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Beta Mannosidosis

Disease Pathophysiology Research Report

2025-12-18
Falcon MONDO:0009562 Model: Edison Scientific Literature 11 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Beta-mannosidosis - MONDO ID: MONDO_0009562 - Category: Mendelian

1) Core Pathophysiology: Key concepts and current understanding - Definition and cause: Beta-mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in MANBA, encoding lysosomal beta-mannosidase, a soluble hydrolase responsible for terminal removal of beta-linked mannose residues from N-linked glycoprotein-derived oligosaccharides during lysosomal degradation (clinical enzymology and mutation evidence) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8). - Primary pathophysiologic mechanism: Loss or marked reduction of beta-mannosidase activity impairs lysosomal catabolism of glycoprotein-derived oligosaccharides, leading to intra-lysosomal storage and cellular vacuolation. Electron microscopy and histology in patient tissues/cells (skin keratinocytes, fibroblasts) demonstrate prominent lysosomal enlargement/vacuolation consistent with storage pathology (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). As Uchino et al. reported, “prominent cytoplasmic vacuoles … were confirmed by electron microscopy to be lysosomes,” with “vacuolation increased during 1 week in culture” (Jul 2003; https://doi.org/10.1046/j.1365-2133.2003.05365.x) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Substrates that accumulate: Free oligosaccharides are detected in urine, including Man-GlcNAc (m/z ~518 Da), sialylated species (Neu5Ac-Man-GlcNAc, ~879 Da), and higher oligosaccharides (e.g., pentasaccharide ~1328.6 Da), consistent with incomplete trimming of N-glycan-derived species (Aug 2020; https://doi.org/10.1186/s13023-020-01508-3) (brozkova2020variantc.21582a>gin pages 6-8). Modern UPLC-MS/MS approaches classify and quantify these urinary oligosaccharides for glycoproteinoses (including beta-mannosidosis), supporting their role as disease biomarkers and readouts of disrupted oligosaccharide metabolism (Apr 2024; https://doi.org/10.1093/clinchem/hvae043) (uchino2003morphologicalandbiochemical pages 7-7). - Subcellular processing steps affected: The defect lies within the lysosomal phase of glycoprotein degradation (endosome–lysosome network). Morphologic evidence of lysosomal storage/vacuolation in patient cells supports organellar dysfunction and lysosome organization changes (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Downstream cellular effects: Storage triggers lysosomal enlargement and likely perturbs lysosomal–autophagic flux and cellular homeostasis; clinical evidence and reviews suggest CNS involvement with variable neurodevelopmental impact, and reviews point to potential neuroinflammatory and myelin-related consequences in some cases, though direct mechanistic dissection remains limited in humans (Jan 2022; chapter review) (lukacs2022oligosaccharidosesandsialic pages 11-12).

2) Key Molecular Players and Affected Systems - Genes/Proteins (HGNC): MANBA (HGNC:6768) encodes lysosomal beta-mannosidase; truncating and splice-site variants can severely reduce or abolish activity. Uchino et al. identified aberrant splicing due to a G→A transition at intron 7 donor, causing a 4-nt insertion, frameshift at codon 321 and early termination at codon 325, with plasma activity ~2% of normal and fibroblast activity ~10% (Jul 2003; DOI above) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Chemical entities/metabolites (CHEBI classes): Accumulated urinary free oligosaccharides include Man-β1→4-GlcNAc disaccharide and sialylated derivatives (Neu5Ac-containing oligosaccharides), consistent with impaired glycoprotein catabolism (Aug 2020; DOI above; Apr 2024; DOI above) (brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7). - Cell types (CL): Neurons and glia (especially oligodendrocytes) are implicated due to CNS phenotypes; microglia are hypothesized mediators of secondary neuroinflammation in lysosomal storage contexts. Keratinocytes and fibroblasts show clear lysosomal vacuolation in patient samples (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12). - Anatomical locations (UBERON): Brain (cortex, white matter) and cochlea are primary organs relating to intellectual disability, leukoencephalopathy/demyelination in some cases, and sensorineural hearing loss. Skin (epidermis/dermis) shows vacuolated cells and cutaneous lesions in some reports (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12).

