Deficiencies of Enzymes That Degrade Glycosaminoglycans Result in Mucopolysaccharidoses

Both exo- and endoglycosidases degrade GAGs. Like most other biomolecules, GAGs are subject to turnover, being both synthesized and degraded. In adult tissues, GAGs generally exhibit relatively slow turnover, their half-lives being days to weeks.

Understanding of the degradative pathways for GAGs, as in the case of glycoproteins (Chapter 47) and glycosphingolipids (Chapter 24), has been greatly aided by elucidation of the specific enzyme deficiencies that occur in certain inborn errors of metabolism. When GAGs are involved, these inborn errors are called mu-copolysaccharidoses (Table 48-7).

Degradation of GAGs is carried out by a battery of lysosomal hydrolases. These include certain endoglycosidases, various exoglycosidases, and sulfatases, generally acting in sequence to degrade the various GAGs. A number of them are indicated in Table 48-7.

The mucopolysaccharidoses share a common mechanism of causation, as illustrated in Figure 48-10. They are inherited in an autosomal recessive manner, with Hurler and Hunter syndromes being perhaps the most widely studied. None are common. In some cases, a family history of a mucopolysaccharidosis is obtained. Specific laboratory investigations of help in their diagnosis are urine testing for the presence of increased ch2oso-

LfoL

OSO-IdUA

LfoL

OH IdUA

HNSO-GlcN

OH GlcUA

Figure 48-9. Structure of heparin. The polymer section illustrates structural features typical of heparin; however, the sequence of variously substituted repeating disaccharide units has been arbitrarily selected. In addition, non-O-sulfated or 3-O-sulfated glucosamine residues may also occur. (Modified, redrawn, and reproduced, with permission, from Lindahl U et al: Structure and biosynthesis of heparin-like polysaccharides. Fed Proc 1977;36:19.)

HNSO-GlcN

OSO-IdUA

HNSO-GlcN

OH IdUA

HNSO-GlcN

OH GlcUA

HNAc GlcNAc

Figure 48-9. Structure of heparin. The polymer section illustrates structural features typical of heparin; however, the sequence of variously substituted repeating disaccharide units has been arbitrarily selected. In addition, non-O-sulfated or 3-O-sulfated glucosamine residues may also occur. (Modified, redrawn, and reproduced, with permission, from Lindahl U et al: Structure and biosynthesis of heparin-like polysaccharides. Fed Proc 1977;36:19.)

CHOSO

Table48-7. Biochemical defects and diagnostic tests in mucopolysaccharidoses (MPS) and mucolipidoses (ML).1

Alternative

Urinary

Name

Designation2,3

Enzymatic Defect

Metabolites

Mucopolysaccharidoses

Hurler, Scheie,

MPS I

a-l-Iduronidase

Dermatan sulfate, heparan sulfate

Hurler-Scheie

(MIM 252800)

Hunter (MIM 309900)

MPS II

Iduronate sulfatase

Dermatan sulfate, heparan sulfate

Sanfilippo A

MPS IIIA

Heparan sulfate N-sulfatase

Heparan sulfate

(MIM 252900)

(sulfamidase)

Sanfilippo B

MPS IIIB

a-N-Acetylglucosaminidase

Heparan sulfate

(MIM 252920)

Sanfilippo C

MPS IIIC

Acetyltransferase

Heparan sulfate

(MIM 252930)

Sanfilippo D

MPS IIID

N-Acetylglucosamine

Heparan sulfate

(MIM 252940)

6-sulfatase

Morquio A

MPS IVA

Galactosamine 6-sulfatase

Keratan sulfate, chondroitin 6-sulfate

(MIM 253000)

Morquio B

MPS IVB

P-Galactosidase

Keratan sulfate

(MIM 253010)

Maroteaux-Lamy

MPS VI

N-Acetylgalactosamine 4-

Dermatan sulfate

(MIM 253200)

sulfatase (arylsulfatase B)

Sly (MIM 253220)

MPS VII

P-Glucuronidase

Dermatan sulfate, heparan sulfate, chondroitin 4-sulfate, chondroitin 6-sulfate

Mucolipidoses

Sialidosis

M LI

Sialidase (neuraminidase)

Glycoprotein fragments

(MIM 256550)

I-cell disease

ML II

UDP-N-acetylglucosamine:

Glycoprotein fragments

(MIM 252500)

glycoprotein N-acetylglu-cosamininylphosphotrans-ferase. (Acid hydrolases thus lack phosphoman-nosyl residues.)

