Expanding the phenotype spectrum of β-mannosidosis

PurposeTo expand the spectrum of clinical and biochemical phenotypes, and brain imaging features of individuals with {beta}-mannosidosis, a rare lysosomal storage disease. MethodsWe describe the clinical features of six patients with {beta}-mannosidosis, their findings on brain magnetic resonance imaging (MRI), and the changes over time in two of them. We also review previously reported patients, analyze the variants in MANBA, the first symptom and spectrum of symptoms, and the ages of onset and of diagnosis of the disease. ResultsForty-four patients have been reported to date, including our patients. The mean age of diagnosis is 12.8 years, and the age of onset of symptoms is 2.4 years. Hearing loss is the most frequently reported initial symptom and intellectual disability is the most frequent symptom overall. Erythromelalgia, nystagmus, macrocephaly, and obsessive-compulsive-like behavior are newly described features associated with {beta}-mannosidosis. 40% of the patients have abnormal brain imaging. Brain MRI showed hypomyelination in one patient and abnormal white matter changes in another patient. Twenty-nine pathogenic variants in MANBA have been reported among the 44 patients; 60.6% of patients have private variants, and 39.4% have the recurrent variant c.2158-2A>G. A new oligosaccharide structure: Neu-Man2-GlcNac2, was found in the urine of two affected patients. ConclusionDue to disease heterogeneity, establishing a genotype-phenotype correlation remains challenging in {beta}-mannosidosis. A spectrum of brain MRI abnormalities are described as manifestations of this condition: delayed myelination, hypomyelination, and abnormal white matter signals. Additional studies are needed to delineate the pathophysiology of this condition.