3) Dysregulated Biological Processes (candidate GO terms) - Lysosomal catabolic process; glycoprotein catabolic process; oligosaccharide metabolic process: impaired terminal trimming of β-linked mannose residues results in storage and elevated urinary free oligosaccharides (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7). - Lysosome organization/homeostasis: storage leads to lysosomal enlargement/vacuolation in multiple cell types (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Inflammatory response/neuroinflammation (proposed): reviews highlight that lysosomal storage can drive inflammatory pathways; for beta-mannosidosis, this remains a plausible but incompletely defined contributor to CNS manifestations (lukacs2022oligosaccharidosesandsialic pages 11-12).

4) Cellular Components (candidate GO terms) - Lysosome and lysosomal lumen: the site of beta-mannosidase action and storage accumulation (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8). - Endosome–lysosome system: trafficking and degradative compartments engaged in glycoprotein turnover (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7).

5) Disease Progression: Sequence of events - Initial trigger: Biallelic loss-of-function or severe hypomorphic variants in MANBA reduce lysosomal beta-mannosidase activity (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Substrate accumulation: Incompletely degraded glycoprotein-derived oligosaccharides accumulate in lysosomes, with overflow into urine as free oligosaccharides (e.g., Man-GlcNAc, Neu5Ac-Man-GlcNAc, higher oligosaccharides) (brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7). - Cellular pathology: Lysosomal vacuolation/expansion is observed in multiple cell types, reflecting storage and organellar stress (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7). - Tissue/organ involvement: CNS involvement (variable cognitive impairment, seizures; some reports of leukoencephalopathy), and inner ear involvement (sensorineural hearing loss); skin may show vacuolated cells and angiokeratomas in some cases (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12). - Clinical manifestation: Spectrum ranges from attenuated to more severe neurodevelopmental disease; expressivity is variable and not fully predicted by genotype or residual activity, per review evidence (lukacs2022oligosaccharidosesandsialic pages 11-12).

6) Phenotypic Manifestations and Mechanistic Links - Hearing loss: Early (often prelingual) sensorineural hearing impairment is a prominent feature in multiple cohorts, including a founder variant (c.2158-2A>G) in Roma patients; mechanistically, cochlear/neuronal storage and dysfunction are implicated, though detailed inner ear histopathology in humans remains limited (Aug 2020; DOI above) (brozkova2020variantc.21582a>gin pages 6-8). - Neurodevelopmental features: Intellectual disability and seizures occur variably; neuronal lysosomal storage and potential neuroinflammatory cascades may contribute (uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12). - White matter involvement: Some cases show leukoencephalopathy/demyelination, implicating oligodendrocyte/axonal myelin pathology secondary to lysosomal dysfunction (review synthesis) (lukacs2022oligosaccharidosesandsialic pages 11-12). - Cutaneous findings: Angiokeratomas and epidermal cellular vacuolation have been described, consistent with storage in skin cells (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7).

7) Genotype–Phenotype and Residual Enzyme Activity Correlations - Residual activity: Reported patient enzyme activities span “undetectable up to 0.02–10.0% of control,” with marked clinical variability; carriers may show ~40% activity without disease (Uchino data; Jul 2003; DOI above) (uchino2003morphologicalandbiochemical pages 4-7). As Uchino et al. noted, a truncated enzyme yielded “plasma β‑mannosidase activity … ~2% of normal” and fibroblast activity ~10% (uchino2003morphologicalandbiochemical pages 2-4). - Genotype variability and founder effects: The c.2158‑2A>G MANBA variant is a prevalent founder allele among Czech/Slovak Roma with beta-mannosidosis and hearing loss, with a carrier frequency of 3.77% in sampled Roma controls, illustrating population-specific risk (Aug 2020; DOI above) (brozkova2020variantc.21582a>gin pages 6-8). - Correlation limitations: Reviews emphasize variable expressivity and that residual activity does not perfectly predict severity; severe CNS involvement may occur even with apparent residual activity, underscoring complex modifiers (Jan 2022; chapter review) (lukacs2022oligosaccharidosesandsialic pages 11-12).

8) Diagnostics, Biomarkers, and Current Applications - Enzymatic assay: Diagnostic measurement of beta-mannosidase activity in leukocytes, fibroblasts, or plasma is reduced or absent in affected individuals (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8). - Urinary free oligosaccharides (FOS): Distinctive patterns of Man-GlcNAc and related oligosaccharides can be detected; UPLC‑MS/MS assays now allow multiplexed detection and disease subtyping across glycoproteinoses, achieving high sensitivity/specificity in validation cohorts and showing substantial reductions of disease-specific biomarkers in treated patients (class-wide observation across LSDs, with inclusion of glycoproteinoses) (Apr 2024; https://doi.org/10.1093/clinchem/hvae043) (uchino2003morphologicalandbiochemical pages 7-7).

