Sphingolipidoses are caused by genetic defects in a series of lysosomal enzymes and other proteins essential for the catabolism of sphingolipids

These enzymes are involved in degradation of lipids that contain sphingosine as the basic building block (Fig. 41-1, Table 41-2) (Chap. 3). Since the nervous system is rich in these lipids, many disorders in this category manifest as neurological disorders. Sphingolipids are degraded by sequential removal of the terminal moieties of the hydrophilic chain: sulfate in the case of sulfatide, phosphorylcholine in the case of sphingomyelin and sialic acid or sugar moieties in others, to ceramide and then to sphingosine and fatty acid. Genetic disorders are known in humans affecting almost every step of the degradative pathway. The mode of inheritance is Mendelian autosomal recessive for all sphingolipidoses, except for Fabry's disease, which is an X-linked disorder (Fig. 41-1, Table 41-2).

Figure 41-1

Chemical and metabolic relationships among the major sphingolipids. Normal catabolic pathways are indicated by arrows connecting adjacent compounds. Biosynthesis of these lipids occurs in the reverse direction. Numbers indicate locations of genetic metabolic (more...)

Table 41-2

Major Sphingolipidoses^a.

Farber's disease, also termed ceramidosis, or Farber's lipogranulomatosis. Primary manifestations of this very rare disorder are painful, progressively deformed joints and subcutaneous granulomatous nodules in infants. Nervous system involvement is variable. The cutaneous nodules, lung and heart are the main sites of abnormal accumulation of ceramide. However, ceramide levels are also increased in the CNS. A mild and probably nonspecific accumulation of simpler gangliosides in the brain is commonly observed. Human ceramidase cDNA has been cloned and characterized.

Niemann-Pick disease. This disease was traditionally classified into types A, B, C and D, primarily according to clinical phenotypes. However, only types A and B are allelic and caused by primary genetic deficiency of lysosomal acid sphingomyelinase. The term Niemann-Pick should be used only for these two types. Patients with either type A or B disease exhibit hepatosplenomegaly and characteristic foamy cells in the bone marrow. Type A disease usually occurs in infants and is characterized by additional severe CNS involvement. Patients rarely survive beyond 5 years. On the other hand, type B patients are normal in intellect and free of neurological manifestations. Onset may vary from birth to adulthood, with varying severity of organomegaly. In both types, there is an enormous accumulation of sphingomyelin in the liver and spleen. Up to a five-fold increase in sphingomyelin occurs in the CNS only in type A patients. The degree of the sphingomyelinase deficiency is similar in the two types when assayed in vitro. However, type A and type B can be differentiated from each other via the loading test, in which degradation of exogenously added sphingomyelin is assessed in living cultured fibroblasts: type B fibroblasts are capable of hydrolyzing a much higher percentage of the added sphingomyelin than type A fibroblasts. Mutation analyses have indicated close association of at least some mutations with clinical phenotypes [6].

Niemann-Pick type C. This disease was originally classified as a juvenile neurological subtype of Niemann-Pick disease because patients exhibit organomegaly, slowly progressive CNS signs and similar foam cells in bone marrow cells, with moderately increased amounts of sphingomyelin in liver and spleen. However, other lipids, in particular unesterified cholesterol and glucosylceramide, accumulate and sphingomyelinase activities, although partially decreased in cultured fibroblasts, are normal in leukocytes and solid tissues. Work during the past 10 years has convincingly shown that lysosomal sequestration of endocytosed low-density lipoprotein (LDL)-derived cholesterol and accompanying anomalies in intracellular sterol trafficking are the hallmark phenotypic features of the disease [6–8]. Impairment of cholesterol egress from lysosomes appears as the key intracellular lesion, resulting in an array of cholesterol-processing errors, including delayed induction of homeostatic responses. Demonstration in cultured cells of a lysosomal accumulation of unesterified cholesterol by fluorescent staining with filipin and of impaired LDL-induced cholesterol esterification are the tests currently used for diagnosing patients.

