From Big Medical Encyclopedia

GLIKOZIDOZA (a glycoside[s] + - osis) — big group of hereditary diseases which reason partial insufficiency or total absence of any enzyme relating to glikozidaza, or one of its forms is.

Were described by clinical physicians long before the molecular mechanisms which are the cornerstone of their pathogeny became known. In 1881 the English oculist of W. Tay, and in 1887 an amer. the neuropathologist Saks (V. of P. Sachs) heavy disturbances of a nervous system at children for the first time described. The disease received the name of a disease Teja — Saks (see. Amaurotic idiocy ). A little later rather rare and earlier unknown diseases and syndromes which were called on surnames of the doctors who for the first time described them were described: diseases to Gosha (see. to Gosha disease ), Fabri (see. Fabri disease ), syndromes Gurler and Gunter (see. Gargoilizm ), etc. Disturbances from a nervous system were characteristic of them, mental retardation, the changes of muscular and bone systems and other disturbances which are often leading to the death of patients at rather early age.

Interpretation of molecular bases of these diseases and bonds of their pathogeny with anomalies lysosomic glikozidaz (the general name of the enzymes catalyzing hydrolytic decomposition of glycosidic linkages) was begun only in 60 — 70 20 century. It became known that as a result of a genetic disorder at absence or insufficiency of any glikozidaza in a cell the lysosomes filled with not split substrate of the corresponding glikozidazny reaction find. For this reason the hereditary G. resulting from genetic defect any glikozidaz are called still diseases of accumulation or lysosomic diseases.

Distinguish four the main G.'s sign: the disease is a disease of accumulation; the accumulated connections are always localized in lysosomes; these connections can be homogeneous or heterogeneous depending on specificity of the absent enzyme; at G. genetic defect only on one enzyme is observed. The picture similar about a wedge, a picture G., can be observed at various euzymatic defects and vice versa: various patol, the phenomena can be caused by lack of the same enzyme. To establish the diagnosis of a disease on the basis only a wedge, data it is quite difficult. Only enzimol, diagnosis in combination with allocation and establishment of a structure of the collecting products can give the answer about

G. G.'s nature hl are inherited. obr. on autosomal recessively type. The exception of this mode of inheritance is made only by two G. — mukopolisakharidoz type II (Gunter's syndrome) and a glycolipidosis (Fabri's disease). At these diseases genetic defect is connected with X-chromosome.

One of the main and most difficult problems connected with G. is clarification of the exact nature of the genetic defect which is a cause of illness. Thanks to development of methods of hybridization of cells the first data on chromosomal localization of structural genes of some glikozidaz are received: beta D - glucuronidases, beta D - galactosidases, alpha D - mannozidazy, etc. However still at one of G. those changes of molecule DNA which lead to development of this or that are not found out yet. These changes can concern various funkts, sites operon (see), enzyme, responsible for synthesis. Except these changes, primary genetic defect can consist in damage of system of replication, system of a transcription, system of broadcasting, system of processing. Therefore the variety of changes of enzymatic activity at is clear.

Mutation (see) can result in total absence of enzyme owing to deletions (see) the respective site of DNA, to reduction in the rate of synthesis of this enzyme as a result of change of a regulator gene, and also to change physical. - chemical and catalytic properties of enzyme at damage of a structural gene.

At such situation at different individuals at genetic inferiority on the same enzymatic activity the disease will be shown absolutely various a wedge, a picture. Diseases Gurler and Sheye can be an example of it (see. Sheye disease ). At that and other disease activity of a - L is considerably reduced - I go - ronidazy. However the syndrome Gurler proceeds as the heaviest mukopolisakharidoz (children perish in several years), and Sheye's disease different from a syndrome Gurler phenotypical, proceeds much easier. Comparison of structure of defective enzyme at these two diseases allows to explain why such distinctions are observed. In some cases in an organism inactive molecules of enzyme are synthesized immunological full, but catalystically. Also the return picture when a part of catalytic activity of defective enzyme remains, and immunol is possible, by methods defective enzyme is not found.

