Beta Mannosidosis

Mendelian MONDO:0009562 Pathograph 19 Lysosomal storage diseases Oligosaccharidoses

A rare autosomal recessive lysosomal storage disorder caused by deficiency of lysosomal beta-mannosidase enzyme, leading to accumulation of mannose-containing oligosaccharides in tissues and body fluids. Clinical manifestations include intellectual disability, hearing loss, and variable neurological involvement.

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0
Mappings
0
Definitions
0
Inheritance
7
Pathophysiology
0
Histopathology
9
Phenotypes
19
Pathograph
1
Genes
1
Treatments
0
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
2
Deep Research
🏷

Classifications

Harrison's Chapter
hereditary disease
⚙

Pathophysiology

7
MANBA lysosomal beta-mannosidase deficiency
Biallelic MANBA pathogenic variants reduce lysosomal beta-mannosidase activity, blocking the terminal step of lysosomal glycoprotein degradation.
MANBA link
glycoprotein catabolic process link ↓ DECREASED
beta-mannosidase activity link ↓ DECREASED
lysosomal lumen link
Downstream
Beta-mannosidase activity MANBA loss directly reduces diagnostic beta-mannosidase activity.
Glycoprotein-derived oligosaccharide storage Reduced beta-mannosidase blocks lysosomal breakdown of glycoprotein-derived oligosaccharides.
Show evidence (2 references)
PMID:41235131 SUPPORT Human Clinical
"β-mannosidosis is an ultra-rare lysosomal storage disorder caused by a deficiency of β-mannosidase, which catalyzes the last step of glycoprotein degradation."
Directly supports the initiating enzyme deficiency and its place in glycoprotein degradation.
PMID:32847582 SUPPORT Human Clinical
"Beta-mannosidosis is an extremely rare metabolic storage disorder resulting from a beta-mannosidase deficiency that is involved in the degradation of glycoproteins."
Supports beta-mannosidase deficiency as the primary metabolic lesion.
Glycoprotein-derived oligosaccharide storage
Impaired lysosomal beta-mannosidase activity leaves glycoprotein-derived oligosaccharides incompletely degraded, with abnormal oligosaccharides detected in patient urine.
glycoprotein catabolic process link ↓ DECREASED oligosaccharide metabolic process link ⚠ ABNORMAL
lysosome link
Downstream
Urinary free oligosaccharides Stored oligosaccharide substrates overflow into urine as diagnostic biomarkers.
Auditory involvement The storage disorder is repeatedly associated with hearing loss, though the exact cochlear intermediate is not resolved.
Neurodevelopmental and behavioral involvement CNS involvement produces intellectual disability, behavioral disturbance, regression, and occasional seizures.
Abnormal brain myelination and neuroimaging Patient series show delayed myelination, diffuse hypomyelination, and other MRI abnormalities.
Recurrent infection involvement Recurrent skin and respiratory infections are reported in a subset of patients, but the specific immune mechanism is unresolved.
Cutaneous involvement Cutaneous manifestations are reported in some patients, including rare angiokeratomas.
Show evidence (2 references)
PMID:32847582 SUPPORT Human Clinical
"Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
Supports urinary accumulation of glycoprotein-derived oligosaccharides.
DOI:10.1093/clinchem/hvae043 PARTIAL Human Clinical
"Oligosaccharides and glycoamino acids have been recognized as biomarkers for MPS and glycoproteinosis."
Supports urinary oligosaccharides as glycoproteinosis biomarkers generally, not beta-mannosidosis specifically.
Auditory involvement
Hearing loss is one of the most prominent and often earliest clinical manifestations in reported beta-mannosidosis cohorts, including the Central European Roma founder-variant series.
cochlea link
Downstream
Sensorineural hearing impairment Auditory involvement clinically manifests as sensorineural hearing impairment.
Show evidence (2 references)
PMID:32847582 SUPPORT Human Clinical
"The most prominent and common clinical manifestations are mental retardation reported in ten patients and hearing loss mentioned in 13 patients (Table 2)."
The Roma cohort establishes hearing loss as a prominent beta-mannosidosis manifestation.
PMID:41235131 SUPPORT Human Clinical
"β-mannosidosis should be considered as a differential diagnosis in patients with syndromic or apparently nonsyndromic hearing loss"
Updated review supports hearing loss as a diagnostic clue.
Neurodevelopmental and behavioral involvement
Central nervous system involvement is variable but commonly includes intellectual disability and behavioral abnormalities; seizures and developmental regression are less frequent features in the expanded phenotype spectrum.
neuron link
brain link
Downstream
Intellectual disability CNS involvement is clinically expressed as intellectual disability.
Atypical behavior Behavioral disturbance includes hyperactivity, obsessive-compulsive-like behavior, autistic features, and aggression in reported patients.
Developmental regression Developmental regression is part of the newly expanded clinical spectrum.
Dysphagia Dysphagia is part of the newly expanded neurologic and esophageal-motility phenotype spectrum.
Seizures Seizures are an occasional neurologic manifestation in severe or early-onset cases.
Show evidence (2 references)
PMID:41235131 SUPPORT Human Clinical
"Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
Updated case series expands the neurodevelopmental and behavioral phenotype spectrum.
PMID:32847582 SUPPORT Human Clinical
"The clinical manifestation varies between mild and severe, involving symptoms such as mental retardation, hyperactivity, behavioural problems, hearing loss, and frequent infections of the skin and respiratory tract."
Supports cognitive and behavioral manifestations.
