There is a considerable overlap of clinical features of distinct types of MPS, and they may be impossible to distinguish based on clinical findings alone. Furthermore, patients suffering from a certain type of MPS may present with subtle changes or severe alterations, so the spectrum of disease presentation is broad - even among those carrying defects of the same gene.

Most commonly, MPS induces mental disability, malformations of the skeletal system, and corneal clouding. Mental retardation may be accompanied by developmental delays and may become apparent in infancy; it may or may not progress throughout life. However, MPS patients may also be of normal intelligence. Malformations of the locomotor system may comprise, but are not limited to, short stature, short neck, lumbar kyphosis, scoliosis, pectus carinatum, genu valgum, and pes cavus [1]. In late stages of the disease, life-threatening spinal cord compression may occur, especially in those suffering from severe skeletal dysplasia [2] [3]. Many patients also have joint contractures. While they may present coarse facial features, the latter rarely prompt a diagnostic workup. Corneal clouding was mentioned as another symptom characteristic of MPS and may be associated with glaucoma, retinal degeneration, and optic nerve swelling with subsequent atrophy. These complications may result in visual impairment and even blindness [4].

Beyond neurological, orthopedic, and ophthalmological findings, macroglossia, tonsillar hypertrophy, otitis media and conductive hearing loss, upper airway obstruction, valvular heart disease, hepatosplenomegaly, and bowel dysfunction are frequently reported [4] [5].

Molecular biological analyses are the gold standard of MPS diagnosis and allow for a reliable identification of the type of the disease. However, diagnostic delays of several years are common. While lumbar kyphosis should definitely raise suspicion as to a lysosomal storage disease, most symptoms are non-specific if considered separately. Thus, MPS diagnostics are not usually carried out until the patient or their parents relate a complex medical history comprising several of the events described in the previous paragraph.

MPS diagnostics should include:

• Imaging studies. Skeletal anomalies are a clinical hallmark of MPS and should be evaluated to assess best treatment options and to prevent severe complications like spinal cord compression. Beyond the clinical findings described above, imaging often reveals macrocephaly, atlantoaxial dislocation, wedge-shaped vertebral bodies and platyspondyly, spatulate ribs, bullet-shaped metacarpals, as well as hypoplastic epiphyses and thickened diaphyses leading to hip dysplasia and deformities of other joints [1] [6]. Focal or diffuse white matter lesions, ventriculomegaly, communicating hydrocephalus, and eventually cerebral atrophy may be visualized by magnetic resonance imaging [6].
• Laboratory analyses of urine samples. The measurement of total glycosaminoglycans is usually followed by the separation of subfractions for qualitative analyses. The excretion pattern of urinary glycosaminoglycans allows for a tentative diagnosis of a specific type of MPS. In detail, patients suffering from MPS types 1 or 2 are likely to excrete abnormal amounts of heparan sulfate and dermatan sulfate. MPS type 3 is associated with an increased excretion of heparan sulfate, whereas MPS type 4 manifests in elevated concentrations of chondroitin 6-sulfate and keratan sulfate. While urine samples from MPS type 6 patients contain large amounts of dermatan sulfate, MPS type 7 is characterized by high urinary levels of heparan, dermatan, and chondroitin sulfate. Finally, MPS type 9 patients excrete hyaluronan [7].
• Before molecular biological tools became widely available, the activity of determined lysosomal enzymes was assessed in fibroblasts or leukocytes.
• Genetic studies to determine the underlying mutation [8].

MPS is considered potentially treatable with enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction therapy, or gene therapy [9]:

