This article includes discussion of GM1 gangliosidosis, familial neurovisceral lipoidosis, generalized gangliosidosis, Landing disease, pseudo-Hurler disease, Tay-Sachs disease with visceral involvement, infantile variant of GM1 gangliosidosis, juvenile variant of GM1 gangliosidosis, adult variant of GM1 gangliosidosis, and chronic variant of GM1 gangliosidosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
GM1 gangliosidosis is caused by a deficiency of beta-galactosidase-1. Three different phenotypes are known, with infantile being the most severe. The gene for beta-galactosidase-1 (GBL1) is located on the short arm of chromosome 3, and specific mutations are responsible for the different phenotypes. In this article, the authors cite therapeutic approaches in animal models using chemical chaperones, adeno-associated virus (AAV)-mediated gene therapy, and intracerebral stem cell therapy. Recent efforts have focused on exploring the effect of various pharmacological chaperones on the activity of the mutant enzyme in the different alleles. Lysosomal storage diseases often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. Research has shown that early-onset genetic testing is being considered among families to interpret potential threats.
• GM1 gangliosidosis is a lysosomal storage disorder.
• There are several phenotypes: infantile, juvenile, and adult.
• There is a Morquio-like phenotype.
Historical note and terminology
Ganglioside storage diseases are a group of heterogeneous inherited disorders characterized by progressive neurologic deterioration and the intraneuronal accumulation of gangliosides and their complex metabolites. Landing and colleagues first recognized gangliosidosis as a distinct entity (Landing et al 1964). The associated enzymatic deficiency of beta-galactosidase-1 was first identified in the brain, liver, spleen, and kidney and shortly thereafter in white blood cells (Okada and O'Brien 1968). In 1976, a variant of Morquio disease with spondyloepiphyseal dysplasia, keratan sulfate in urine, and beta-galactosidase-1 deficiency was described (O'Brien et al 1976). Because this enzyme deficiency is different than that in Morquio A disease, the Morquio with beta-galactosidase deficiency has been referred to as Morquio B.
The molecular basis of the phenotypes of beta-galactosidase-1 deficiency has become clearer following the cloning of the GBL1 gene. The gene for beta-galactosidase-1 (GLB1) maps to the short arm of chromosome 3 and contains 16 exons (Oshima et al 1988). The mutations that give the phenotype of GM1 gangliosidosis are different than those in Morquio B (Oshima et al 1988). The crystal structure of human beta-galactosidase gives clearer insight regarding the molecular defects of beta-galactosidase and the disease-causing mutations (Ohto et al 2012).
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