Phenotype variability in six new patients with beta-mannosidosis.

Abstract

Beta-mannosidosis is a lysosomal storage disorder caused by pathogenic variants in the MANBA gene, resulting in deficiency of beta-mannosidase. This enzyme is essential for terminal glycoprotein degradation within lysosomes, and its deficiency leads to glycoprotein accumulation in the brain and other organs. Clinical manifestations are heterogenous and may include hearing loss, developmental delay, seizures, angiokeratomas, vision abnormalities, and intellectual disability. Currently, no disease-specific treatment exists. We previously reviewed clinical features in 46 individuals worldwide. This study highlights six new cases of beta-mannosidosis. Patient 1, an 8-year-old male, presented with a failed newborn hearing screening and compound heterozygote c.550-1G > A and c.562 T > G variants. Patient 2, a 40-year-old male, was diagnosed at age 3 with language delay, hearing loss and behavioral issues. He has c.375_378del, p.Tyr126Alafs*11 and c.1513 T > C variants. Patient 3, a 6-year-old female, developed gait disturbances and visual difficulties at 3 years and is homozygous for the c.188 A > G variant. She also has homocystinuria. Patient 4, a 15-year-old female with sensorineural hearing loss at age 2 years, carries variants c.1454_1455del and c.550-3C > A. Patient 5 presented at age 12 years with sensorineural hearing loss, intellectual disability, juvenile glaucoma and is homozygous for the c.1452_1453del variant. Patient 6, a 14-year-old male failed the newborn hearing screening. He is homozygous for variant c.378 + 1G > A. Analysis of these patients highlights marked phenotypic variability with no clear genotype-phenotype correlation. Early screening may enable prompt diagnosis, improve management, and support future therapeutic development.