The wide clinical spectrum of the disease has been discussed extensively [1,6] and is also illustrated by the various names under which patients have been described in the literature, including “juvenile dystonic lipidosis,” “giant-cell hepatitis,” “neurovisceral storage disease with vertical supranuclear ophthalmoplegia,” “lipidosis with vertical gaze palsy,” “lactosylceramidosis, maladie de Neville,” “down-gaze paresis, ataxia, foam cells (DAF) syndrome” and “adult neurovisceral lipidosis.” Cardinal neurological symptoms in the most common juvenile presentation include ataxia, dysarthria, cataplexia, learning difficulties and almost constantly, vertical supranuclear gaze palsy. Linkage and complementation analyses have shown that genetic defects in two separate genes, NPC1, which is mapped to 18q11, 90% of patients, and NPC2, induce similar clinical and biochemical phenotypes [9]. The so-called Niemann-Pick type D appears to be only one particular variant, the Nova-Scotian form, within group 1. These new findings clearly argue against the term Niemann-Pick for this disorder. Conceptually, there is no evidence that Neimann-Pick type C disease is a sphingolipidosis. The NPC1 gene has been cloned and is homologous to known cholesterol homeostasis genes [10].

Globoid cell leukodystrophy (Krabbe's disease). This disorder and metachromatic leukodystrophy are two of the classical genetic myelin disorders simply because they involve abnormal degradation of two sphingolipids highly localized in the myelin sheath, galactosylceramide and sulfatide (Fig. 41-1) (see also Chap. 39). The disease is usually infantile, although rarer late-onset forms are also known. Clinicopathological manifestations are almost exclusively those of the white matter and the peripheral nerves. The unique globoid cells are hematogenous histiocytic cells that infiltrate the white matter in response to undigested galactosylceramide. Unlike other storage diseases, the primary natural substrate of the defective enzyme, galactosylceramide (psychosine), not only does not accumulate abnormally but it is almost always much lower than normal because of a rapid and almost complete destruction of the oligodendroglia and the consequent early cessation of myelination. On the other hand, a toxic metabolite, galactosylsphingosine, does accumulate and appears to be responsible for the devastating pathology of the disease [11,12]. Effects of psychosine, including early cessation of myelination and possibly overlapping substrate specificities between the two lysosomal β-galactosidases, galactosylceramidase and GM1-ganglioside β-galactosidase, are important in understanding the pathogenesis of this disease [1]. The galactosylceramidase gene has been cloned, and over 60 disease-causing mutations have been identified, including the one underlying the classic Nordic infantile disease.

Metachromatic leukodystrophy. The enzymatic defect in metachromatic leukodystrophy is one step before that in Krabbe's disease (Fig. 41-1). While these two diseases share many common features, there are significant differences that suggest different pathogenetic mechanisms. Clinically, relatively large proportions of patients with metachromatic leukodystrophy are of juvenile or adult form. Pathologically, the reduction in the number of oligodendrocytes is less severe. Remaining oligodendrocytes contain acid-phosphatase-positive lamellar inclusions, which exhibit metachromasia, or yellow—brown staining with cresyl violet at acidic pH at the light microscopic level. Unlike in globoid cell leukodystrophy, the affected substrate, sulfatide, is always abnormally increased. Both cDNA and the gene coding for human arylsulfatase A have been cloned, and several mutations causing the clinical disease of metachromatic leukodystrophy have been described [1]. A pseudodeficiency allele occurs relatively frequently. Bone marrow transplantation treatment has been tried in patients with late-onset forms of the disease with some degree of positive effects. A metachromatic leukodystrophy-like disorder, which is due to a deficiency in the sulfatidase activator protein has also been observed (see below).

Multiple sulfatase deficiency (MSD). Phenotypically, this disease combines features of metachromatic leukodystrophy and mucopolysaccharidoses. In addition to clinical manifestations of metachromatic leukodystrophy, patients present with craniofacial abnormalities, skeletal deformities and hepatosplenomegaly. There is abnormal urinary excretion of sulfatide, dermatan sulfate and heparan sulfate. Pathological findings are also combinations of the two conditions. Inheritance is mendelian autosomal recessive. Nevertheless, activities of a series of sulfatases are deficient, including arylsulfatases A, B and C; steroid sulfatases; and sulfatases related to mucopolysaccharide degradation (see below). Greater understanding of the underlying genetic defect has been achieved by the discovery of a novel co- or post-translational modification common to many sulfatases [13]. The mechanism involves modification of a cysteine residue to formyl glycine, also termed 2-amino-3-oxypropionic acid. This modification appears to be prerequisite for catalytic activity of the sulfatases. In two sulfatases known to be deficient in MSD, this conversion did not take place. The exact metabolic mechanism for the conversion is not yet known.

Gaucher's disease. Traditionally Gaucher's disease has been classified as one of three types: type I, non-neuropathic, with a widely varying age of onset, and by far the most common; type II, infantile, severely neuropathic; and type III, intermediate phenotype. Type I is highly prevalent in the Jewish population, while a large distinct group of type III patients exists in northern Sweden. All types are allelic and are caused by defective glucosylceramidase activity. Glucosylceramide is present in great excess in the enlarged liver and spleen in all types of the disease. The brain, in which glucosylceramide is normally almost nonexistent, accumulates only small amounts of this substrate in type II patients. By analogy to Niemann-Pick disease, non-neuropathic Gaucher patients are free of neurological involvement and survive for decades, while type II neuropathic patients die within a few years with severe CNS involvement. The difference in the pathogenetic mechanisms in these phenotypes is not known. As is the case for globoid cell leukodystrophy, the accumulation of a toxic metabolite, glucosylsphingosine, may play an important role in the pathogenesis of Gaucher's disease. The degree of CNS involvement parallels the concentrations of glucopsychosine in the brain. The gene for glucosylceramidase has been cloned and characterized, and many mutations responsible for the disease state have been identified [1]. Genotypic and phenotypic correlations have been studied in large populations of patients. The most common N370S mutation has never been found associated with a neuropathic phenotype, either alone or in association with another mutation. On the other hand, patients with another frequent mutation, L444P, initially thought typical of type III, may also present as type I or II. The most intensive enzyme replacement therapy has been tried in patients with the non-neuropathic form of Gaucher's disease. With the use of purified or recombinant enzyme modified at the carbohydrate moiety to increase efficiency of macrophage targeting, the positive outcome of enzyme therapy has been established and is widely used as the standard treatment for non-neuropathic forms of the disease. See below for details of a Gaucher-like disorder which is due to deficiency of an endogenous activator protein.

Fabry's disease. Unlike most other sphingolipidoses, Fabry's disease is an X-linked disorder, occurring mostly in adults. It is also primarily a systemic disease, and neurological manifestations, when present, are largely secondary. Cutaneous angiokeratoma is the most conspicuous early sign. The affected lipids, trihexosylceramide (gal-gal-glc-ceramide) and digalactosylceramide, are nearly absent in neural tissues from normal individuals. There are some accumulations of these lipids in the brain of patients, thought to be contributed primarily by those in the blood vessels. Cerebrovascular pathology commonly results in secondary neurological symptoms. Most patients succumb to renal failure and other vascular diseases. Consequently, transplantation of normal kidney has been attempted as a form of treatment. However, the results were not sufficiently encouraging to pursue further. The enzyme responsible for degradation of these sphingolipids with the terminal α-galactose residue is α-galactosidase A, a mutation of which causes the disease. A normal cDNA coding for α-galactosidase A has been cloned, and several mutations have been identified [1]. An enzyme replacement therapy analogous to that for Gaucher's disease is being initiated.

GM1-gangliosidosis. The infantile form of this disease shows, in addition to psychomotor retardation and other neurological manifestations, mucopolysaccharidosis-like clinical features. The late-onset form is relatively free of systemic signs. Morquio's disease type B is a unique adult phenotype of this disorder, also caused by genetic defects in GM1-ganglioside β-galactosidase, also termed acid β-galactosidase (see below). These pleomorphic phenotypes are consequences of the wide substrate specificity of the defective enzyme, GM1-ganglioside β-galactosidase, which hydrolyzes not only GM1-ganglioside, asialo-GM1-ganglioside and lactosylceramide but also terminal β-galactosyl residues of carbohydrate chains of various glycoproteins and intermediate degradation products of keratan sulfate. Distinct mutations in the gene could differentially inactivate catalytic activity toward different substrates. Large accumulations of GM1-ganglioside occur primarily in the brains of patients with the infantile and late-infantile forms of the disease. The major materials accumulated in the systemic organs are fragments of glycopeptides. It is not known whether GM1-ganglioside accumulates in the brain of patients with Morquio's B disease. The human acid β-galactosidase cDNA and the gene have been isolated and characterized, and many mutations have been identified [1]. Within the relatively limited number of patients examined so far, there appears to be an excellent correlation between the clinical phenotypes and underlying mutations.

Tay-Sachs disease. The classic Tay-Sachs disease prevalent among the Ashkenazi Jewish population is the prototype of human sphingolipidoses. It is caused by a mutation in the β-hexosaminidase α-subunit gene. Normally, the hexosaminidase α and β subunits form two catalytically active isozymes, β-hexosaminidase A (αβ) and B (ββ). A defect in the α subunit thus results in defective hexosaminidase A with normal hexosaminidase B. Hexosaminidase A can hydrolyze all known natural substrates with terminal β-N-acetylgalactosamine or β-N-acetylglucosamine residues, while hexosaminidase B hydrolyzes all of these substrates except GM2-ganglioside. As a result, a relatively specific accumulation of GM2-ganglioside occurs in genetic hexosaminidase α-deficiency states.

A few genetic variants are known on the basis of clinical and enzymatic criteria. Patients with the adult form may not develop clinical symptoms until the second or third decade of life. The enzymologically unique B1 variant is characterized by essentially normal hexosaminidases A and B when assayed with the standard artificial substrates but completely defective hexosaminidase A against the natural substrate GM2-ganglioside and an artificial substrate, 4-methylumbelliferyl glcNAc-6-sulfate. These enzymatic variants are caused by genetic defects in the hexosaminidase α-subunit gene. In contrast, the AB variant, which is phenotypically indistinguishable from the infantile hexosaminidase α defect, is caused by an entirely different genetic mechanism, a mutation in a specific activator protein (GM2 activator protein) (see below).

While all of these phenotypic and enzymological differentiations have been useful, a molecular genetic understanding of these diseases is progressing. Normal cDNA and the gene for the hexosaminidase α chain have been cloned and characterized [14]. Patients with some forms of the disease lack enzyme activity and exhibit an immunologically reactive α subunit, while others lack enzyme activity but exhibit immunoreactivity for the α subunit. Availability of cDNA for the α subunit has shown that the presence or absence of cross-reactive material largely corresponds to the presence or absence of the relevant mRNA. Both the classic Tay-Sachs disease and a phenotypically indistinguishable disease occurring in the French-Canadian population are mRNA-negative, while the B1 variant and some other unusual forms are mRNA-positive. Contrary to earlier expectations of a single mutation, two mutations underlying the classic Jewish infantile form of the disease have been identified: a splicing defect and a four-base insertion, the latter accounting for two-thirds to three-fourths of the Jewish infantile alleles [1]. The French-Canadian form showed a major deletion in the 5′ end of the hexosaminidase α gene of approximately 7 kb, spanning from the putative promoter region to beyond the first exon into the first intron. The first point mutation in the hexosaminidase α gene was identified in a patient with the B1 variant form of the disease [15]. The normal arginine at residue 178 was substituted by histidine. Computer analysis suggested substantial changes in the secondary structure of the enzyme protein around the mutation, consistent with the unusual enzymological characteristic of this variant. The possible origin of this particular mutation has been traced to northern Portugal. Since the mid-1980s, over 60 mutations that cause Tay-Sachs disease or its variants have been identified within the β-hexosaminidase α gene. The expected complexity of abnormalities at the level of the gene is likely to render the traditional clinical and enzymatic classification of the disease obsolete.

Sandhoff's disease. When the hexosaminidase β gene is genetically defective, it results in inactivation of both hexosaminidases A (αβ) and B (ββ). While the typical infantile form of Sandhoff's disease cannot be readily distinguished clinically from infantile hexosaminidase α defect, histochemical and biochemical studies reveal accumulation of additional materials other than GM2-ganglioside in the brain. All sphingolipids with the terminal β-hexosamine residue are affected, including GM2-ganglioside, asialo-GM2-ganglioside and globoside (Fig. 41-1). Since globoside is primarily a systemic lipid, it also accumulates in systemic organs. The cDNA and the gene for the hexosaminidase β subunit have also been cloned and many mutations characterized [1]. It is of interest that, despite the localization on different chromosomes, α on chromosome 15 and β on chromosome 5, hexosaminidase α and β chains are homologous. These two subunit genes, located on different chromosomes, appear to have been separated from a single gene relatively recently in the evolutionary time scale.

Activator deficiencies. In vivo degradation of the highly hydrophobic lipids often requires, in addition to the specific hydrolases, a third component, commonly referred to as the activator protein. These generally are small glycoproteins localized within the lysosomes but are not enzymes themselves. When such an activator protein is essential for in vivo degradation of the substrates and when it is genetically defective, the end results are very similar to deficiency of the enzyme itself. GM2-gangliosidosis AB variant is caused by genetic absence of the activator required for in vivo degradation of GM2-ganglioside. The degradative enzyme β-hexosaminidase A is normal in these patients. Conceptually similar diseases have been described in patients showing metachromatic leukodystrophy-like and Gaucher-like clinical phenotypes and in whom activator proteins, rather than the hydrolases arylsulfatase A and glucosylceramidase, respectively, were genetically defective. Both of these activator proteins, sulfatide activator, also termed sap-B or saposin B, and the glucosylceramidase activator, also termed sap-C or saposin C, are homologous proteins coded by a single gene. A single transcript generates a large polypeptide, which is subsequently proteolytically processed into four small, homologous proteins, including the sulfatide activator and the glucosylceramidase activator. The fourth domain, saposin D (sap-D) has been shown to stimulate ceramide degradation in cultured fibroblasts. Evidence exists that suggests that the first domain, saposin A (sap-A) also has sphingolipid activator function. No human disease is known to be caused by mutations in the A or D domain. Several mutations in these activator proteins responsible for the clinical diseases have been characterized, including a point mutation in the initiation codon resulting in complete loss of all four activator proteins and, consequently, a highly complex clinical and biochemical phenotype [1]. A murine model in which all saposins have been eliminated by gene targeting displayed characteristics of the human disease [16].

Mucopolysaccharidoses are caused by genetic enzymatic defects in the degradation of carbohydrate chains of glycosaminoglycans

The carbohydrate chains of glycosaminoglycans are sequentially degraded by a series of lysosomal enzymes (Table 41-3). By analogy to sphingolipidoses, genetic enzymatic defects in these degradative steps cause the accumulation of undegradable metabolites, resulting in the various forms of mucopolysaccharidoses. These materials are also excreted into urine in massive amounts. The standard classification of mucopolysaccharidoses is based on clinical manifestations and the nature of the accumulated and excreted materials. The enzymatic classification does not necessarily correspond to the traditional classification; a single classic disease often consists of more than one nonallelic disorder, while two disorders classified earlier as different may be allelic. All mucopolysaccharidoses are inherited as autosomal recessive traits, except for the X-linked Hunter's disease [1].

Table 41-3

Mucopolysaccharidoses.

Hurler's disease and Scheie's disease (mucopolysaccharidosis IH and IS). Hurler's syndrome is the prototype of the mucopolysaccharidoses. It is caused by a genetic deficiency in α-iduronidase activity. Scheie's disease was once considered to be a separate disease and classified as mucopolysaccharidosis V; it is now known to be a milder allelic variant of Hurler's syndrome. Neurons in the brain are commonly distended and contain characteristic lamellar inclusions, known as zebra bodies. They are the site of abnormal ganglioside accumulation commonly found in this and other mucopolysaccharidoses. While the increase is nonspecific and is mainly in normally minor monosialogangliosides, the degree of the increase is often substantial, up to several fold above normal. Polysulfated mucopolysaccharides are inhibitory to some lysosomal enzymes in vitro. Similar inhibition in vivo might be responsible for the ganglioside increase. Whether the ganglioside accumulation and neuronal distention contribute to the neurological manifestations of the disease is not known.

Hunter's syndrome (mucopolysaccharidosis II). Other than being an X-linked disorder and generally milder and slower in the clinical features and course, patients with Hunter's syndrome resemble closely those with Hurler syndrome. The responsible enzyme, α-iduronate sulfatase, has been cloned.

Sanfilippo's disease (mucopolysaccharidosis III). This is an excellent example of a disease identified on the basis of clinicopathological criteria, which has turned out to be a mixture of more than one genetically distinct disease. Four enzymatically different and nonallelic diseases are included under the eponym, Sanfilippo's disease. All four defective enzymes are involved at different steps of heparan sulfate degradation. Thus, the end results are essentially identical. Differential diagnosis cannot be established without appropriate enzyme assays.

Morquio's disease (mucopolysaccharidosis IV). Unlike other mucopolysaccharidoses, Morquio's disease is primarily a skeletal disorder. Neurological involvement is almost always secondary to skeletal abnormalities. The most common neurological complications are traumatic lesions of the spinal cord at the cervical level due to vertebral deformity. There are two genetically distinct types: type A, which is an N-acetylgalactosamine 6-sulfatase deficiency, and type B, which is a β-galactosidase deficiency. Patients with type A disease are clinically more severely affected. Since the type B disease is allelic with GM1-gangliosidosis, mutations responsible for Morquio's B phenotype have been identified in the β-galactosidase gene. N-Acetylgalactosamine 6-sulfatase has been cloned, and a few mutations responsible for the type A disease have been described.

Maroteaux-Lamy disease (mucopolysaccharidosis VI). This disease is another of the Hurler-like syndromes but can be differentiated from Hurler's syndrome by relatively well-preserved intellectual capacity. Urinary excretion of mucopolysaccharides is predominantly dermatan sulfate. Clinical severity and duration varies among apparently allelic cases.

β-Glucuronidase deficiency (mucopolysaccharidosis VII). The first case of this disease was reported by Sly et al. in 1973 [17]. While the general clinical picture is that of a mucopolysaccharidosis, the degrees of severity in skeletal abnormalities, organomegaly and nervous system involvement appear widely variable. β-Glucuronidase was one of the first lysosomal enzymes cloned [18]. A complete “cure” of the disease with restoration of β-glucuronidase activity has been reported in mutant mice genetically deficient in glucuronidase activity, when the normal human β-glucuronidase gene was transgenically introduced [19].

Glycoprotein disorders result from defects in lysosomal hydrolases

Natural substrates of certain lysosomal glycosidases are primarily carbohydrate chains of glycoproteins. When such enzymes are genetically defective, the results are accumulation and urinary excretion of undigested sugar chains and small glycopeptides since the protein backbone is usually degradable by proteases, which are genetically normal in patients (Table 41-4).

Table 41-4

Glycoprotein Storage Diseases and Mucolipidoses.

Sialidosis (neuraminidase deficiency, mucolipidosis I). Apparently, two dissimilar phenotypes result from enzymatic defects in the same lysosomal α-neuraminidase, also termed sialidase. The infantile form had been known as mucolipidosis I because of the mucopolysaccharidosis-like appearance of patients. Neurological involvement is severe to moderate, including impaired intellectual capacity. The second type occurs in the juvenile age group. Three findings stand out: typical macular cherry red spots, intractable myoclonic seizures and intact intellect. The α-neuraminidase deficient in sialidosis cleaves both α-2,6 and α-2,3 sialyl linkages but is apparently distinct from neuraminidase(s), which hydrolyzes sialic acid from gangliosides. Thus, patients accumulate and excrete excess sialic acid-containing materials derived from complex carbohydrate chains of glycoproteins, but there is no evidence for increased levels of gangliosides in the brain and elsewhere as the consequence of the genetic defect. The lysosomal acid sialidase has been cloned and a few disease-causing mutations identified [20,21] (see Galactosialidosis, below).

I-Cell disease (mucolipidosis II) and pseudo-Hurler's polydystrophy (mucolipidosis III). Among the disorders primarily affecting glycoprotein metabolism, I-cell disease and pseudo-Hurler's polydystrophy are conceptually unique. These two disorders had been considered separate entities on the basis of phenotypic manifestations. However, they are now known to be allelic variants of the same disease. Activities of many, but not all, lysosomal hydrolases are deficient in cultured fibroblasts. Notable exceptions are glucosylceramidase and acid phosphatase. Activities of those that are deficient in fibroblasts are dramatically much higher than normal in serum and other extracellular fluids, including the culture media in which patients' fibroblasts are grown. The primary genetic cause of the disease is not in any of the individual lysosomal enzymes but in the UDPglcNAc:lysosomal enzyme glcNAc phosphotransferase, which is localized in the Golgi apparatus and is essential for the normal processing and packaging of lysosomal enzymes. Without this enzyme, lysosomal enzymes cannot acquire the mannose 6-phosphate recognition marker which allows them to be properly routed to the lysosome. As the result, lysosomal enzymes are abnormally routed out of the cell. While lack of lysosomal enzyme activities must be primarily responsible for clinicopathological manifestations, this disease does not rigorously satisfy the two classic criteria of Hers [2] for inherited lysosomal disease.

α-Mannosidosis. α-Mannosidases, which participate in the processing of carbohydrate chains of glycoproteins, are localized in the Golgi apparatus and are genetically intact in α-mannosidosis. The lysosomal α-mannosidase deficient in this disease degrades the carbohydrate chains. Therefore, abnormal accumulations and urinary excretion of undegraded oligosaccharides with terminal α-mannose residues derived from normally synthesized and processed glycoproteins occur as a consequence of the genetic defect. A plant toxin, swainsonine, inhibits α-mannosidases, and its chronic ingestion creates an experimental condition that mimics many aspects of genetic α-mannosidosis. A limitation of this model, however, is that swainsonine inhibits both lysosomal and Golgi α-mannosidases.

β-Mannosidosis. This is the only disorder among those dealt with in this chapter that was discovered first in another mammalian species before an equivalent disease was found in humans. For several years, β-mannosidase deficiency was known in the goat. Affected goats show severe neurological signs almost from birth. The goat disease is rapidly fatal, and an almost complete lack of myelination is the unique feature of the neuropathology. A human patient with β-mannosidase deficiency has now been identified [22]. Unlike in the goat disease, the clinical picture was relatively mild, presenting with Sanfilippo-like features. There was urinary excretion of a disaccharide, β-mannose-glcNAc, and heparan sulfate. The same disaccharide is excreted in the goat disease. It is thought to derive from the innermost mannose in the glycoprotein carbohydrate chains. The parents of the patient possessed intermediate activities of the enzyme, consistent with the deficiency being the primary genetic defect. There was also a concomitant lack of heparan sulfamidase activity, which was normal in one parent and intermediate in the other. Human β-mannosidosis occurring in infants has also been described. The clinical features are more similar to those of the goat disease.

α-Fucosidosis. α-Fucoside residues are present in carbohydrate chains of both sphingoglycolipids and glycoproteins. Although fucosylated glycolipids are quantitatively minor, they are functionally important tissue constituents. Many blood-group antigens are fucosylated glycosphingolipids. In patients with genetic α-fucosidase deficiency, accumulations and urinary excretion of fucose-terminated oligosaccharides and fucosylated sphingolipids are observed.

Galactosialidosis (combined sialidase—β-galactosidase deficiency). The concept of the protective protein is relatively new. Lysosomal β-galactosidase and sialidase appear to exist as a complex with a third small protein within the lysosome. This protein protects these enzymes from being degraded by acid proteases also present in the lysosome, and when it is absent, both enzymes are degraded rapidly. Genetic abnormality of this protective protein results in deficient activities of both sialidase and β-galactosidase [23]. The protein also possesses carboxypeptidase activity. Thus, assays for carboxypeptidase activity can be used for diagnosis. The disease is generally a slowly progressive neurological disorder, resembling the later-onset form of GM1-gangliosidosis. The cDNA and the gene coding for the protective protein have been cloned and several mutations characterized [1].

There are other genetic disorders due to abnormalities in lysosomal function

Some of the major disorders are listed here and readers are referred to appropriate chapters in Scriver et al. [1]: α-glucosidase deficiency, also termed Pompe's disease; acid lipase deficiency, also termed Wolman's disease and cholesterol ester storage disease; N-acetyl α-galactosaminidase deficiency, also termed Schindler's disease; pycnodysostosis (cathepsin K defect); aspartylglycosaminuria; sialic acid storage disease, also termed Salla's disease and generalized sialic acid storage disorder; and cystinosis. The last two disorders are caused by genetic defects in transport of sialic acid and cysteine, respectively, across the lysosomal membrane.