Inherited sequence variants in genes that encode the lysosomal enzymes that comprise the GSL catabolic pathway are the cause of a severe group of inborn errors of metabolism, the glycosphingolipid lysosomal storage diseases4). This family of diseases are often neurodegenerative and are characterised by the build-up (so called “storage”) of GSLs in the lysosome of multiple tissues including the brain4). By contrast, it was thought for many years that defects in genes encoding enzymes involved in GSL biosynthesis would be lethal in utero, as mice deficient in GlcCer synthase are embryonically lethal 5). However, it was unclear whether deficiency of transferases responsible for the synthesis of more complex GSLs, such as gangliosides, could result in disease, but had yet to be identified. The Windows of Hope (www.WOHproject.com) study is a UK-led initiative, which aims to learn about the nature and spectrum of genetic disorders that affect Anabaptist (Amish and Mennonite) families to aid genetic diagnostic initiatives for that community. The project is co-led by our collaborators Andrew Crosby and Emma Baple (University of Exeter). In 2004, the Exeter team and colleagues identified a gene responsible for a severe form of epilepsy. The gene in question was the result of a loss of function mutation in GM3 synthase (SIAT9) a sialyltransferase responsible for the conversion of LacCer to GM3. In collaboration with Andrew Crosby and colleagues we showed that individuals with GM3 synthase deficiency lacked GM3 derived from the liver in their blood plasma. Additionally, precursors in the biosynthetic pathway accumulate. It remains unclear if the loss of complex gangliosides, the build-up of precursors, or changes in neutral to charged GSL ratios in neuronal membranes is responsible for the severe epilepsy characteristic of this disease. We speculated in the arising publication that there may be other sialyltransferase genes responsible for other rare neurological diseases6). A Mizutani grant award helped us to work on another ganglioside biosynthetic disease identified by the Exeter team and their colleagues. This disease involved the GM2 synthase (B4GALNT1) gene, which encodes another step in the ganglioside biosynthetic pathway (Figure 1). The Exeter team initially identified GM2 synthase deficiency, a complex form of hereditary spastic paraplegia (SPG26; a primarily upper motor neuron degenerative disorder), in families from Kuwait, Italy and the Old Order Amish. The B4GALNT1 Figure 2. The Glycosphingolipid biosynthetic pathway, simplified to just include key enzymes and GSL species GM3 synthase deficiency results in the loss of GM3 and all the more complex gangliosides downstream as indicated by the red box. Gangliosides that are absent in GM2 synthase deficiency are indicated by the blue box. The overlap of the red and blue boxes indicates common gangliosides lost in both diseases. Key enzymes are: ceramide glucosyl transferase (UGCG), lactosyl ceramide synthase (B4GALT5/6), GM3 synthase (ST3GAL5), GM2 synthase (B4GALNAT1) and GM1 synthase (B3GALT4). Please note that there may be other diseases, as yet unknown, caused by deficiencies in GM1, GD1 and GT1 synthases, for example.107
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