One more important feature of G. is the chemical reorganization of fabric connected with accumulation of products of which is normal in this fabric do not find. So, in a cornea of an eye of healthy people there is no der-matansulfat, at the same time at some types of mukopolisakharidoz in it find significant amounts of a dermatansulfat. Normal in tissue of a brain there are only galaktotserebrozida, and at Krabbe's disease (see. Leukodystrophy ) from globoidal cells of gray and white matter of a brain, except the galaktotserebrozid collecting at this disease, glucocerebrosides are emitted. At a fukozidoza not only fukozosoderzhashchy connections, but also abnormal glycolipids, usual on a structure, as a part of which carbohydrate part the fukoza, as a rule, does not meet collect.

These examples demonstrate that emergence of connections which in this fabric normal are not found can not always be explained with insufficiency of a certain splitting enzyme. It is possible to assume that at disturbances of processes of disintegration of uglevodsoderzhashchy connections and substantial increase in a cell of their concentration of a glikoziltransferaza atypical acceptors with formation of new molecules are capable to glikozilirovat.

Often at G. in case of insufficiency of one of glikozidaz increase in activity of some other enzymes is observed. Fukozidoz is followed by increase in activity of an alpha galactosidase — more than by 7 times, beta ksilozidaza — by 6 times and a-glucosidases — almost by 5 times. Much the increased general activity of lysosomic enzymes often serves as justification for searches of insufficiency of one of glikozidaz.

Depending on the nature of the accumulated connections distinguish G. called mukopolisakharidozam (see), glycolipidoses, mukolipidoza and glikoproteidoza. Such division of G. in a nek-swarm of degree is conditional since owing to wide substrate specificity (heterocatalytic properties) glikozidaz at G. of this or that type uglevodsoderzhashchy connections of various nature usually collect.

Mukopolisakharidoza are characterized patol, accumulation of glikozaminoglikan in various bodies and sharp increase in their removal with urine. If normal at the person with urine it is allocated apprx. 15 mg of glikozaminoglikan a day, then at mukopolisakharidoza their quantity reaches 100 mg and more.

Insufficiency alpha L - iduronosulfatsulfatazy leads to Gunter's syndrome (mukopolisakharidoz the II type). In the absence of alpha L - iduronidazy develop diseases Gurler and Sheye, absence leads N-atsetilgalaktozaminsul-fatsulfatazy (arylsulphatases B) to a course of a disease of Maroto — Lamy (see. Maroto — Lamy a disease ), genetic insufficiency of geparansulfat-sulphatase, N - acetyl - alpha D - glyukozaminidazy and alpha glyukozaminidazy is the reason of diseases of Sanfilippo And, In and With respectively (see. Sanfilippo disease ). The block of beta glucuronidase (see. Glucuronidase ) causes corresponding mukopolisakharidoz and, at last, insufficiency хондроитинсульфат-N-ацетилгексозоаминсульфатазы leads to a course of a disease of Morkio (see. Morkio disease ).


concern To this big group G. diseases at which there is a disturbance of disintegration of a carbohydrate component glycolipids (see). In a human body and animals the most widespread glycolipids are representatives of sfingoglikolipid: cerebrosides (tseramidmonogeksozid), sulfatides (sulfates of cerebrosides), the tseramidolipoglikozida incorporating more than one carbohydrate rest, and gangliosides which carbohydrate chain contains sialine to - you; such glycolipidoses call gangliozidozam.

Glikozidaza which insufficiency leads to development of various glycolipidoses among which gangliozidoza are especially widespread are listed in the table. A wedge, manifestations of gangliozidoz are similar and are characterized by the progressing lag in intellectual and physical. development. Children are born externally healthy, but in 6 months, and sometimes and in 3 — 4 lose ability to sit and stand, become sluggish, do not react to a surrounding situation, gradually lose hearing and sight, become completely motionless. Swallowing at such patients is broken, it is necessary to feed them via the probe. Patients perish at the age of 3 — 6 years, is frequent from the accompanying infections.


several types of gangliozidoz Are known.