Abnormal brain myelination and neuroimaging
Brain MRI findings in beta-mannosidosis include delayed myelination, diffuse hypomyelination, white matter hyperintensities, calcification, atrophy, and hydrocephalus, indicating CNS structural involvement beyond isolated cognitive symptoms.
oligodendrocyte link
myelination link ↓ DECREASED
brain link
Downstream
Delayed myelination MRI-defined myelination delay is the phenotype-level expression of this CNS imaging node.
Show evidence (2 references)
PMID:41235131 SUPPORT Human Clinical
"Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter."
Directly supports delayed and reduced myelination in the reported cohort.
PMID:41235131 SUPPORT Human Clinical
"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."
Supports broader CNS imaging involvement across published cases.
Recurrent infection involvement
Recurrent skin and respiratory infections are reported in a subset of beta-mannosidosis patients; one case report links recurrent respiratory infections to aspiration-prone swallowing and esophageal motility abnormalities, while the broader immune mechanism is not established in the cached evidence.
Downstream
Recurrent respiratory infections Respiratory infections are the recurrent-infection phenotype supported by the clinical reports.
Show evidence (2 references)
PMID:32847582 SUPPORT Human Clinical
"frequent infections of the skin and respiratory tract"
Supports recurrent skin and respiratory infections as part of the clinical spectrum.
PMID:9097826 SUPPORT Human Clinical
"Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
Case report supports swallowing and esophageal motility abnormalities as one documented contributor to recurrent respiratory infections.
Cutaneous involvement
Cutaneous involvement is reported in some beta-mannosidosis patients, including rare angiokeratomas and recurrent skin infections. The current cached evidence supports the clinical association but not a precise skin-cell storage mechanism.
Downstream
Angiokeratoma Cutaneous involvement is reported in some patients, though angiokeratoma is a rare manifestation.
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"Additional rare clinical signs such as angiokeratomas"
Supports angiokeratoma as a rare cutaneous feature.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Beta Mannosidosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Cardiovascular 1
Angiokeratoma OCCASIONAL Angiokeratoma (HP:0001014)
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"Additional rare clinical signs such as angiokeratomas"
Supports angiokeratomas as rare manifestations in some patients.
Digestive 1
Dysphagia Dysphagia (HP:0002015)
Show evidence (2 references)
PMID:41235131 SUPPORT Human Clinical
"Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
The updated cohort explicitly identifies dysphagia as a newly described beta-mannosidosis feature.
PMID:9097826 SUPPORT Human Clinical
"Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
Earlier case report supports clinically significant swallowing and esophageal motility abnormalities.
Ear 1
Sensorineural hearing impairment VERY_FREQUENT Sensorineural hearing impairment (HP:0000407)
Show evidence (2 references)
PMID:32847582 SUPPORT Human Clinical
"at least three out of five siblings suffer from early onset sensorineural hearing loss."
Supports sensorineural hearing loss as a reported hearing phenotype.
PMID:32847582 SUPPORT Human Clinical
"hearing loss mentioned in 13 patients"
Supports hearing loss as a very common manifestation in the Roma founder-variant cohort.
Immune 1
Recurrent respiratory infections Recurrent respiratory infections (HP:0002205)
Show evidence (2 references)
PMID:9097826 SUPPORT Human Clinical
"recurring respiratory infections, previously reported in some other cases."
Case report supports recurrent respiratory infections and notes prior reports.
PMID:32847582 SUPPORT Human Clinical
"respiratory and skin infections reported in five patients"
Founder-variant cohort review supports respiratory and skin infections in a subset of patients.
Nervous System 5
Intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)
Show evidence (2 references)
PMID:32847582 SUPPORT Human Clinical
"clinical manifestation includes deafness and mental retardation"
Mental retardation (intellectual disability) is explicitly listed as a clinical manifestation of beta-mannosidosis.
PMID:41235131 SUPPORT Human Clinical
"intellectual disability was the most frequent symptom overall."
Updated cohort and literature review supports intellectual disability as the most frequent symptom.
Atypical behavior Atypical behavior (HP:0000708)
Show evidence (2 references)
PMID:32847582 SUPPORT Human Clinical
"mental retardation, hyperactivity, behavioural problems, hearing loss"
The clinical review lists behavioral problems and hyperactivity in the beta-mannosidosis spectrum.
PMID:41235131 SUPPORT Human Clinical
"obsessive-compulsive-like behavior"
Updated cohort identifies obsessive-compulsive-like behavior as a newly described feature.
Developmental regression Developmental regression (HP:0002376)
Show evidence (1 reference)
PMID:41235131 SUPPORT Human Clinical
"Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
The new cohort directly reports developmental regression.
Delayed myelination Delayed myelination (HP:0012448)
Show evidence (1 reference)
PMID:41235131 SUPPORT Human Clinical
"Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter."
Directly supports delayed myelination as a neuroimaging phenotype.
Seizures OCCASIONAL Seizure (HP:0001250)
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"neonatal epilepsy"
The review lists neonatal epilepsy among rare severe clinical phenotypes.
🧬

