• glycopathology



Mucopolysaccharidosis is a group of genetic diseases caused by an inherited defect in the metabolic enzymes of glycosaminoglycans (1-4). Hindrance of normal degradation of glycosaminoglycans leads to their accumulation in the body. It is a heterogeneous subgroup of lysosomal diseases (lysosomal storage disorders). Since glycosaminoglycans used to be called mucopolysaccharides, this disease was named mucopolysaccharidosis. Glycosaminoglycan oligosaccharides excreted in urine can be utilized for the diagnosis of this disease, and it also used to be called mucopolysacchariduria.

The degradative pathway of glycosaminoglycans inside cells proceeds as follows (see “Degradation of Glycosaminoglycans”): Glycosaminoglycans or proteoglycans are internalized by endocytosis, and cleaved by endo-type hydrolases in endosomes or early lysosomes, to transform a long polymer into shorter oligosaccharides. Then, they are degraded to monosaccharide units by exo-type hydrolases sequentially from the nonreducing ends within lysosomes. Each exo-enzyme in lysosomes can act on its substrate located only at the nonreducing end of the oligosaccharide. If one of the exo-enzymes is deficient, the degradation process cannot proceed and pauses at that step, leading to the accumulation of oligosaccharides with the same nonreducing terminal structure. This abnormal accumulation causes damage to cells, and symptoms of mucopolysaccharidoses appear. Mucopolysaccharidosis from type I to IX has been reported. The deficient enzyme as well as stored substrates in each disease are summarized in Table 1.

Mucopolysaccharidosis type I includes three subtypes: Hurler, Scheie, and Hurler-Scheie (medium type) syndromes, which are named after their discoverers. The severity of this disease depends on the mutation site in the causative gene encoding the enzyme, α-iduronidase. Symptoms of Hurler syndrome are severer than those of Scheie syndrome. Scheie syndrome used to be called mucopolysaccharidosis type V. Mucopolysaccharidosis type II caused by mutation of the gene encoding iduronate-2-sulfatase, is also called Hunter syndrome, which is classified into severe and mild forms depending on the residual enzyme activity. Mucopolysaccharidosis type III is also known as Sanfilippo syndrome, characterized by the accumulation of heparan sulfate oligosaccharides because of defects in enzymes responsible for its degradation. Mucopolysaccharidosis type III includes four subtypes: A to D, differing in their causative enzymes. Mucopolysaccharidosis type IV, Morquio syndrome, is characterized by the accumulation of keratan sulfate oligosaccharides. It is caused by mutations in genes coding for galactose-6-sulfatase and β-galactosidase, and classified into two subtypes: IVA and IVB. Since galactose-6-sulfatase is the same molecule as N-acetylgalactosamine-6-sulfatase, which is responsible for the degradation of chondroitin sulfate, the accumulation of chondroitin sulfate oligosaccharides also occurs in patients with mucopolysaccharidosis type IVA. Mucopolysaccharidoses type V and type VIII are missing under the present classification. Mucopolysaccharidosis type VI, known as Maroteaux-Lamy syndrome, is caused by mutations in the gene encoding the enzyme N-acetylgalactosamine-4-sulfatase. Mutations in the gene coding for β-glucuronidase causes mucopolysaccharidosis type VII, Sly syndrome. Reports of mucopolysaccharidosis type IX are very few and its symptoms are mild, caused by mutations of the gene encoding endo-type hyaluronan/chondroitin sulfate-degrading enzyme, hyaluronidase 1.

Major symptoms of mucopolysaccharidoses are summarized in Table 1. Skeletal abnormalities are commonly found. This may be related to the fact that glycosaminoglycans are major components of cartilage and that they play important roles in bone development. Severe mental retardation is characteristically found in patients with some mucopolysaccharidoses involving the accumulation of heparan sulfate.

The most successful therapeutic approach to mucopolysaccharidoses at present is enzyme replacement therapy. However, this treatment has some limitations that need to be taken into account. The cost of this medical treatment is very expensive, the enzyme often needs to be injected into patients, enzyme proteins are hardly delivered to some organs including the brain, heart, and bone, and antibodies against the injected enzyme are raised. Alternative approaches to treat this disease are developing. Substrate reduction therapy inhibits the biosynthetic enzymes of glycosaminoglycans to reduce the substrates of the lysosome enzymes. Pharmacological chaperon therapy helps the mutated enzyme proteins to adopt their correct steric conformation to restore enzyme activity. Hematopoietic stem cell transplantation and gene therapy are under evaluation. None of these approaches supersede enzyme replacement therapy, but they could be potential alternatives.

Table 1. Mucopolysaccharidoses (MPS)

Type Eponym Enzyme deficiency Stored substrates Clinical
MPS type I Hurler α-Iduronidase HS, DS Severe mental retardation, coarsening of facial features, hepatosplenomegaly, skeletal deformities, articular contracture, cloudy corneas, hearing loss, short stature
Scheie Joint stiffness, cloudy corneas
MPS type II
(X-linked recessive inheritance)
Hunter Iduronate-2-sulfatase HS, DS (Severe form) severe mental retardation, coarsening of facial features, hepatosplenomegaly, skeletal deformities
(Mild form) articular contracture
MPS type IIISanfiloppoHS Mild somatic manifestations.
Severe mental retardation
MPS type IVMorquioShort stature, skeletal deformities, cloudy corneas
AGalactose-6-sulfataseKS, CS
MPS type VI Maroteaux - Lamy N-Acetylgalactosamine-4-sulfatase DS Skeletal deformities, cloudy corneas, hepatosplenomegaly, cardiac disease
MPS type VII Sly β-Glucuronidase HS, CS, DS Skeletal deformities, cloudy corneas, mental retardation
MPS type IX Hyaluronidase-1 HA Mild short stature

HS, heparan sulfate; DS, dermatan sulfate; KS, keratan sulfate; CS, chondroitin sulfate; HA, hyaluronan

Shuhei Yamada
(Faculty of Pharmacy, Meijo University)

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(3) Sun A: Lysosomal storage disease overview. Ann. Transl. Med. 6, 476, 2018
(4) Leal AF, Benincore-Flórez E, Rintz E, Herreño-Pachón AM, Celik B, Ago Y, Alméciga-Díaz CJ, Tomatsu S: Mucopolysaccharidoses: cellular consequences of glycosaminoglycans accumulation and potential targets. Int. J. Mol. Sci. 24, 477, 202

Jun. 15, 2023

glycoword index