Disease Teja — the Saxophone (Gm2-gangliozidoz I of type) — the most often meeting gangliozidoz. Definition of a disease Teja — the Saxophone as G. became possible after in a brain of patients with this disease substantial increase (by 100 — 300 times in comparison with norm) quantities of Gm2-gangliosides and lack of the A-isoenzyme of N-atsetilgeksozaminidazy participating in splitting of gangliosides was revealed. Activity of other form of enzyme — N-atsetilgeksozaminidazy B — in the same case was considerably increased. It was established that only the geksozaminidaza And is capable to chip off from a Gm2-ganglioside N-acetyl galaktozamin. Substrate for a geksozaminidaza In is deprived neuraminic to - you are the Gm2-ganglioside split geksozaminidazy And. The reasons of accumulation of a Gm2-ganglioside at a disease Teja — the Saxophone are not clear since activity of a neuraminidase in a brain at this disease does not change. Assume that key enzyme in the Gm2_gangliozida transformation is the geksozaminidaza And, at presence the cut substantially raises efficiency of action of a neuraminidase on a Gm2-ganglioside. Activity of a geksozaminidaza And is stimulated in presence of the specific thermostable proteinaceous activator.

Detailed studying of activity geksozaminidaz showed that at a disease Teja — the Saxophone there can be various combinations in the level of activity of both enzymes. At so-called zero option of this disease — Sandgoff's disease (Gm2-gangliozidoz II of type) in tissues of patients does not have activity of a geksozaminidaza And yes Century. At option B there is no activity of a geksozaminidaza And. The option of AV is characterized by increase in activity of both enzymes at hydrolytic decomposition of synthetic substrate, however in tissue of a brain the quantity of a Gm2-ganglioside considerably increases that demonstrates change of substrate specificity of one or both geksozaminidaz in relation to natural substrate.

Cases of insufficiency of a geksozaminidaza at healthy people whose members of families have a disease Teja — the Saxophone are described. Appeared also this about absence geksozaminidaz And yes In at adults without any a wedge, manifestations of gangliozidoz and about atypical option of a disease Teja — the Saxophone,

Krom of a disease of Sandgoff which is characterized by absence N-atsetilgeksozaminidazy B., distinguish: youthful GM2 ганглиозидоз, characterized by reduction of activity of a geksozaminidaza And, and two gangliozidoz connected with disturbance of metabolism of a Gm1-ganglioside — generalized GM1 ганглиозидоз and youthful Gm1-gangliozidoz. Three forms of a beta galactosidase are not at generalized Gm1-gangliozidoz (And, In and C), participating normal in splitting of a GMt-ganglioside.

Youthful Gm1-gangliozidoz is characterized by considerable decrease of the activity In - and S-forms of a beta galactosidase. As disintegration of a Gm1-ganglioside under the influence of various forms of a beta galactosidase is carried out, remains still unknown. However it is shown that for hydrolysis of a Gm1-ganglioside of one of forms of a beta galactosidase as well as for a geksozaminidaza And, the specific thermostable proteinaceous factor is necessary.

Ideas of the mechanism of development of gangliozidoz were connected with deficit of the gangliosides defined glikozidaz, participating in disintegration. However there were data on new type of a gangliozidoz which, most likely, develops as a result of disturbance of biosynthesis of gangliosides. This gangliozidoz was characterized by accumulation in a liver and a brain of a gematozid (Gm3-ganglioside) and a Gd3-ganglioside at considerable decrease of the activity of N-of atsetilgalaktozaminil-transferase.

Fabri's disease — the only thing among glycolipidoses a hereditary disease, at Krom genetic defect is connected with X-chromosome. Gemizigotny sick (men) have skin diseases like angiokeratoma, extremity pains, peripheral hypostases, renal failures owing to which the disease at mature age comes to an end with death. At heterozygous sick (women) the disease proceeds more easily. At Fabri's disease in fabrics, fibroblasts and leukocytes of patients a large number of a tseramidtrigeksozid who is removed with urine collects. The disease develops as a result of absence tseramidtrigeksozid - alpha galactosidases And, chipping off the trailer galaktozilny rest in a molecule of a tseramidtrigeksozid. Deficit of this enzyme never happens full, and its residual activity makes 10 — 20% of total activity. Normal in leukocytes and fibroblasts of the person this enzyme exists in two forms: And (80 — 90%) and In (10 — 20%). At Fabri's disease there is no A-form, and the V-form tseramidtrigeksozid - alpha galactosidases And probably does not chip off a galactose from a tseramidtrigeksozid.

