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Sphingolipidoses J Clin Pathol: first published as 10.1136/jcp.27.Suppl_8.94 on 1 January 1974. Downloaded from J. clini. Path., 27, Suppl. (Roy. Coll. Path.), 8, 94-105 Sphingolipidoses KONRAD SANDHOFF From the Max-Planck Institute for Psychiatry, Neurochemische Abteilung, Muntich, Gernmany Sphingolipidoses are inborn errors of metabolism, 1882; Sachs, 1896; Fabry, 1898; Anderson, 1898; characterized by the accumulation of sphingo- Alzheimer, 1910; Niemann, 1914; Krabbe, 1916; lipids. These lysosomal diseases (Hers, 1965) are due Scholz, 1925). With progress in the analysis of lipids to a deficiency in the degradative pathway (for these diseases have been more accurately defined as references see Hers and Van Hoof, 1973). So far, specific lipid storage diseases, and it has become neither changes in the extent of sphingolipid bio- feasible to classify them more systematically on the synthesis, ie, an overproduction, nor a deficiency basis of the main accumulating lipid (Aghion, 1934; of a transferase activity have been observed. The Klenk, 1934, 1942; Jatzkewitz, 1958; Svennerholm, latter could result in the absence of the enzyme 1962). However, these nomenclatures, the first product and/or accumulation of its substrates. based on clinical and pathomorphological descrip- Recessive inherited deficiencies of sphingolipid tions and the second based on the main accumulating degrading enzyme activities have been found in all lipid, are not always congruent. For example, tissues that have been tested. The sphingolipid diseases such as infantile GM2-gangliosidosis (Tay- hydrolases studied thus far have been shown to be of Sachs disease) are ganglioside storage diseases, lysosomal origin (for references, see Vaes, 1973). while no ganglioside accumulation has been found Most of these enzymes display an optimal activity in neuronal ceroid-lipofuscinoses (Batten-Vogt dis- in an acidic pH range. With the remarkable exception ease), even though these diseases have been classified copyright. of Krabbe's disease, the storage material is found in in the same group of familial amaurotic idiocies vacuoles or storage granules which represent pro- (for references, see Zeman and Siakotos, 1973). foundly modified lysosomes incapable of degrading Different biochemical defects can therefore result the accumulating lipids (fig 1; for references, see in a similar clinical and pathological picture. Hers, 1973). Some of these storage granules, eg, the Furthermore, biochemical analysis has shown that membranous cytoplasmic bodies in Tay-Sachs infantile amaurotic idiocy (Tay-Sachs disease), disease, have been shown to contain lysosomal-like defined by clinical and pathomorphological criteria, enzymatic activities (Tallman, Brady, and Suzuki, includes at least two closely related but nevertheless of in different diseases: the variants 0 and 1971). The amount stored material is highest biochemically http://jcp.bmj.com/ tissues which exhibit the greatest biosynthetic rates B of infantile GM2-gangliosidosis (Sandhoff, Harzer, for the accumulated lipids. The pathogenesis of this Wassle, and Jatzkewitz, 1971). process seems to be especially severe when the ner- The classification of the sphingolipidoses based vous tissue is involved. on the accumulation of lipid appears to be more The physiological role of sphingolipids is still precise than the one based on clinical and patho- poorly understood, and almost no knowledge exists morphological criteria but is also unsatisfactory. about the mechanism by which the lipid accumula- In many of these diseases, several lipids accumulate tion finally causes dysfunction and death of the simultaneously, often concomitant with the accumu- on October 1, 2021 by guest. Protected affected cells. It seems obvious, however, that an lation of polysaccharides, as in GM1-gangliosidosis elevated concentration of a single sphingolipid (for references, see Van Hoof, 1973). The main reason may cause a variety of changes in the cells, including for this is believed to be the broad substrate speci- changes in incorporation of lipid into membranes ficity of certain sphingolipid hydrolases. Many of as well as mechanical distortion of the cell due to the these enzymes catalyze the breakdown of several deposition of the storage compound in granules and substances that have one chemical feature in com- vacuoles (fig 1) which finally may occupy an abnorm- mon, and the deficiency of such an enzyme can ally large portion of the cytoplasm. easily result in the accumulation of several com- pounds. Therefore, the enzymatic deficiencies should Nomenclature be characterized in order to obtain a final classifica- As clinical entities, many of these diseases have long tion of the storage diseases based on primary meta- been known by eponyms (Tay, 1881; Gauchei, bolic defects. 