Diseases of glycosphingolipid biosynthesis

Whereas the glycosyltransferase defects related to the ABO and P blood group polymorphisms are apathogenic, two additional defects or glycosphingolipid biosynthesis have been associated with diseases. The first disease is called Amish Infantile Epilepsy Syndrome (OMIM 609056) and is caused by mutations in the α2-3 sialyltransferase ST3GAL5 gene, which mediates the formation of the ganglioside GM3. The loss of this ganglioside leads to epilepsy, failure to thrive, psychomotor retardation, poor feeding, vomiting, muscular weakness and blindness. Interestingly, most of these symptoms are also found in disorders of N-glycosylation and in several metabolic disorders, which explains the difficulty in recognizing the disease clinically. GM3 deficiency can be confirmed by structural analysis of glycosphingolipids isolated from blood serum. This analysis is unlike serum transferrin IEF not a routine procedure, thus requiring specialized techniques to confirm the structural defects biochemically. A second defect of ganglioside biosynthesis has been related to mutations in the b1-4 GalNAc-transferase B4GALNT1 gene, which causes a peripheral neurological disorder called autosomal recessive spastic paraplegia-26 (OMIM 609195). The affected patients show a stiffness of lower limbs during childhood, walking difficulties and muscle weakness. Mild to moderate intellectual disability was reported in most patients. Some male patients showed low testosterone levels, which concurs with the defect of testosterone secretion described in B4galnt1 knockoutmice. The detection of endocrine defects in mice and humans lacking complex gangliosides illustrates the broad involvement of glycosphingolipids in mammalian physiology. 

The ganglioside GM1 has also been involved in the etiology of a disease, namely the autoimmune disorder Guillain-Barré syndrome. This syndrome is a rare condition affecting about 1 in 100’000 individuals yearly, and is characterized by a progressive paralysis caused by an inflammatory demyelination of peripheral nerves. The most famous patient was probably Franklin D. Roosvelt. Although his paralysis was long attributed to poliomyelitis, a retrospective study has put forward that Guillain-Barré syndrome may be the likely cause of his paralysis. The demyelination process is related to the emergence of antibodies targeting GM1.

The production of anti-GM1 antibiodies in Guillain-Barré syndrome is related in about 40% of the cases to a previous infection with Campylobacter jejuni. The bacterial infection itself leads to a transient gastroenteritis but also to the production of antibodies against lipo-oligosaccharides expressed on the bacterial cell wall. Because these lipo-oligosaccharides are structurally related to GM1, some antibodies cross-react with the endogenous ganglioside, thereby leading to an inflammatory response against nerves expressing GM1. The molecular similarity between microbial and endogenous structures is called antigen mimicry.

FIG: CAMPYLOBACTER GM1 MIMICRY