Disease to Gosha. Existence of various forms of a disease to Gosha, perhaps, is result of different mutations in same (or similar) a genetic locus. A key product of accumulation at a disease to Gosha is tseramidglyukozid (glucocerebroside) which collects in reticuloendothelial cells. Accumulation of this product leads to emergence in cells (so-called cells to Gosha) the numerous deposits having the glycolipidic nature. At this disease there is no acid betv-glucosidase (glyukotsereb-rozidaza), the optimum of activity a cut is at pH 4,0. Activity of other form of beta glucosidase with an optimum of activity at pH 5,0 at a disease to Gosha almost does not change (see. Glucosidases ).

In experiences of in vitro the possibility of reconstruction of «sick» enzyme was established. The essence of this phenomenon is that normal the molecule of beta glucosidase consists of two parts (factors). One of them which received the name of a factor With (English control), was found in healthy people in the beginning. At people with a disease to Gosha this factor is absent, but other factor — P (English patient) was found in them. The factor With termolabilen, is connected with fraction of lipoproteidny membranes of lysosomes, the pier is characterized. it is powerful (weighing) 200 000 and 2% of residual activity of beta glucosidase possess; thereof the factor With received the name of catalytic protein. The cleared factor of P was extremely thermostable water-soluble glycoprotein of cytosol about a pier. it is powerful (weighing) less than 20 000 (see. Glycoproteins ). He had no beta glyukozidaznoy activity at all and received the name of effector protein. During the mixing of both factors at pH 4,0 and 37 ° in 30 min. there is a full reconstruction of beta glucosidase.

As a result of the researches conducted in the second half of the 70th of 20 century it is shown that in a normal cell «start» beta glyukozidaznoy systems happens in the presence of three components: the catalytic protein connected with a lysosomic membrane (a factor C), cytoplasmatic effector protein (a factor P) and a lipidic membrane or its phospholipidic component — phosphatidylserine. At a disease to Gosha, apparently, there is an insufficiency of a factor S.

Odnim from unresolved questions at a disease to Gosha lack of accumulation of a tseramidglyukozid in tissue of a brain where intensively there is a disintegration of gangliosides is. It is known that tseramidglyukozid is a structural component of these connections. Therefore at insufficiency of beta glucosidase it would have to collect.

It is supposed that disintegration of the «free» and «connected» tseramidglyukozid (which is formed at consecutive degradation of gangliosides) is catalyzed by various fermental systems. One of these systems catalyzes hydrolysis of the «free» tseramidglyukozid which is synthesized preferential in a liver, a spleen, marrow and is acid beta glucosidase, insufficiency a cut causes a disease to Gosha. Other fermental system enters the multifermental complex connected with cellular membranes which is carrying out splitting of complex glycolipids which structural component is tseramidglyukozid. Activity of the beta glucosidase entering this multifermental complex does not change at a disease to Gosha, than and lack of accumulation of a tseramidglyukozid in nervous tissue at disintegration of glycolipids speaks.

Krabbe's disease (a globoidal leukodystrophy) — a disease of a nervous system with the progressing heavy disturbances of motor functions and intelligence. Children seldom live up to two years. Morfol, changes are observed in white matter of a brain, in Krom find numerous globoidal cells. They are formed as a result of accumulation of a tseramidgalaktozid (galaktotserebrozid) in the absence of a beta galactosidase (tseramidgalaktozidaza).


