Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis.

Gaurav V. Harlalka, Anna Lehman, Barry Chioza, Emma L. Baple, Reza Maroofian, Harold Cross, Ajith Sreekantan-Nair, David A. Priestman, Saeed Al-Turki, Meriel E. McEntagart, Christos Proukakis, Louise Royle, Radoslaw P. Kozak, Laila Bastaki, Michael Patton, Karin Wagner, Roselyn Coblentz, Joy Price, Michelle Mezei, Kamilla Schlade-BartusiakFrances M. Platt, Matthew E. Hurles, Andrew H. Crosby

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3618-3624
Number of pages7
JournalBrain : a journal of neurology
Issue numberPt 12
StatePublished - Dec 2013

ASJC Scopus subject areas

  • Clinical Neurology


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