Genetic Associations

1
MANBA gene mutations (Causative)
Autosomal recessive
Show evidence (3 references)
PMID:32847582 SUPPORT Human Clinical
"carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database"
Identifies a founder variant with high carrier frequency in Roma populations, demonstrating genetic basis of the disease.
PMID:41235131 SUPPORT Human Clinical
"Across the cohort, 29 pathogenic MANBA variants were identified"
Updated cohort and literature review supports MANBA variant heterogeneity in beta-mannosidosis.
CGGV:assertion_d70d38aa-f7e9-4c93-8160-58dec9cec010-2022-08-02T160000.000Z SUPPORT Other
"MANBA | HGNC:6831 | beta-mannosidosis | MONDO:0009562 | AR | Definitive"
ClinGen classifies the MANBA-beta-mannosidosis gene-disease relationship as definitive with autosomal recessive inheritance.
💊

Treatments

1
Supportive care
Action: supportive care MAXO:0000950
Symptom management including speech therapy, physical therapy, educational support, and management of hearing impairment with hearing aids or cochlear implants.
🔬

Biochemical Markers

2
Urinary free oligosaccharides (INCREASED)
Context: Diagnostic biomarker
Pathograph Readouts
Readout Of Glycoprotein-derived oligosaccharide storage Positive Diagnostic
Increased urinary free oligosaccharides report overflow of incompletely degraded glycoprotein-derived substrates from lysosomal storage.
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
Patient urine testing directly supports urinary oligosaccharides as a diagnostic readout of glycoprotein-derived oligosaccharide storage.
Show evidence (2 references)
PMID:32847582 SUPPORT Human Clinical
"Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
Supports urinary oligosaccharides as a diagnostic biochemical finding.
DOI:10.1093/clinchem/hvae043 PARTIAL Human Clinical
"The assay is suitable for the accurate diagnosis and subtyping of MPS and glycoproteinosis"
Supports UPLC-MS/MS urinary oligosaccharide testing as a diagnostic approach for glycoproteinoses generally, not beta-mannosidosis specifically.
Beta-mannosidase activity (DECREASED)
Context: Diagnostic enzymatic assay
Pathograph Readouts
Readout Of MANBA lysosomal beta-mannosidase deficiency Negative Diagnostic
Decreased beta-mannosidase activity directly reports the primary MANBA lysosomal enzyme deficiency.
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"a decreased activity of the beta-mannosidase enzyme in different cells, particularly in leukocytes"
Patient cell assays support reduced beta-mannosidase activity as a direct diagnostic readout of MANBA enzyme deficiency.
Show evidence (1 reference)
PMID:32847582 SUPPORT Human Clinical
"a decreased activity of the beta-mannosidase enzyme in different cells, particularly in leukocytes"
Supports decreased beta-mannosidase activity in patient cells.
{ }

