications during anaesthesia. These complications include apnoea and may lead to tracheostomy, which has a lasting impact on the patient’s life. It is therefore necessary to very carefully evaluate the risks and benefits of any surgical intervention and perform them in a setting where care by a multidisciplinary team is available.
Many MPS patients have sleep abnormalities and respiratory problems, including sleep apnoea. In this case an oxygen mask (CPAP) can prevent further harmful consequences, but enlarged tonsils and adenoids as well as swollen mucous membranes might narrow respiratory airways. Due to abnormalities of facial bones, causing a small nose or a deep base of the nose, masks must be adjusted very carefully and individually. This single problem is but one example of why the inclusion of different medical specialists is necessary.
Some patients show severe disturbances in circadian rhythm, which results in hyperactivity during the night. This has very stressful consequences for both patients and family members or carers. Treatment with medications typically used in such situations may show unwanted side effects in MPS patients, or effects different from those expected. Again, appropriate medical and behavioural interventions from different medical disciplines are required.
MPS – the need for multidisciplinary management
MPS patients necessitate a multidisciplinary approach in both medical and care management, which is available in most paediatric departments, especially those experienced in inborn metabolic diseases. Due to new therapies – such as haematopoietic stem cell transplantation, enzyme replacement therapy, and life-saving operations – many patients have an increased life span and reach adulthood.
Adult medicine includes many different disciplines that individually cannot cover the needs of MPS patients who suffer multi-organ involvement. Once patients leave the paediatric setting, medical and care management usually take a turn for the worse as they reach adulthood. In this new setting, they would need to see many different medical specialists, which is especially daunting for physically and mentally disturbed patients. Unfortunately, despite efforts to improve the transition from paediatric to adult medicine, sufficient and satisfying care and treatment of adult patients cannot yet be guaranteed in many parts of Europe.
About the authors
Susanne Kircher is the co-founder and honorary member of the Austrian and German MPS societies. Her book, Mucopolysaccharidoses – A Guide for Physicians and Parents, has been published in several languages and editions. In 2016 she was awarded with the International Scientific Award of the International MPS Working Party.
Center of Pathobiochemistry and Genetics
Lysosomal Screening Unit
Medical University of Vienna
Währingerstrasse 10, 1090 Vienna, Austria
Thomas Taylor was a colleague of Susanne Kircher for years in the Genetic Counselling Unit at the Medical University of Vienna, before beginning work at a Viennese hospital.
Mag Dr Thomas Taylor
Sozialmedizinisches Zentrum Ost – Donauspital
Langobardenstraße 122, 1220 Vienna, Austria