94 J Clin Pathol: first published as 10.1136/jcp.27.Suppl_8.94 on 1 January 1974. Downloaded from Sphinigolipidoses 95 IN < .; t^--* o.. i . - AK F.7 .. k ..%:.-.t ::oj i...e; mS,:.w+' '''_f;; -,.1 C9<>);h g a. .\ ., S. *: ...,.... {. * w> XJ t> tz._.Saiw.S \. 4. Wk !!. .. - **e.:'2.-w;._:.:.w :ki copyright. .... ON I http://jcp.bmj.com/ L .% on October 1, 2021 by guest. Protected t-eR i% = Fig 1 Neurone from cortex ofa child with Tay-Sachs disease. Tightly packed membranous cytoplasmic bodies (MCB) x 56 000 (electron micrograph; courtesy of B. W. Volk, Isaac Albert Research Institute of the Kingsbrook Jewish Medical Center; New York). J Clin Pathol: first published as 10.1136/jcp.27.Suppl_8.94 on 1 January 1974. Downloaded from 96 Sandhoff 0 HN ~^ - HOCH2 4 OH Ceram id* W'/NW Gal - GaINAc-Gal GIc Ceramide Neu Ac copyright. Ganglioside GM, Fig 2 Structure ofceramide and ganglioside GM1. GA1, asialoganglioside GM1; GA2, asialoganglioside GM2; Cer, ceramide (= N-acyl-sphingosine); FA, fatty acid; Gal, D-galactose; GalNAc, N-acetyl-D-galactosamine, GM1, ganglioside GM1; GM2, ganglioside GM2; Glc, D-glucose; NeuAc, N-acetylneuraminic acid; sialic acid, N-acylneuraminic acid; Sph, sphingosine. Catabolism of Sphingolipids and Enzyme Deficiencies oligosialo-gangliosides or of ganglioside GM3 (fig 3), in Sphingolipidoses has never been observed. It may be that a neuramini- http://jcp.bmj.com/ dase deficiency is incompatible with life and there- Sphingolipids have in common a hydrophobic fore lethal at very early stages of development. ceramide (ceramide = N-acylsphingosine) residue bound to either a hydrophilic mono- or oligo- saccharide chain (fig 2), or in the case of sphingo- Variant Forms of Sphingolipidoses myelin, phosphorylcholine. Figure 3 shows schem- the of atically degradative pathway sphingolipids. The schematic representation of sphingolipidoses on October 1, 2021 by guest. Protected The degradation always starts from the hydrophilic given in figure 3 is complicated by the fact end of the molecule (for references, see Gatt and that many sphingolipid storage diseases exist as Bahrenholz, 1973; Leeden and Yu, 1973; Sugita, variant forms. Analysis of the enzymes involved in Dulaney, and Moser, 1972). Each step is catalyzed the breakdown of sphingolipids has shown that by a lysosomal hydrolase that removes the terminal many of them occur as multiple forms, or iso- non-reducing sugar moiety in the case of ceramide enzymes, of which one or more can be deficient in oligosaccharides, sulphate in the case of sulphatides, different forms of a lipid storage disease. A further or phosphorylcholine in the case of sphingomyelin. heterogeneity seems to be due to the fact that dif- It is of special interest to note that there is a disease ferent degrees of enzyme deficiency have been known for each degradation step in which the respect- observed in different families affected with a given ive hydrolase activity is deficient (fig 3), with one storage disease. Patients with higher residual important exception: a neuraminidase deficiency, enzymatic activity appear to have a longer life span which should result in a primary accumulation of than those with almost complete enzyme deficiency. J Clin Pathol: first published as 10.1136/jcp.27.Suppl_8.94 on 1 January 1974. Downloaded from Sphingolipidoses 97 Oligosialogangliosides Gal "INAc- al-Glc -Cer ----oGl-GlAc -G -Glc -Cer (GM1) (GAS) C INAc -Gal-Gal-CGlc -Ce r Ga lNAc-Gal-Glc -Ce r GalNAc -Gal1-Glc -Cer (globoside) (G ) I (0,2) * 10 9,10 10 Fig 3 Catabolism ofsphingolipids and enzyme Gal-G-Glc-Cer Ga1 -Cer deficiencies in sphingolipidoses. Abbreviations as in figure 2. Gal1-Glc+8+-Cer GJ1al-Ga-Cer Phosphory lcholine -Ce r Glc -Cer Gal1-Cer+Gal1-Cer ( sphingoye lin) I8 cceebros ide ) 56(sulph.at ide ) +3 > ~~~~~~5,6 Cer5md e Sp + FA Number Disease Major Storage Compound Deficient Enzyme Activity 1 Farber's disease (ceramidosis) Ceramide Ceramidase 2 Niemann-Pick disease Sphingomyelin Sphingomyelinase (sphingomyelinosis) 3 Gaucher's disease Glucocerebroside Glucocerebroside ,-glucosidase (glucocerebrosidosis) copyright. 4 Krabbe's disease Galactocerebroside Galactocerebroside ,B-galactosidase (galactocerebrosidosis) 5 Metachromatic leucodystrophy Cerebrosidesulphates Cerebrosidesulphatase, (sulphatidosis, 'variant B') (arylsulphatase A) 6 Metachromatic leucodystrophy Cerebrosidesulphatases and steroid Arylsulphatases A, B, C and steroid (sulphatidosis, 'Variant 0') sulphates 7 Lactosylceramidosis Lactosylceramide Lactosylceramide B-galactosidase 8 Fabry's disease (a-galactosyl- a-Galactosyl-lactosylceramide a-Galactosidase lactosyl-ceramidosis) 9 Tay-Sachs disease (GM2- Ganglioside GM2 N-Acetyl-g-D-hexosaminidase A gangliosidosis, variant B1) 10 GM2-gangliosidosis,
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