Source YAML

click to show 
name: Beta Mannosidosis
creation_date: '2025-12-19T01:18:09Z'
updated_date: "2026-05-21T07:47:19Z"
description: >
  A rare autosomal recessive lysosomal storage disorder caused by deficiency of
  lysosomal beta-mannosidase enzyme, leading to accumulation of mannose-containing
  oligosaccharides in tissues and body fluids. Clinical manifestations include
  intellectual disability, hearing loss, and variable neurological involvement.
category: Mendelian
disease_term:
  preferred_term: beta-mannosidosis
  term:
    id: MONDO:0009562
    label: beta-mannosidosis
parents:
- Lysosomal storage diseases
- Oligosaccharidoses
prevalence:
- population: Global reported literature
  percentage: Unknown
  notes: >-
    Population prevalence has not been established. Beta-mannosidosis remains
    an ultra-rare disorder described largely through case reports and small
    series; reported case counts increased from 11 patients in the 1990s to 46
    cases from 37 families in a 2025 review.
  evidence:
  - reference: PMID:9097826
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 11 cases of beta mannosidase deficiency have been reported until now."
    explanation: >-
      This 1997 case report documents the extremely small number of reported
      cases in the early literature, supporting the ultra-rare prevalence framing.
  - reference: PMID:41235131
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Including our 6 patients, a total of 46 cases from 37 different families have been reported."
    explanation: >-
      This contemporary review provides an updated literature-based case count,
      supporting that prevalence remains unknown but exceptionally low.
pathophysiology:
- name: MANBA lysosomal beta-mannosidase deficiency
  description: >
    Biallelic MANBA pathogenic variants reduce lysosomal beta-mannosidase
    activity, blocking the terminal step of lysosomal glycoprotein degradation.
  genes:
  - preferred_term: MANBA
    term:
      id: hgnc:6831
      label: MANBA
  molecular_functions:
  - preferred_term: beta-mannosidase activity
    modifier: DECREASED
    term:
      id: GO:0004567
      label: beta-mannosidase activity
  biological_processes:
  - preferred_term: glycoprotein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006516
      label: glycoprotein catabolic process
  cellular_components:
  - preferred_term: lysosomal lumen
    term:
      id: GO:0043202
      label: lysosomal lumen
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "β-mannosidosis is an ultra-rare lysosomal storage disorder caused by a deficiency of β-mannosidase, which catalyzes the last step of glycoprotein degradation."
    explanation: Directly supports the initiating enzyme deficiency and its place in glycoprotein degradation.
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beta-mannosidosis is an extremely rare metabolic storage disorder resulting from a beta-mannosidase deficiency that is involved in the degradation of glycoproteins."
    explanation: Supports beta-mannosidase deficiency as the primary metabolic lesion.
  downstream:
  - target: Beta-mannosidase activity
    description: MANBA loss directly reduces diagnostic beta-mannosidase activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32847582
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a decreased activity of the beta-mannosidase enzyme in different cells, particularly in leukocytes"
      explanation: Patient biochemical data support reduced beta-mannosidase activity.
  - target: Glycoprotein-derived oligosaccharide storage
    description: Reduced beta-mannosidase blocks lysosomal breakdown of glycoprotein-derived oligosaccharides.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "which catalyzes the last step of glycoprotein degradation"
      explanation: Loss of the terminal glycoprotein-degradation enzyme directly supports storage of incompletely degraded substrates.
- name: Glycoprotein-derived oligosaccharide storage
  description: >
    Impaired lysosomal beta-mannosidase activity leaves glycoprotein-derived
    oligosaccharides incompletely degraded, with abnormal oligosaccharides
    detected in patient urine.
  biological_processes:
  - preferred_term: glycoprotein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006516
      label: glycoprotein catabolic process
  - preferred_term: oligosaccharide metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0009311
      label: oligosaccharide metabolic process
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
    explanation: Supports urinary accumulation of glycoprotein-derived oligosaccharides.
  - reference: DOI:10.1093/clinchem/hvae043
