Abstract
Glycosphingolipids are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons. Deficiencies in their catabolic pathways give rise to a large and well-studied group of inherited disorders, the lysosomal storage diseases. Although many glycosphingolipid catabolic defects have been defined, only one proven inherited disease arising from a defect in ganglioside biosynthesis is known. This disease, because of defects in the first step of ganglioside biosynthesis (GM3 synthase), results in a severe epileptic disorder found at high frequency amongst the Old Order Amish. Here we investigated an unusual neurodegenerative phenotype, most commonly classified as a complex form of hereditary spastic paraplegia, present in families from Kuwait, Italy and the Old Order Amish. Our genetic studies identified mutations in B4GALNT1 (GM2 synthase), encoding the enzyme that catalyzes the second step in complex ganglioside biosynthesis, as the cause of this neurodegenerative phenotype. Biochemical profiling of glycosphingolipid biosynthesis confirmed a lack of GM2 in affected subjects in association with a predictable increase in levels of its precursor, GM3, a finding that will greatly facilitate diagnosis of this condition. With the description of two neurological human diseases involving defects in two sequentially acting enzymes in ganglioside biosynthesis, there is the real possibility that a previously unidentified family of ganglioside deficiency diseases exist. The study of patients and animal models of these disorders will pave the way for a greater understanding of the role gangliosides play in neuronal structure and function and provide insights into the development of effective treatment therapies.
Highlights
Glycosphingolipids (GSLs) are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons (Schnar, 2005)
Proven disorders include a defect in serine palmitoyltransferase long chain subunit 1 (SPTLC1), which catalyzes the first step in sphingolipid biosynthesis leading to downstream ceramide and sphingolipids biosynthesis, which is associated with hereditary sensory and autonomic neuropathy (HSAN1) (Bejaoui et al, 2001)
A clinical diagnosis of complicated hereditary spastic paraplegia had been assigned to these families, there are additional features present in some affected individuals that provide evidence of a broader phenotype associated with GM2 synthase deficiency
Summary
Glycosphingolipids (GSLs) are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons (Schnar, 2005) Deficiencies in their catabolic pathways give rise to excessive intralysosomal accumulation of these lipids associated with a large and well-studied group of inherited disorders, the lysosomal storage diseases (Platt and Walkley, 2004; Ballabio and Gieselmann, 2009). Proven disorders include a defect in serine palmitoyltransferase long chain subunit 1 (SPTLC1), which catalyzes the first step in sphingolipid biosynthesis leading to downstream ceramide and sphingolipids biosynthesis, which is associated with hereditary sensory and autonomic neuropathy (HSAN1) (Bejaoui et al, 2001) These patients retain the ability to synthesize GSLs by using L-alanine as the precursor instead of serine. As gangliosides are conserved lipids, expressed at high levels in the nervous system of mammals, we hypothesized that any such conditions would likely display neurological ( neurodegenerative) phenotypes
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