• With regard to the former, laronidase, idursulfase, and galsulfase have been approved for the treatment of MPS types 1, 2, and 6, respectively. These enzymes are effective in controlling somatic manifestations of MPS, but skeletal anomalies and valvular heart disease don't usually respond to this kind of therapy. Furthermore, neither of these recombinant human enzymes is able to cross the blood-brain-barrier, so MPS-related central nervous system disorders won't be alleviated either.
• Hematopoietic stem cells of a healthy donor are a life-long source of lysosomal enzymes. Due to morbidity and mortality associated with the procedure, hematopoietic stem cell transplantation is usually reserved for those suffering from severe MPS. It should also be noted that disease progression has been reported years after the successful transplantation of stem cells. In order to improve the outcome, the transplantation should be performed as early as possible, and the donor shouldn't be a carrier of MPS-related mutations [10].
• To date, substrate reduction and gene therapy remain in experimental stages. Substrate reduction therapy aims at limiting the formation of glycosaminoglycans, thereby reducing the necessity of enzymatic degradation. Promising results have been achieved in cell culture and animal models with rhodamine B and genistein. What's more, the latter has been used in small clinical trials and has been demonstrated to improve joint mobility [11]. Gene therapy of MPS has not yet been realized in men. However, vector-mediated gene transfer has been shown to mitigate peripheral and central symptoms and to prolong survival [9].

Beyond that symptomatic and supportive care should be provided according to the individual needs of the patient.

Severe MPS is usually fatal within the first two decades of life. If the disorder causes hydrops fetalis, stillbirth or death in the neonatal period is likely. Patients may also succumb to cardiac or respiratory failure, or fall into a vegetative state during later stages of life [9]. By contrast, mild forms of the disease are associated with near-to-normal life expectancy.

All types of MPS are monogenic disorders. In detail, they are triggered by pathogenic mutations of one of the genes encoding for lysosomal enzymes that are required for the degradation of glycosaminoglycans. Except for MPS type 2, all forms of MPS are inherited in an autosomal recessive manner. The gene related to MPS type 2 is located on the X chromosome, so this disease is classified as an X-linked metabolic disorder [5]. Mutations of the following genes have been associated with single types of MPS:

• MPS type 1 - IDUA, to be found on 4p16.3, encoding for α-L-iduronidase
• MPS type 2 - IDS, to be found on Xq28, encoding for iduronate 2-sulfatase
• MPS type 3 - SGSH, NAGLU, HGSNAT, or GNS, to be found on 17q25.3, 17q21.2, 8p11.21, and 12q14.3, encoding for N-sulfoglucosamine sulfohydrolase, N-acetyl-α-glucosaminidase, heparan-α-glucosaminide N-acetyltransferase, and N-acetylglucosamine-6-sulfatase, respectively
• MPS type 4 - GALNS or GLB1, to be found on 16q24.3 and 3p22.3, encoding for N-acetylgalactosamine-6-sulfatase and galactosidase β1, respectively
• MPS type 6 - ARSB, to be found on 5q14, encoding for arylsulfatase B
• MPS type 7 - GUSB, to be found on 7q11.21, encoding for glucuronidase β
• MPS type 9 - HYAL1, to be found on 3p21.31, encoding for hyaluronidase 1

The overall incidence of MPS has been estimated to be 1 in 25,000 life births [5] [6]. Still, the incidence rates vary greatly between distinct types of MPS. The most common type of MPS is MPS type 2, which may account for more than half of all cases [5]. The least common type of MPS is MPS type 9. This disease has been described by Natowicz et al. in 1996, and only four patients have been reported to date [12] [13] [14].

While both males and females may be affected by MPS, MPS type 2 is generally diagnosed in males. This is because the causal mutation is located on the X-chromosome. Nevertheless, heterozygous females have been described to present symptoms characteristic of this type of MPS [5].

Glycosaminoglycans are to found on the cell surface and in the extracellular matrix. They are involved in a myriad of physiological processes, e.g., in ligand-receptor interaction and cell proliferation. In the central nervous system, they are required as promoters of neurogenesis and enhancers of synaptic plasticity. Eventually, they are taken up by endocytosis or autophagy, and the respective vesicles fuse with lysosomes. Glycosaminoglycans may be recycled or degraded in lysosomes, namely be those enzymes that are deficient in MPS patients. Thus, undegraded or partially degraded substrates accumulate in the lysosomes, which initially causes the dysfunction of that organelle but eventually interferes with the function of the whole cell [9].

Via the bloodstream, poorly degraded glycosaminoglycans may reach virtually all tissues and organs. Therefore, all types of MPS are multisystem diseases, even though the activity of the affected enzyme is physiologically limited to determined types of cells [5]. Furthermore, glycosaminoglycans have been speculated to induce the secretion of cytokines, which may mediate degenerative joint disorders [9].