    reference_title: Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Analysis of Urinary Oligosaccharides and Glycoamino Acids for the Diagnosis of Mucopolysaccharidosis and Glycoproteinosis
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Oligosaccharides and glycoamino acids have been recognized as biomarkers for MPS and glycoproteinosis."
    explanation: Supports urinary oligosaccharides as glycoproteinosis biomarkers generally, not beta-mannosidosis specifically.
  downstream:
  - target: Urinary free oligosaccharides
    description: Stored oligosaccharide substrates overflow into urine as diagnostic biomarkers.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32847582
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
      explanation: Directly supports urinary oligosaccharides as a downstream biomarker.
  - target: Auditory involvement
    description: The storage disorder is repeatedly associated with hearing loss, though the exact cochlear intermediate is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hearing loss was the initial symptom most frequently reported"
      explanation: Supports hearing loss as a major clinical consequence of the disorder.
  - target: Neurodevelopmental and behavioral involvement
    description: CNS involvement produces intellectual disability, behavioral disturbance, regression, and occasional seizures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "intellectual disability was the most frequent symptom overall."
      explanation: Supports CNS clinical involvement as a common downstream manifestation.
  - target: Abnormal brain myelination and neuroimaging
    description: Patient series show delayed myelination, diffuse hypomyelination, and other MRI abnormalities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41235131
      reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter."
      explanation: Supports brain myelination abnormalities as part of the beta-mannosidosis spectrum.
  - target: Recurrent infection involvement
    description: Recurrent skin and respiratory infections are reported in a subset of patients, but the specific immune mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32847582
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "frequent infections of the skin and respiratory tract"
      explanation: Supports recurrent infection involvement as a clinical manifestation associated with beta-mannosidosis.
  - target: Cutaneous involvement
    description: Cutaneous manifestations are reported in some patients, including rare angiokeratomas.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32847582
      reference_title: "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."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional rare clinical signs such as angiokeratomas"
      explanation: Supports rare cutaneous involvement but does not define the intermediate mechanism.
- name: Auditory involvement
  description: >
    Hearing loss is one of the most prominent and often earliest clinical
    manifestations in reported beta-mannosidosis cohorts, including the
    Central European Roma founder-variant series.
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most prominent and common clinical manifestations are mental retardation reported in ten patients and hearing loss mentioned in 13 patients (Table 2)."
    explanation: The Roma cohort establishes hearing loss as a prominent beta-mannosidosis manifestation.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "β-mannosidosis should be considered as a differential diagnosis in patients with syndromic or apparently nonsyndromic hearing loss"
    explanation: Updated review supports hearing loss as a diagnostic clue.
  downstream:
  - target: Sensorineural hearing impairment
    description: Auditory involvement clinically manifests as sensorineural hearing impairment.
    causal_link_type: DIRECT
- name: Neurodevelopmental and behavioral involvement
  description: >
    Central nervous system involvement is variable but commonly includes
    intellectual disability and behavioral abnormalities; seizures and
    developmental regression are less frequent features in the expanded
    phenotype spectrum.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
    explanation: Updated case series expands the neurodevelopmental and behavioral phenotype spectrum.
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestation varies between mild and severe, involving symptoms such as mental retardation, hyperactivity, behavioural problems, hearing loss, and frequent infections of the skin and respiratory tract."
    explanation: Supports cognitive and behavioral manifestations.
  downstream:
  - target: Intellectual disability
    description: CNS involvement is clinically expressed as intellectual disability.
    causal_link_type: DIRECT
  - target: Atypical behavior
    description: Behavioral disturbance includes hyperactivity, obsessive-compulsive-like behavior, autistic features, and aggression in reported patients.
    causal_link_type: DIRECT
  - target: Developmental regression
    description: Developmental regression is part of the newly expanded clinical spectrum.
    causal_link_type: DIRECT
  - target: Dysphagia
    description: Dysphagia is part of the newly expanded neurologic and esophageal-motility phenotype spectrum.
    causal_link_type: DIRECT
  - target: Seizures
    description: Seizures are an occasional neurologic manifestation in severe or early-onset cases.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Abnormal brain myelination and neuroimaging
  description: >
    Brain MRI findings in beta-mannosidosis include delayed myelination,
    diffuse hypomyelination, white matter hyperintensities, calcification,
    atrophy, and hydrocephalus, indicating CNS structural involvement beyond
    isolated cognitive symptoms.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: myelination
    modifier: DECREASED
    term:
      id: GO:0042552
      label: myelination
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter."
    explanation: Directly supports delayed and reduced myelination in the reported cohort.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Supports broader CNS imaging involvement across published cases.
  downstream:
  - target: Delayed myelination
    description: MRI-defined myelination delay is the phenotype-level expression of this CNS imaging node.
    causal_link_type: DIRECT
- name: Recurrent infection involvement
  description: >
    Recurrent skin and respiratory infections are reported in a subset of
    beta-mannosidosis patients; one case report links recurrent respiratory
    infections to aspiration-prone swallowing and esophageal motility
    abnormalities, while the broader immune mechanism is not established in
    the cached evidence.
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "frequent infections of the skin and respiratory tract"
    explanation: Supports recurrent skin and respiratory infections as part of the clinical spectrum.
  - reference: PMID:9097826
    reference_title: "[Beta mannosidosis: a new case]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
    explanation: Case report supports swallowing and esophageal motility abnormalities as one documented contributor to recurrent respiratory infections.
  downstream:
  - target: Recurrent respiratory infections
    description: Respiratory infections are the recurrent-infection phenotype supported by the clinical reports.
    causal_link_type: DIRECT
- name: Cutaneous involvement
  description: >
    Cutaneous involvement is reported in some beta-mannosidosis patients,
    including rare angiokeratomas and recurrent skin infections. The current
    cached evidence supports the clinical association but not a precise
    skin-cell storage mechanism.
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional rare clinical signs such as angiokeratomas"
    explanation: Supports angiokeratoma as a rare cutaneous feature.
  downstream:
  - target: Angiokeratoma
    description: Cutaneous involvement is reported in some patients, though angiokeratoma is a rare manifestation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32847582
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional rare clinical signs such as angiokeratomas"
      explanation: Supports angiokeratoma as a rare cutaneous manifestation.
phenotypes:
- name: Intellectual disability
  description: Variable cognitive impairment reported across patients, degree correlates imperfectly with genotype or residual activity.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clinical manifestation includes deafness and mental retardation
    explanation: >-
      Mental retardation (intellectual disability) is explicitly listed as
      a clinical manifestation of beta-mannosidosis.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intellectual disability was the most frequent symptom overall."
    explanation: Updated cohort and literature review supports intellectual disability as the most frequent symptom.
- name: Sensorineural hearing impairment
  description: Early, often prelingual sensorineural hearing loss is a common and characteristic clinical feature.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at least three out of five siblings suffer from early onset sensorineural hearing loss."
    explanation: Supports sensorineural hearing loss as a reported hearing phenotype.