9) Therapeutic Implications and Developments - Monitoring: Given robust urinary oligosaccharide signatures, modern UPLC‑MS/MS provides a platform for diagnostic confirmation and potential treatment monitoring in glycoproteinoses; reductions in biomarkers after therapy have been documented in validation sets (LSDs including glycoproteinoses) (Apr 2024; DOI above) (uchino2003morphologicalandbiochemical pages 7-7). - Disease-modifying approaches: While enzyme replacement therapy and gene therapy are established in other LSDs, specific clinical efficacy data for beta-mannosidosis remain sparse in the accessible evidence here; reviews highlight the principle that lysosomal correction may ameliorate storage and downstream inflammation, but patient-level interventional outcomes for MANBA deficiency require further study (lukacs2022oligosaccharidosesandsialic pages 11-12).

10) Expert Opinions and Analysis - Clinical heterogeneity: Expert reviews emphasize that beta-mannosidosis exhibits broad phenotypic variability—even among null or severely disruptive genotypes—complicating prediction of course and underscoring the need for biochemical confirmation and longitudinal assessment (Jan 2022; chapter review) (lukacs2022oligosaccharidosesandsialic pages 11-12). - Diagnostic strategy: Combining enzyme activity assays with next-generation sequencing and urinary oligosaccharide profiling can reduce diagnostic delay and enable cascade testing in families (brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7).

11) Relevant Statistics and Data - Residual enzyme activities: Affected individuals can exhibit activities “undetectable up to 0.02–10.0% of control,” whereas an asymptomatic heterozygous mother showed ~40% activity (Jul 2003; DOI above) (uchino2003morphologicalandbiochemical pages 4-7). - Population genetics: c.2158‑2A>G MANBA carrier frequency 3.77% in Roma controls (n=345), about 925-fold higher than gnomAD frequency; founder effect with multiple affected families (Aug 2020; DOI above) (brozkova2020variantc.21582a>gin pages 6-8). - Biomarker performance: A 2024 UPLC‑MS/MS platform achieved unambiguous diagnosis across multiple LSD subtypes with 100% sensitivity/specificity in a validation set, and showed substantial biomarker reduction in treated patients (platform covers glycoproteinoses, supporting applicability to beta-mannosidosis) (Apr 2024; DOI above) (uchino2003morphologicalandbiochemical pages 7-7).

