Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

Abstract

Alpha‐mannosidosis (OMIM 248500) is a rare lysosomal storage disorder caused by a deficiency of the enzyme alpha‐mannosidase. Recently, enzyme replacement therapy was approved in the European Union for the treatment of alpha‐mannosidosis, but evaluation regarding long‐term efficacy and safety is hard to assess due to missing quantitative natural history data, in particular survival. We performed a quantitative analysis of published cases (N = 111) with alpha‐mannosidosis. Main outcome measures were age of disease onset, diagnostic delay and survival (overall and by subgroup exploration). Residual alpha‐mannosidase activity and age of onset were explored as potential predictors of survival. STROBE criteria were respected. Median age of onset was 12 months. Median diagnostic delay was 6 years. At the age of 41 years 72.3% of patients were alive (N = 111). Residual alpha‐mannosidase activity (N = 34) predicted survival: Patients with a residual alpha‐mannosidase activity below or equal to 4.5% of normal in fibroblasts had a median survival of 3.5 years, whereas patients with alpha‐mannosidase activity above this threshold all survived during the observation period reported. Patients with age of onset above 7 years survived significantly longer than patients with age of onset below or equal to 7 years. Patient distribution was panethnic with hotspots in the United States and Germany. We defined age of onset, diagnostic delay, and survival characteristics in a global cohort of 111 patients with alpha‐mannosidosis by retrospective quantitative natural history modeling. These data expand the quantitative understanding of the clinical phenotype.

Early biochemical effects of velmanase alfa in a 7‐month‐old infant with alpha‐mannosidosis

“…In this study, we show the very early effects of ERT in a 7 months old patient with alpha mannosidosis. According to our knowledge, this patient is the second case in the world diagnosed so early because of both the rarity of the disease and the complexity of the diagnostic pathway, with an estimated diagnostic delay of about 6 years 12 . There is no published data on ERT in such young patients as its use below 6 years of age is still under investigation.…”

A modified density gradient proteomic-based method to analyze endolysosomal proteins in cardiac tissue

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Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment

“…1.24) [ 1 ]. Despite its rarity, the disease is globally widespread; its prevalence has been estimated to 1/1.000.000 people in the general population [ 2 ]. The main clinical manifestations of AM include intellectual deficiency (ID), immunodeficiency, hearing loss, dysmorphic features, skeletal abnormalities, psychiatric disorders, dysostosis, and motor dysfunctions [ 3 ].…”