On a wedge, this disease reminds a picture mukopolisakharidoza and glycolipidoses. However at a mukolipidoza the volume of internals can not increase, the amount of mucopolysaccharides in urine most often are normal. In the fibroblasts received from patients numerous cytoplasmic inclusions which at a submicroscopy were identified as the lysosomes filled with undigested fragments of subcellular membranes are observed. It formed the basis to call mukolipidoz I (English inclusion inclusion) a cellular disease (cell disease). In fibroblasts of patients mukolipidozy, except acid phosphatase and beta glucosidase which activity did not change, substantially (to 80 — 90%) activity of many lysosomic hydrolases decreases: arylsulphatases A, beta galactosidases, beta glucuronidases, N-atsetilgeksozaminidazy, alpha L - fukozidazy, etc. At the same time activity of these enzymes several times increases in cultural liquid, in a cut the culture of fibroblasts was grown up. It turned out that hydrolases of patients mukolipidozy differ from normal enzymes in the lowered ability to get and keep in fibroblasts, scarce on this or that hydrolase. So, fibroblasts from patients with total absence of N-atsetilgeksozaminidaznoy of activity absorbed the N-atsetilgeksozaminida-storage of normal cells much quicker, than the same enzyme received from fibroblasts of patients mukolipidozy. It is supposed that at a mukolipidoza the carbohydrate part of a molecule of hydrolase responsible for «recognition» enzyme a cell and the subsequent deduction of enzyme in in lysosomes changes.

Glikoproteidoza arise at disturbances of disintegration of glycoproteins. Among glikoproteidoz are known fukozidoz — full or partial insufficiency alpha to L - fukozidazy or one of its forms (see. Fukoza ), mannozidoz — insufficiency And - and V-forms alpha D - mannozidazy (see. Mannose ) and an aspartilglyukozaminuriya — insufficiency beta D - aspartilglyukozaminidazy.

Existence of one more type of a glikoproteidoz — the sialidosis which is followed by decrease of the activity of a neuraminidase and emergence in urine of such patients of a large amount of the oligosaccharides containing is supposed sialic acids (see).


In biochemical, G.'s diagnosis great success is achieved. The existing highly sensitive methods of definition of activity glikozidaz in an amniotic fluid, a blood plasma, leukocytes, in culture of fibroblasts and in urine allow not only to make the diagnosis of a disease, but also to reveal carriers of an abnormal gene and to carry out prenatal diagnosis when there is a risk of the birth of the sick child. Prenatal diagnosis — the only still effective way of fight against G.


As for hereditary G.' treatment, achievements in this area are still small. Attempts to enter the enzyme lacking an organism by means of organ transplantation (e.g., spleens), by plasma transfusion of blood with leukocytes, administrations of enzymes in specially manufactured semipermeable capsules of the lipidic nature — liposomes are made. However methods of replaceable enzymotherapy, and also attempt of activation of missing enzyme, including introduction of synthetic rather low-molecular activators, are insufficiently effective so far. Difficulty of overcoming immune responses of an organism remains the main problem.

The prospect of treatment of hereditary diseases by direct correction of defect of a gene — so-called therapy of a gene is discussed. This direction is based on a basic opportunity or to synthesize genes, or to selectively take them from other organisms. Theoretically introduction of such genes by means of various carriers (a method of transduction), napr, viruses, can lead to correction of the struck genome.

A wedge, separate G.' manifestation — see the relevant articles (e.g., to Gosha disease , Maroto — Lamy a disease , Morkio disease , Sanfilippo disease , Fabri disease , Sheye disease etc.).

Bibliography: Vidershayn G. Ya. The hereditary diseases connected with disturbance of disintegration of uglevodsoderzhashchy connections, Usp. sovr, biol., t. 77, century 3, page 434, 1974, bibliogr.; about N, Glikozidaza in a normal cell and at inherited disorders of disintegration of uglevodsoderzhashchy connections, in book: Usp. biol, chemical, under the editorship of B. N. Stepanenko, etc., t. 18, page 185, M., 1977, bibliogr.; Makkyyusik V. A. Ancestral features of the person, the lane with English, M., 1976; Harris G. Fundamentals of biochemical genetics of the person, the lane with English, M., 1973, bibliogr.; Lysosomes and storage diseases, ed. by H. G. Hers a. F. van Hoof, p. 148, N. Y. — L., 1973; The metabolic basis of inherited disease, ed. by J. B. Stanbury a. o., N.Y., 1972; Neufeld E.,

L i m T. W. a. Shapiro L. Inherited disorders of lysosomal metabolism, Ann. Rev. Biochem., v. 44, p. 357, 1975.

G. Ya. Vidershayn.