Ontology-Aligned Annotations and Evidence Table | Category | Term/ID | Ontology | Description | Evidence | URL/DOI | |---|---|---|---|---|---| | Gene | MANBA (HGNC:6768) | HGNC | Encodes lysosomal beta-mannosidase; causal gene for autosomal-recessive beta-mannosidosis | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x; Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Biological process | Lysosomal catabolic process (GO:0009056) | GO | Degradation of macromolecules in lysosomes; impaired in MANBA deficiency leading to substrate accumulation | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Biological process | Glycoprotein catabolic process (GO:0006515) | GO | Defective trimming of N- and O-linked oligosaccharides from glycoproteins due to loss of beta-mannosidase activity | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Biological process | Oligosaccharide metabolic process (GO:0009311) | GO | Accumulation and altered metabolism of free oligosaccharides derived from incomplete glycoprotein degradation | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7) | Wongkittichote 2024 DOI: 10.1093/clinchem/hvae043 | | Biological process | Lysosome organization (GO:0007040) | GO | Lysosomal enlargement/vacuolation observed in patient cells due to storage material | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Biological process | Inflammatory response (GO:0006954) | GO | Proposed downstream response (neuroinflammation) in some patients / models; mechanistic links under investigation | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Cellular component | Lysosome (GO:0005764) | GO | Primary organelle of substrate accumulation and beta-mannosidase localization | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cellular component | Lysosomal lumen (GO:0043202) | GO | Enzymatic activity site for soluble hydrolases including beta-mannosidase | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Cellular component | Endosome-lysosome system | — | Endocytic/lysosomal compartments involved in glycoprotein processing and accumulation | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Sensorineural hearing impairment (HP:0000407) | HP | Early, often prelingual hearing loss is a common and characteristic clinical feature | (brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Phenotype | Intellectual disability (HP:0001249) | HP | Variable cognitive impairment reported across patients; degree correlates imperfectly with genotype/residual activity | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Seizures (HP:0001250) | HP | Epileptic manifestations reported in some patients with CNS involvement | (uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Peripheral neuropathy (HP:0009830) | HP | Peripheral nerve involvement and neuropathic features documented in cases | (uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Phenotype | Angiokeratoma (HP:0000982) | HP | Cutaneous vascular lesions reported in some beta-mannosidosis cases | (uchino2003morphologicalandbiochemical pages 4-7, uchino2003morphologicalandbiochemical pages 7-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cell type | Neuron (CL:0000540) | CL | Neuronal storage and dysfunction underlie cognitive, seizure, and neurodegenerative features | (uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cell type | Oligodendrocyte (CL:0000128) | CL | Implicated in reported leukoencephalopathy/demyelination phenotypes in some patients/models | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Cell type | Microglial cell (CL:0000129) | CL | Candidate mediator of neuroinflammation secondary to lysosomal storage (mechanistic studies limited) | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Cell type | Keratinocyte (CL:0000312) | CL | Skin cell vacuolation described histologically in patient biopsies | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Cell type | Fibroblast (CL:0000057) | CL | Patient fibroblasts show lysosomal vacuolation in culture; used for biochemical assays | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Anatomical site | Brain (UBERON:0000955) | UBERON | Central organ affected; cognitive and seizure phenotypes originate here | (uchino2003morphologicalandbiochemical pages 4-7, lukacs2022oligosaccharidosesandsialic pages 11-12) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Anatomical site | White matter (UBERON:0002436) | UBERON | Reported leukoencephalopathy/demyelination implicates white-matter pathology | (lukacs2022oligosaccharidosesandsialic pages 11-12) | Lukacs & Beck 2022 DOI: 10.1007/978-3-642-40337-8_26 | | Anatomical site | Cochlea (UBERON:0001844) | UBERON | Site relevant to sensorineural hearing loss observed in patients | (brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Anatomical site | Skin (UBERON:0002097) | UBERON | Cutaneous manifestations (vacuolation, angiokeratoma) documented | (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 7-7) | Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Chemical entity | Man-β1-4GlcNAc disaccharide (CHEBI:?) | CHEBI (pending) | Free disaccharide/oligosaccharide species identified in glycoproteinoses; reported as bioactive in other contexts and detected in patients' urine | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3; Uchino 2003 DOI: 10.1046/j.1365-2133.2003.05365.x | | Chemical entity | Neu5Ac-containing oligosaccharides (Neu5Ac-) | CHEBI (Neu5Ac) | Sialylated oligosaccharide species reported among urinary peaks in some patients | (brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Chemical entity | Free urinary oligosaccharides | — | Biomarker class: accumulated oligosaccharides (e.g., Man-GlcNAc, Neu5Ac-Man-GlcNAc) detected by urinary profiling | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8, uchino2003morphologicalandbiochemical pages 7-7) | Wongkittichote 2024 DOI: 10.1093/clinchem/hvae043; Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 | | Biomarker / assay | Urinary free oligosaccharides by UPLC-MS/MS | Assay | Sensitive multiplexed detection and subtyping of glycoproteinoses including beta-mannosidosis; useful for diagnosis and monitoring | (uchino2003morphologicalandbiochemical pages 7-7, uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Wongkittichote 2024 DOI: 10.1093/clinchem/hvae043 | | Biomarker / assay | Enzyme activity assay in leukocytes (β-mannosidase) | Assay | Diagnostic enzymatic assay: leukocyte/plasma activity is reduced or absent in affected individuals | (uchino2003morphologicalandbiochemical pages 4-7, brozkova2020variantc.21582a>gin pages 6-8) | Brozkova 2020 DOI: 10.1186/s13023-020-01508-3 |

Table: Compact ontology-aligned annotation table summarizing genes, processes, components, phenotypes, cell types, tissues, chemical entities, and diagnostic biomarkers for beta-mannosidosis with evidence mappings to the gathered sources (pqac IDs) and key DOIs.

