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Identification of a novel pseudodeficiency allele in the GLB1 gene in a carrier of GM1 gangliosidosis

The term ‘pseudodeficiency’ is used in lysosomal storage diseases to denote the situation in which individuals show greatly reduced enzyme activity but remain clinically healthy. Pseudodeficiencies have been reported for several lysosomal hydrolases. GM1 gangliosidosis is a rare autosomal recessive lysosomal storage disorder caused by β‐galactosidase hydrolase deficiency as a result of mutations in the GLB1 gene. Until now, two variants altering the β‐galactosidase activity have been described, p.Arg521Cys and p.Ser532Gly. Here we report the new variant p.Arg595Trp in the GLB1 gene, which markedly reduces β‐galactosidase activity when expressed in COS‐1 cells. The variant was identified in the healthy father of a girl with GM1 gangliosidosis. He was a heterozygous compound with p.Arg595Trp in trans with one of the disease‐causing mutations identified in his daughter; in leukocytes and plasma he showed lower β‐galactosidase activity than that observed in GM1 gangliosidosis carriers. As this family originated from the Basque Country in the north of Spain, we decided to analyse individuals of Basque and non‐Basque origin, finding the p.Arg595Trp allele in 3.2% of Basque and in 0.8% of non‐Basque alleles. The detection of the presence of alterations resulting in pseudodeficient activity in leukocytes and plasma is important for the correct diagnosis of GM1 gangliosidosis.