Pseudo-Hurler

ML III

As for ML II but deficiency

Glycoprotein fragments

polydystrophy

is incomplete

(MIM 252600)

'Modified and reproduced, with permission, from DiNatale P, Neufeld EF: The biochemical diagnosis of mucopolysaccharidoses, mucolipidoses and related disorders. In: Perspectives in Inherited Metabolic Diseases, vol 2. Barr B et al (editors). Editiones Ermes (Milan), 1979.

fibroblasts, leukocytes, tissues, amniotic fluid cells, or serum can be used for the assay of many of the above enzymes. Patients with these disorders exhibit a variety of clinical findings that may include cloudy corneas, mental retardation, stiff joints, cardiac abnormalities, hepatosplenomegaly, and short stature, depending on the specific disease and its severity.

3The term MPS V is no longer used. The existence of MPS VIII (suspected glucosamine 6-sulfatase deficiency: MIM 253230) has not been confirmed. At least one case of hyaluronidase deficiency (MPS IX; MIM 601492) has been reported.

amounts of GAGs and assays of suspected enzymes in white cells, fibroblasts, or sometimes in serum. In certain cases, a tissue biopsy is performed and the GAG that has accumulated can be determined by elec-trophoresis. DNA tests are increasingly available. Prenatal diagnosis can be made using amniotic cells or chorionic villus biopsy.

The term "mucolipidosis" was introduced to denote diseases that combined features common to both mucopolysaccharidoses and sphingolipidoses (Chapter 24). Three mucolipidoses are listed in Table 48-7. In sialidosis (mucolipidosis I, ML-I), various oligosaccha-rides derived from glycoproteins and certain ganglio-sides can accumulate in tissues. I-cell disease (ML-II)

Figure 48-10. Simplified scheme of causation of a mucopolysaccharidosis, such as Hurler syndrome (MIM 252800), in which the affected enzyme is a-L-iduroni-dase. Marked accumulation of the GAGs in the tissues mentioned in the figure could cause hepatomegaly, splenomegaly, disturbances of growth, coarse facies, and mental retardation, respectively.

Figure 48-10. Simplified scheme of causation of a mucopolysaccharidosis, such as Hurler syndrome (MIM 252800), in which the affected enzyme is a-L-iduroni-dase. Marked accumulation of the GAGs in the tissues mentioned in the figure could cause hepatomegaly, splenomegaly, disturbances of growth, coarse facies, and mental retardation, respectively.

and pseudo-Hurler polydystrophy (ML-III) are described in Chapter 47. The term "mucolipidosis" is retained because it is still in relatively widespread clinical usage, but it is not appropriate for these two latter diseases since the mechanism of their causation involves mislocation of certain lysosomal enzymes. Genetic defects of the catabolism of the oligosaccharide chains of glycoproteins (eg, mannosidosis, fucosidosis) are also described in Chapter 47. Most of these defects are characterized by increased excretion of various fragments of glycoproteins in the urine, which accumulate because of the metabolic block, as in the case of the mucolipi-doses.

Hyaluronidase is one important enzyme involved in the catabolism of both hyaluronic acid and chondro-itin sulfate. It is a widely distributed endoglycosidase that cleaves hexosaminidic linkages. From hyaluronic acid, the enzyme will generate a tetrasaccharide with the structure (GlcUA-P-1,3-GlcNAc-P-1,4)2, which can be degraded further by a P-glucuronidase and P-A-acetylhexosaminidase. Surprisingly, only one case of an apparent genetic deficiency of this enzyme appears to have been reported.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment