Abstract
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Hereditary deficiency of lysosomal acid β-galactosidase (β-galactosidosis) is expressed clinically as two different diseases, GM1 gangliosidosis (OMIM 230500) and Morquio B disease (OMIM 253010). The mode of inheritance is autosomal recessive. GM1 gangliosidosis is a neurosomatic disease occurring mainly in early infancy (infantile form, type 1). Developmental arrest is observed a few months after birth, followed by progressive neurologic deterioration and generalized rigospasticity with sensorimotor and psychointellectual dysfunctions. Macular cherry-red spots, facial dysmorphism, hepatosplenomegaly, and generalized skeletal dysplasia are usually present in infantile cases. Cases of later onset have been described as the late infantile/juvenile form (type 2) or adult/chronic form (type 3). They are observed as progressive neurologic diseases in children or young adults. Dysmorphic changes are less prominent or absent in these clinical forms, although vertebral dysplasia is often detected by radiographic studies. No specific neurologic manifestations are known for late infantile/juvenile patients with GM1 gangliosidosis. Extrapyramidal signs of protracted course, mainly presenting as dystonia, are the major neurologic manifestation in adults with GM1 gangliosidosis.
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Morquio B disease is a clinically mild phenotype of Morquio A disease. It is expressed as generalized skeletal dysplasia with corneal clouding, resulting in short stature, pectus carinatum (sternal protrusion), platyspondylia, odontoid hypoplasia, kyphoscoliosis, and genu valgum. There is no central nervous system involvement, although spinal cord compression may occur at the late stage of the disease. Intelligence is normal, and hepatosplenomegaly is not present. X-ray changes are of pathognomonic significance.
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There is diffuse atrophy of the brain in patients with early-onset GM1 gangliosidosis. Neurons are filled with numerous membranous cytoplasmic bodies (MCBs), and inclusions of other types are observed in glial cells: pleomorphic lipid bodies, membranovesicular bodies, or large, compact oval deposits. There are histiocytes with distended cytoplasm in visceral organs. Cytoplasmic inclusions observed under electron microscopy are different from MCBs in neurons. They are vacuoles filled with fine granular, tubular, or amorphous osmiophilic material. These changes are less prominent in cases of mild phenotypic expression.
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Glycoconjugates with terminal β-linked galactose are increased in tissues and urine from patients with GM1 gangliosidosis and Morquio B disease. Ganglioside GM1 and its asialo derivative GA1 accumulate in the GM1 gangliosidosis brain. High amounts of oligosaccharides derived from keratan sulfate and glycoproteins have been reported in visceral organs and urine from GM1 gangliosidosis or Morquio B disease patients. Undersulfated keratan sulfate also has been described.
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Two lysosomal enzymes are known for hydrolysis of terminal β-linked galactose at acidic pH in various glycoconjugates. One is an enzyme usually called β-galactosidase (EC 3.2.1.23), catabolizing ganglioside GM1, galactose-containing oligosaccharides, keratan sulfate, and other β-galactose-containing glycoconjugates (GM1 β-galactosidase). The enzyme activity is markedly reduced or almost completely deficient in cells and body fluids from patients with β-galactosidosis. Heterogeneous kinetic or physicochemical properties have been found in the mutant enzymes. The degree of substrate storage and residual enzyme activity is correlated with the severity of each clinical phenotype; infantile GM1 gangliosidosis shows the highest substrate storage and the lowest residual enzyme activity compared with other, milder phenotypes. Distribution of the substrate storage in Morquio B disease is different from that in GM1 gangliosidosis. The major storage material in Morquio B disease is keratan sulfate and its partial degradation products. The second genetically different β-galactosidase is galactosylceramidase (galactocerebrosidase; EC 3.2.1.46), catabolizing galactosylceramide, galactosylsphingosine, and other lipid compounds. Genetic deficiency of this enzyme results in globoid cell leukodystrophy, which is another neurometabolic disease.
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The human β-galactosidase gene (GLB1) has been mapped on chromosome 3 (3p21.33). The cDNA codes for a protein of 677 amino acids, including a putative signal sequence of 23 amino acids and 7 potential asparagine-linked glycosylation sites. The gene GLB1 spans more than 60 kb and contains 16 exons. It produces two alternatively spliced transcripts that encode the lysosomal enzyme β-galactosidase (GLB1) and the 67-kDa enzymatically inactive elastin-binding protein (EBP). The promoter has the characteristics of a housekeeping gene, with GC-rich stretches and five SP1 transcription elements on the two strands. Mutations at the GLB1 locus may affect either both proteins or GLB1 only. The mutation of EBP contributes to the specific features of GM1 gangliosidosis phenotype, such as cardiomyopathy and connective tissue abnormalities. Heterogeneous gene mutations have been found in all clinical forms of β-galactosidosis, such as missense/nonsense mutations, insertion/duplication mutations, and insertions causing splicing defects. Neither the type nor location of the mutation in the gene is correlated with the clinical phenotype. Five common mutations have been known: R482H in Italian patients with infantile GM1 gangliosidosis, R208C in American patients with infantile GM1 gangliosidosis, R201C in Japanese patients with juvenile GM1 gangliosidosis, I51T in Japanese patients with adult GM1 gangliosidosis, and W273L in Caucasian patients with Morquio B disease. Restriction analysis has been performed successfully for diagnosis of the common mutations in new patients.
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Morphologic, pharmacologic, and biochemical aberrations have been found in the brains of GM1 gangliosidosis patients and animals. Meganeurites and ectopic dendrogenesis are observed in GM1 gangliosidosis, and the extent of meganeurite development is related to the onset, severity, and clinical course of the disease. Various pharmacologic abnormalities have been observed in feline GM1 gangliosidosis, such as cholinergic dysfunction, neuroaxonal dystrophy in GABAergic neurons, alteration of phospholipase C and adenyl cyclase activities, reduced calcium flux in synaptosomes, and alteration of evoked synaptic activity patterns in cortical pyramidal neurons. These data suggest that morphologic and metabolic effects occur in the presence of excessive storage of ganglioside GM1.
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GM1 gangliosidosis has been recorded in cats, dogs, sheep, and calves. These animals showed various central nervous system manifestations. β-Galactosidase is deficient, and storage of GM1 and oligosaccharides has been confirmed. Furthermore, mouse models have been generated by disruption of the β-galactosidase gene. The β-galactosidase-deficient knockout mouse presented with progressive neurologic manifestations a few months after birth. Clinical, pathologic, and biochemical analyses indicated that this also is an authentic model of human GM1 gangliosidosis. In addition, phenotype-specific model mice have been produced by introducing human mutant genes, resulting in various clinical forms of β-galactosidosis (knockout transgenic mice). These mice models are used for new therapeutic approaches to human β-galactosidosis patients.
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The mouse model of juvenile GM1 gangliosidosis expressing the R201C mutation was used for a new molecular therapy using a low-molecular-weight compound, N-octyle-4-epi-β-valienamine (NOEV). Orally fed NOEV passed through the blood-brain barrier, enhanced the deficient β-galactosidase activity, and induced degradation of GM1 and GA1 in the central nervous system. This new molecular therapy (i.e., chemical chaperone therapy) will be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
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