Expanding the Phenotype Spectrum of β-Mannosidosis.
β-mannosidosis is an ultra-rare lysosomal storage disorder caused by a deficiency of β-mannosidase, which catalyzes the last step of glycoprotein degradation. Owing to the limited number of reported cases, information on the natural history of the disease and brain imaging is scarce. We report 6 new cases and review them together with all the previously reported cases in the literature. We describe the clinical features of 6 unrelated patients with β-mannosidosis, their variants in , enzyme activity, urine oligosaccharide profiles, brain MRI findings, and longitudinal MRI changes in 2 of them. We also review previously reported patients to broaden the spectrum of clinical features and identify genotype-phenotype correlations. Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort. Nystagmus in association with β-mannosidosis was also found in 1 patient. Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter. A new oligosaccharide was found in the urine of the 2 most severely affected patients. Including our 6 patients, a total of 46 cases from 37 different families have been reported. The mean age of diagnosis is 12.8 years, and the mean age of symptom onset is 2.4 years. Hearing loss was the initial symptom most frequently reported, and intellectual disability was the most frequent symptom overall. Across the cohort, 29 pathogenic variants were identified, 61.8% were private, and 38.2% have the recurrent c.2158-2A>G variant. Neuroimaging abnormalities were reported in 40% of published cases and included cortical and subcortical atrophy, basal ganglia and white matter calcification, hydrocephalus, periventricular and subcortical white matter hyperintensities, and delayed myelination. Genotype-phenotype correlation in β-mannosidosis remains elusive, likely due to phenotypic variability, disease rarity, and lack of association between the enzyme activity and the clinical severity. Modifier genes in the N-glycan degradation pathway, such as , may influence disease expression. β-mannosidosis should be considered as a differential diagnosis in patients with syndromic or apparently nonsyndromic hearing loss, unexplained brain hypomyelination, behavioral disturbances, and intellectual disability.