B4GALT5 deficiency impairs glycosphingolipid biosynthesis: a new Congenital Disorder of Glycosylation?

Biallelic loss-of-function B4GALT5 variants abolishing lactosylceramide and glycosphingolipid synthesis

The authors report the first human case of biallelic loss-of-function B4GALT5 variants, in a child with microcephaly, mild cognitive impairment and bilateral cataracts. In B4GALT5/6 double-KO cells, the patient variants abolish lactosylceramide synthase activity and glycosphingolipid production, with predicted decreased protein stability and impaired UDP-Gal binding. Patient plasma and fibroblasts show about 80% reduction in glycosphingolipids. Unexpectedly, human B4GALT6 showed lower expression and activity, questioning its capacity to compensate.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A solid functional case for a new CDG involving glycosphingolipid metabolism, despite a single-patient cohort. The in-cellulo demonstration is convincing; independent replication will consolidate the gene-disease relationship. The target is captured by WES: the challenge will be recognizing this mechanism during interpretation.

Analysis by Dr Thibaut Benquey