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hearing loss mentioned in 13 patients"
    explanation: Supports hearing loss as a very common manifestation in the Roma founder-variant cohort.
- name: Atypical behavior
  description: >
    Behavioral manifestations include hyperactivity, obsessive-compulsive-like
    behavior, autistic features, aggression, and other behavioral problems in
    reported patients.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mental retardation, hyperactivity, behavioural problems, hearing loss"
    explanation: The clinical review lists behavioral problems and hyperactivity in the beta-mannosidosis spectrum.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "obsessive-compulsive-like behavior"
    explanation: Updated cohort identifies obsessive-compulsive-like behavior as a newly described feature.
- name: Developmental regression
  description: Developmental regression was newly described in the expanded 2025 patient cohort.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
    explanation: The new cohort directly reports developmental regression.
- name: Dysphagia
  description: >
    Dysphagia and related swallowing or esophageal motility abnormalities are
    reported in beta-mannosidosis, including a 2025 cohort and an earlier case
    with recurrent respiratory infections.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental regression, dysphagia, obsessive-compulsive-like behavior, and erythromelalgia are newly described features associated with β-mannosidosis among the 6 patients from our cohort."
    explanation: The updated cohort explicitly identifies dysphagia as a newly described beta-mannosidosis feature.
  - reference: PMID:9097826
    reference_title: "[Beta mannosidosis: a new case]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient presented with abnormalities of swallowing and esophageal motility resulting in recurring respiratory infections, previously reported in some other cases."
    explanation: Earlier case report supports clinically significant swallowing and esophageal motility abnormalities.
- name: Delayed myelination
  description: Brain MRI can show delayed myelination in infancy and diffuse hypomyelination later in childhood.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half the patients have abnormal brain MRIs, showing delayed myelination before 2 years of age and diffuse hypomyelination thereafter."
    explanation: Directly supports delayed myelination as a neuroimaging phenotype.
- name: Recurrent respiratory infections
  description: Respiratory infections are reported in case reports and in the Roma founder-variant cohort.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:9097826
    reference_title: "[Beta mannosidosis: a new case]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurring respiratory infections, previously reported in some other cases."
    explanation: Case report supports recurrent respiratory infections and notes prior reports.
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory and skin infections reported in five patients"
    explanation: Founder-variant cohort review supports respiratory and skin infections in a subset of patients.
- name: Seizures
  description: Epileptic manifestations reported in some patients with CNS involvement.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal epilepsy"
    explanation: The review lists neonatal epilepsy among rare severe clinical phenotypes.
- name: Angiokeratoma
  description: Cutaneous vascular lesions reported in some cases, with skin cell vacuolation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Angiokeratoma
    term:
      id: HP:0001014
      label: Angiokeratoma
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional rare clinical signs such as angiokeratomas"
    explanation: Supports angiokeratomas as rare manifestations in some patients.
genetic:
- name: MANBA gene mutations
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MANBA
    term:
      id: hgnc:6831
      label: MANBA
  variant_origin: GERMLINE
  notes: >
    Biallelic pathogenic variants in MANBA cause beta-mannosidosis. The c.2158-2A>G
    variant is a prevalent founder allele among Czech/Slovak Roma with carrier
    frequency of 3.77%, about 925 times higher than gnomAD frequency.
  inheritance:
  - name: Autosomal recessive
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      carrier/heterozygote frequency of 3.77%. This is about 925 times higher
      than the frequency of this variant in the gnomAD public database
    explanation: >-
      Identifies a founder variant with high carrier frequency in Roma populations,