Genetic counseling should be offered to affected families, and they should be informed that both a child's genotype and phenotype can be determined prenatally. However, prenatal screens for MPS are not carried out on a routine basis and in the absence of a positive family history, parents may not be aware they carry a pathogenic mutation. Indeed, more than one-fifth of IDS mutations, which account for MPS type 2, are de novo mutations [8]. In this context, and because an early diagnosis is crucial for an optimum outcome, newborn screenings for MPS and other lysosomal storage diseases have been proposed in distinct countries, but no consensus has yet been reached on how to achieve high sensitivity, high specificity, and cost-effectiveness. While some authors prefer the assessment of enzyme activities [15], others favor the measurement of glycosaminoglycan concentrations in blood samples [16]. At the same time, costly follow-ups of false-positive cases have to be avoided [17].

MPS refers to a group of heterogeneous metabolic disorders. Affected individuals carry mutations of one of eleven genes that encode for lysosomal enzymes involved in the breakdown of glycosaminoglycans. Glycosaminoglycans are - usually highly sulfated - polysaccharides comprising disaccharide repeats, and they may also be referred to as mucopolysaccharides. The type of disaccharide to be found in glycosaminoglycans varies and is the basis of their classification as heparin sulfate/heparan sulfate, chondroitin sulfate/dermatan sulfate, keratan sulfate or non-sulfated hyaluronan. Glycosaminoglycans are part of the synovial fluid, the articular cartilage and bones, of heart valves, cornea and vitreous humor as well as mast cell granules, among others. In MPS patients, they progressively accumulate in the respective tissues but eventually reach the bloodstream and are excreted in urine. Therefore, additional tissues and distant organs are generally involved in the disease, and urine analyses are very useful in MPS diagnostics.

A total of seven types of MPS are distinguished to date, namely MPS types 1 to 9, except for types 5 and 8, which are no longer considered distinct entities. It should be noted that subtypes are differentiated in case of MPS type 1 (Scheie syndrome, Hurler Scheie syndrome, Hurler syndrome), MPS type 3 (Sanfilippo syndromes A to D), and MPS type 4 (types 4A and 4B, which are also referred to as Morquio A and Morquio B). MPS types 6 and 7 are also known as Maroteaux-Lamy syndrome and Sly syndrome, respectively. MPS type 9 is a rare entity that may also be referred to as Natowicz syndrome. All types of MPS have been associated with determined genetic defects, so molecular biological studies have become the gold standard for their diagnosis.

Mucopolysaccharidosis (MPS) is a general term referring to a group of hereditary disorders. The cells of MPS patients are unable to properly degrade glycosaminoglycans, compounds to be found in joints and bones, heart valves, ocular tissues and others. This is due pathogenic mutations of those genes that encode for the enzymes required for the breakdown of glycosaminoglycans. Consequently, glycosaminoglycans - which may also be referred to as mucopolysaccharides - accumulate within cells, reach the bloodstream, are distributed throughout the body, and interfere with the function of multiple tissues and organs.

The spectrum of disease presentation is broad. The clinical hallmarks of MPS are mental retardation, short stature and further anomalies of the skeleton, and visual impairment, but between individual patients, there are considerable differences regarding the symptoms and their severity. Thus, the diagnosis cannot be made based on clinical findings alone. Because glycosaminoglycans are excreted in urine, the analysis of urine samples is very useful in the workup of a suspected case. The tentative diagnosis can be confirmed once the activity of the deficient lysosomal enzyme is measured or the underlying mutation is determined.

Treatment options depend on the type of MPS. There are at least seven variants of the disease, and enzyme replacement therapy is available for only three of them. Patients suffering from severe MPS may undergo hematopoietic stem cell transplantation, but the procedure is associated with significant morbidity and mortality. New therapeutic approaches are substrate reduction therapy and gene therapy, but to date, they remain in the experimental stage. In sum, the prognosis of an individual patient largely depends on the severity of their disease: While those affected by mild MPS may have a near-to-normal life expectancy, severe MPS is often fatal before adulthood.

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