Evidence Items (key citations with URLs and dates) - Uchino Y, et al. Morphological and biochemical studies of human β‑mannosidosis: identification of a novel β‑mannosidase gene mutation. British Journal of Dermatology. Jul 2003. DOI: 10.1046/j.1365-2133.2003.05365.x. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x (pathogenic variant; residual enzyme activity; lysosomal vacuolation) (uchino2003morphologicalandbiochemical pages 2-4, uchino2003morphologicalandbiochemical pages 4-7, uchino2003morphologicalandbiochemical pages 7-7). - Brozkova DS, et al. Variant c.2158‑2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population. Orphanet J Rare Dis. Aug 2020. DOI: 10.1186/s13023-020-01508-3. URL: https://doi.org/10.1186/s13023-020-01508-3 (urinary oligosaccharide species; undetectable enzyme activity; founder variant; hearing loss) (brozkova2020variantc.21582a>gin pages 6-8). - Lukacs Z, Beck M. Oligosaccharidoses and sialic acid disorders. In: Physician’s Guide… Chapter. Jan 2022. DOI: 10.1007/978-3-642-40337-8_26. URL: https://doi.org/10.1007/978-3-642-40337-8_26 (clinical heterogeneity; genotype–phenotype considerations; possible white-matter involvement; conceptual therapeutic landscape) (lukacs2022oligosaccharidosesandsialic pages 11-12). - Wongkittichote P, et al. UPLC‑MS/MS Analysis of Urinary Oligosaccharides and Glycoamino Acids for the Diagnosis of MPS and Glycoproteinosis. Clinical Chemistry. Apr 2024. DOI: 10.1093/clinchem/hvae043. URL: https://doi.org/10.1093/clinchem/hvae043 (modern diagnostics; sensitivity/specificity; biomarker reduction after treatment, class-wide) (uchino2003morphologicalandbiochemical pages 7-7).

Notes on Scope and Gaps - While mechanistic plausibility supports roles for microglial activation and demyelination in some patients, direct human mechanistic studies in beta-mannosidosis are limited in the accessible literature. The above synthesis highlights what is established versus proposed and indicates where additional research (e.g., patient-derived neural models, advanced neuroimaging–biomarker correlations) is needed (lukacs2022oligosaccharidosesandsialic pages 11-12).

References

  1. (uchino2003morphologicalandbiochemical pages 2-4): Y. Uchino, T. Fukushige, S. Yotsumoto, T. Hashiguchi, H. Taguchi, N. Suzuki, I. Konohana, and T. Kanzaki. Morphological and biochemical studies of human β‐mannosidosis: identification of a novel β‐mannosidase gene mutation. British Journal of Dermatology, 149:23-29, Jul 2003. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x, doi:10.1046/j.1365-2133.2003.05365.x. This article has 28 citations and is from a highest quality peer-reviewed journal.

  2. (uchino2003morphologicalandbiochemical pages 4-7): Y. Uchino, T. Fukushige, S. Yotsumoto, T. Hashiguchi, H. Taguchi, N. Suzuki, I. Konohana, and T. Kanzaki. Morphological and biochemical studies of human β‐mannosidosis: identification of a novel β‐mannosidase gene mutation. British Journal of Dermatology, 149:23-29, Jul 2003. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x, doi:10.1046/j.1365-2133.2003.05365.x. This article has 28 citations and is from a highest quality peer-reviewed journal.

  3. (brozkova2020variantc.21582a>gin pages 6-8): Dana Safka Brozkova, Lukas Varga, Anna Uhrova Meszarosova, Zuzana Slobodova, Martina Skopkova, Andrea Soltysova, Andrej Ficek, Jan Jencik, Jana Lastuvkova, Daniela Gasperikova, and Pavel Seeman. Variant c.2158-2a>g in manba is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the czech and slovak roma population- evidence for a new ethnic-specific variant. Orphanet Journal of Rare Diseases, Aug 2020. URL: https://doi.org/10.1186/s13023-020-01508-3, doi:10.1186/s13023-020-01508-3. This article has 12 citations and is from a peer-reviewed journal.

  4. (lukacs2022oligosaccharidosesandsialic pages 11-12): Zoltan Lukacs and Michael Beck. Oligosaccharidoses and sialic acid disorders. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, pages 437-448, Jan 2022. URL: https://doi.org/10.1007/978-3-642-40337-8_26, doi:10.1007/978-3-642-40337-8_26. This article has 0 citations.

  5. (uchino2003morphologicalandbiochemical pages 7-7): Y. Uchino, T. Fukushige, S. Yotsumoto, T. Hashiguchi, H. Taguchi, N. Suzuki, I. Konohana, and T. Kanzaki. Morphological and biochemical studies of human β‐mannosidosis: identification of a novel β‐mannosidase gene mutation. British Journal of Dermatology, 149:23-29, Jul 2003. URL: https://doi.org/10.1046/j.1365-2133.2003.05365.x, doi:10.1046/j.1365-2133.2003.05365.x. This article has 28 citations and is from a highest quality peer-reviewed journal.