      demonstrating genetic basis of the disease.
  - reference: PMID:41235131
    reference_title: Expanding the Phenotype Spectrum of beta-Mannosidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Across the cohort, 29 pathogenic MANBA variants were identified"
    explanation: Updated cohort and literature review supports MANBA variant heterogeneity in beta-mannosidosis.
  - reference: CGGV:assertion_d70d38aa-f7e9-4c93-8160-58dec9cec010-2022-08-02T160000.000Z
    reference_title: "MANBA / beta-mannosidosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MANBA | HGNC:6831 | beta-mannosidosis | MONDO:0009562 | AR | Definitive"
    explanation: ClinGen classifies the MANBA-beta-mannosidosis gene-disease relationship as definitive with autosomal recessive inheritance.
biochemical:
- name: Urinary free oligosaccharides
  presence: INCREASED
  context: Diagnostic biomarker
  notes: >
    Accumulated oligosaccharides including Man-GlcNAc disaccharide and sialylated
    derivatives are detected in urine. Modern UPLC-MS/MS allows multiplexed detection
    for glycoproteinoses.
  readouts:
  - target: Glycoprotein-derived oligosaccharide storage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary free oligosaccharides report overflow of incompletely
      degraded glycoprotein-derived substrates from lysosomal storage.
    evidence:
    - reference: PMID:32847582
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
      explanation: Patient urine testing directly supports urinary oligosaccharides as a diagnostic readout of glycoprotein-derived oligosaccharide storage.
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical diagnostics confirmed the typical disaccharides (primarily Man (beta1 → 4) GlcNac) in the urine of affected patients"
    explanation: Supports urinary oligosaccharides as a diagnostic biochemical finding.
  - reference: DOI:10.1093/clinchem/hvae043
    reference_title: Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Analysis of Urinary Oligosaccharides and Glycoamino Acids for the Diagnosis of Mucopolysaccharidosis and Glycoproteinosis
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The assay is suitable for the accurate diagnosis and subtyping of MPS and glycoproteinosis"
    explanation: Supports UPLC-MS/MS urinary oligosaccharide testing as a diagnostic approach for glycoproteinoses generally, not beta-mannosidosis specifically.
- name: Beta-mannosidase activity
  presence: DECREASED
  context: Diagnostic enzymatic assay
  notes: >
    Affected individuals exhibit enzyme activities ranging from undetectable up to
    2-10% of normal controls. Carriers may show approximately 40% activity.
  readouts:
  - target: MANBA lysosomal beta-mannosidase deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Decreased beta-mannosidase activity directly reports the primary MANBA
      lysosomal enzyme deficiency.
    evidence:
    - reference: PMID:32847582
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a decreased activity of the beta-mannosidase enzyme in different cells, particularly in leukocytes"
      explanation: Patient cell assays support reduced beta-mannosidase activity as a direct diagnostic readout of MANBA enzyme deficiency.
  evidence:
  - reference: PMID:32847582
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a decreased activity of the beta-mannosidase enzyme in different cells, particularly in leukocytes"
    explanation: Supports decreased beta-mannosidase activity in patient cells.
treatments:
- name: Supportive care
  description: >
    Symptom management including speech therapy, physical therapy, educational support,
    and management of hearing impairment with hearing aids or cochlear implants.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
notes: >
  Beta-mannosidosis is extremely rare, with a 2025 review reporting 46 cases
  from 37 families. The disease shows marked clinical variability even among
  individuals with similar genotypes. The c.2158-2A>G founder variant is
  particularly important in Central European Roma populations.
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
datasets:
📚

References & Deep Research

Deep Research

2
Disorder ▸

Disorder

  • Name: Beta Mannosidosis
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 8

Key Pathophysiology Nodes

  • Beta-mannosidase deficiency
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/978-3-642-40337-8_26
  • DOI:10.1007/978-3-642-40337-8_26
  • DOI:10.1046/j.1365-2133.2003.05365.x
  • DOI:10.1093/clinchem/hvae043
  • DOI:10.1186/s13023-020-01508-3
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 11 citations 2025-12-18T13:53:45.754720

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.